Kinematic analysis of kinases and their oncogenic mutations - Kinases and their mutation kinematic analysis.

Protein kinases are crucial cellular enzymes that facilitate the transfer of phosphates from adenosine triphosphate (ATP) to their substrates, thereby regulating numerous cellular activities. Dysfunctional kinase activity often leads to oncogenic conditions. Chosen by using structural similarity to 5UG9, we selected 79 crystal structures from the PDB and based on the position of the phenylalanine side chain in the DFG motif, we classified these 79 crystal structures into 5 group clusters. Our approach applies our kinematic flexibility analysis (KFA) to explore the flexibility of kinases in various activity states and examine the impact of the activation loop on kinase structure. KFA enables the rapid decomposition of macromolecules into different flexibility regions, allowing comprehensive analysis of conformational structures. The results reveal that the activation loop of kinases acts as a "lock" that stabilizes the active conformation of kinases by rigidifying the adjacent α-helices. Furthermore, we investigate specific kinase mutations, such as the L858R mutation commonly associated with non-small cell lung cancer, which induces increased flexibility in active-state kinases. In addition, through analyzing the hydrogen bond pattern, we examine the substructure of kinases in different states. Notably, active-state kinases exhibit a higher occurrence of α-helices compared to inactive-state kinases. This study contributes to the understanding of biomolecular conformation at a level relevant to drug development.

The relationship between appearance anxiety and depression among students in a medical university in China: a serial multiple mediation model.

Background: Appearance anxiety and depression have become common and global public health problems worldwide, especially among adolescents. However, few studies have revealed the mechanisms between them. This study aimed to explore the multiple mediating roles of interpersonal sensitivity and social support between appearance anxiety and depression among medical college students. Methods: With 13 invalid samples excluded, 724 college students participated in our survey and completed questionnaires. The average age of 724 samples was 19.8 ± 2.02 including freshman to senior year and graduate school and above; 31.9% of the participants were male and 68.1% were female. SPSS 25.0 and Hayes' PROCESS macro were used for statistical description, correlation analysis and built multiple mediation models. Results: Appearance anxiety can not only directly affect depression, but also indirectly affect depression through three significant mediating pathways: (1) IS (B = 0.106, 95% CI [0.082-0.132]), which accounted for 49.77% of the total effect, (2) SS (B = 0.018, 95% CI [0.008-0.031]), which accounted for 8.45% of the total effect, and (3) IS and SS (B = 0.008, 95% CI [0.003-0.014]), which accounted for 3.76% of the total effect. And the total mediating effect was 61.97%. Limitations: It is a cross-sectional research method and the causal relationship is unclear. Conclusions: This study found that lower interpersonal sensitivity and higher social support can effectively reduce depression caused by appearance anxiety among college students. The schools and relevant departments should take measures to reduce the interpersonal sensitivity of college students and establish reliable social support, so as to reduce the occurrence of depression.

Graph Convolutional Network-Enhanced Model for Screening Persistent, Mobile, and Toxic and Very Persistent and Very Mobile Substances.

The global management for persistent, mobile, and toxic (PMT) and very persistent and very mobile (vPvM) substances has been further strengthened with the rapid increase of emerging contaminants. The development of a ready-to-use and publicly available tool for the high-throughput screening of PMT/vPvM substances is thus urgently needed. However, the current model building with the coupling of conventional algorithms, small-scale data set, and simplistic features hinders the development of a robust model for screening PMT/vPvM with wide application domains. Here, we construct a graph convolutional network (GCN)-enhanced model with feature fusion of a molecular graph and molecular descriptors to effectively utilize the significant correlation between critical descriptors and PMT/vPvM substances. The model is built with 213,084 substances following the latest PMT classification criteria. The application domains of the GCN-enhanced model assessed by kernel density estimation demonstrate the high suitability for high-throughput screening PMT/vPvM substances with both a high accuracy rate (86.6%) and a low false-negative rate (6.8%). An online server named PMT/vPvM profiler is further developed with a user-friendly web interface (http://www.pmt.zj.cn/). Our study facilitates a more efficient evaluation of PMT/vPvM substances with a globally accessible screening platform.

Key genes involved in nonalcoholic steatohepatitis improvement after bariatric surgery.

Background: Nonalcoholic steatohepatitis (NASH) is the advanced stage of nonalcoholic fatty liver disease (NAFLD), one of the most prevalent chronic liver diseases. The effectiveness of bariatric surgery in treating NASH and preventing or even reversing liver fibrosis has been demonstrated in numerous clinical studies, but the underlying mechanisms and crucial variables remain unknown. Methods: Using the GSE135251 dataset, we examined the gene expression levels of NASH and healthy livers. Then, the differentially expressed genes (DEGs) of patients with NASH, at baseline and one year after bariatric surgery, were identified in GSE83452. We overlapped the hub genes performed by protein-protein interaction (PPI) networks and DEGs with different expression trends in both datasets to obtain key genes. Genomic enrichment analysis (GSEA) and genomic variation analysis (GSVA) were performed to search for signaling pathways of key genes. Meanwhile, key molecules that regulate the key genes are found through the construction of the ceRNA network. NASH mice were induced by a high-fat diet (HFD) and underwent sleeve gastrectomy (SG). We then cross-linked the DEGs in clinical and animal samples using quantitative polymerase chain reaction (qPCR) and validated the key genes. Results: Seven key genes (FASN, SCD, CD68, HMGCS1, SQLE, CXCL10, IGF1) with different expression trends in GSE135251 and GSE83452 were obtained with the top 30 hub genes selected by PPI. The expression of seven key genes in mice after SG was validated by qPCR. Combined with the qPCR results from NASH mice, the four genes FASN, SCD, HMGCS1, and CXCL10 are consistent with the biological analysis. The GSEA results showed that the 'cholesterol homeostasis' pathway was enriched in the FASN, SCD, HMGCS1, and SQLE high-expression groups. The high-expression groups of CD68 and CXCL10 were extremely enriched in inflammation-related pathways. The construction of the ceRNA network obtained microRNAs and ceRNAs that can regulate seven key genes expression. Conclusion: In summary, this study contributes to our understanding of the mechanisms by which bariatric surgery improves NASH, and to the development of potential biomarkers for the treatment of NASH.

Magnetically Manipulated Optoelectronic Hybrid Microrobots for Optically Targeted Non-Genetic Neuromodulation.

Optically controlled neuromodulation is a promising approach for basic research of neural circuits and the clinical treatment of neurological diseases. However, developing a non-invasive and well-controllable system to deliver accurate and effective neural stimulation is challenging. Micro/nanorobots have shown great potential in various biomedical applications because of their precise controllability. Here, a magnetically-manipulated optoelectronic hybrid microrobot (MOHR) is presented for optically targeted non-genetic neuromodulation. By integrating the magnetic component into the metal-insulator-semiconductor junction design, the MOHR has excellent magnetic controllability and optoelectronic properties. The MOHR displays a variety of magnetic manipulation modes that enables precise and efficient navigation in different biofluids. Furthermore, the MOHR could achieve precision neuromodulation at the single-cell level because of its accurate targeting ability. This neuromodulation is achieved by the MOHR's photoelectric response to visible light irradiation, which enhances the excitability of the targeted cells. Finally, it is shown that the well-controllable MOHRs effectively restore neuronal activity in neurons damaged by ß-amyloid, a pathogenic agent of Alzheimer's disease. By coupling precise controllability with efficient optoelectronic properties, the hybrid microrobot system is a promising strategy for targeted on-demand optical neuromodulation.

Core-Sheath Heterogeneous Interlocked Conductive Fiber Enables Smart Textile for Personalized Healthcare and Thermal Management.

Whereas thermal comfort and healthcare management during long-term wear are essentially required for wearable system, simultaneously achieving them remains challenge. Herein, a highly comfortable and breathable smart textile for personal healthcare and thermal management is developed, via assembling stimuli-responsive core-sheath dual network that silver nanowires(AgNWs) core interlocked graphene sheath induced by MXene. Small MXene nanosheets with abundant groups is proposed as a novel "dispersant" to graphene according to "like dissolves like" theory, while simultaneously acting as "cross-linker" between AgNWs and graphene networks by filling the voids between them. The core-sheath heterogeneous interlocked conductive fiber induced by MXene "cross-linking" exhibits a reliable response to various mechanical/electrical/light stimuli, even under large mechanical deformations(100%). The core-sheath conductive fiber-enabled smart textile can adapt to movements of human body seamlessly, and convert these mechanical deformations into character signals for accurate healthcare monitoring with rapid response(440 ms). Moreover, smart textile with excellent Joule heating and photothermal effect exhibits instant thermal energy harvesting/storage during the stimuli-response process, which can be developed as self-powered thermal management and dynamic camouflage when integrated with phase change and thermochromic layer. The smart fibers/textiles with core-sheath heterogeneous interlocked structures hold great promise in personalized healthcare and thermal management.

Isomeric Dual-Pore Two-Dimensional Covalent Organic Frameworks.

Two-dimensional (2D) covalent organic frameworks (COFs) with hierarchical porosity have been increasingly recognized as promising materials in various fields. Besides, the 2D COFs with kagome (kgm) topology can exhibit unique optoelectronic features and have extensive applications. However, rational synthesis of the COFs with kgm topology remains challenging because of competition with a square-lattice topology. Herein, we report two isomeric dual-pore 2D COFs with kgm topology using a novel geometric strategy to reduce the symmetry of their building blocks, which are four-armed naphthalene-based and azulene-based isomeric monomers. Owing to the large dipole moment of azulene, as-prepared azulene-based COF (COF-Az) possesses a considerably narrow band gap of down to 1.37 eV, which is much narrower than the naphthalene-based 2D COF (COF-Nap: 2.28 eV) and is the lowest band gap among reported imine-linked dual-pore 2D COFs. Moreover, COF-Az was used as electrode material in a gas sensor and exhibits high selectivity for NO2, including a high response rate (58.7%) to NO2 (10 ppm), fast recovery (72 s), up to 10 weeks of stability, and resistance to 80% relative humidity, which are superior to those of reported COF-based NO2 gas sensors. The calculation and in situ experimental results indicate that the large dipole moment of azulene boosts the sensitivity of the imine linkages. The usage of isomeric building blocks not only enables the synthesis of 2D COFs with isometric kgm topology but also provides an azulene-based 2D platform for studying the structure-property correlations of COFs.

Association between UGS patterns and residents' health status: A report on residents' health in China's old industrial areas.

BACKGROUND: Old industrial areas have low quality and spatial differentiation of urban green space (UGS), which makes it difficult to meet the public's physical activity needs and leads to increased health risks. The purpose of this study is to explore the equity of UGS patterns in old industrial areas and its internal relationship with residents' health status. METHODS: This study selecteds relevant indicators to evaluate the equity of UGS patterns in the Harbin area and used linear regression analysis to explore the correlation between attributes of old industrial areas and UGS patterns. Additionally, this study explored the spatial correlation of UGSs using Moran's index and hotspot analysis. Finally, a report on residents' health was generated through a questionnaire survey, using linear regression analysis to explore the factors affecting residents' self-rated health and the significance of their correlation. RESULTS: The results showed that there is an excess supply around the core industrial zone in the west, while the rural areas in the south face a serious shortage of supply. The significance between the factors representing age and income in industrial attributes and UGS pattern was less than 0.05. We observed that residents' self-rated health was positively affected by the intensity of physical activity (low intensity B = 2.073, medium intensity B = 2.359, high intensity B = 2.512) and the frequency of physical activity (B = 1.174). Ages (B = -0.597) and three generations living together (B = -3.191), which represent the industrial attributes, had a negative impact on residents' self-rated health. CONCLUSION: To a certain extent, industrial attributes aggravate the mismatch of UGS patterns, leading to abnormal areas in spatial clustering. The quality of UGS in the old industrial zone is low and the movement is not strong; thus, the population characteristics and income have become the important factors affecting the health of residents.

MoTe2/InN van der Waals heterostructures for gas sensors: a DFT study.

Vertical van der Waals (vdW) heterostructures have shown potential for gas sensing owing to their remarkable sensitivity. However, the optimization process for achieving the best gas sensing performance is complicated by the heterostructure's reliance on both physical and electrical characteristics. This study employs density functional theory (DFT) to analyse the structural and electronic parameters of a MoTe2/InN vdW heterostructure. The findings of this study indicate that the vdW heterostructure has a type-II band alignment with higher adsorption energy towards NH3, NO2, and SO2 than the individual monolayers. In specific, the heterostructure is well suited for NO2 detection but has limitations in reliably detecting NH3 and SO2 due to longer recovery times. We find significant hybridization between the adsorbate and interacting surfaces' orbitals and a notable presence of NO2 molecular orbitals in proximity to the Fermi level. Additionally, dielectric and work function modulations offer a viable means to develop optical-based gas sensors that can selectively detect NO2. Our research provides valuable insights into vdW heterostructure design for high-performance gas sensors.

Effect of Cutting Surface Integrity on Fatigue Properties of TC17 Titanium Alloy.

The turning process of titanium alloy material will affect the surface structure of the material and lead to a change in its service life. In this paper, the fatigue behavior of the TC17 titanium alloy turning sample was studied through the bending fatigue test. The fatigue life variation rule under the action of thermal coupling was then discussed. This revealed the fatigue fracture mechanism of TC17; the cracks originated from the surface of the source region, and the transient fault region was a ductile fracture. The mathematical model of turning parameters and surface integrity (roughness, microhardness and residual stress) was established, and the influence of turning parameters on fatigue life was analyzed with a mathematical relationship. Drawing a conclusion, the effects of turning parameters on fatigue life at normal temperature are as follows: Feed > Cutting depth > Cutting speed. The fatigue life of vc = 30 m/min, f = 0.25 mm/r, ap = 0.3 mm is only 40,586 cycles per week, the fatigue life of vc = 30 m/min, f = 0.05 mm/r, ap = 0.1 mm has 539,400 cycles per week, that is, the longest fatigue life is 16.6 times the smallest. Small cutting speed, feed, and large cut depth can be chosen based on ensuring practical processing efficiency. The fatigue fracture of the TC17 sample occurred after a certain cycle, and the fatigue fracture mechanism was revealed in this paper.

Measurement of Creep Stress Exponent of TC17 Titanium Alloy by Nanoindentation Method at Room Temperature.

The creep stress exponent is commonly employed to characterize the deformation mechanism during the steady-state creep stage, serving as an indicator of creep behavior. The creep phenomenon of high melting point metallic materials is not obvious at room temperature. However, the nanoindentation method proves suitable for investigating the creep properties of metallic materials under such conditions. Consequently, this paper places emphasis on measuring the creep stress exponent of TC17 titanium alloy at room temperature using the load preservation stage of the nanoindentation method with a constant loading rate. In order to investigate the effects of loading rate and maximum load on the experimental results, different loading rates were applied to the diamond Berkovich indenter to reach different maximum loads. The indenter was held under the maximum load for a duration of 360 s, and the relationship between the indentation strain rate and indentation stress during the holding process was used to obtain the creep stress exponent of the material at room temperature. The findings indicate that within the loading rate range of 1.25 to 15 mN/s and maximum load range of 50 to 300 mN, the influence on the experimental results is insignificant. Ultimately, the distribution range of the creep stress exponent for TC17 titanium alloy at room temperature was measured to be 8.524-8.687.

Graft conditioning with fluticasone propionate reduces graft-versus-host disease upon allogeneic hematopoietic cell transplantation in mice.

Hematopoietic cell transplantation (HCT) treats many blood conditions but remains underused due to complications such as graft-versus-host disease (GvHD). In GvHD, donor immune cells attack the patient, requiring powerful immunosuppressive drugs like glucocorticoids (GCs) to prevent death. In this study, we tested the hypothesis that donor cell conditioning with the glucocorticoid fluticasone propionate (FLU) prior to transplantation could increase hematopoietic stem cell (HSC) engraftment and reduce GvHD. Murine HSCs treated with FLU had increased HSC engraftment and reduced severity and incidence of GvHD after transplantation into allogeneic hosts. While most T cells died upon FLU treatment, donor T cells repopulated in the hosts and appeared less inflammatory and alloreactive. Regulatory T cells (Tregs) are immunomodulatory and survived FLU treatment, resulting in an increased ratio of Tregs to conventional T cells. Our results implicate an important role for Tregs in maintaining allogeneic tolerance in FLU-treated grafts and suggest a therapeutic strategy of pre-treating donor cells (and not the patients directly) with GCs to simultaneously enhance engraftment and reduce GvHD upon allogeneic HCT.

SARS-CoV-2 main protease mutation analysis via a kinematic method.

The Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) is the virus responsible for the COVID-19 pandemic. COVID-19 continues to cause millions of deaths globally in part due to immune-evading mutations. SARS-CoV-2 main protease (Mpro) is an important enzyme for viral replication and potentially an effective drug target. Mutations affect the dynamics of enzymes and thereby their activity and ability to bind ligands. Here, we use kinematic flexibility analysis (KFA) to identify how mutations and ligand binding changes the conformational flexibility of Mpro. KFA decomposes macromolecules into regions of different flexibility near-instantly from a static structure, allowing conformational dynamics analysis at scale. Altogether, we analyzed 47 mutation sites across 69 Mpro-ligand complexes resulting in more than 3300 different structures which includes 69 mutated structures with all 47 sites mutated simultaneously and 3243 single residue mutated structures. We found that mutations generally increased the conformational flexibility of the protein. Understanding the impact of mutations on the flexibility of Mpro is essential for identifying potential drug targets in the treatment of SARS-CoV-2. Further studies in this area can offer valuable insights into the mechanisms of molecular recognition.

Effects of oxidative stress on hepatic encephalopathy pathogenesis in mice.

Oxidative stress plays a crucial role in the pathogenesis of hepatic encephalopathy (HE), but the mechanism remains unclear. GABAergic neurons in substantia nigra pars reticulata (SNr) contribute to the motor deficit of HE. The present study aims to investigate the effects of oxidative stress on HE in male mice. The results validate the existence of oxidative stress in both liver and SNr across two murine models of HE induced by thioacetamide (TAA) and bile duct ligation (BDL). Systemic mitochondria-targeted antioxidative drug mitoquinone (Mito-Q) rescues mitochondrial dysfunction and oxidative injury in SNr, so as to restore the locomotor impairment in TAA and BDL mice. Furthermore, the GAD2-expressing SNr population (SNrGAD2) is activated by HE. Both overexpression of mitochondrial uncoupling protein 2 (UCP2) targeted to SNrGAD2 and SNrGAD2-targeted chemogenetic inhibition targeted to SNrGAD2 rescue mitochondrial dysfunction in TAA-induced HE. These results define the key role of oxidative stress in the pathogenesis of HE.

Outstanding Humidity Chemiresistors Based on Imine-Linked Covalent Organic Framework Films for Human Respiration Monitoring.

Human metabolite moisture detection is important in health monitoring and non-invasive diagnosis. However, ultra-sensitive quantitative extraction of respiration information in real-time remains a great challenge. Herein, chemiresistors based on imine-linked covalent organic framework (COF) films with dual-active sites are fabricated to address this issue, which demonstrates an amplified humidity-sensing signal performance. By regulation of monomers and functional groups, these COF films can be pre-engineered to achieve high response, wide detection range, fast response, and recovery time. Under the condition of relative humidity ranging from 13 to 98%, the COFTAPB-DHTA film-based humidity sensor exhibits outstanding humidity sensing performance with an expanded response value of 390 times. Furthermore, the response values of the COF film-based sensor are highly linear to the relative humidity in the range below 60%, reflecting a quantitative sensing mechanism at the molecular level. Based on the dual-site adsorption of the (-C=N-) and (C-N) stretching vibrations, the reversible tautomerism induced by hydrogen bonding with water molecules is demonstrated to be the main intrinsic mechanism for this effective humidity detection. In addition, the synthesized COF films can be further exploited to effectively detect human nasal and oral breathing as well as fabric permeability, which will inspire novel designs for effective humidity-detection devices.

Two-Dimensional Bimetallic Phthalocyanine Covalent-Organic-Framework-Based Chemiresistive Gas Sensor for ppb-Level NO2 Detection.

Two-dimensional (2D) phthalocyanine-based covalent organic frameworks (COFs) provide an ideal platform for efficient and rapid gas sensing-this can be attributed to their regular structure, moderate conductivity, and a large number of scalable metal active centers. However, there remains a need to explore structural modification strategies for optimizing the sluggish desorption process caused by the extensive porosity and strong adsorption effect of metal sites. Herein, we reported a 2D bimetallic phthalocyanine-based COF (COF-CuNiPc) as chemiresistive gas sensors that exhibited a high gas-sensing performance to nitrogen dioxide (NO2). Bimetallic COF-CuNiPc with an asymmetric synergistic effect achieves a fast adsorption/desorption process to NO2. It is demonstrated that the COF-CuNiPc can detect 50 ppb NO2 with a recovery time of 7 s assisted by ultraviolet illumination. Compared with single-metal phthalocyanine-based COFs (COF-CuPc and COF-NiPc), the bimetallic structure of COF-CuNiPc can provide a proper band gap to interact with NO2 gas molecules. The CuNiPc heterometallic active site expands the overlap of d-orbitals, and the optimized electronic arrangement accelerates the adsorption/desorption processes. The concept of a synergistic effect enabled by bimetallic phthalocyanines in this work can provide an innovative direction to design high-performance chemiresistive gas sensors.

Plants of the Genus Mahonia as a Potential Traditional Chinese Medicine for the Prevention and Treatment of Alzheimer's Disease.

Alzheimer's disease (AD), a prevalent multiple neurodegenerative disease, has gained attention, particularly in the aging population. However, presently available therapies merely focus on alleviating the symptoms of AD and fail to slow disease progression significantly. Traditional Chinese medicine (TCM) has been used to ameliorate symptoms or interfere with the pathogenesis of aging-associated diseases for many years based on disease-modifying in multiple pathological roles with multi-targets, multi-systems and multi-aspects. Mahonia species as a TCM present potential for anti-inflammatory activity, antioxidant activity, anti-acetylcholinesterase activity, and antiamyloid- beta activity that was briefly discussed in this review. They are regarded as promising drug candidates for AD therapy. The findings in this review support the use of Mahonia species as an alternative therapy source for treating AD.

Identification and quantification of nine compounds in Fangwen Jiuwei decoction by liquid chromatography-mass spectrometry.

Fangwen Jiuwei Decoction is a traditional Chinese medicine preparation for the treatment of pneumonia developed by Shenzhen Bao'an Chinese Medicine Hospital, which shows remarkable clinical responses. Qualitative and quantitative analyses of the main active compounds are crucial for the quality control of traditional Chinese medicine prescription in clinical application. In this study, we identified nine active compounds essential for the pharmacological effects of Fangwen Jiuwei Decoction based on the analysis of the Network Pharmacology and relevant literature. Moreover, these compounds can interact with several crucial drug targets in pneumonia based on molecular docking. We applied high-performance liquid chromatography-tandem mass spectrometry method was established these nine active ingredients' qualitative and quantitative detections. The possible cleavage pathways of nine active components were determined based on secondary ions mass spectrometry. The results of high-performance liquid chromatography-tandem mass spectrometry were further validated, which show a satisfactory correlation coefficient (r > 0.99), recovery rate (≥93.31%), repeatability rate (≤5.62%), stability (≤7.95%), intra-day precision (≤6.68%), and inter-day precision (≤9.78%). The limit of detection was as low as 0.01 ng/ml. In this study, we established a high-performance liquid chromatography-tandem mass spectrometry method to qualitatively and quantitatively analyze the chemical components in the Fangwen Jiuwei Decoction extract.

A water-soluble NIR fluorescent probe capable of rapid response and selective detection of hydrogen sulfide in food samples and living cells.

DDAO (1,3-Dichloro-7-hydroxy-9,9-dimethyl-2(9H)-acridone) is a near-infrared (NIR) fluorophore that has received increasing attention in recent years, exhibiting near-infrared emission at 658 nm, low pKa (∼5.0), good water solubility and high quantum yield (Φ = 0.39). The reported DDAO-based fluorescent probes can be applied to biological imaging ofenzymes and other substances in vivo with high sensitivity and selectivity. Herein, using -OCN as the detection group, a novel NIR H2S fluorescent probe DDAO-CN based on DDAO was designed and synthesized. In PBS buffer (10 mM, pH 7.4), probe DDAO-CN displayed specific selection, short response time (within 10 s) and low detection limit (4.3 nM) towards to H2S under the catalysis of CTAB. At the same time, the probe is able to sense H2S gas produced by food spoilage via the fluorescent test strip loaded with DDAO-CN. Moreover, since the probe has optimal pH range (6.0-9.0), it has been successfully used for bioimaging H2S in the HeLa cells with low cytotoxicity.