Identification of sanguinarine as c-MYC transcription inhibitor through enhancing the G-quadruplex-NM23-H2 interactions.

c-MYC is a proto-oncogene ubiquitously overexpressed in various cancers. The formation of G-quadruplex (G4) structures within the c-MYC promoter region can regulate its transcription by interfering with protein binding. Consequently, small molecules targeting c-MYC G4 have emerged as promising anticancer agents. Herein, we report that sanguinarine (SG) and its analogs exhibit a high affinity for c-MYC G4 and potently modulate G4-protein interactions within a natural product library. Notably, SG uniquely enhances NM23-H2 binding to c-MYC G4, both in vitro and in cellular contexts, leading to c-MYC transcriptional repression and subsequent inhibition of cancer cell growth in an NM23-H2-dependent manner. Mechanistic studies and molecular modeling suggest that SG binds to the c-MYC G4/NM23-H2 interface, acting as an orthosteric stabilizer of the DNA-protein complex and preventing c-MYC transcription. Our findings identify SG as a potent c-MYC transcription inhibitor and provide a novel strategy for developing G4-targeting anticancer therapeutics through modulation of G4-protein interactions.

Public Attitudes towards and Management Strategies for Community Cats in Urban China.

Managing community cats in urban China is a contentious and emerging issue, with debates centering on the most effective and humane approaches. This study aimed to investigate public attitudes towards community cats and various management strategies. A survey was conducted involving 5382 urban residents in China. Their attitudes towards the positive and negative roles of community cats in urban areas and their support for different management methods were examined, including trap-and-kill, taking no action, centralized management, and trap-neuter-return (TNR) and its variations. Results indicated that 63% of participants were willing to coexist with community cats, 71% opposed trap-and-kill, and 61% agreed or strongly agreed with the TNR method and its variations. Older residents or those with higher incomes were more likely to support coexistence with community cats. In contrast, younger or lower-income residents were more likely to support non-coexistence. Residents in first- or second-tier cities (e.g., Beijing, Hangzhou, and Jinan Cities in China) were more inclined to support trap-and-kill and less likely to support coexistence than their counterparts in fourth-tier cities (e.g., county-level cities in China). Moreover, those with lower education or incomes were more supportive of trap-and-kill and taking no action as the methods to manage community cats than those with relatively higher education or incomes. Those with higher incomes held more positive attitudes towards community cats and were more supportive of TNR and its variations than their counterparts with lower incomes. Males were more inclined to support trap-and-kill and taking no action and less inclined to support centralized management and TNR than females. The implications of the findings on TNR with adoption programs in urban China are discussed. These novel findings underscore the need for targeted educational campaigns to promote humane and effective management strategies, addressing public concerns and community cats' welfare. The study's insights are critical for informing policy and improving community cat management in urban China.

Early diagnosis of Cladosporium fulvum in greenhouse tomato plants based on visible/near-infrared (VIS/NIR) and near-infrared (NIR) data fusion.

Plant diseases can inflict varying degrees of damage on agricultural production. Therefore, identifying a rapid, non-destructive early diagnostic method is crucial for safeguarding plants. Cladosporium fulvum (C. fulvum) is one of the major diseases in tomato growth. This work presents a method of data fusion using two hyperspectral imaging systems of visible/near-infrared (VIS/NIR) and near-infrared (NIR) spectroscopy for the early diagnosis of C. fulvum in greenhouse tomatoes. First, hyperspectral images of samples at health and different times of infection were collected. The average spectral data of the image regions of interest were extracted and preprocessed for subsequent spectral datasets. Then different classification models were established for VIS/NIR and NIR data, optimized through various variable selection and data fusion methods. The principal component analysis-radial basis function neural network (PCA-RBF) model established using low-level data fusion achieved optimal results, achieving accuracies of 100% and 99.3% for calibration and prediction, respectively. Moreover, both the macro-averaged F1 (Macro-F1) values reached 1, and the geometric mean (G-mean) values reached 1 and 1, respectively. The results indicated that it was feasible to establish a PCA-RBF model by using the hyperspectral technique with low-level data fusion for the early detection of C. fulvum in greenhouse tomatoes.

Research on non-destructive and rapid detection technology of foxtail millet moisture content based on capacitance method and Logistic-SSA-ELM modelling.

Moisture content testing of agricultural products is critical for quality control, processing efficiency and storage management. Testing foxtail millet moisture content ensures stable foxtail millet quality and helps farmers determine the best time to harvest. A differential capacitance moisture content detection device was designed based on STM32 and PCAP01 capacitance digital converter chip. The capacitance method combined with the back-propagation(BP) algorithm and the extreme learning machine(ELM) algorithm was chosen to construct an analytical model for foxtail millet moisture content, temperature, and volume duty cycle. This work performs capacitance measurements on foxtail millet with different moisture contents, temperatures, and proportions of the measured substance occupying the detection area (that is, the volumetric duty cycle). On this foundation, the sparrow search algorithm (SSA) is used to optimize the BP and ELM models. However, SSA may encounter problems such as falling into local optimization solutions due to the reduction of population diversity in the late iterations. As a consequence, Logistic algorithm is introduced to optimize SSA, making it more appropriate for solving specific problems. Upon comparative analysis, the model predicted using the Logistic-SSA-ELM algorithm was more accurate. The results indicate that the predicted values of prediction set coefficient of determination (RP), prediction set root mean square error (RMSEP) and prediction set ratio performance deviation (RPDP) were 0.7016, 3.7150 and 1.4035, respectively. This algorithm has excellent prediction performance and can be used as a model for detection of foxtail millet moisture content. In view of the important role of foxtail millet moisture content detection in acquisition and storage, it is particularly important to study a nondestructive and fast online real-time detection method. The designed capacitive sensor with differential structure has well stabilization and high accuracy, which can be further studied in depth and gradually move towards the general trend of agricultural development of smart agriculture and precision agriculture.

A solvent-free processed low-temperature tolerant adhesive.

Ultra-low temperature resistant adhesive is highly desired yet scarce for material adhesion for the potential usage in Arctic/Antarctic or outer space exploration. Here we develop a solvent-free processed low-temperature tolerant adhesive with excellent adhesion strength and organic solvent stability, wide tolerable temperature range (i.e. -196 to 55 °C), long-lasting adhesion effect ( > 60 days, -196 °C) that exceeds the classic commercial hot melt adhesives. Furthermore, combine experimental results with theoretical calculations, the strong interaction energy between polyoxometalate and polymer is the main factor for the low-temperature tolerant adhesive, possessing enhanced cohesion strength, suppressed polymer crystallization and volumetric contraction. Notably, manufacturing at scale can be easily achieved by the facile scale-up solvent-free processing, showing much potential towards practical application in Arctic/Antarctic or planetary exploration.

Covid-19 psychological pressures, depression and FOMO: the mediating role of online social support and emotional regulation.

BACKGROUND: The spread of the coronavirus has led to significant anxiety among university students, resulting in various mental health problems that could potentially impact their academic performance. METHOD: To examine the mediating role of emotional regulation and online social support in the relationships between COVID-19 psychological pressures, depression, and the fear of missing out (FoMO) among young adult university students, a cross-sectional research design was employed using an online survey. The sample consisted of 521 full-time university students from China, currently enrolled in undergraduate and postgraduate programs. RESULTS: Findings revealed that more than half (55.09%, n=287) of the university students experienced COVID-19 psychological pressures. These pressures directly contributed to increased levels of depression (ß = 0.339, p < .001) and fear of missing out (ß = 0.236, p < .001). Moreover, online social support and emotional regulation exhibited partial mediating effects on the association between COVID-19 psychological pressures, depression, and the fear of missing out. The results indicated that COVID-19 psychological pressures were linked to higher levels of depressive symptoms and a greater fear of missing out among university students. CONCLUSIONS: However, the provision of timely and adequate online social support, as well as the implementation of emotional regulation strategies, mitigated the negative effects of the pandemic on students' social and emotional well-being. Consequently, this led to reduced levels of depression and fear of missing out.

A Survey of Public Opinion on Community Cats' General Health and Relationship Quality with Residents in Urban China.

The management and coexistence of community cats in urban areas is a growing concern amid global urbanization. Through a survey-based investigation, we examine the residents' perceptions of the general health of community cats and human-cat relationships in urban China. The data from 5382 participants revealed that approximately 70% of participants perceived community cats as being in good health, and 60% reported harmonious or non-conflict coexistence between residents and these cats. Around 45% of the participants rescued or helped community cats, 38% expressed their intention to adopt, and 18% complained about the issues of community cats to management staff. Linear, logistic, and multilevel-logistic regressions were employed to examine the associations between the types of cities and communities or the participants' socio-demographics and the perceived well-being of community cats or human-cat relationships. The results show that the cats in fourth-tier cities (e.g., county-level cities) had poorer living conditions than in first-tier cities (e.g., Beijing), while the cats in urban village communities (e.g., villages in the city) were less likely to exhibit good health than in ordinary commercial housing communities. The results also show that socio-demographic variables, such as educational attainment, marital status, and income level, predicted participants' relationships with community cats. This study is the first of its kind. It provides valuable insights for stakeholders to develop effective policies and interventions on cat management, emphasizing the need for tailored strategies in diverse urban settings and populations.

Black phosphorus-incorporated novel Ti-12Mo-10Zr implant for multimodal treatment of osteosarcoma.

The repair and reconstruction of large bone defects after bone tumor resection is still a great clinical challenge. At present, orthopedic implant reconstruction is the mainstream treatment for repairing bone defects. However, according to clinical feedback, local tumor recurrence and nonunion of bone graft are common reasons leading to the failure of bone defect repair and reconstruction after bone tumor resection, which seriously threaten the physical and mental health of patients. On this basis, here the self-developed low modulus Ti-12Mo-10Zr alloy (TMZ) was chosen as substrate material. To improve its biological activity and osteointegration, calcium, oxygen, and phosphorus co-doped microporous coating was prepared on TMZ alloy by microarc oxidation (MAO). Then, black phosphorus (BP) nanosheets were incorporated onto MAO treated TMZ alloy to obtain multifunctional composites. The obtained BP-MAO-TMZ implant exhibited excellent photothermal effects and effective ablation of osteosarcoma cancer cells under the irradiation of 808 nm near infrared laser, while no photothermal or therapeutic effects were observed for TMZ alloy. Meanwhile, the structure/component bionic coating obtained after MAO treatment as well as the P-driven in situ biomineralization performance after incorporation of BP nanosheets endowed BP-MAO-TMZ implant with synergistic promoting effect on MC3T3-E1 osteoblasts' activity, proliferation and differentiation ability. This study is expected to provide effective clinical solutions for problems of difficult bone regeneration and tumor recurrence after tumor resection in patients with bone tumors and to solve a series of medical problems such as poor prognosis and poor postoperative quality of patients life with malignant bone tumors.

The causal configurations of provincial health policy innovation in China: an analysis of the food safety standard filing policy.

Introduction: According to China's Food Safety Law of 2015, the filing of food safety enterprise standards is a policy innovation led by p9rovincial governments in China. However, there are significant differences in the development of the "Food Safety Enterprise Standard Filing Policy" between provincial governments across the country. This study aims to explore the internal mechanisms driving autonomous innovation by provincial governments in the absence of administrative pressure from the central government, to better understand the policy innovation mechanism in the Chinese context. Methods: Crispy Set Qualitative Comparative Analysis (csQCA) method is used to identify the innovation mechanism. Results: This study found that provinces with good provincial economic resources and strong government capabilities are prone to policy innovation, and the influence of internal factors of provincial governments is stronger than that of external factors. Discussion: When provincial economic resources and capacity are weak, endogenous factors in the province also help achieve proactive policy innovation by provincial governments. The research results reveal how provincial governments construct local policies in the absence of administrative pressure from the central government.

Latest advances: Improving the anti-inflammatory and immunomodulatory properties of PEEK materials.

Excellent biocompatibility, mechanical properties, chemical stability, and elastic modulus close to bone tissue make polyetheretherketone (PEEK) a promising orthopedic implant material. However, biological inertness has hindered the clinical applications of PEEK. The immune responses and inflammatory reactions after implantation would interfere with the osteogenic process. Eventually, the proliferation of fibrous tissue and the formation of fibrous capsules would result in a loose connection between PEEK and bone, leading to implantation failure. Previous studies focused on improving the osteogenic properties and antibacterial ability of PEEK with various modification techniques. However, few studies have been conducted on the immunomodulatory capacity of PEEK. New clinical applications and advances in processing technology, research, and reports on the immunomodulatory capacity of PEEK have received increasing attention in recent years. Researchers have designed numerous modification techniques, including drug delivery systems, surface chemical modifications, and surface porous treatments, to modulate the post-implantation immune response to address the regulatory factors of the mechanism. These studies provide essential ideas and technical preconditions for the development and research of the next generation of PEEK biological implant materials. This paper summarizes the mechanism by which the immune response after PEEK implantation leads to fibrous capsule formation; it also focuses on modification techniques to improve the anti-inflammatory and immunomodulatory abilities of PEEK. We also discuss the limitations of the existing modification techniques and present the corresponding future perspectives.

Injectable cell-laden hydrogels fabricated with cellulose and chitosan nanofibers for bioprinted liver tissues.

Bio-based hydrogels as three-dimensional (3D) constructs have attracted attention in advanced tissue engineering. Compared with conventional two-dimensional (2D) cell culture, cells grown in 3D scaffolds are expected to demonstrate the inherent behavior of living organisms of cellular spheroids. Herein, we constructed cell-laden nanofiber-based hydrogels in combination with 2,2,6,6-tetramethylpiperidine 1-oxyl-oxidized cellulose nanofiber (TOCNF) and chitosan nanofiber (CsNF) for bioadaptive liver tissue engineering. The carboxylates of TOCNF and amines of CsNF were directly crosslinked via EDC/NHS chemistry. The rheological properties of the solutions for the nanofibers and hydrogels revealed sufficient physical properties for the injection, printing, and plotting process, as well as significant encapsulation of living cells. As-designed hydrogels exhibited excellent viscoelastic properties with typical shear-thinning behavior, and had a storage modulus of 1234 Pa ± 68 Pa, suitable for cell culture. Non-cytotoxicity was confirmed using a live/dead assay with mouse-derived fibroblast NIH/3T3 cells. Human hepatocellular carcinoma HepG2 cells could be cultured on a gel surface (2D environment) and encapsulated in the gel structure (3D environment), which enabled 10 d growth with high gene expression level of albumin of HepG2 spheroids in the 3D gels. The biodegradable cell-laden hydrogels are expected to mimic the cellular microenvironment and provide potential for bioadaptive 3D cell cultures in biomedical applications.

Epidermis-on-a-chip system to develop skin barrier and melanin mimicking model.

In vitro skin models are rapidly developing and have been widely used in various fields as an alternative to traditional animal experiments. However, most traditional static skin models are constructed on Transwell plates without a dynamic three-dimensional (3D) culture microenvironment. Compared with native human and animal skin, such in vitro skin models are not completely biomimetic, especially regarding their thickness and permeability. Therefore, there is an urgent need to develop an automated biomimetic human microphysiological system (MPS), which can be used to construct in vitro skin models and improve bionic performance. In this work, we describe the development of a triple-well microfluidic-based epidermis-on-a-chip (EoC) system, possessing epidermis barrier and melanin-mimicking functions, as well as being semi-solid specimen friendly. The special design of our EoC system allows pasty and semi-solid substances to be effectively utilized in testing, as well as allowing for long-term culturing and imaging. The epidermis in this EoC system is well-differentiated, including basal, spinous, granular, and cornified layers with appropriate epidermis marker (e.g. keratin-10, keratin-14, involucrin, loricrin, and filaggrin) expression levels in corresponding layers. We further demonstrate that this organotypic chip can prevent permeation of over 99.83% of cascade blue (a 607 Da fluorescent molecule), and prednisone acetate (PA) was applied to test percutaneous penetration in the EoC. Finally, we tested the whitening effect of a cosmetic on the proposed EoC, thus demonstrating its efficacy. In summary, we developed a biomimetic EoC system for epidermis recreation, which could potentially serve as a useful tool for skin irritation, permeability, cosmetic evaluation, and drug safety tests.

Room-Temperature Self-Healing Conductive Elastomers for Modular Assembly as a Microfluidic Electrochemical Biosensing Platform for the Detection of Colorectal Cancer Exosomes.

Modular components for rapid assembly of microfluidics must put extra effort into solving leakage and alignment problems between individual modules. Here, we demonstrate a conductive elastomer with self-healing properties and propose a modular microfluidic component configuration system that utilizes self-healing without needing external interfaces as an alternative to the traditional chip form. Specifically, dual dynamic covalent bond crosslinks (imine and borate ester bonds) established between Polyurethane (PU) and 2-Formylbenzeneboronic acid (2-FPBA) are the key to a hard room-temperature self-healing elastomeric substrate PP (PU/2-FPBA). An MG (MXene/GO) conductive network with stable layer spacing (Al-O bonds) obtained from MXene and graphene oxide (GO) by in situ reduction of metals confers photothermal conductivity to PP. One-step liquid molding obtained a standardized modular component library of puzzle shapes from PP and MGPP (MG/PP). The exosomes were used to validate the performance of the constructed microfluidic electrochemical biosensing platform. The device has a wide detection range (50-105 particles/µL) and a low limit of detection (LOD) (42 particles/µL) (S/N = 3), providing a disposable, reusable, cost-effective, and rapid analysis platform for quantitative detection of colorectal cancer exosomes. In addition, to our knowledge, this is the first exploration of self-healing conductive elastomers for a modular microfluidic electrochemical biosensing platform.

Generation of 3D Tumor Spheroids for Drug Evaluation Studies.

In recent decades, in addition to monolayer-cultured cells, three-dimensional tumor spheroids have been developed as a potentially powerful tool for the evaluation of anticancer drugs. However, the conventional culture methods lack the ability to manipulate the tumor spheroids in a homogeneous manner at the three-dimensional level. To address this limitation, in this paper, we present a convenient and effective method of constructing average-sized tumor spheroids. Additionally, we describe a method of image-based analysis using artificial intelligence-based analysis software that can scan the whole plate and obtain data on three-dimensional spheroids. Several parameters were studied. By using a standard method of tumor spheroid construction and a high-throughput imaging and analysis system, the effectiveness and accuracy of drug tests performed on three-dimensional spheroids can be dramatically increased.

Design, synthesis and evaluation of N3-substituted quinazolinone derivatives as potential Bloom's Syndrome protein (BLM) helicase inhibitor for sensitization treatment of colorectal cancer.

The homologous recombination repair (HRR) pathway is critical for repairing double-strand breaks (DSB). Inhibition of the HRR pathway is usually considered a promising strategy for anticancer therapy. The Bloom's Syndrome Protein (BLM), a DNA helicase, is essential for promoting the HRR pathway. Previously, we discovered quinazolinone derivative 9h as a potential BLM inhibitor, which suppressed the proliferation of colorectal cancer (CRC) cell HCT116. Herein, a new series of quinazolinone derivatives with N3-substitution was designed and synthesized to improve the anticancer activity and explore the structure-activity relationship (SAR). After evaluating their BLM inhibitory activity, the SAR was discussed, leading to identifying compound 21 as a promising BLM inhibitor. 21 exhibited the potent BLM-dependent cytotoxicity against the CRC cells but weak against normal cells. Further evaluation revealed that 21 could disrupt the HRR level while inhibiting BLM located on the DSB site and trigger DNA damage in the CRC cells. This compound effectively suppressed the proliferation and invasion of CRC cells, along with cell cycle arrest and apoptosis. Consequently, 21 might be a promising candidate for treating CRC, and the BLM might be a new potential therapeutic target for CRC.

Unraveling the mechanisms of intervertebral disc degeneration: an exploration of the p38 MAPK signaling pathway.

Intervertebral disc (IVD) degeneration (IDD) is a worldwide spinal degenerative disease. Low back pain (LBP) is frequently caused by a variety of conditions brought on by IDD, including IVD herniation and spinal stenosis, etc. These conditions bring substantial physical and psychological pressure and economic burden to patients. IDD is closely tied with the structural or functional changes of the IVD tissue and can be caused by various complex factors like senescence, genetics, and trauma. The IVD dysfunction and structural changes can result from extracellular matrix (ECM) degradation, differentiation, inflammation, oxidative stress, mechanical stress, and senescence of IVD cells. At present, the treatment of IDD is basically to alleviate the symptoms, but not from the pathophysiological changes of IVD. Interestingly, the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway is involved in many processes of IDD, including inflammation, ECM degradation, apoptosis, senescence, proliferation, oxidative stress, and autophagy. These activities in degenerated IVD tissue are closely relevant to the development trend of IDD. Hence, the p38 MAPK signaling pathway may be a fitting curative target for IDD. In order to better understand the pathophysiological alterations of the intervertebral disc tissue during IDD and offer potential paths for targeted treatments for intervertebral disc degeneration, this article reviews the purpose of the p38 MAPK signaling pathway in IDD.

Evaluation of AMG510 Therapy on KRAS-Mutant Non-Small Cell Lung Cancer and Colorectal Cancer Cell Using a 3D Invasive Tumor Spheroid System under Normoxia and Hypoxia.

A 3D tumor spheroid has been increasingly applied in pharmaceutical development for its simulation of the tumor structure and microenvironment. The embedded-culture of a tumor spheroid within a hydrogel microenvironment could help to improve the mimicking of in vivo cell growth and the development of 3D models for tumor invasiveness evaluation, which could enhance its drug efficiency prediction together with cell viability detection. NCI-H23 spheroids and CT-26 spheroids, from a non-small cell lung cancer and colorectal cancer cell line, respectively, together with extracellular matrix were generated for evaluating their sensitivity to AMG510 (a KRASG12C inhibitor) under normoxia and hypoxia conditions, which were created by an on-stage environmental chamber. Results demonstrated that NCI-H23, the KRASG12C moderate expression cell line, only mildly responded to AMG510 treatment in normal 2D and 3D cultures and could be clearly evaluated by our system in hypoxia conditions, while the negative control CT-26 (G12D-mutant) spheroid exhibited no significant response to AMG510 treatment. In summary, our system, together with a controlled microenvironment and imaging methodology, provided an easily assessable and effective methodology for 3D in vitro drug efficiency testing and screenings.

Solvent effects on the motion of a crown ether/amino rotaxane.

Solvents have been recognized as a significant factor for modulating the shuttle of rotaxanes and regulating their functions regarding molecular machines by a lot of published studies. The mechanism of the effects of solvents on the motion of crown ether/amino rotaxanes, however, remains unclear. In this work, a rotaxane, formed by dibenzo-24-crown-8 (C[8]) and a dumbbell-shaped axle with two positively charged amino groups, was investigated at the atom level. Two-dimensional free-energy landscapes characterizing the conformational change of C[8] and the shuttling motions in chloroform and water were mapped. The results indicated that the barriers in water were evidently lower than those in chloroform. By analyzing the trajectories, there was no obvious steric effect during shuttling. Instead, the main driving force of shuttling was verified from electrostatic interactions, especially strong hydrogen bonding interactions between the axle and water, which resulted in the fast shuttling rate of the rotaxane. All in all, the polarity and hydrogen bond-forming ability of solvents are the main factors in affecting the shuttling rate of a crown ether/amino rotaxane. In addition, C[8] would adopt S-shaped conformations during shuttling except for situating in the amino sites with C-shaped ones adopted due to π-π stacking interactions. The results of this research improve the comprehension of the solvent modulation ability for shuttling in crown ether-based rotaxanes and illustrate the effects of structural modifications on motions. These new insights are expected to serve the efficient design and construction of molecular machines.