Core Mechanism Research Articles

Anti-inflammatory effects of LCB 03-0110 on human corneal epithelial and murine T helper 17 cells.

Dry eye disease (DED) is a complicated disorder that impacts ocular surface and tear-film stability. Inflammation has recently been reported as the core mechanism and main therapeutic target of DED. Although anti-inflammatory drugs have been developed, they still have limited efficacy and various side effects. Recent reports have suggested that kinase inhibitors are beneficial for relieving inflammation. Therefore, this study aimed to investigate the anti-inflammatory effects of LCB 03-0110, a multi-tyrosine kinase inhibitor, on representative cell-based models (HCE- 2 and Th17 cells) of DED. While tacrolimus and tofacitinib, two different anti-inflammatory drugs that have entered clinical trials for DED treatment, did not induce any anti-inflammatory responses in HCE-2 cells, LCB 03-0110 significantly suppressed the phosphorylation of P38 and ERK and reduced the expression levels of IL-6 and IL-8 in HCE-2 cells treated with either LPS or poly(I:C). Moreover, LCB 03-0110 notably decreased the expression level of IL-17A in Th17 cells in a dose-dependent manner, whereas tofacitinib promoted IL-17A production at low concentrations but inhibited its expression at concentrations greater than 1 μM. In addition, LCB 03-0110 was found to be non-toxic to both HCE-2 and Th17 cells. In conclusion, these results suggest that LCB 03-0110 would be a promising drug candidate for the treatment of DED because of its advantages over tacrolimus and tofacitinib.

Quercetin Boosts Pulsatile Gonadotropin-Releasing Hormone Release to Improve Luteal Function via Inhibiting NF-κB/NLRP3-Mediated Neuron Pyroptosis.

Luteal phase deficiency (LPD) is the main cause of infertility without an effective cure. Quercetin (QUE) is a bioactive flavonoid with antioxidant properties, while its role in treating LPD remains unclear. This study aims to investigate the therapeutic effects of QUE on infertility and menstrual disorders induced by LPD, thus further exploring the underlying mechanism. Mifepristone-induced rats are used to explore the protective effects of QUE against LPD. QUE stimulates the spontaneous secretion of progesterone to improve luteal function and endometrial receptivity in LPD rats by activating the kisspeptin/GPR54 system to facilitate the gonadotropin-releasing hormone (GnRH) pulsatility. Bioinformatics analysis reveals that the core mechanism of QUE in treating LPD is to attenuate the GnRH neuron pyroptosis by inhibiting the NF-κB pathway, which is further verified in LPD rats and lipopolysaccharide (LPS)-treated GT1-7, as QUE significantly reduces the expression of key factors concerning NF-κB pathway and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome. This study first proposes that neuron pyroptosis-induced GnRH pulsatility disruption accounts for the pathogenesis of LPD, and QUE facilitates the pulse secretion of GnRH to boost the spontaneous progesterone secretion by inhibiting NF-κB/NLRP3-mediated neuron pyroptosis, which provides a new therapeutic target and strategy for LPD.

Efficacy and Mechanisms of Jiyin Fang (Granule) Against Postmenopausal Coronary Heart Disease Complicated with Osteoporosis

Purpose To explore the efficacy and mechanisms of Jiyin Fang (JYF) against postmenopausal coronary heart disease (CHD) complicated with osteoporosis (OP). Methods Firstly, collected ingredients and relative targets of JYF from TCMSP and BATMAN-TCM database, disease targets of CHD and OP from GeneCards, TTD and OMIM database. By use of protein to protein (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, obtained core targets and mechanism pathways. Finally, preliminarily explore the pharmacological effect and major targets partly to explain the mechanism, through experiment of ovariectomized CHD with OP model rats treated with JYF. Results Total of 112 ingredients and 253 related targets of JYF, 173 disease targets common to CHD and OP were screened out. PPI network indicated 9 core targets. GO and KEGG enrichment analysis showed 20 major signal pathway. Rats experiment displayed that JYF could ameliorate the structural injury of aortic arch and femur; reduce the abnormal changes of ST segment and T wave of ECG; decrease the content of BGP, OPG, ALP, CTX, IL-6 and TNFα, increase the levels of PINP in serum; inhibit P53, MAPK, NF-κB and IKK protein expression, promote PPARG protein expression of aortic arch; inhibit NRF2, AKT protein expression and up-regulate p-STAT1, MMP9 protein expression in femur. Conclusion JYF can achieve the purpose of anti postmenopausal CHD complicated with OP. The potential mechanism may relate to P53/MAPK/NF-κB in aortic arch, and AKT/NRF2/p-STAT1 in bone, due to IL-6 and TNFα.

Core mechanism for the stability preparation of lithium slag-based SOD zeolite: Evolution of trans-crystallization nucleation/growth kinetics of crystals

SOD nano-zeolite has been widely applied in the separation of small gas molecules since these advantages comprise a high-density framework and favorable acid/alkali resistance. Moreover, the bottleneck for the lithium sector can be ameliorated by industrializing the manufacture of SOD zeolite (SLS) from the hazardous waste lithium slag (LS). However, the stability in industrial production is restricted owing to the ambiguous nature of the lattice nucleation/transformation mechanism. Herein, it was discovered that the highest relative crystallinity (98.8 %) of SLS with a layered spherical structure could be achieved under the crystallization condition of heating at 95 °C for 8 h. The nucleation and growth mechanisms of SLS crystals demonstrated a three-dimensional crystal growth pattern characterized by sporadic and transient nucleation, which is essentially consistent with that of crystallization kinetics. Specifically, the activation energies of the induction, transformation and crystallization phases were 41.33, 27.99 and 46.99 kJ·mol−1, respectively, implying that the directional induction of the transition phase is crucial for obtaining SLS with high crystallinity. Two nucleation processes can also be observed in the transformation stage, involving homogeneous nucleation and polymorphic transformation. Our study explored the crystallization and assembly mechanism of SLS crystals, providing a well-defined concept for the regulation of stability preparation.

Sex dimorphism and tissue specificity of gene expression changes in aging mice

BackgroundAging is a complex process that involves all tissues in an organism and shows sex dimorphism. While transcriptional changes in aging have been well characterized, the majority of studies have focused on a single sex and sex differences in gene expression in aging are poorly understood. In this study, we explore sex dimorphism in gene expression in aging mice across three tissues.MethodsWe collected gastrocnemius muscle, liver and white adipose tissue from young (6 months, n = 14) and old (24 months, n = 14) female and male C57BL/6NIA mice and performed RNA-seq. To investigate sex dimorphism in aging, we considered two levels of comparisons: (a) differentially expressed genes between females and males in the old age group and (b) comparisons between females and males across the aging process. We utilized differential expression analysis and gene feature selection to investigate candidate genes. Gene set enrichment analysis was performed to identify candidate molecular pathways. Furthermore, we performed a co-expression network analysis and chose the gene module(s) associated with aging independent of sex or tissue-type.ResultsWe identified both tissue-specific and tissue-independent genes associated with sex dimorphism in aged mice. Unique differentially expressed genes between old males and females across tissues were mainly enriched for pathways related to specific tissue function. We found similar results when exploring sex differences in the aging process, with the exception that in the liver genes enriched for lipid metabolism and digestive system were identified in both females and males. Combining enriched pathways across analyses, we identified amino acid metabolism, digestive system, and lipid metabolism as the core mechanisms of sex dimorphism in aging. Although the vast majority of age-related genes were sex and tissue specific, we identified 127 hub genes contributing to aging independent of sex and tissue that were enriched for the immune system and signal transduction.ConclusionsThere are clear sex differences in gene expression in aging across liver, muscle and white adipose. Core pathways, including amino acid metabolism, digestive system and lipid metabolism, contribute to sex differences in aging.

An Evidence-Based Nurse-Led Intervention to Reduce Diabetes Distress Among Adults With Type 1 Diabetes and Diabetes Distress (REDUCE): Development of a Complex Intervention Using Qualitative Methods Informed by the Medical Research Council Framework.

Diabetes distress refers to the negative emotional reaction to living with the demands of diabetes; it occurs in >40% of adults with type 1 diabetes (T1D). However, no interventions to reduce diabetes distress are specifically designed to be an integral part of diabetes care. This study aims to modify and adapt existing evidence-based methods into a nurse-led group intervention to reduce diabetes distress among adults with T1D and moderate to severe diabetes distress. The overall framework of this study was informed by the initial phase of the Medical Research Council's complex intervention framework that focused on undertaking intervention identification and development to guide the adaptation of the intervention. This study took place at 2 specialized diabetes centers in Denmark from November 2019 to June 2021. A total of 36 adults with T1D participated in 10 parallel workshops. A total of 12 diabetes-specialized nurses were interviewed and participated in 1 cocreation workshop; 12 multidisciplinary specialists, including psychologists, educational specialists, and researchers, participated in 4 cocreation workshops and 14 feedback meetings. Data were analyzed by applying a deductive analytic approach. The intervention included 5 biweekly 2.5-hour small group sessions involving adults with T1D and diabetes distress. Guided by a detailed step-by-step manual, the intervention was delivered by 2 trained diabetes specialist nurses. The intervention material included visual conversation tools covering seven diabetes-specific sources derived from the 28-item Type 1 Diabetes Distress Scale for measuring diabetes distress: (1) powerlessness, (2) self-management, (3) fear of hypoglycemia, (4) food and eating, (5) friends and family, (6) negative social perception, and (7) physician distress. The tools are designed to kick-start awareness and sharing of diabetes-specific challenges and strengths, individual reflections, as well as plenary and peer-to-peer discussions about strategies to manage diabetes distress, providing new perspectives on diabetes worries and strategies to overcome negative emotions. Diabetes specialist nurses expressed a need for a manual with descriptions of methods and detailed guidelines for using the tools. To deliver the intervention, nurses need increased knowledge about diabetes distress, how to support diabetes distress reduction, and training and supervision to improve skills. This co-design study describes the adaptation of a complex intervention with a strong evidence base, including detailed reporting of the theoretical underpinnings and core mechanisms.

Tumor-associated macrophages/C-X-C motif chemokine ligand 1 promotes breast cancer autophagy-mediated chemoresistance via IGF1R/STAT3/HMGB1 signaling

Autophagy-mediated chemoresistance is the core mechanism for therapeutic failure and poor prognosis in breast cancer. Breast cancer chemotherapy resistance is believed to be influenced by tumor-associated macrophages (TAMs), by which C-X-C motif chemokine ligand 1 (CXCL1) is the most abundant cytokine secreted. Yet, its role in mediating autophagy-related chemoresistance is still unknown. This study aimed to explore the molecular mechanisms by which TAMs/CXCL1 induced autophagy-mediated chemoresistance in breast cancer. It was found that TAMs/CXCL1 promoted chemoresistance of breast cancer cells through autophagy activation in vitro, and CXCL1 silence could enhance the chemosensitivity of paclitaxel-resistant breast cancer cells via autophagy inhibition. A high-throughput quantitative PCR chip and subsequent target validation showed that CXCL1 induced autophagy-mediated chemoresistance by inhibiting VHL-mediated IGF1R ubiquitination. The elevated IGF1R then promoted STAT3/HMGB1 signaling to facilitate autophagy. Additionally, TAMs/CXCL1 silence improved paclitaxel chemosensitivity by suppressing autophagy in breast cancer mice xenografts, and clinical studies further linked CXCL1 to IGF1R/HMGB1 signaling, as well as shorter free survival of recurrence. Taken together, these results not only uncover the crucial role of TAMs/CXCL1 signaling in mediating breast cancer chemoresistance through enhancing autophagy, but also shed novel light on the molecular mechanism of IGF1R/STAT3/HMGB1 pathway in regulating autophagy and its impact on cancer prognosis.

Enhancing Team Cohesion Through a Custom MOBA Game: Development, Implementation & Impact

The quality of a team in organizations has an impact on the success of the team in achieving their goals. Team building activities are one of the elements which can improve relationships in different kinds of teams. One of those can be playing competitive digital games, whether for teams working remotely or on site. This paper presents a case study that explores the design and development process of an innovative online game that combines elements of third-person action and multiplayer online battle arena (MOBA) games to provide an experience that strengthens team cohesion. The game design and mechanics support distribution of team roles based on Belbin's theory, highlighting the importance of diverse roles for balanced team functionality. By integrating unique character functions, the game encourages players to understand and appreciate the different roles individuals play in a team, enhancing empathy and mutual respect among team members. The game is uniquely designed to be simpler and more accessible than typical MOBAs, making it an ideal tool for educational and organizational settings to boost team cohesion and communication skills among people from various backgrounds. The leveling of the playing field allows individuals with minimal gaming experience to participate fully and effectively. The design principles ensure that the core mechanics of the game encourage teamwork and effective communication over individual skill, emphasizing collective success. The case study delves into the development process, the challenges faced, the solutions implemented, and the outcomes observed as part of a research project conducted between 2022-2023. The findings suggest that game-based learning can significantly transform traditional team-building methods, introducing a new paradigm for fostering high-performance teams in an increasingly digital world.

Core Mechanisms in Mediating eHealth Implementation and Uptake: A Case Study of Eastern Uganda

Researchers agree that, globally, in both developing and developed countries, healthcare management is faced with acute challenges: expanding areas of health needs, operationalizing health management, constrained budget allocations, as well as resource limitations. Hence, there is an imminent drive to find solutions to stimulate health system transformation through health system innovation. Therefore, effective national operational strategies to minimize resource wastage and contain the costs of health service delivery are critical. The study adopted a methodology that incorporated different research approaches and strategies. Deductive and inductive approaches were used; the strategies were surveys and case studies. A sample of 178 health professionals and administrators in three Health care facilities in Eastern Uganda, were determined and surveyed. Eligible respondents were stratified and selected through simple random sampling. Self-administered questionnaires and interview guides were used to gather the data. The captured data was analysed using Stata version 17. Regression analysis was used to determine the impact of eHealth Implementation core mechanisms on Quality Health Service Delivery. From the results of regression analysis, the core mechanisms variable had a p-value of 0.049 which was significant. For eHealth Implementation Core Mechanisms, the respondents have less control over them since they are dependent on several environmental factors, such as government funding or grants, Government regulations, and policies among others.

Visual colorimetric label for real-time monitoring of SO2 concentration change in grape and mango during storage

Sulfur dioxide (SO2) is widely utilized as a preservative in food transportation and storage, but excessive consumption poses health risks. This study presents a novel and efficient method for the real-time detection of SO2 using a sensor named TK, synthesized from triphenylamine and 2-cyanomethyl-1-methyl-quinolinium. The core mechanism involves the Michael addition reaction of the CC bond in TK with SO2, which disrupts the intramolecular charge transfer process, resulting in a significant color change and a blue shift in fluorescence emission. Methodologically, the sensor's response was quantified by the change in fluorescence intensity ratio (I425/I647) within a SO2 concentration range of 0–180 μM. The sensor exhibited high sensitivity and selectivity. For practical application, TK was incorporated into hydrophilic polyvinyl alcohol to create a smart label capable of visual colorimetry and fluorescence analysis. SO2 concentration changes were monitored by using this label, demonstrated by the color transition from burgundy red to colorless, yielding a maximum color difference (ΔE) of 73.6. The smart label was successfully used to monitor the quality of various grapes and mangoes during long-term storage, providing a reliable, equipment-independent method suitable for household use. The study offers a new tool for enhancing food safety and mitigating health risks associated with SO2 exposure.

Chronic microcystin-leucine-arginine exposure induces osteoporosis by breaking the balance of osteoblasts and osteoclasts

Microcystin-leucine-arginine (MC-LR) produced by cyanobacterial harmful algal blooms are hazardous materials. However, the toxicity and mechanisms of continuous exposure to MC-LR on the occurrence of osteoporosis remains poorly documented. In this study, to mimic the chronic influences of MC-LR on the bone tissues in humans, an animal model was constructed in which mice were treated with MC-LR through drinking water at an environmentally relevant level (1–30 μg/L) for 6 months. MC-LR was enriched in the skeletal system, leading to the destruction of bone microstructure, the decrease of bone trabecular number, the reduction of osteoblasts, the enhanced content of lipid droplets, and the activation of osteoclasts, which is the characteristic of osteoporosis. Herein, we revealed ferroptosis is a vital mechanism of osteoblast death in mouse models of MC-LR. MC-LR exposure activates AMPK/ULK1 signaling, further promotes ferritin selective autophagy, causes free iron release and lipid peroxidation deposition, and eventually leads to ferroptosis of osteoblasts. Importantly, the use of AMPK or ferroptosis inhibitors in vivo markedly reduced MC-LR-induced osteoblast death and impaired osteogenic differentiation. Interestingly, MC-LR exposure promotes iron uptake in bone marrow macrophages through the TF-TFR1 pathway, leading to its transformation to TRAP-positive pre-osteoclast cells, thereby promoting bone resorption. Overall, our data innovatively revealed the core mechanism of MC-LR-induced osteoporosis, providing the bi-directional regulation of MC-LR on osteoblast-osteoclast from the perspective of iron homeostasis imbalance.

How to enable human-centric collaboration in social product development paradigm: A practical and theoretical exploration

Since 2012, social product development (SPD) has emerged as a potential paradigm for new product development (NPD). However, the emerging SPD practices are difficult to remain and promote after their early success. The lack of sustainable human-centric collaborative settings will hinder the release of crowd-based collective intelligence in NPD. Currently, the core mechanisms of human-centric collaboration (HCC) in SPD are not clear. To narrow the gap between theory and practice, a two-way empirical study is conducted through an in-deep industrial practice investigation and theory-oriented research based on cooperative inquiry. An extreme case of a famous automotive company is sampled as the object of the cooperative inquiry. The proposed theoretical models are verified by two real SPD pilot projects. Inspired by the discipline of Collaborative Engineering, this study explores the HCC issues and it core mechanisms in the context of SPD. Two novel foundation theoretical models are developed to address the focused scientific problem and engineering challenge. A bottom-up model is developed to structurally elicit the HCC requirements and develop reasonable information modules for specific HCC work practices. A top-down model is developed to improve the manageability and reusability of the learnable experience from historical HCC work practices for better business-technology-system alignment. This study put forward novel theoretical models for designing and deploying collaborative work practices for HCC in SPD. A classification-based Descriptive Model of Collaboration (DMoC) is proposed, which is domain-agnostic and customized for SPD requirements. Our model inherits and outperforms in modelling capability than five other proven modelling approaches.

Advocacy for DOHaD research optimizing child kidney health

Emerging antenatal risk factors have been associated with an increased risk of kidney disease throughout the offspring's life course. However, the intricate kidney programming mechanisms underlying these risks remain complex and are incompletely understood, but they are rooted in structural and functional alterations within the kidneys. The Developmental Origins of Health and Disease (DOHaD) theory underscores the significance of elucidating core mechanisms initiated through the maternal-fetal interface, which trigger kidney programming. Furthermore, it offers a promising avenue for preventing kidney disease at its earliest stages through a process known as reprogramming. This concise review aims to synthesize existing knowledge regarding the impact of kidney programming on offspring kidney disease and to provide an overview of documented reprogramming strategies as observed in animal models of kidney programming. By consolidating this information, we aim to expedite the translation of research breakthroughs into practical clinical solutions, ultimately resulting in enhanced outcomes for children facing kidney-related issues.

Formulating the Relationship Between Intermolecular Interactions and Photodynamic Effects Based on the Optical Regularity Exhibited by Rare Earth‐BODIPY Crystalline Frameworks System

AbstractThis research commenced with an exploration of how metal nodes in metal‐organic frameworks (MOFs) influence photodynamic therapy (PDT) outcomes. Ultimately, it is revealed that intermolecular interactions are the core mechanism determining the optical properties and PDT efficacy of MOFs. An advanced system of MOFs based on the integration of twelve rare earth ions (RE3+) with boron dipyrromethene (BODIPY)‐derived ligands is reported. Intriguingly, this series of MOFs exhibits a reverse relationship between the radius of RE3+ and PDT efficacy. Single‐crystal X‐ray diffraction analyses along with theoretical calculations indicate that varying RE3+ results in a spatial displacement of the ligands along the dipole direction, diminishing electrostatic (dipole–dipole) interactions while enhancing dispersion (π–π) interactions, thereby enhancing the generation of triplet excitons. Consequently, a novel parameter, Ae‐v = EvdW / Eint × 100%, is proposed to quantify the interplay between non‐radiative energy dissipation via electrostatic interactions and efficient energy utilization in generating singlet oxygen through dispersion interactions. Furthermore, with consistent acoustic sensitivity aligned with the sonoluminescence mechanism, RE‐DCBs are employed in sono‐photodynamic cancer therapy, attaining significant therapeutic results in tumor treatment during in vivo experiments.

Salvia officinalis L. resilience under chromium stress: An integrated study of growth, physiology, biochemical changes and rosmarinic acid production

Medicinal plants are increasingly challenged by rising chromium (Cr) levels in agricultural soil and water bodies due to industrialization and human activities. This research examines the impact of various chromium concentrations on Salvia officinalis L., a medicinal herb, over 3 specific time periods: 30, 60 and 90 days. As the duration of Cr exposure increases, various growth parameters showed an upward trend at the lowest concentrations, with the most robust growth observed in the 20 ppm Cr treatment group after 90 days. However, higher chromium concentrations resulted in reduced plant growth compared to untreated plants. Chromium primarily accumulates in the roots, stems and leaves, with the highest accumulation observed at 100 ppm. However, chlorophyll content declined with prolonged Cr exposure, particularly at higher concentrations. Carbohydrate levels initially increased at lower Cr concentrations but decreased with greater exposure, while protein content consistently decreased with elevated Cr levels. Proline levels exhibited mixed responses, rising at lower concentrations and declining at higher ones. Malondialdehyde (MDA) content increased with higher Cr levels and extended exposure. The enzymatic antioxidant system showed an initial increase followed by a decline with prolonged exposure. Rosmarinic acid content increased with chromium (Cr) exposure upto 60 ppm but subsequently decreased beyond that threshold. In the first 30 days, plants treated with Cr demonstrated a 17 % increase in rosmarinic acid production compared to the control (48.9 mg/g DW). However, with continued Cr exposure, there was a decline in rosmarinic acid production ranging from 10 % to 20 % compared to the control level (67.02 mg/g DW) at 90 days post-treatment. These findings underscore the complex and contrasting responses of Salvia officinalis to Cr toxicity, highlighting the necessity for extended study into the core mechanisms governing these responses and the development of strategies to alleviate heavy metal stress in plants.

Integrating network pharmacology, molecular docking and experimental verification to explore the therapeutic effect and potential mechanism of nomilin against triple-negative breast cancer

BackgroundNomilin is a limonoid compound known for its multiple biological activities, but its role in triple negative breast cancer (TNBC) remains unclear. This study aims to uncover the potential therapeutic effect of nomilin on TNBC and elucidate the specific mechanism of its action.MethodsWe employed weighted gene co-expression network analysis (WGCNA), differential expression analysis, and the GeneCards database to identify potential targets for TNBC. Simultaneously, we utilized the Swiss Target Prediction, ChEMBL, and STITCH databases to identify potential targets of nomilin. The core targets and mechanisms of nomilin against TNBC were predicted through protein-protein interaction (PPI) network analysis, molecular docking, and enrichment analysis. The results of the network pharmacology were corroborated by conducting experiments.ResultsA total of 17,204 TNBC targets were screened, and 301 potential targets of nomilin were identified. Through the PPI network, eight core targets of nomilin against TNBC were pinpointed, namely BCL2, Caspase3, CyclinD1, EGFR, HSP90AA1, KRAS, PARP1, and TNF. Molecular docking, molecular dynamics simulation and proteome microarray revealed that nomilin exhibits strong binding activity to these core proteins. Enrichment analysis results indicated that the anti-TNBC effect of nomilin is associated with PI3K/Akt pathway. In vitro and in vivo experiments have demonstrated that nomilin inhibits TNBC cell proliferation and migration while promoting cell apoptosis through the PI3K/Akt pathway.ConclusionFor the first time, the research effectively discovered the objectives and mechanisms of nomilin in combating TNBC using network pharmacology, molecular docking, molecular dynamics simulation, proteome microarray and experimental confirmation, presenting a hopeful approach for treating TNBC.Graphical

Legal infrastructure construction and audit opinion: Evidence from the implementation of China's new securities law

Based on the background of the implementation of China's New Securities Law (NSL) and the data of Chinese listed enterprises from 2016 to 2023, this paper investigates the influence of the new-updated legal infrastructure construction on auditors’ behavior of issuing audit opinion. The findings depict that the implementation of NSL can significantly improve the possibility of issuing non-standard audit opinion by auditors. Mechanism tests confirm that reducing audit market concentration and increasing disciplinary risks are core mechanism approaches. Further discussion reveals that the incentive effect of NSL implementation on the possibility of issuing non-standard audit opinion is more prominent under the synergy of both the stock exchange inquiry and the scrutiny action of the CICPA interview. This paper makes practical implications for standardizing auditors’ behavior, improving the quality of audit verification responsibility, and consequently protecting the legitimate rights of investors.

Pharmacologically Targeting Ferroptosis and Cuproptosis in Neuroblastoma.

Neuroblastoma is a deadly pediatric cancer that originates from the neural crest and frequently develops in the abdomen or adrenal gland. Although multiple approaches, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, are recommended for treating neuroblastoma, the tumor will eventually develop resistance, leading to treatment failure and cancer relapse. Therefore, a firm understanding of the molecular mechanisms underlying therapeutic resistance is vital for the development of new effective therapies. Recent research suggests that cancer-specific modifications to multiple subtypes of nonapoptotic regulated cell death (RCD), such as ferroptosis and cuproptosis, contribute to therapeutic resistance in neuroblastoma. Targeting these specific types of RCD may be viable novel targets for future drug discovery in the treatment of neuroblastoma. In this review, we summarize the core mechanisms by which the inability to properly execute ferroptosis and cuproptosis can enhance the pathogenesis of neuroblastoma. Therefore, we focus on emerging therapeutic compounds that can induce ferroptosis or cuproptosis, delineating their beneficial pharmacodynamic effects in neuroblastoma treatment. Cumulatively, we suggest that the pharmacological stimulation of ferroptosis and ferroptosis may be a novel and therapeutically viable strategy to target neuroblastoma.

Recovery of bacterial network complexity and stability after simulated extreme rainfall is mediated by K−/r-strategy dominance

The complexity and stability of belowground microbial communities are among the core mechanisms that drive ecosystem functions. Disturbances, such as climate extremes, can exert a substantial influence on these microbial attributes. However, the role of the microbial life history strategy in determining the complexity and stability of desert soil microbial communities after extreme rainfall is poorly understood. Here, we explored the response patterns of bacterial network complexity and stability and characterized the bacterial life history strategy on the basis of the oligotroph (K-strategist)-to-copiotroph (r-strategist) ratio after three extreme rainfall treatments (11, 15, and 25 mm). Experimental results demonstrated that the bacterial communities immediately shifted from the K-strategy to the r-strategy one day after extreme rainfall and gradually recovered to the K-strategy over time, as verified by the increase (31.46 %–125.51 %) then decrease (41.51 % – 95.78 %) in the weighted rrn copy number. Meanwhile, bacterial network complexity and stability showed three-phase patterns [dramatic decline (decreased by 211.67 %–388.46 %)–gradual recovery (increased by 45.60 %–103.65 %)–insignificant change] after three extreme rainfall events. The decline/recovery of these bacterial attributes was highly pronounced/slow after the large extreme rainfall treatment. Specifically, the responses of bacterial network complexity and stability to extreme rainfall showed negative correlations with the response of the weighted rrn copy number (R = -0.55 – -0.74, P < 0.01). The mechanisms underlying the response patterns of bacterial network complexity and stability were related to the prevalence of the r-strategy of the bacterial communities (Phase 1) and the shifts from the r-strategy to the K-strategy due to the gradual reduction in soil moisture (Phase 2 and 3). These results emphasize the importance of the microbial life history strategy in maintaining network complexity and stability and help in understanding how belowground communities can withstand future disturbances.

A question of perspective: Perspective as a feature in stimulus-response binding

ABSTRACT In action control research, stimulus-response binding and retrieval processes are assumed core mechanisms. Stimulus and response features are integrated into event files when they occur together. This event file is retrieved if any feature is repeated. Partial mismatches between current and retrieved episodes cause conflicts, leading to performance costs, while full matches improve performance (the difference between these conditions is known as binding effects). Such binding effects have been found for different stimulus features like colour, shape, or location, using stimulus material that is often kept very simple. In our study, we manipulated the perspective on a real-world three-dimensional distractor stimulus. We found that perspective was bound to the response, independent of stimulus identity. It seems that perspective is treated as a stimulus feature in action control. This result enhances the way we discuss what a feature actually is and how features are bound in event files.