Key Mechanism Research Articles

Targeting the Main Sources of Reactive Oxygen Species Production: Possible Therapeutic Implications in Chronic Pain.

Humans have long been combating chronic pain. In clinical practice, opioids are firstchoice analgesics, but long-term use of these drugs can lead to serious adverse reactions. Finding new, safe and effective pain relievers that are useful treatments for chronic pain is an urgent medical need. Based on accumulating evidence from numerous studies, excess reactive oxygen species (ROS) contribute to the development and maintenance of chronic pain. Some antioxidants are potentially beneficial analgesics in the clinic, but ROS-dependent pathways are completely inhibited only by scavenging ROS directly targeting cellular or subcellular sites. Unfortunately, current antioxidant treatments do not achieve this effect. Furthermore, some antioxidants interfere with physiological redox signaling pathways and fail to reverse oxidative damage. Therefore, the key upstream processes and mechanisms of ROS production that lead to chronic pain in vivo must be identified to discover potential therapeutic targets related to the pathways that control ROS production in vivo. In this review, we summarize the sites and pathways involved in analgesia based on the three main mechanisms by which ROS are generated in vivo, discuss the preclinical evidence for the therapeutic potential of targeting these pathways in chronic pain, note the shortcomings of current research and highlight possible future research directions to provide new targets and evidence for the development of clinical analgesics.

Potential Mechanisms Underlying the Therapeutic Roles of Gancao fuzi Decoction in Cold-dampness Obstruction Syndrome-type Knee Osteoarthritis.

The key active components and potential molecular mechanism of Gancao Fuzi</i> decoction (GFD) in the treatment of cold-dampness obstruction-type knee osteoarthritis (KOA) remain unclear. To explore the mechanism of GFD in the treatment of cold-dampness obstruction syndrome-type KOA by network pharmacology. The potential active components and targets of the four herbs in GFD (Fuzi, Guizhi, Baizhu, and Gancao) were screened using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. The targets of KOA were obtained with the Comparative Toxicogenomics Database (CTD), the GeneCards database, and the DisGeNET database, and the common targets of the drugs and disease were ultimately obtained. Cytoscape (v.3.7.1) was used to draw the active component-target network, and the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) (v.11.0) database was used to construct the protein interaction network. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used for the Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the intersecting targets. A total of 102 potential active components and 208 targets of GFD in the treatment of cold-dampness obstruction syndrome-type KOA were screened. GFD treatment was found to be closely related to many inflammatory signalling pathways in the treatment of KOA. The effect of GFD on cold-dampness obstruction syndrome-type KOA is mediated by multicomponent, multitarget, and multichannel mechanisms, which provides the basis for further experimental study of its pharmacodynamic material basis and mechanism.

Dietary Plant Metabolites Induced Epigenetic Modification as a Novel Strategy for the Management of Prostate Cancer.

Prostate cancer is a widespread malignancy among men, with a substantial global impact on morbidity and mortality. Despite advances in conventional therapies, the need for innovative and less toxic treatments remains a priority. Emerging evidence suggests that dietary plant metabolites possess epigenetic-modifying properties, making them attractive candidates for prostate cancer treatment. The present work reviews the epigenetic effects of dietary plant metabolites in the context of prostate cancer therapy. We first outline the key epigenetic mechanisms involved in prostate cancer pathogenesis, including histone modifications, DNA methylation, and miRNA or Long Noncoding RNA (lncRNA) dysregulation. Next, we delve into the vast array of dietary plant metabolites that have demonstrated promising anti-cancer effects through epigenetic regulation. Resveratrol, minerals, isothiocyanates, curcumin, tea polyphenols, soy isoflavones and phytoestrogens, garlic compounds, anthocyanins, lycopene, and indoles are among the most extensively studied compounds. These plant-derived bioactive compounds have been shown to influence DNA methylation patterns, histone modifications, and microRNA expression, thereby altering the gene expression allied with prostate cancer progression, cell proliferation, and apoptosis. We also explore preclinical and clinical studies investigating the efficacy of dietary plant metabolites as standalone treatments or in combination with traditional treatments for people with prostate cancer. The present work highlights the potential of dietary plant metabolites as epigenetic modulators to treat prostate cancer. Continued research in this field may pave the way for personalized and precision medicine approaches, moving us closer to the goal of improved prostate cancer management.

Aldosterone Effect on Cardiac Structure and Function.

Cardiac remodelling could be a key mechanism in aldosteronemediated cardiovascular morbidity and mortality. Experimental and clinical evidence has demonstrated that aldosterone causes cardiac structural remodelling and dysfunction by its profibrotic and pro-hypertrophic effects, which result mainly from the direct effects on myocardial collagen deposition, inflammation, and oxidative stress. Clinical studies have investigated the aldosterone effects on the heart in different clinical conditions, including general population, essential hypertension, primary aldosteronism, heart failure, and atrial fibrillation. Robust findings indicate that aldosterone or the activation of the cardiac mineralocorticoid receptor can cause damage to myocardial tissue by mechanisms independent of the blood pressure, leading to tissue hypertrophy, fibrosis, and dysfunction. Aldosterone-mediated cardiovascular morbidity and mortality mainly result from cardiac structural and functional alterations. In different clinical settings, aldosterone can induce cardiac structural remodelling and dysfunction via several pathological mechanisms, including cardiac fibrosis, inflammation, and oxidative stress. Aldosterone antagonists could effectively decrease or reverse the detrimental aldosterone-mediated changes in the heart.

Speech-induced suppression and vocal feedback sensitivity in human cortex.

Across the animal kingdom, neural responses in the auditory cortex are suppressed during vocalization, and humans are no exception. A common hypothesis is that suppression increases sensitivity to auditory feedback, enabling the detection of vocalization errors. This hypothesis has been previously confirmed in non-human primates, however a direct link between auditory suppression and sensitivity in human speech monitoring remains elusive. To address this issue, we obtained intracranial electroencephalography (iEEG) recordings from 35 neurosurgical participants during speech production. We first characterized the detailed topography of auditory suppression, which varied across superior temporal gyrus (STG). Next, we performed a delayed auditory feedback (DAF) task to determine whether the suppressed sites were also sensitive to auditory feedback alterations. Indeed, overlapping sites showed enhanced responses to feedback, indicating sensitivity. Importantly, there was a strong correlation between the degree of auditory suppression and feedback sensitivity, suggesting suppression might be a key mechanism that underlies speech monitoring. Further, we found that when participants produced speech with simultaneous auditory feedback, posterior STG was selectively activated if participants were engaged in a DAF paradigm, suggesting that increased attentional load can modulate auditory feedback sensitivity.

FIGNL1 Promotes Hepatocellular Carcinoma Formation via Remodeling ECM-receptor Interaction Pathway Mediated by HMMR.

The development of novel biomarkers is crucial for the treatment of HCC. In this study, we investigated a new molecular therapeutic target for HCC. Fidgetin-like 1 (FIGNL1) has been reported to play a vital role in lung adenocarcinoma. However, the potential function of FIGNL1 in HCC is still unknown. This study aims to investigate the key regulatory mechanisms of FIGNL1 in the formation of HCC. The regulatory effect of FIGNL1 on HCC was studied by lentivirus infection. In vitro, the effects of FIGNL1 on the proliferation, migration and apoptosis of cells were investigated by CCK8, colony formation assay, transwell and flow cytometry. Meanwhile, the regulation of FIGNL1 on HCC formation in vivo was studied by subcutaneous transplanted tumors. In addition, using transcriptome sequencing technology, we further explored the specific molecular mechanism of FIGNL1 regulating the formation of HCC. Functionally, we demonstrated that FIGNL1 knockdown significantly inhibited HCC cell proliferation, migration and promoted cell apoptosis in vitro. Similarly, the knockdown of FIGNL1 meaningfully weakened hepatocarcinogenesis in nude mice. Transcriptome sequencing revealed that FIGNL1 affected the expression of genes involved in extracellular matrix-receptor (ECM-receptor) interaction pathway, such as hyaluronan mediated motility receptor (HMMR). Further validation found that overexpression of HMMR based on knockdown FIGNL1 can rescue the expression abundance of related genes involved in the ECM-receptor interaction pathway. Our study revealed that FIGNL1 could modulate the ECM-receptor interaction pathway through the regulation of HMMR, thus regulating the formation of HCC.

Network pharmacology analysis and clinical efficacy of the traditional Chinese medicine Bu-Shen-Jian-Pi. Part2: Modulation of hypoxia, redox status, and mitochondrial protection ina neuroblastoma cell line, SH-SY5Y.

To examine the mitochondrial protective effects of icariin, naringenin, kaempferol, and formononetin, potentially active agents in Bu-Shen-Jian-Pi formula (BSJP) identified using network pharmacology analysis. Mitochondrial protection activity was determined using a hypoxia-reoxygenation in vitro model based on the neuroblastoma cell line SH-SY5Y and measurements of anti-ferroptotic activity. Icariin, naringenin, kaempferol, and formononetin showed mitochondrial protective activity involving diverse signaling pathways. The cytoprotective effects of formononetin depended on the inhibition of ferroptosis. Hypoxia-reoxygenation stimulation induced ferroptosis in SH-SY5Y cells. Ferroptosis is a key mechanism in nervous system diseases and is associated with hypoxia-reoxygenation injury. Naringenin and kaempferol were devoid of anti-ferroptotic activity. Evidence has been obtained showing that the core components: icariin, naringenin, kaempferol, and formononetin in BSJP formula have anti-hypoxic and mitochondrial protective activity of potential clinical importance in the treatment of amyotrophic lateral sclerosis and patients with symptoms of hypoxia.

A randomized wait-list controlled trial of Men in Mind: Enhancing mental health practitioners' self-rated clinical competencies to work with men.

Improved engagement of men in psychotherapy is an essential element in improving male health outcomes. This trial examined whether the Men in Mind intervention improved practitioners' self-rated clinical competencies to engage and respond to male clients in therapy. A parallel, single-blind, wait-list randomized controlled trial was conducted with Australian-based mental health practitioners, currently administering psychotherapy to males, fluent in English, and not currently completing their undergraduate degree. Participants were randomly assigned 1:1, through variable-sized blocks stratified by gender, to either the intervention (Men in Mind) or wait-list control. Men in Mind was offered as a self-led 6-week, five-module online program to upskill practitioners to engage and respond to male clients. The primary outcome was self-reported competency in engaging men in psychotherapy, measured by the Engaging Men in Therapy Scale (EMITS) at 6 weeks. All analyses were by intention-to-treat. Between January 16 and March 17, 2022, 587 participants were randomly assigned to the intervention (n = 300) or wait-list control (n = 287). In total, 492 (84%) participants completed the primary endpoint assessment at 6 weeks. Men in Mind demonstrated a large effect of improved EMITS scores compared to the control group (d = 2.63, 95% CI [2.39, 2.87], p < .001). Men in Mind was effective at increasing mental health practitioners' self-reported efficacy to work with men, which is potentially a key change mechanism in their ability to improve health outcomes for male clients. A limitation of the trial was the use of a bespoke, self-reported primary outcome, while a strength was the gender-responsive intervention design. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A trust based secure access control using authentication mechanism for interoperability in internet of things

The internet of things (IoT) is a revolutionary innovation in many aspects of our society including interactions, financial activity, and global security such as the military and battlefield internet. Due to the limited energy and processing capacity of network devices, security, energy consumption, compatibility, and device heterogeneity are the long-term IoT problems. As a result, energy and security are critical for data transmission across edge and IoT networks. Existing IoT interoperability techniques need more computation time, have unreliable authentication mechanisms that break easily, lose data easily, and have low confidentiality. In this paper, a key agreement protocol-based authentication mechanism for IoT devices is offered as a solution to this issue. This system makes use of information exchange, which must be secured to prevent access by unauthorized users. Using a compact contiki/cooja simulator, the performance and design of the suggested framework are validated. The simulation findings are evaluated based on detection of malicious nodes after 60 minutes of simulation. The suggested trust method, which is based on privacy access control, reduced packet loss ratio to 0.32%, consumed 0.39% power, and had the greatest average residual energy of 0.99 mJoules at 10 nodes.

Coupling effects of multiple strengthening mechanisms in spheroidal microstructure eutectic high-entropy alloys

The yield strength of metallic materials is commonly estimated using linear superposition methods, but this method has limited adaptability to new materials. The mapping relationship between input and output in machine learning methods is difficult to quantify. This study employs a rapid screening method to identify the key strengthening mechanisms that influence the yield strength of typical homogeneous and heterogeneous metallic materials. A non-linear physical neural information network model is developed to describe the yield strength of heterogeneous structures, capturing the main parameters contributing to yield strength from selected physical quantity data. By considering the non-linear strengthening mechanisms arising from interactions among multiple strengthening mechanisms in heterogeneous metal structures, the microstructure and mechanical properties of eutectic high-entropy alloys are optimized through warm rolling and short-time annealing. By inducing microstructural spheroidization and introducing nanoscale precipitates, significant coupling effects of multiple strengthening mechanisms are achieved for eutectic high-entropy alloys. As a result, the yield strength increases by approximately 2.5 times, while plasticity remains nearly unchanged. Transmission electron microscopy, scanning electron microscopy, and electron backscatter diffraction observations provide evidence for the sources of these coupling effects. This study offers guidance for accelerating material design and exploring the physical relationship between microstructure and mechanical properties.

Still a work in progress: the ongoing evolution of the role conception underlying China’s Belt and Road initiative

ABSTRACT Ten years after its proposition, the Belt and Road Initiative (BRI) has become a cornerstone of China’s foreign policy. It paved the way for China to develop into an active global power shaping global norms and institutions. Applying a role theoretical perspective, the key principles and mechanisms at the heart of the BRI are outlined as well as the dynamic evolution of both the BRI narrative and key contents by highlighting in the Belt and Road Forums of 2017 and 2019. The paper argues that the BRI constitute a unilateral change of China’s role conception for global economic gov7ernance (GEG). This interpretation of the BRI demonstrates that China is now presenting a model for GEG to other countries and that both the contents and the way it is presented continues to evolve. In this regard, a role theoretical reading of the BRI highlights both dynamic as well as pragmatic elements of foreign policy making under Xi Jinping.

Abstract 4665: USP18 promotes anlotinib resistance in medullary thyroid carcinoma by stabilizing aurora B kinase

Abstract Targeted therapy resistance is the main cause of disease progression in advanced medullary thyroid carcinoma (MTC). However, the key molecules and mechanisms remain unclear. We previously performed a genome-wide in vitro screen of Anlotinib resistance-related genes in human MTC cell line TT using CRISPR-dCas9-SAM system and identified ubiquitin-specific protease 18 (USP18) as a key molecule mediating Anlotinib resistance in MTC. However, its downstream mechanism needs further clarification. Based on the high-throughput DNA sequencing results of the control group and the Anlotinib screening group, a group of key genes related to Anlotinib resistance in MTC was screened through the MAGeCK algorithm and the enrichment ratio of sgRNA in the Anlotinib screening group. Among them, USP18 ranked first in the enrichment results. Analysis of the correlation between the expression level of USP18 in MTC patient specimens and survival revealed that patients with high USP18 expression in tumor cells had poorer prognosis. Overexpression of USP18 in MTC tumor cells significantly promoted the growth of subcutaneous xenograft tumors in NOD/SCID mice treated with Anlotinib. In vitro cell experiments also showed that overexpression of USP18 promoted the proliferation of MTC tumor cells and significantly inhibited the proportion of cell apoptosis after Anlotinib treatment. Further research found that USP18, as a deubiquitinating enzyme that can specifically remove ISG15-like ubiquitin-like proteins from substrate proteins, can improve the kinase stability of Aurora B by removing ISG15-like ubiquitin modification and promote MTC tumor cell proliferation through the activation of PI3K-Akt signaling regulated by Aurora B kinase. Application of Aurora B kinase inhibitor in Anlotinib-resistant MTC cell lines significantly inhibited tumor cell proliferation, and Aurora B kinase inhibitor significantly increased the proportion of cell apoptosis in MTC tumor cells overexpressing USP18. In the subcutaneous xenograft tumor model of MTC in NOD/SCID mice, the growth of xenograft tumors in the Anlotinib combined with Aurora B kinase inhibitor treatment group was also significantly inhibited. In summary, overexpressed USP18 can activate PI3K-Akt signaling and promote tumor cell proliferation by increasing the stability of Aurora B kinase, ultimately leading to the formation of Anlotinib resistance in MTC patients. Combined use of Aurora B kinase inhibitor is a potentially effective combined treatment strategy for Anlotinib-resistant MTC patients. Citation Format: Xuan Qin, Xing Wan, Dapeng Li, Yimeng Liu, Xianhui Ruan, Fangkun Luan, Kejia Xu, Jia Li, Rong Xiang, Yongjun Piao, Yi Shi, Xiangqian Zheng. USP18 promotes anlotinib resistance in medullary thyroid carcinoma by stabilizing aurora B kinase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4665.

Sulfide catabolism in hibernation and neuroprotection

The mammalian brain is exquisitely vulnerable to lack of oxygen. However, the mechanism underlying the brain's sensitivity to hypoxia is incompletely understood. In this narrative review, we present a case for sulfide catabolism as a key defense mechanism of the brain against acute oxygen shortage. We will examine literature on the role of sulfide in hypoxia/ischemia, deep hibernation, and leigh syndrome patients, and present our recent data that support the neuroprotective effects of sulfide catabolism and persulfide production. When oxygen levels become low, hydrogen sulfide (H2S) accumulates in brain cells and impairs the ability of these cells to use the remaining, available oxygen to produce energy. In recent studies, we found that hibernating ground squirrels, which can withstand very low levels of oxygen, have high levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize hydrogen sulfide in the brain. Silencing SQOR increased the sensitivity of the brain of squirrels and mice to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury in mice. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological agents that scavenge sulfide and/or increase persulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to ischemic injury to the brain or spinal cord. Drugs that oxidize hydrogen sulfide and/or increase persulfide may prove to be an effective approach to the treatment of patients experiencing brain injury caused by oxygen deprivation or mitochondrial dysfunction.

Electrophysiological Mechanisms of Memory Consolidation in Human Non-rapid Eye Movement Sleep

Abstract Purpose of Review Pioneering work in rodents has shown that the reactivation of recently acquired memories during sleep is a key mechanism underlying the beneficial effect of sleep on memory consolidation. In this review, we consider recent evidence of memory reactivation processes in human sleep. Recent Findings The precise temporal coupling of sleep spindles to slow oscillations during non-rapid eye movement sleep plays a central role in sleep-associated memory consolidation. Both correlational studies and studies directly manipulating oscillatory activity in the sleeping brain have confirmed that spindles coupled to slow oscillations are better predictors of memory than uncoupled spindles and that the greatest memory benefit comes when spindles are tightly coupled to the up-state of the slow oscillation. Recent evidence suggests that memory content is reactivated during sleep, with a functional benefit for memory performance after sleep. Reactivation events are time-locked around slow oscillation-spindle coupling events, as well as sharp-wave ripples in hippocampus. Summary Memory reactivation, which is facilitated by slow oscillation-spindle coupling events, can be observed during human sleep and shows promise as a prime mechanism underlying sleep’s beneficial effects on memory.

Lessons and Untapped Potential of Smartphone-Based Physical Activity Interventions for Mental Health: Narrative Review.

Physical activity has well-known and broad health benefits, including antidepressive and anxiolytic effects. However, only approximately half of Americans meet even the minimum exercise recommendations. Individuals with anxiety, depression, or related conditions are even less likely to do so. With the advent of mobile sensors and phones, experts have quickly noted the utility of technology for the enhanced measurement of and intervention for physical activity. In addition to being more accessible than in-person approaches, technology-driven interventions may uniquely engage key mechanisms of behavior change such as self-awareness. This study aims to provide a narrative overview and specific recommendations for future research on smartphone-based physical activity interventions for psychological disorders or concerns. In this paper, we summarized early efforts to adapt and test smartphone-based or smartphone-supported physical activity interventions for mental health. The included articles described or reported smartphone-delivered or smartphone-supported interventions intended to increase physical activity or reduce sedentary behavior and included an emotional disorder, concern, or symptom as an outcome measure. We attempted to extract details regarding the intervention designs, trial designs, study populations, outcome measures, and inclusion of adaptations specifically for mental health. In taking a narrative lens, we drew attention to the type of work that has been done and used these exemplars to discuss key directions to build on. To date, most studies have examined mental health outcomes as secondary or exploratory variables largely in the context of managing medical concerns (eg, cancer and diabetes). Few trials have recruited psychiatric populations or explicitly aimed to target psychiatric concerns. Consequently, although there are encouraging signals that smartphone-based physical activity interventions could be feasible, acceptable, and efficacious for individuals with mental illnesses, this remains an underexplored area. Promising avenues for tailoring validated smartphone-based interventions include adding psychoeducation (eg, the relationship between depression, physical activity, and inactivity), offering psychosocial treatment in parallel (eg, cognitive restructuring), and adding personalized coaching. To conclude, we offer specific recommendations for future research, treatment development, and implementation in this area, which remains open and promising for flexible, highly scalable support.

Molecular Insights into Plant-Microbe Interactions: A Comprehensive Review of Key Mechanisms.

In most ecosystems, plants establish complex symbiotic relationships with organisms, such as bacteria and fungi, which significantly influence their health by promoting or inhibiting growth. These relationships involve biochemical exchanges at the cellular level that affect plant physiology and have evolutionary implications, such as species diversification, horizontal gene transfer, symbiosis and mutualism, environmental adaptation, and positive impacts on community structure and biodiversity. For these reasons, contemporary research, moving beyond observational studies, seeks to elucidate the molecular basis of these interactions; however, gaps in knowledge remain. This is particularly noticeable in understanding how plants distinguish between beneficial and antagonistic microorganisms. In light of the above, this literature review aims to address some of these gaps by exploring the key mechanisms in common interspecies relationships. Thus, our study presents novel insights into these evolutionary archetypes, focusing on the antibiosis process and microbial signaling, including chemotaxis and quorum sensing. Additionally, it examined the biochemical basis of endophytism, pre-mRNA splicing, and transcriptional plasticity, highlighting the roles of transcription factors and epigenetic regulation in the functions of the interacting organisms. These findings emphasize the importance of understanding these confluences in natural environments, which are crucial for future theoretical and practical applications, such as improving plant nutrition, protecting against pathogens, developing transgenic crops, sustainable agriculture, and researching disease mechanisms. It was concluded that because of the characteristics of the various biomolecules involved in these biological interactions, there are interconnected molecular networks in nature that give rise to different ecological scaffolds. These networks integrate a myriad of functionally organic units that belong to various kingdoms. This interweaving underscores the complexity and multidisciplinary integration required to understand plant-microbe interactions at the molecular level. Regarding the limitations inherent in this study, it is recognized that researchers face significant obstacles. These include technical difficulties in experimentation and fieldwork, as well as the arduous task of consolidating and summarizing findings for academic articles. Challenges range from understanding complex ecological and molecular dynamics to unbiased and objective interpretation of diverse and ever-changing literature.

Transkingdom Network Analysis (TkNA): a systems framework for inferring causal factors underlying host-microbiota and other multi-omic interactions.

We present Transkingdom Network Analysis (TkNA), a unique causal-inference analytical framework that offers a holistic view of biological systems by integrating data from multiple cohorts and diverse omics types. TkNA helps to decipher key players and mechanisms governing host-microbiota (or any multi-omic data) interactions in specific conditions or diseases. TkNA reconstructs a network that represents a statistical model capturing the complex relationships between different omics in the biological system. It identifies robust and reproducible patterns of fold change direction and correlation sign across several cohorts to select differential features and their per-group correlations. The framework then uses causality-sensitive metrics, statistical thresholds and topological criteria to determine the final edges forming the transkingdom network. With the subsequent network's topological features, TkNA identifies nodes controlling a given subnetwork or governing communication between kingdoms and/or subnetworks. The computational time for the millions of correlations necessary for network reconstruction in TkNA typically takes only a few minutes, varying with the study design. Unlike most other multi-omics approaches that find only associations, TkNA focuses on establishing causality while accounting for the complex structure of multi-omic data. It achieves this without requiring huge sample sizes. Moreover, the TkNA protocol is user friendly, requiring minimal installation and basic familiarity with Unix. Researchers can access the TkNA software at https://github.com/CAnBioNet/TkNA/ .

Aberrant TIMP-1 production in tumor-associated fibroblasts drives the selective benefits of nintedanib in lung adenocarcinoma.

The fibrotic tumor microenvironment is a pivotal therapeutic target. Nintedanib, a clinically approved multikinase antifibrotic inhibitor, is effective against lung adenocarcinoma (ADC) but not squamous cell carcinoma (SCC). Previous studies have implicated the secretome of tumor-associated fibroblasts (TAFs) in the selective effects of nintedanib in ADC, but the driving factor(s) remained unidentified. Here we examined the role of tissue inhibitor of metalloproteinase-1 (TIMP-1), a tumor-promoting cytokine overproduced in ADC-TAFs. To this aim, we combined genetic approaches with invitro and invivo preclinical models based on patient-derived TAFs. Nintedanib reduced TIMP-1 production more efficiently in ADC-TAFs than SCC-TAFs through a SMAD3-dependent mechanism. Cell culture experiments indicated that silencing TIMP1 in ADC-TAFs abolished the therapeutic effects of nintedanib on cancer cell growth and invasion, which were otherwise enhanced by the TAF secretome. Consistently, co-injecting ADC cells with TIMP1-knockdown ADC-TAFs into immunocompromised mice elicited a less effective reduction of tumor growth and invasion under nintedanib treatment compared to tumors bearing unmodified fibroblasts. Our results unveil a key mechanism underlying the selective mode of action of nintedanib in ADC based on the excessive production of TIMP-1 in ADC-TAFs. We further pinpoint reduced SMAD3 expression and consequent limited TIMP-1 production in SCC-TAFs as key for the resistance of SCC to nintedanib. These observations strongly support the emerging role of TIMP-1 as a critical regulator of therapy response in solid tumors.

Cross-owners as monitors: more supervisory or distracted? Evidence from China

ABSTRACT In recent decades, cross-ownership becomes a rapidly growing phenomenon in capital markets across various countries. However, there remains an absence of consensus regarding the efficacy of cross-shareholders in monitoring within the realm of corporate governance. This study delves into this quandary by employing regression analysis on data spanning the years 2007–2018 from Chinese listed firms. Our findings reveal that cross-ownership significantly mitigates agency costs, a conclusion robustly supported through a battery of tests. Key mechanisms driving this phenomenon include information advantage and governance experience, facilitated through channels such as increased shareholding and director appointments. Notably, this positive effect is more pronounced in non-state firms, firms with less concentrated ownership, greater analyst attention, and less trustworthy auditors. In sum, our results underscore the constructive role played by cross-owners in fortifying corporate governance structures.

SGLT2 inhibitors: from glucose-lowering to cardiovascular benefits.

An increasing number of individuals are at high risk of type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), and eventually premature death. The sodium-glucose co-transporter-2 (SGLT2) protein sits in the proximal tubule of human nephrons to regulate glucose reabsorption and its inhibition by gliflozins represents the cornerstone of contemporary T2D and HF management. Herein, we aim to provide an updated overview of the pleiotropy of gliflozins, provide mechanistic insights and delineate related cardiovascular (CV) benefits. By discussing contemporary evidence obtained in preclinical models and landmark randomized controlled trials, we move from bench to bedside across the broad spectrum of cardio- and cerebrovascular diseases. With landmark randomized controlled trials confirming a reduction in major adverse CV events (MACE; composite endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke), SGLT2 inhibitors strongly mitigate the risk for heart failure hospitalization in diabetics and non-diabetics alike while conferring renoprotection in specific patient populations. Along four major pathophysiological axes (i.e. at systemic, vascular, cardiac, and renal levels), we provide insights into the key mechanisms that may underlie their beneficial effects, including gliflozins' role in the modulation of inflammation, oxidative stress, cellular energy metabolism, and housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, and hyperuricaemia, collectively contributing to their pleiotropic effects. Finally, evolving data in the setting of cerebrovascular diseases and arrhythmias are presented and potential implications for future research and clinical practice are comprehensively reviewed.