Signaling Mechanisms Research Articles

Beneficial effects of resveratrol on diabetes mellitus and its complications: focus on mechanisms of action.

Diabetes mellitus (DM) is a significant global health issue, associated with various microvascular and macrovascular complications that significantly impair patients' quality of lifeas well as healthspan and lifespan. Despite the availability of several anti-diabetic medications with different mechanisms of action, there remains no definite curative treatment. Hence, discovering new efficient complementarytherapies is essential. Natural products have received significant attention due to their advantages in various pathological conditions. Resveratrol is a natural polyphenol that possesses antioxidant and anti-inflammatory properties, and its efficacy has been previously investigated in several diseases, including DM. Herein, we aimed to provide a holistic view of the signaling pathways and mechanisms of action through which resveratrol exerts its effects against DM and its complications.

Agonists of the nuclear receptor PPARγ can produce biased signaling.

Biased signaling and ligand bias, often termed functional selectivity or selective nuclear receptor modulation, have been reported for nuclear receptor partial agonists over the past 20 years. Whether signaling differences produced by partial agonists result from less intense modulation, off-target effects, or biased signaling remains unclear. A commonly postulated mechanism for biased signaling is coactivator favoritism, where agonists induce different coactivator recruitment profiles. We find that both GW1929 (full agonist) and MRL24 (partial agonist) favor recruitment of 100-300 residue regions from S-motif coactivators compared to a reference full agonist (rosiglitazone), yielding 95% bias value confidence intervals of 0.05-0.17 and 0.29-0.38 respectively. Calculations based on these data indicate that GW1929 and MRL24 would induce 30-60% higher S-motif coactivator occupancy at the receptor compared to rosiglitazone. We compare the transcriptional effects of these same three ligands on human adipocytes using RNA sequencing and exploratory KEGG pathway analysis. Only 50% (rosiglitazone) and 77% (GW1929) of all gene expression changes are shared between these full agonists after 3 hours of exposure. After 24 hours of exposure, 13/98 KEGG pathways appear more intensely modulated by rosiglitazone than GW1929 (e.g., 95% CI of bias in the regulation of lipolysis in adipocytes pathway is 0.03-0.09), despite similar signaling for the remaining 85 affected pathways. Similarly, rosiglitazone has an unusually large effect on several lipid metabolism-related pathways compared to the partial agonist MRL24. These data indicate that nuclear receptor full and partial agonists can induce biased signaling, likely through differences in coactivator recruitment. Significance Statement Many nuclear receptor partial agonists cause fewer adverse effects and similar efficacy compared to full agonists, potentially by inducing biased agonism. Our data support the idea that partial agonists, and a full agonist, of the nuclear receptor Peroxisome proliferator-activated receptor gamma (PPARγ) are biased agonists, causing different signaling by inducing PPARγ to favor different coactivators. These data indicate that biased agonism can occur in nuclear receptors and should be considered in efforts to develop improved nuclear receptor-targeted drugs.

Decoding Sustainability Reporting: Insights from Text Mining and Classification Models for SDGs

Objective: This study aims to investigate the signaling effects of Sustainability Reporting (SR) in listed Singapore firms, particularly in demonstrating firm capitalization and sustainability performance. The research focuses on identifying distinct SR signals using advanced text mining and classification techniques, and their alignment with the United Nations' Sustainable Development Goals (SDGs). Theoretical Framework: The study is grounded in signaling theory, which posits that firms communicate observable characteristics (SR content) to signal unobservable attributes (firm capabilities and sustainability performance). By applying this framework, we analyze how SR may act as a signaling mechanism for large-cap firms and sustainability leaders. Method: This research collects 1,844 sustainability reports from listed Singapore firms between 2016 and 2022. Using a combination of Structural Topic Modeling (STM) and Random Forest (RF) classification models, we extracted and analyzed the key SR signals that differentiate firms by size and sustainability performance. Results: The results indicate that SR signals such as community engagement, climate risk, and compliance are effective in distinguishing between large firms and firms with strong sustainability performance. The Random Forest models achieved high accuracy in identifying these groups. Community engagement, compliance with the Global Reporting Initiative (GRI), and sustainable construction were among the most impactful topics, with large firms focusing more on scope and governance, while sustainability leaders emphasized environmental risks and compliance. Research Implications: The findings provide insights into the practical and theoretical implications of SR as a signaling tool. Key SR topics are identified as critical signals for firms with large capitalization and high sustainability performance, guiding firms in utilizing SR in the context of SDGs. Originality/Value: The findings show that SR topics such as community engagement, climate risk, and compliance serve as key signals for differentiating firms by size and sustainability performance. Firms can strategically emphasize these areas to enhance their SR practices while contributing to broader SDGs.The findings provide insights into the practical and theoretical implications of SR as a signaling tool. Key SR topics are identified as critical signals for firms with large capitalization and high sustainability performance, guiding firms in enhancing their SR strategies.

High‐speed escape jumps in haptophytes: Mechanism and triggering fluid signal

AbstractSome planktonic organisms can remotely sense and evade predators by powerful escape jumps. Remote perception typically happens through the fluid disturbance generated by the approaching predator or its feeding current. In copepods and ciliates with mechanosensors, the perception and jump mechanisms are well understood. But how some flagellates perceive the fluid disturbance and achieve similar relative speeds with only two flagella is less explored. Here, we examined the ability of three haptophytes, Chrysochromulina simplex, Prymnesium polylepis, and Prymnesium parvum, to sense and evade the fluid disturbance generated by the feeding current of a copepod nauplius. Chrysochromulina simplex has a long haptonema (14 cell diameters), while the haptonema of the two other species are shorter (1 and 0.5 cell diameters). Only C. simplex responded to the fluid disturbance by fleeing at high speeds. The jump mechanism consists of two phases: the rapid coiling of the haptonema that pulls the cell about two cell diameters in the direction of the haptonema, followed by flagellar reversal and high‐speed swimming (70 cell lengths per second) in the opposite direction. We rationalize cell displacements and escape speeds from haptonema and flagellar kinematics and fluid dynamics. Using a microfluidic channel, we demonstrate that the component of the fluid signal that triggers the jumps is the maximum deformation rate rather than the magnitude of deformation. High‐speed escape jumps may be an avoidance mechanism evolved by haptophytes with long and coiling haptonema, while species with shorter haptonema may use other defense mechanisms, such as stealth and toxicity.

Advancements of anticancer agents by targeting the Hippo signalling pathway: biological activity, selectivity, docking analysis, and structure-activity relationship.

The Hippo signalling pathway is prominent andgoverns cell proliferation and stem cell activity, acting as a growth regulator and tumour suppressor. Defects in Hippo signalling and hyperactivation of its downstream effector's Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play roles in cancer development, implying that pharmacological inhibition of YAP and TAZ activity could be an effective cancer treatment strategy. Conversely, YAP and TAZ can also have beneficial effects in promoting tissue repair and regeneration following damage, therefore their activation may be therapeutically effective in certain instances. Recently, a complex network of intracellular and extracellular signalling mechanisms that affect YAP and TAZ activity has been uncovered. The YAP/TAZ-TEAD interaction leads to tumour development and the protein structure of YAP/TAZ-TEAD includes three interfaces and one hydrophobic pocket. There are clinical and preclinical trial drugs available to inhibit the hippo signalling pathway, but these drugs have moderate to severe side effects, so researchers are in search of novel, potent, and selective hippo signalling pathway inhibitors. In this review, we have discussed the hippo pathway in detail, including its structure, activation, and role in cancer. We have also provided the various inhibitors under clinical and preclinical trials, and advancement of small molecules their detailed docking analysis, structure-activity relationship, and biological activity. We anticipate that the current study will be a helpful resource for researchers.

Bioinformatic insights into sugar signaling pathways in sugarcane growth

The SnRK1, hexokinase, and TORC1 (TOR, LST8, RAPTOR) are three pivotal kinases at the core of sugar level sensing, significantly impacting plant metabolism and development. We retrieved and analyzed protein sequences of these three kinase pathways from seven sugarcane transcriptome and genome datasets, identifying protein domains, phylogenetic relationships, sequence ancestry, and in silico expression levels. Additionally, we predicted HXK subcellular localization and assessed its enzymatic activity in sugarcane leaves and culms along development in the field. We retrieved 11 TOR, 23 RAPTOR, 55 LST8, 95 SnRK1α, 98 HXK, and 14 HXK-like putative full-length sequences containing all the conserved domains. Most of these transcripts seem to share a common origin with the three ancestral species of sugarcane: Saccharum officinarum, Saccharum spontaneum, and Saccharum barberi. We accessed the expression profile of sequences from one sugarcane transcriptome. We found the highest enzymatic activity of HXK in culms in the first month, which, at this stage, provides carbon (sucrose) and nitrogen (amino acids) for initial plant development. Our approach places novel sugar sensing sequences that work as a guideline for further research into the underlying signaling mechanisms and biotechnology applications in sugarcane.

Evidence for Greater Marking along Ethnic Boundaries.

The coordination of beliefs, norms, and behaviors is foundational to theories of group formation. However, because beliefs and norms are not directly observable, signaling mechanisms are required to build reliable signals of latent traits. Although the mathematical theory behind these signals is robust, there is very little testing of ethnic marker theory or of its key propositions that markers become more prevalent along ethnic boundaries and where more than two cultural groups are in contact. We present an ethnographic test of this theory with phonetic differences serving as potential group signals. The data derive from an ethnographic and linguistic investigation in two contrasting secondary school settings in Utah, one that is majority European American and one that is ethnically more diverse. Word list recordings were collected as part of interviews with teens from different backgrounds. We extracted acoustic data from the speech of European Americans (EAs) and Pacific Islanders (PIs), then analyzed differences in the pronunciation of the vowel in words such as "bit." We found evidence of greater phonetic marking at the more diverse school, along more prominent boundaries of ethnic interaction. These results align with predictions made by the theoretical models. This initial empirical test of model predictions provides justification for the development of more complex models that could account for more variables within the environment.

From TCR fundamental research to innovative chimeric antigen receptor design.

Engineered T cells that express chimeric antigen receptors (CARs) have transformed the treatment of haematological cancers. CARs combine the tumour-antigen-binding function of antibodies with the signalling functions of the T-=cell receptor (TCR) ζ chain and co-stimulatory receptors. The resulting constructs aim to mimic the TCR-based and co-receptor-based activation of T cells. Although these have been successful for some types of cancer, new CAR formats are needed, to limit side effects and broaden their use to solid cancers. Insights into the mechanisms of TCR signalling, including the identification of signalling motifs that are not present in the TCR ζ chain and mechanistic insights in TCR activation, have enabled the development of CAR formats that outcompete the current CARs in preclinical mouse models and clinical trials. In this Perspective, we explore the mechanistic rationale behind new CAR designs.

Stability‐Enhanced Variable Stiffness Metamaterial with Controllable Force‐Transferring Path

AbstractSelf‐contact variable stiffness (SVS) metamaterial offers specific patterns of elastic strain energy storage by changing its force‐transferring path. The change of the elastic strain energy storage patterns further influences the stiffness variation of the SVS metamaterials. However, challenges still arise because typically fabricated SVS metamaterials inevitably contain structural irregularities, eccentricities, and defects. These microstructural imperfections impede the stable generation of designed strain energy storage patterns in the metamaterial, implying that the SVS metamaterials cannot achieve expected stiffness variations. To address this burning question, an SVS metamaterial/meta‐structure design paradigm with eccentric unit designs is proposed, which can realize both stable stiffness variations and high load‐bearing. The theoretical, simulation, and experimental results demonstrate that the SVS chain meta‐structure achieves ≈110 times stiffness variation between the low and high loading conditions. Its load‐bearing can reach more than 1500 N when the meta‐structure falls into the high stiffness stage. Furthermore, some typical functions are demonstrated using the stability‐enhanced SVS metamaterial, including customized mechanical protections for human joints and information transformation regulated by remote mechanical input signals. The results can provide a useful solution for generating a more feasible stability‐enhanced SVS metamaterial/meta‐structure and promote their potential applications in aerospace, medical devices, and robotics.

Multi-omics profiling reveals the molecular mechanisms of H2O2-induced detrimental effects on Thamnaconus septentrionalis

BackgroundHydrogen peroxide (H2O2), a novel water treatment agent, can be used for disinfection, water quality adjustment, and disease prevention, while excessive H2O2 can injure farm animals, even leading to death. Hydrogen peroxide is a recommended disinfectant and bactericide for treating gill diseases and vibriosis in the greenfin horse-faced filefish Thamnaconus septentrionalis. However, its cumulative effect, toxic molecular mechanism and relevant signal transduction/metabolic networks in marine fishes are largely unknown.ResultsWe employed a multi-omics approach to investigate the detrimental effects of 50 mg/L H2O2 exposure (2 h/d) on filefish for 2 d, 4 d, and 6 d. Transcriptome sequencing showed that differentially expressed genes (DEGs) were mainly classified into functions such as signal transduction, nervous system, liver and bile acid metabolism, energy metabolism, cell adhesion and communication, inflammation and immune response. Metabolomic analysis found that the significantly changed metabolites (SCMs) were involved in phenylalanine metabolism, inflammatory mediator regulation, linoleic acid metabolism, and necroptosis. The main SCMs were cholic acid, carnitine C12:1, dimethylmalonic acid, glutamic acid, L-lactic acid, shikimic acid, 2-methylsuccinic acid, and others. Moreover, H2O2-induced oxidative stress also disturbs the balance of the gut microbiota, altering the microbial composition and affecting digestive processes.ConclusionsIntegrated multiomics analysis revealed that H2O2-induced detrimental impacts include mucosal damage, inflammatory and immune responses, altered energy metabolism, and gut microbiota disorders. These findings offer novel insights into the harmful effects and signal transduction/metabolic pathways triggered by H2O2 exposure in marine fishes.

Role of mechanosensitive channel Piezo1 protein in intestinal inflammation regulation: A potential target.

The intestine is a hollow tract that primarily transports and digests food. It often encounters mechanical forces and exotic threats, resulting in increased intestinal inflammation attributed to the consistent threat of foreign pathogens. Piezo1, a mechanosensitive ion channel, is distributed broadly and abundantly in the intestinal tissue. It transduces mechanical signals into electrochemical signals and participates in many critical life activities, such as proliferation, differentiation, cell apoptosis, immune cell activation, and migration. Its effect on inflammation has been discussed in detail in systems, such as musculoskeletal (osteoarthritis) and cardiac (myocarditis), but the effects on intestinal inflammation remain unelucidated. Piezo1 regulates mucosal layer and epithelial barrier homeostasis during the complex intestinal handling of foreign antigens and tissue trauma. It initiates and spreads immune responses and causes distant effects of inflammation in the vascular and lymphatic systems, but reports of the effects of Piezo1 in intestinal inflammation are scarce. Therefore, this study aimed to discuss the role of Piezo1 in intestinal inflammation and explore novel therapeutic targets.

The role of NOP58 in prostate cancer progression through SUMOylation regulation and drug response.

Prostate cancer is one of the leading causes of cancer-related deaths in men. Its molecular pathogenesis is closely linked to various genetic and epigenetic alterations, including posttranslational modifications like SUMOylation. Identifying biomarkers that predict outcomes and specific therapeutic targets depends on a comprehensive understanding of these processes. With growing interest in SUMOylation as a mechanism affecting prostate cancer-related genes, this study aimed to investigate the central role of SUMOylation in prostate cancer prognostics, focusing on the significance of NOP58. We conducted a comprehensive bioinformatics analysis, integrating differential expression analysis, survival analysis, gene set enrichment analysis (GSEA), and single-cell transcriptomic analyses using data from The Cancer Genome Atlas (TCGA). Key genes were identified through intersections of Venn diagrams, Boralta algorithm signatures, and machine learning models. These signaling mechanisms were validated through experimental studies, including immunohistochemical staining and gene ontology analyses. The dual-gene molecular subtype analysis with SUMO1, SUMO2, and XPO1 genes revealed significant differences in survival outcomes across molecular subtypes, further emphasizing the potential impact of NOP58 on SUMOylation, a key post-translational modification, in prostate cancer. NOP58 overexpression was strongly associated with shorter overall survival (OS), progression-free interval (PFI), and disease-specific death in prostate cancer patients. Immunohistochemical analysis confirmed that NOP58 was significantly overexpressed in prostate cancer tissues compared to normal tissues. ROC curve analysis demonstrated that NOP58 could distinguish prostate cancer from control samples with high diagnostic accuracy. Gene Ontology analysis, along with GSVA and GSEA, suggested that NOP58 may be involved in cell cycle regulation and DNA repair pathways. Moreover, NOP58 knockdown led to increased BCL2 expression and decreased Ki67 levels, promoting apoptosis and inhibiting cell proliferation. Colony formation assays further showed that NOP58 knockdown inhibited, while its overexpression promoted, colony formation, highlighting the critical role of NOP58 in prostate cancer cell growth and survival. Additionally, NOP58 was linked to drug responses, including Methotrexate, Rapamycin, Sorafenib, and Vorinostat. NOP58 is a key regulator of prostate cancer progression through its mediation of the SUMOylation pathway. Its expression level serves as a reliable prognostic biomarker and an actionable therapeutic target, advancing precision medicine for prostate cancer. Targeting NOP58 may enhance therapeutic efficacy and improve outcomes in oncology.

Wnt specifically induces FZD5/8 endocytosis and degradation and the involvement of RSPO-ZNRF3/RNF43 and DVL.

Frizzled (FZD) proteins are the principal receptors of the Wnt signaling pathway. However, whether Wnt ligands induce FZD endocytosis and degradation remains elusive. The transmembrane E3 ubiquitin ligases ZNRF3 and RNF43 promote the endocytosis and degradation of FZD receptors to inhibit Wnt signaling, and their function is antagonized by R-spondin (RSPO) proteins. However, the dependency of RSPO-ZNRF3/RNF43-mediated FZD endocytosis and degradation on Wnt stimulation, as well as the specificity of this degradation for different FZD, remains unclear. Here, we demonstrated that Wnt specifically induces FZD5/8 endocytosis and degradation in a ZNRF3/RNF43-dependent manner. ZNRF3/RNF43 selectively targets FZD5/8 for degradation upon Wnt stimulation. RSPO1 enhances Wnt signaling by specifically stabilizing FZD5/8. Wnt promotes the interaction between FZD5 and RNF43. We further demonstrated that DVL proteins promote ligand-independent endocytosis of FZD but are dispensable for Wnt-induced FZD5/8 endocytosis and degradation. Our results reveal a novel negative regulatory mechanism of Wnt signaling at the receptor level and illuminate the mechanism by which RSPO-ZNRF3/RNF43 regulates Wnt signaling, which may provide new insights into regenerative medicine and cancer therapy.

A flagellar accessory protein links chemotaxis to surface sensing.

Bacteria find suitable locations for colonization by sensing and responding to surfaces. Complex signaling repertoires control surface colonization, and surface contact sensing by the flagellum plays a central role in activating colonization programs. Caulobacter crescentus adheres to surfaces using a polysaccharide adhesin called the holdfast. In C. crescentus, disruption of the flagellum through interactions with a surface or mutation of flagellar genes increases holdfast production. Our group previously identified several C. crescentus genes involved in flagellar surface sensing. One of these, fssF, codes for a protein with homology to the flagellar C-ring protein FliN. We show here that a fluorescently tagged FssF protein localizes to the flagellated pole of the cell and requires all components of the flagellar C-ring for proper localization, supporting the model that FssF associates with the C-ring. Deleting fssF results in a severe motility defect, which we show is due to a disruption of chemotaxis. Epistasis experiments demonstrate that fssF promotes adhesion through a stator-dependent pathway when late-stage flagellar mutants are disrupted. Separately, we find that disruption of chemotaxis through deletion of fssF or other chemotaxis genes results in a hyperadhesion phenotype. Key genes in the surface sensing network (pleD, motB, and dgcB) contribute to both ∆flgH-dependent and ∆fssF-dependent hyperadhesion, but these genes affect adhesion differently in the two hyperadhesive backgrounds. Our results support a model in which the stator subunits of the flagella incorporate both mechanical and chemical signals to regulate adhesion.IMPORTANCEBacterial biofilms pose a threat in clinical and industrial settings. Surface sensing is one of the first steps in biofilm formation. Studying surface sensing can improve our understanding of biofilm formation and develop preventative strategies. In this study, we use the freshwater bacterium Caulobacter crescentus to study surface sensing and the regulation of surface attachment. We characterize a previously unstudied gene, fssF, and find that it localizes to the cell pole in the presence of three proteins that make up a component of the flagellum called the C-ring. Additionally, we find that fssF is required for chemotaxis behavior but dispensable for swimming motility. Lastly, our results indicate that deletion of fssF and other genes required for chemotaxis results in a hyperadhesive phenotype. These results support that surface sensing requires chemotaxis for a robust response to a surface.

Insights into Metabolic Reprogramming in Tumor Evolution and Therapy.

Background: Cancer remains a global health challenge, characterized not just by uncontrolled cell proliferation but also by the complex metabolic reprogramming that underlies its development and progression. Objectives: This review delves into the intricate relationship between cancer and its metabolic alterations, drawing an innovative comparison with the cosmological concepts of dark matter and dark energy to highlight the pivotal yet often overlooked role of metabolic reprogramming in tumor evolution. Methods: It scrutinizes the Warburg effect and other metabolic adaptations, such as shifts in lipid synthesis, amino acid turnover, and mitochondrial function, driven by mutations in key regulatory genes. Results: This review emphasizes the significance of targeting these metabolic pathways for therapeutic intervention, outlining the potential to disrupt cancer's energy supply and signaling mechanisms. It calls for an interdisciplinary research approach to fully understand and exploit the intricacies of cancer metabolism, pointing toward metabolic reprogramming as a promising frontier for developing more effective cancer treatments. Conclusion: By equating cancer's metabolic complexity with the enigmatic nature of dark matter and energy, this review underscores the critical need for innovative strategies in oncology, highlighting the importance of unveiling and targeting the "dark energy" within cancer cells to revolutionize future therapy and research.

Single molecule tracking based drug screening

The single-molecule tracking of transmembrane receptors in living cells has provided significant insights into signaling mechanisms, such as mobility and clustering upon their activation/inactivation, making it a potential screening method for drug discovery. Here we show that single-molecule tracking-based screening can be used to explore compounds both detectable and undetectable by conventional methods for disease-related receptors. Using an automated system for a fast large-scale single-molecule analysis, we screen for epidermal growth factor receptor (EGFR) from 1134 of FDA approved drugs. The 18 hit compounds include all EGFR-targeted tyrosine kinase inhibitors (TKIs) in the library that suppress any phosphorylation-dependent mobility shift of EGFR, proving the concept of this approach. The remaining hit compounds are not reported as EGFR-targeted drugs and do not inhibit EGF-induced EGFR phosphorylation. These non-TKI compounds affect the mobility and/or clustering of EGFR without EGF and induce EGFR internalization, to impede EGFR-dependent cell growth. Thus, single-molecule tracking provides an alternative modality for discovering therapeutics on various receptor functions with previously untargeted mechanisms.

Ghrelin Modulates Voltage-Gated Ca2+ Channels through Voltage-Dependent and Voltage-Independent Pathways in Rat Gastric Vagal Afferent Neurons.

The orexigenic gut peptide ghrelin is an endogenous ligand for the growth hormone secretagogue receptor type 1a (GHSR1a). Systemic ghrelin administration has previously been shown to increase gastric motility and emptying. While these effects are known to be mediated by the vagus nerve, the cellular mechanism underlying these effects remains unclear. Therefore, the purpose of the present study was to investigate the signaling mechanism by which GHSR1a inhibits voltage-gated Ca2+ channels in isolated rat gastric vagal afferent neurons using whole-cell patch-clamp electrophysiology. The ghrelin pharmacological profile indicated that Ca2+ currents were inhibited with a log (Ic50) = -2.10 ± 0.44 and a maximal inhibition of 42.8 ± 5.0%. Exposure to the GHSR1a receptor antagonist (D-Lys3)-GHRP-6 reduced ghrelin-mediated Ca2+ channel inhibition (29.4 ± 16.7% vs. 1.9 ± 2.5%, n = 6, P = 0.0064). Interestingly, we observed that activation of GHSR1a inhibited Ca2+ currents through both voltage-dependent and voltage-independent pathways. We also treated the gastric neurons with either pertussis toxin (PTX) or YM-254890 to examine whether the Ca2+ current inhibition was mediated by the Gα i/o or Gα q/11 family of subunits. Treatment with both PTX (Ca2+ current inhibition = 15.7 ± 10.6%, n = 8, P = 0.0327) and YM-254890 (15.2 ± 11.9%, n = 8, P = 0.0269) blocked ghrelin's effects on Ca2+ currents, as compared with control neurons (34.3 ± 18.9%, n = 8). These results indicate GHSR1a can couple to both Gα i/o and Gα q/11 in gastric vagal afferent neurons. Overall, our findings suggest GHSR1a-mediated inhibition of Ca2+ currents occurs through two distinct pathways, offering necessary insights into the cellular mechanisms underlying ghrelin's regulation of gastric vagal afferents. SIGNIFICANCE STATEMENT: This study demonstrated that in gastric vagal afferent neurons, activation of GHSR1a by ghrelin inhibits voltage-gated Ca2+ channels through both voltage-dependent and voltage-independent signaling pathways. These results provide necessary insights into the cellular mechanism underlying ghrelin regulation of gastric vagal afferent activity, which may benefit future studies investigating ghrelin mimetics to treat gastric motility disorders.

Ironing Out the Mechanism of gp130 Signaling.

gp130 functions as a shared signal-transducing subunit not only for interleukin (IL)-6 but also for eight other human cytokine receptor complexes. The IL-6 signaling pathway mediated through gp130 encompasses classical, trans, or cluster signaling, intricately regulated by a diverse array of modulators affecting IL-6, its receptor, and gp130. Currently, only a limited number of small molecule antagonists and agonists for gp130 are known. This review aims to comprehensively examine the current knowledge of these modulators and provide insights into their pharmacological properties, particularly in the context of cancer and other diseases. Notably, the prominent gp130 modulators SC144, bazedoxifene, and raloxifene are discussed in detail, with a specific focus on the discovery of SC144's iron-chelating properties. This adds a new dimension to the understanding of its pharmacological effects and therapeutic potential in conditions where iron homeostasis is significant. Our bioinformatic analysis of gp130 and genes related to iron homeostasis reveals insightful correlations, implicating the role of iron in the gp130 signaling pathway. Overall, this review contributes to the evolving understanding of gp130 modulation and its potential therapeutic applications in various disease contexts. SIGNIFICANCE STATEMENT: This perspective provides a timely and comprehensive analysis of advancements in gp130 signaling research, emphasizing the therapeutic implications of the currently available modulators. Bioinformatic analysis demonstrates potential interplay between gp130 and genes that regulate iron homeostasis, suggesting new therapeutic avenues. By combining original research findings with a broader discussion of gp130's therapeutic potential, this perspective significantly contributes to the field.

Elite university bachelor’s degree salary premium for master’s graduates: empirical evidence from China

ABSTRACT The labor market’s response to the signaling value of multiple qualifications (bachelor’s and master’s degrees) held by master’s graduates influences labor market efficiency and individual decisions to invest in education. Using data from the ‘Sample Survey of Chinese Higher Education Institutions’ conducted in 2017 and 2019, this study analyzes whether master’s graduates with bachelor’s degrees from elite universities earn salary premiums. The findings indicate that bachelor’s degrees from elite universities provide approximately a 12% salary premium for master’s graduates, attributable to both human capital and labor market signaling mechanisms. When accounting for individual human capital differences, the salary premium is approximately 9.1%. Furthermore, the empirical results show that these premiums are statistically significant only for master’s graduates from elite universities. The distribution of salary premiums exhibits a U-shaped trend, increasing from low to high salary quantiles. The signaling/screening mechanism’s salary premiums rise with starting salaries, while negative signaling effects are observed at lower quantiles.

Evolution and development of the conduction system in the vertebrate heart: a role for hemodynamics and the epicardium.

Development of the heart is a very intricate and multiplex process as it involves not only the three spatial dimensions but also the fourth or time dimension. Over time, the heart of an embryo needs to adapt its function to serve the increasing complexity of differentiation and growth towards adulthood. It becomes even more perplexing by expanding time into millions of years, allocating related species in the tree of life. As the evolution of soft tissues can hardly be studied, we have to rely on comparative embryology, supported heavily by genetic and molecular approaches. These techniques provide insight into relationships, not only between species, but also between cell populations, signaling mechanisms, molecular interactions and physical factors such as hemodynamics. Heart development depends on differentiation of a mesodermal cell population that - in more derived taxa - continues in segmentation of the first and second heart field. These fields deliver not only the cardiomyocytes, forming the three-dimensionally looping cardiac tube as a basis for the chambered heart, but also the enveloping epicardium. The synchronized beating of the heart is then organized by the conduction system. In this Review, the epicardium is introduced as an important player in cardiac differentiation, including the conduction system.