Modulatory Activity Research Articles

Improving Outcomes in Hepatocellular Carcinoma through Integration of Machine Learning: Development of a Tumor-Associated Macrophage Signature.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors globally. Macrophages, as essential components of the immune system, play crucial roles in immune regulation, inflammation modulation, and antitumor activity. However, it remains unclear whether tumor-associated macrophages can serve as prognostic markers for HCC. First, we identified tumor-associated macrophages based on single-cell data from GSE140228. Then, using a machine learning approach with a combination of 101 module genes, we constructed an optimal prognostic model. Subsequently, we compared our constructed model with other published prognostic models for HCC. Finally, we utilized the generated model score to predict the response to chemotherapy and immune therapy. First, we identified clusters of tumor-associated macrophages using single-cell data. Subsequently, we calculated the tumor-associated macrophage score based on module genes from the previous step. Compared to traditional clinical indicators, tumor-associated macrophage signature (TAMS) exhibits significant advantages. The TAMS C-index not only predicts overall survival, but also recurrence-free survival in HCC patients. Additionally, there was a higher prevalence of TP53 mutations in HCC patients with high TAMS. Furthermore, patients with low TAMS showed greater sensitivity to immunotherapy compared to those with high TAMS. Notably, the number and intensity of interactions between TAM and other T lymphocytes were significantly higher than those involving other cell populations. Interestingly, the high TAMS group exhibited significantly elevated levels of immune checkpoint markers and M2 macrophage markers. TAMS can serve as a novel and potent tool, offering improved treatment options and prognostic assessment for patients with HCC.

The Role of Adaptogenic Herbs in Combating Stress: A Review of Scientific Evidence

Adaptogens are bioactive compounds which allow the body to cope with stress, to be on homeostasis again. Its history dates back thousands of years, when Ayurvedic and Traditional Chinese Medicine developed knowledge on adaptogenic compounds and functions, specifically on modulatory aspects of the hypothalamic-pituitary-adrenal axis and of cortisol regulatory pathways. The present review explores the history and classification of adaptogens as well as the underlying mechanisms, including hormone modulation, neurobiological pathways, and antioxidant activity. Botanical examples are Withaniasomnifera and Rhodiolarosea, as well as some non-botanical adaptogens including fungi and nutraceuticals. Preclinical and clinical evidence is presented as proof of the efficacy of the substances in diminishing stress, augmenting cognitive ability, and promoting physical endurance. Discussions on modern trends of formulations like teas, capsules, and functional foods in relation to practical uses regarding stress management and maintenance of psychological well-being and avoidance of burnout will be covered. Although generally safe, adaptogen risks include high dose toxicity and inter-medication interactions. Current challenges include variability in standardization of preparations and limitations in understanding long-term effects and associated molecular mechanisms. This review draws attention to the potential therapeutic role of adaptogens in modern life, provides insights into their safe and effective use, and points out areas for further work. Specific practical recommendations are given for how to select and combine adaptogens tailored to individual stress profiles, thus paving the way for their further integration into health care and wellness practice.

Conditional requirement for dimerization of the membrane-binding module for BTK signaling in lymphocyte cell lines.

Bruton's tyrosine kinase (BTK) is a major drug target in immune cells. The membrane-binding pleckstrin homology and tec homology (PH-TH) domains of BTK are required for signaling. Dimerization of the PH-TH module strongly stimulates the kinase activity of BTK in vitro. Here, we investigated whether BTK dimerizes in cells using the PH-TH module and whether this dimerization is necessary for signaling. To address this question, we developed high-throughput mutagenesis assays for BTK function in Ramos B cells and Jurkat T cells. We measured the fitness costs for thousands of point mutations in the PH-TH module and kinase domain to assess whether dimerization of the PH-TH module and BTK kinase activity were necessary for function. In Ramos cells, we found that neither PH-TH dimerization nor kinase activity was required for BTK signaling. Instead, in Ramos cells, BTK signaling was enhanced by PH-TH module mutations that increased membrane adsorption, even at the cost of reduced PH-TH dimerization. In contrast, in Jurkat cells, we found that BTK signaling depended on both PH-TH dimerization and kinase activity. Evolutionary analysis indicated that BTK proteins in organisms that evolved before the divergence of ray-finned fishes lacked PH-TH dimerization but had active kinase domains, similar to other Tec family kinases. Thus, PH-TH dimerization is a distinct feature of BTK that evolved to exert stricter regulatory control on kinase activity as adaptive immune systems gained increased complexity.

Effect of CFTR modulators Elexacaftor/Tezacaftor/Ivacaftor on lipid metabolism in human bronchial epithelial cells.

Cystic Fibrosis (CF) is a life-threatening hereditary disease resulting from mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene that encodes a chloride channel essential for ion transport in epithelial cells. Mutations in CFTR, notably the prevalent F508del mutation, impair chloride transport, severely affecting the respiratory system and leading to recurrent infections. Recent therapeutic advancements include CFTR modulators such as ETI, a combination of two correctors (Elexacaftor and Tezacaftor) and a potentiator (Ivacaftor), that can improve CFTR function in patients with the F508del mutation. This study investigated ETI's impact on the maturation of the mutated CFTR, the expression levels of its scaffolding proteins, and lipid composition of cells using bronchial epithelial cell lines expressing both wild-type and F508del CFTR. Our findings revealed that ETI treatment enhances CFTR and its scaffolding proteins expression and aids in rescuing mature F508del CFTR, causing also significant alterations in the lipid profile including reduced levels of lactosylceramide and increased content of gangliosides GM1 and GD1a. These changes were linked to ETI's influence on enzymes involved in the sphingolipid metabolism, in particular GM3 synthase and sialidase. Through this work, we aim to deepen understanding CFTR interactions with lipids, and to elucidate the mechanisms of action of CFTR modulators. Our findings may support the development of potential therapeutic strategies contributing to the ongoing efforts to design effective correctors and potentiators for CF treatment.

The future of lactoferrin: A closer look at LipoDuo technology

Background Lactoferrin (Lf), a multifunctional glycoprotein known for its roles in immune modulation, iron metabolism, and antimicrobial activity, has limited therapeutic efficacy due to poor bioavailability. Liposomal encapsulation of lactoferrin (LLf) offers a potential solution by improving its stability, absorption, and sustained release, making it a promising candidate for various clinical applications. This study aims to compare the effectiveness of LLf and plain Lf in cellular uptake, proliferation, and wound healing using HEK-293T and Caco-2 cell lines. Methods Cell uptake, proliferation, and wound healing assays were conducted using HEK-293T and Caco-2 cells to evaluate the bioavailability and therapeutic efficacy of LLf compared to plain Lf. The cellular uptake was assessed over a 24-h period using an indirect ELISA method. Cell proliferation was measured using the MTT assay, while wound healing was evaluated using a scratch assay to observe cell migration over 48 h. Results LLf demonstrated significantly higher cellular uptake in both HEK-293T and Caco-2 cells, with peak internalization at 4 h, compared to plain Lf. In proliferation studies, LLf showed a dose-dependent increase in cell growth, achieving a 71% proliferation rate at 75 µg/mL, while plain Lf reached only 53%. LLf also accelerated wound healing, with nearly complete closure by 48 h, compared to 51.3% closure with plain Lf. Conclusion The results indicate that liposomal encapsulation significantly enhances lactoferrin’s bioavailability, proliferation-inducing capacity, and wound healing efficacy. LLf’s superior performance in these key areas suggests its potential for broader therapeutic applications, particularly in wound care, immune modulation, and tissue regeneration. Future clinical studies are warranted to validate the therapeutic benefits of LLf in vivo.

The microbiome and metabolome modulating activity of dietary cholesterol: Insight from the small and large intestine

Cholesterol is an important lipid molecule that can affect the gut microbiome upon ingestion. We systematically investigated the effects of cholesterol on the microbiota of the large and small intestines...

Decoding Plant-Pathogen Interactions: A Comprehensive Exploration of Effector-Plant Transcription Factor Dynamics.

In the coevolutionary process between plant pathogens and hosts, pathogen effectors, primarily proteinaceous, engage in interactions with host proteins, such as plant transcription factors (TFs), during the infection process. This review delves into the intricate interplay between TFs and effectors, a key aspect in the prolonged and complex battle between plants and pathogens. Effectors strategically manipulate TFs using diverse tactics. These include modulating activity of TFs, influencing their incorporation into multimeric complexes, directly changing TF expression levels, promoting their degradation via the ubiquitin-proteasome system, and inducing their subcellular relocalization. The review systematically presents documented interactions, elucidating key mechanisms and their profound impact on host-pathogen dynamics. It emphasises the central role of TFs in plant defence and investigates the convergent evolution of effectors targeting TFs. By providing this overview, we offer valuable insights into this dynamic interaction landscape and suggest potential directions for future research.

Suppression of TLR4/NF-κB signaling by kaurenoic acid in a mice model of monosodium urate crystals-induced acute gout.

The aim of the current study was to investigate the potential therapeutic effect of kaurenoic acid (KA) against Monosodium Urate Crystals (MSU)- induced acute gout by downregulation of NF-κB signaling pathway, mitigating inflammation and oxidative stress produced by MSU crystals. KA potentially targeted NF-κB pathway activation and provided comprehensive insights through multiple approaches. This was accomplished by advanced analytical techniques. This methodology highlighted the efficacy of KA in acute gout attacks offering new approach for gout management. In-vivo model of acute gout was established in BALB/c mice. Anti-inflammatory and urate-lowering potential was determined through pain behavioral evaluation, biochemical analyses, histological and immunohistochemistry assays, molecular docking simulations, radiological assessments, Fourier Transform Infrared (FTIR) analysis, and computational analysis. The paw edema, joint thickness, and the frequency and duration of acute gout flare-ups were all significantly (p<0.001) decreased by the administration of KA. A considerable reversal of inflammation and deterioration was observed in the KA-treated groups in X-ray examination. The FTIR spectroscopy indicated the changes in the molecular makeup of tissues, and modifications of biomolecules including proteins, lipids, and carbohydrates. Histopathological changes showed marked (p<0.001) improvements in cellular infiltration in the paw, and inflammatory cell infiltration in the treatment groups. Trichrome staining revealed suppressed collagen deposition, inflammation, and tissue repair in the paw. In paw tissues, the KA therapy up-regulated IκB-α expression while down-regulating toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) expression. On the other hand, KA therapy greatly increased antioxidants and decreased oxidative stress indicators significantly (p<0.001). According to Evans's blue permeability analysis, results showed that the treatment groups' vascular permeability was intensely reduced in comparison to the diseased group. Molecular docking studies indicated that KA appeared to have a high tendency to bind to protein targets. KA was associated with the drop in the cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β). In conclusion, this study highlighted the potential therapeutic effect of KA in alleviating MSU-induced gout by suppressing the NF-κB signaling pathway. The anti-inflammatory and antioxidant activity was demonstrated by behavioral studies and advanced biochemical evaluations including blood analysis and oxido-nitrosative stress markers. Histopathological analysis, including H&E staining, immunohistochemistry, and Masson Trichrome staining, revealed tissue preservation, while FTIR and X-ray revealed structural improvements. Molecular docking verified strong binding affinity to NF-κB-related targets, verifying its mechanistic action. These findings suggest promising applications of KA in acute gout management due to its potent NF-κB modulating activity.

Photodynamic hemostatic silk fibroin film with photo-controllable modulation of macrophages for bacteria-infected wound healing.

Massive hemorrhage and chronic wounds caused by bacterial infections after trauma are significant challenges in clinical practice. An ideal hemostatic wound dressing should simultaneously manage bleeding and prevent bacterial infections and also hold excellent biocompatibility and bioactivities to successfully modulate immune microenvironments to promote wound healing. In this study, a silk fibroin-based light-responsive film was demonstrated to possess effective capacity of light-induced non-compressible hemostasis on liver hemorrhage and tail bleeding in vivo by binding with blood platelets to promote the clotting cascade. The blood loss of the rats was significantly less after C-MASiF films were applied, which were 1223.33 ± 347.9 mg (liver trauma) and 363.33 ± 60.28 mg (tail trimming). Importantly, the films exhibited photo-controllable modulation activity on macrophages through repeated near-infrared irradiation to regulate the immune microenvironment to enhance photodynamic antibacterial therapy. Moreover, the light-responsive silk fibroin film effectively promoted Staphylococcus aureus infected burn wound healing in vivo. The quantity of residual bacteria in the wound sites of mice in the C-MASiF films group (0.05 ± 0.0047 × 108 CFU mL-1) was considerably less than that in the control group (3.18 ± 0.75 × 108 CFU mL-1), and the wound area in the C-MASiF group (78.03% ± 4.12%) was considerably smaller than that in the control group (60.33% ± 8.81%) after 14 days. Overall, this light-responsive silk fibroin film can provide a powerful strategy for wound healing of burns.

Exploring the Chemopreventive Potential of Artemisia annua Methanolic Extract in Colorectal Cancer Induced by Azoxymethane in Mice.

Background/Objectives: Colorectal cancer (CRC) remains a major global health burden, necessitating innovative preventive approaches. Artemisia annua (A. annua), known for its extensive pharmacological properties, has shown potential in cancer therapy. This study investigates the chemopreventive efficacy of methanolic extract of A. annua (MEA) in an azoxymethane (AOM)-induced murine model of CRC, with a focus on its antioxidant, biomarker modulation, and pro-apoptotic activities. Methods: MEA was obtained via cold solvent extraction, yielding 39%, and demonstrated potent in vitro cytotoxicity against HCT116 and RKO colon cancer cell lines, with IC50 values of 20 µg/mL and 15 µg/mL, respectively. Swiss albino mice were treated with MEA beginning two weeks before AOM induction, with treatment continuing for 21 weeks. Survival was monitored for 40 weeks. Key outcomes included serum biomarker levels (ADA, GGT, CD73, LDH), antioxidant enzyme activities (SOD, CAT, GPx1, MDA), reactive oxygen species (ROS) modulation, apoptosis induction, and histopathological evaluation. Results: MEA significantly improved survival rates, reduced AOM-induced weight loss, and modulated cancer biomarkers, with marked reductions in ADA, GGT, CD73, and LDH levels. Antioxidant defenses were restored, as evidenced by increased SOD, CAT, and GPx1 activities and decreased MDA levels. ROS levels were significantly reduced, and apoptosis in colonic cells was effectively induced. Histopathological analysis revealed substantial mitigation of CRC-associated morphological abnormalities. Conclusions: MEA exhibits robust chemopreventive properties, demonstrating its potential to reduce oxidative stress, modulate key biomarkers, and induce apoptosis in CRC. These findings position MEA as a promising natural candidate for CRC prevention and therapy, warranting further exploration for clinical application.

From Atrial Small-conductance Calcium-activated Potassium Channels to New Antiarrhythmics.

Despite significant advances in its management, AF remains a major healthcare burden affecting millions of individuals. Rhythm control with antiarrhythmic drugs or catheter ablation has been shown to improve symptoms and outcomes in AF patients, but current treatment options have limited efficacy and/or significant side-effects. Novel mechanism-based approaches could potentially be more effective, enabling improved therapeutic strategies for managing AF. Small-conductance calcium-activated potassium (SK or KCa2.x) channels encoded by KCNN1-3 have recently gathered interest as novel antiarrhythmic targets with potential atrial-predominant effects. Here, the molecular composition of smallconductance calcium-activated potassium channels and their complex regulation in AF as the basis for understanding the distinct mechanism of action of pore-blockers (apamin, UCL1684, ICAGEN) and modulators of calcium-dependent activation (NS8593, AP14145, AP30663) are summarised. Furthermore, the preclinical and early clinical evidence for the role of small-conductance calcium-activated potassium channel inhibitors in the treatment of AF are reviewed.

Modulation of 8-Oxoguanine DNA Glycosylase 1 (OGG1) Alleviated Anemia Severity and Excessive Cytokines Release during Plasmodium berghei Malaria in Mice.

The interplay of OGG1, 8-Oxoguanine, and oxidative stress triggers the exaggerated release of cytokines during malaria, which worsens the outcome of the disease. We aimed to investigate the involvement of OGG1 in malaria and assess the effect of modulating its activity on the cytokine environment and anemia during P. berghei malaria in mice. Plasmodium berghei ANKA infection in ICR mice was used as a malaria model. OGG1 concentration and oxidative stress levels in P. berghei-infected mice and their control counterparts were assessed during malaria using enzyme-linked immunosorbent assay. OGG1 activity in malaria mice was modulated using treatment with TH5487 and O8-OGG1 inhibitors. The effects of modulating OGG1 activity using OGG1 inhibitors on cytokine release and anemia during P. berghei malaria infection were assessed by cytometric bead array and measurement of total normal red blood cell count respectively. The plasma OGG1 level was significantly upregulated and positively correlated with parasitemia during P. berghei malaria in mice. Modulation of OGG1 ameliorated malaria severity by improving the total normal RBC count in TH5487 and O8-treated mice. Modulation of OGG1 with TH5487 caused significant reductions in serum levels of TNF-α, IFN-γ, IL-6, and IL-10. Similarly, OGG1 modulation activity using an O8-OGG1 inhibitor caused a significant reduction in serum levels of TNF-α, IL-2, IL-6, and IL-10. The findings indicate the involvement of OGG1 in the P. berghei malaria infection. OGG1 inhibition by TH5487 and O8-OGG1 inhibitors suppressed excessive cytokine release, and this may represent a novel therapeutic strategy for ameliorating the severity of malaria infection.

ATAC and SAGA histone acetyltransferase modules facilitate transcription factor binding to nucleosomes independent of their acetylation activity.

Transcription initiation involves the coordination of multiple events, starting with activators binding specific DNA target sequences, which recruit transcription coactivators to open chromatin and enable binding of general transcription factors and RNA polymerase II to promoters. Two key human transcriptional coactivator complexes, ATAC (ADA-two-A-containing) and SAGA (Spt-Ada-Gcn5 acetyltransferase), containing histone acetyltransferase (HAT) activity, target genomic loci to increase promoter accessibility. To better understand the function of ATAC and SAGA HAT complexes, we used in vitro biochemical and biophysical assays to characterize human ATAC and SAGA HAT module interactions with nucleosomes and how a transcription factor (TF) coordinates these interactions. We found that ATAC and SAGA HAT modules bind nucleosomes with high affinity, independent of their HAT activity and the tested TF. ATAC and SAGA HAT modules directly interact with the VP16 activator domain and this domain enhances acetylation activity of both HAT modules. Surprisingly, ATAC and SAGA HAT modules increase TF binding to its DNA target site within the nucleosome by an order of magnitude independent of histone acetylation. Altogether, our results reveal synergistic coordination between HAT modules and a TF, where ATAC and SAGA HAT modules (i) acetylate histones to open chromatin and (ii) facilitate TF targeting within nucleosomes independently of their acetylation activity.

Recent Achievements in Heterogeneous Bimetallic Atomically Dispersed Catalysts for Zn-Air Batteries: A Minireview.

Rechargeable Zn-air batteries (ZABs) hold promise as the next-generation energy-storage devices owing to their affordability, environmental friendliness, and safety. However, cathodic catalysts are easily inactivated in prolonged redox potential environments, resulting in inadequate energy efficiency and poor cycle stability. To address these challenges, anodic active sites require multiple-atom combinations, that is, ensembles of metals. Heterogeneous bimetallic atomically dispersed catalysts (HBADCs), consisting of heterogeneous isolated single atoms and atomic pairs, are expected to synergistically boost the cyclic oxygen reduction and evolution reactions of ZABs owing to their tuneable microenvironments. This minireview revisits recent achievements in HBADCs for ZABs. Coordination environment engineering and catalytic substrate structure optimization strategies are summarized to predict the innovation direction for HBADCs in ZAB performance enhancement. These HBADCs are divided into ferrous and nonferrous dual sites with unique microenvironments, including synergistic effects, ion modulation, electronic coupling, and catalytic activity. Finally, conclusions and perspectives relating to future challenges and potential opportunities are provided to optimise the performance of ZABs.

An In Silico Investigation of the Pathogenic G151R G Protein-Gated Inwardly Rectifying K+ Channel 4 Variant to Identify Small Molecule Modulators

Primary aldosteronism is characterised by the excessive production of aldosterone, which is a key regulator of salt metabolism, and is the most common cause of secondary hypertension. Studies have investigated the association between primary aldosteronism and genetic alterations, with pathogenic mutations being identified. This includes a glycine-to-arginine substitution at position 151 (G151R) of the G protein-activated inward rectifier potassium (K+) channel 4 (GIRK4), which is encoded by the KCNJ5 gene. Mutations in GIRK4 have been found to reduce the selectivity for K+ ions, resulting in membrane depolarisation, the activation of voltage-gated Ca2+ channels, and an increase in aldosterone secretion. As a result, there is an interest in identifying and exploring the mechanisms of action of small molecule modulators of wildtype (WT) and mutant channels. In order to investigate the potential modulation of homotetrameric GIRK4WT and GIRK4G151R channels, homology models were generated. Molecular dynamics (MD) simulations were performed, followed by a cluster analysis to extract starting structures for molecular docking. The central cavity has been previously identified as a binding site for small molecules, including natural compounds. The OliveNetTM database, which consists of over 600 compounds from Olea europaea, was subsequently screened against the central cavity. The binding affinities and interactions of the docked ligands against the GIRK4WT and GIRK4G151R channels were then examined. Based on the results, luteolin-7-O-rutinoside, pheophorbide a, and corosolic acid were identified as potential lead compounds. The modulatory activity of olive-derived compounds against the WT and mutated forms of the GIRK4 channel can be evaluated further in vitro.

In Vitro Evaluation of Endocrine-Related Adverse Effects of 5-Fluoroindole Derived Melatonin Analogues with Antioxidant Activity.

Melatonin (MLT) is a natural indolic hormone with well documented antioxidant properties, but it can also modulate the estrogen signaling pathway by inhibiting the aromatase enzyme and estrogen receptor modulating activity. This dual activity raises concerns about potential endocrine-related adverse effects when using MLT and its analogues as therapeutic agents in the prevention and treatment of oxidative stress related diseases. In this study, 34 novel 5-fluoroindole derivatives of MLT were synthesized and evaluated for their antioxidant, estrogen receptor modulatory, and aromatase inhibitory activities.Three compounds (4c, 5c, and 6c) demonstrated significant antioxidant activity, with compound 4c showing the highest efficacy in reducing intracellular reactive oxygen species (ROS) by 65 % in CHO-K1 cells and displaying DPPH radical scavenging comparable to the standard antioxidant, BHT. However, these same compounds also exhibited antiestrogenic effects in the E-Screen assay, with IC50 values of 3.36×10-5 M, 1.31×10-7 M, and 1.9×10-7 M, respectively, and inhibited aromatase activity by up to 29 % in a direct enzymatic assay. These findings indicate that, while the compounds have potent antioxidant properties, their significant antiestrogenic and aromatase inhibitory activities may pose risks for unintended endocrine related effects. Further studies are needed to better understand the implications of these activities in vivo and to balance the benefits and risks of such compounds in therapeutic applications.

Unraveling GPCRs Allosteric Modulation. Cannabinoid 1 Receptor as a Case Study.

G-protein-coupled receptors (GPCRs) constitute one of the most prominent families of integral membrane receptor proteins that mediate most transmembrane signaling processes. Malfunction of these signal transduction processes is one of the underlying causes of many human pathologies (Parkinson's, Huntington's, heart diseases, etc), provoking that GPCRs are the largest family of druggable proteins. However, these receptors have been targeted traditionally by orthosteric ligands, which usually causes side effects due to the simultaneous targeting of homologous receptor subtypes. Allosteric modulation offers a promising alternative approach to circumvent this problematic and, thus, comprehending its details is a most important task. Here we use the Cannabinoid type-1 receptor (CB1R) in trying to shed light on this issue, focusing on positive allosteric modulation. This is done by using the protein-dipole Langevin-dipole (PDLD) within the linear response approximation (LRA) framework (PDLD/S-2000) along with our coarse-grained (CG) model of membrane proteins to evaluate the dissociation constants (KBs) and cooperativity factors (αs) for a diverse series of CB1R positive allosteric modulators belonging to the 2-phenylindole structural class, considering CP55940 as an agonist. The agreement with the experimental data evinces that significantly populated allosteric modulator:CB1R and allosteric modulator:CP55940:CB1R complexes have been identified and characterized successfully. Analyzing them, it has been determined that CB1R positive allosteric modulation lies in an outwards displacement of transmembrane α helix (TM) 4 extracellular end and in the regulation of the range of motion of a compound TM7 movement for binary and ternary complexes, respectively. In this respect, we achieved a better comprehension of the molecular architecture of CB1R positive allosteric site, identifying Lys1923.28 and Gly1943.30 as key residues regarding electrostatic interactions inside this cavity, and to rationalize (at both structural and molecular level) the exhibited stereoselectivity in relation to positive allosteric modulation activity by considered CB1R allosteric modulators. Additionally, putative/postulated allosteric binding sites have been screened successfully, identifying the real CB1R positive allosteric site, and most structure-activity relationship (SAR) studies of CB1R 2-phenylindole allosteric modulators have been rationalized. All these findings point out towards the predictive value of the methodology used in the current work, which can be applied to other biophysical systems of interest. The results presented in this study contribute significantly to understand GPCRs allosteric modulation and, hopefully, will encourage a more thorough exploration of the topic.

Enhancing Engagement in Business Communication Course Content Development through Stakeholder Mapping and Analysis at South African HEIs: A Review of Literature

The role of stakeholder engagement in higher education institutions has received attention from academics and industry practitioners. This paper thus aims to gain insights into the assumption of stakeholder mapping and analysis by South African higher education institutions in the course content development activities of business communication modules. Although stakeholders are assumed to form an integral part of decision-making in HEIs, questions have been raised about the efficacy of engagement initiatives that are directed towards them, and whether or not the said initiatives are delivered to the relevant constituents. Within the context of course content development, effective stakeholder engagement is the cornerstone of curating educational experiences that enhance the learning experiences of students. A desk research methodology was undertaken to explore data from existing studies that are centred on stakeholder analysis and mapping, in order to examine findings from studies that have investigated utilising this approach to enhance engagement with stakeholders for module development purposes. The researcher analysed articles, e-books, reports and websites, extracted from electronic databases such as Google Scholar, EBSCOhost and ResearchGate. The findings conveyed the value of involving stakeholders in course content development, they also highlighted the importance of stakeholder mapping and analysis in getting Higher Education Institutions to classify their stakeholders accordingly. This promotes an inclusive approach, ensuring that no one is left behind in conversations, relating to business communication course content development, it also ensures that the requirements of all stakeholders are fulfilled. Collaboration with stakeholders leads to the creation of effective business communication modules that meet contemporary workplace demands.

Cell Adhesion Molecules as Modulators of the Epidermal Growth Factor Receptor.

Cell adhesion molecules (CAMs) are cell surface glycoproteins mediating interactions of cells with other cells and the extracellular matrix. By mediating the adhesion and modulating activity of other plasma membrane proteins, CAMs are involved in regulating a multitude of cellular processes, including growth, proliferation, migration, and survival of cells. In this review, we present evidence showing that various CAMs interact with the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase inducing pro-proliferative and anti-apoptotic intracellular signaling in response to binding to several soluble ligands, including the epidermal growth factor. We discuss that CAMs are involved in regulating EGFR signaling by either potentiating or inhibiting the soluble ligand-dependent activation of EGFR. In addition, CAMs induce soluble ligand-independent forms of EGFR activity and regulate the levels of EGFR and its ligand-induced degradation. The CAM-dependent modulation of EGFR activity plays a key role in regulating the growth, proliferation, and survival of cells. Future research is needed to determine whether these processes can be targeted in both normal and cancerous cells by regulating interactions of EGFR with various CAMs.

Transforming STEM Education with Design Thinking

This poster showcases the Technology-Enhanced Learning (TEL) pedagogy designed for a health discipline course at an Australian University. The use of the design thinking process for problem-based learning was implemented to enhance first-year students' creative and digital skills. Collaboration with the industry partners enabled an authentic learning experience. In the post-COVID era, students are more diverse, demanding, discerning, and inclined towards flexible learning to shape their educational experiences. To meet these evolving needs, we adhered to digital accessibility guidelines and Universal Design for Learning (UDL) principles, promoting inclusive education. A student-centric approach to TEL pedagogy is essential for delivering authentic and connected learning experiences (Ní Shé, 2022). In our health course, we designed interactive content using HTML5 Package (H5P) to create engaging learning materials and activities in health course modules. This included multiple-choice questions, interactive text, images, and videos, providing opportunities for students to answer questions, solve problems, and explore content knowledge. This also included formative feedback and opportunities for students to test their understanding. Additionally, design thinking was incorporated to allow students to test their understanding of the health applications, solve ‘wicked’ real-world problems and create human-centric solutions (Brenner et al., 2016). In a three-week course module, Week 1 presented an open-ended real-world problem, designed and developed in collaboration with an industry partner, to help students understand user needs and pain points. Later in the week, students defined the problem by narrowing the scope down and identifying characteristics of the user persona. In Week 2, students ideated multiple responses to the defined problem, utilising problem-solving skills and creativity (Jia, Jalaludin, &amp; Rasul, 2023) to think critically and brainstorm the appropriate solutions using Miro, and then created a low-fidelity prototype to meet the user requirements. In Week 3, students applied their knowledge to test the solution against user needs, constructively aligned with the industry practices. Through the experience of design thinking to solve open-ended, real-world problems, we employed problem-solving learning pedagogy to develop an iterative process of group work (Dam?a &amp; Wittek, 2020). Academics acted as facilitators rather than traditional lecturers, providing support and resources as needed, but allowing students to take the lead. Students took responsibility for their learning by collaborating to explore design thinking and refining their solutions as they gathered information and feedback from various sources, integrating their own disciplinary knowledge as jigsaw pieces (Calkins &amp; Rivnary 2022). For the purpose of authentic assessment, we designed challenging activities that required students to apply design thinking in problem-solving. The assessment tasks focused on both the process and the final solution, as well as the reflective component, including self-assessment and peer assessment. Students increased their effort towards this problem-based assessment because it held more real-life relevance and allowed them to apply their knowledge and skills in practical contexts.