Detailed Action Research Articles

The implementation of ijarah muntahiyah bittamlik in infrastructure project financing within the public-private partnership models: A collaborative governance perspective

This paper investigates the implementation of ijarah muntahiyah bittamlik (IMBT) as an infrastructure project financing scheme within the Public-Private Partnership (PPP) models from a collaborative governance perspective. This paper follows a case study methodology. It focuses on two Indonesian non-toll road infrastructure projects, i.e., the preservation of the East Sumatra Highway projects, each in South Sumatra province and Riau province. The findings revealed that Indonesia’s infrastructure development priorities and its vision to become a global leader in Islamic finance characterized the system context that shaped the implementation of IMBT as an infrastructure project financing scheme within the PPP-AP model. Key drivers include leadership from the government, stakeholder interdependence, and financial incentives for the partnering business entity to adopt off-balance sheet solutions. Principled engagement, shared motivation, and the capacity for joint action characterized the collaboration dynamics, leading to detailed collaborative actions crucial for implementing IMBT as a financing scheme.

Dietary Solid-state-fermentation product of Bacillus velezensis T23 alleviate hepatic steatosis, oxidative stress, gut barrier damage, and microbiota dysbiosis in juvenile genetically improved farmed tilapia (GIFT, Oreochromis niloticus)

The application of commensal probiotic bacteria is one of the preferable green feed additives for antibiotic substitution in aquaculture, while the application methods and detailed action mechanisms of commensal bacteria isolated from aquatic animals are not consistent with normal mammalian-derived probiotics. The purpose of this study was to evaluate the effects of solid-state fermentation product of autochthonous Bacillus velezensis T23 on improving hepatic steatosis, liver antioxidation capacity, gut injury and gut microbiota profile of genetically improved farmed tilapia (GIFT, Oreochromis niloticus). The T23 probiotic was added to the basal diet at a level of 0.00, 0.05, 0.1, 0.2 and 0.3 g/kg to develop five experimental diets, respectively. After 4 weeks of the feeding trial, the results showed that T23 supplementation notably reduced the hepatocytes vacuolization and the content of liver TAGs by downregulated the mRNA expression of the lipogenesis gene (fas), while upregulated the mRNA expression of lipid degradation genes (cpt1 and pparα) (p < 0.05). Compared with the control, the 0.3T23 group showed significantly upregulated expression levels of anti-inflammatory cytokine genes (tgf-β and il-10) in the liver of the fish (p < 0.05). Besides, the activities of antioxidase SOD and CAT were significantly upregulated in T23 treatment groups, compared with the control (p < 0.05). Fish groups fed with 0.2 g/kg and 0.3 g/kg T23 supplemented diet also exhibited significantly lower intestinal injury and intestinal inflammation via upregulating the expression of tight junction protein gene claudin, anti-inflammatory factor gene il-10 (p < 0.05). However, markedly downregulation of the mRNA level of pro-inflammatory cytokine il-1β (p < 0.05) was observed in 0.05 and 0.3T23 groups, compared with the control. 16S rRNA sequencing analysis data on gut microbiota indicated that supplementation of T23 at lower levels (0.05, 0.1 and 0.2) resulted in a remarkable elevation of the abundance of phylum Firmicutes and reduced the abundance of Proteobacteria, and the ratio of (Firmicutes +Bacteroidota +Fusobacteria) /Proteobacteria. On the contrary, feeding with 0.3T23 negatively affects the gut microbiota diversity and structure of tilapia. Therefore, a 0.2 g/kg dose is suggested to supplement the diet of Nile tilapia to improve liver health and modulate the gut microbiota profile of the fish positively. Overall, these findings provide a shred of beneficial evidence of the application of B. velezensis T23 as a green feed additive to improve the productivity and profitability of tilapia farming.

Toxicity of Flonicamid to Diaphorina citri (Hemiptera: Liviidae) and Its Identification and Expression of Kir Channel Genes.

Flonicamid is a selective insecticide effective against piercing-sucking insects. Although its molecular target has been identified in other species, the specific effects and detailed mechanism of action in Diaphorina citri Kuwayama remain poorly understood. In this study, we determined that the LC50 of flonicamid for D. citri adults was 16.6 mg AI L-1 after 4 days of exposure. To explore the relevant mechanisms, the treatments with acetone and with 20 mg AI L-1 flonicamid for 96 h were collected as samples for RNA-Seq. The analysis of the transcriptomes revealed 345 differentially expressed genes (DEGs) in D. citri adults subjected to different treatments. Among these DEGs, we focused on the inward-rectifying potassium (Kir) channel genes, which have been extensively studied as potential targets of flonicamid. Three Kir subunit genes (Dckir1, Dckir2, Dckir3) in D. citri were successfully cloned and identified. Furthermore, the expression profiles of these DcKirs were investigated using RT-qPCR and showed that their expression significantly increased after D. citri eclosion to adulthood, particularly for DcKir3. The DcKirs were predominantly expressed in gut tissues, with DcKir1 and DcKir2 exhibiting high expression levels in the hindgut and midgut, respectively, while DcKir3 showing high expression in the midgut and Malpighian tubules. This study provides insights into the potential roles of Kir subunits in D. citri and enhances our understanding of the physiological effects of flonicamid in this pest.

Excitatory amino acids as therapeutic agents: Reversing neurodegenerative trajectory by tackling excitotoxicity.

Neurodegenerative diseases pose significant challenges to healthcare systems globally due to their complex etiology and relentless progression, often rendering conventional treatments ineffective. Recent advances have spotlighted excitatory amino acids, particularly D-amino acids, once considered as products of metabolism of the microbiota or deriving from food intake. This review explores the role of D-amino acids in mitigating excitotoxicity-a process characterized by excessive calcium influx through aberrant N-methyl-D-aspartate receptor (NMDAR) activation, which is implicated in the pathogenesis of diseases like Alzheimer's disease. By providing alternative pathways for neuronal signaling and protecting against excitotoxic damage, D-amino acids offer a novel approach to reversing neurodegenerative trajectories. Future research should focus on elucidating the detailed mechanisms of action of these compounds, evaluating their therapeutic potential through rigorous preclinical and clinical trials, and developing effective delivery systems to optimize their neuroprotective effects. This emerging field holds promise for developing innovative treatment strategies that could significantly improve outcomes for patients with neurodegenerative disorders.

A risk-based approach to mitigating the Gen(AI) challenge to assessment integrity

In the evolving landscape of higher education, emerging technologies such as Generative AI (GenAI) present both opportunities and challenges. The rapid increase in access to, and sophistication of, GenAI poses significant challenges for our institution and the wider sector (Bearman &amp; Luckin 2020, Bobula 2024, Chan &amp; Hu 2023). The most immediate of these challenges is the increased risk to the existing approaches used to assure that students achieve the stated outcomes of their learning experiences. Director of Higher Education Integrity Unit, TEQSA, Dr Helen Gniel argues ‘We are entering an age where institutions can no longer ensure the integrity of every single assessment, and it makes sense to think at that bigger level […] what are the mechanisms that you have in place to be confident that an individual has demonstrated the learning outcomes to receive that degree’(TEQSA information request: AI risk mitigation, webinar, 21 March 2024). While higher education institutions are exploring opportunities to realise the potential benefits of GenAI, our immediate focus is on mitigating these risks. This poster describes institutional Programmatic Assessment Security Project (PASP) at the University of Newcastle (UON), a pioneering four-stage initiative designed to address academic integrity risks associated with inappropriate uses of GenAI in summative assessment (Lodge 2024). Academic integrity risks in this context refers to the potential for students to engage in academic misconduct by using GenAI tools in ways that violate institutional policies or ethical standards for assessment. These risks pose a threat to the validity and reliability of summative assessments, potentially compromising the integrity of academic qualifications and the learning process itself. Led by the central teaching and learning support unit, in collaboration with the Artificial Intelligence Working Group (AIWG) a group of expert practitioners and academic stakeholders at UON, the PASP aims to secure assessments across a program of study, assuring student attainment of program learning outcomes. This innovative approach aligns with the sector’s focus on programmatic assessment and supports compliance with regulatory requirements, including TEQSA’s mid 2024 request for institutions to submit a detailed action plan to mitigate the risks that GenAI poses to the integrity of awards (TEQSA 2024). This poster showcases exemplary innovation in practice through the PASP, advancing research and practice in technology-enhanced learning (TEL). The PASP employs a risk-based approach, identifying seven risk factors for inappropriate student use of GenAI in assessment tasks. The first step in this project involved Course Coordinators completing an Assessment Reflection Survey, guiding them to reflect on individual assessment tasks in relation to these risk factors. The survey data were then used to compile an understanding of the varying levels of assessment risk across the institution’s programs. The PASP will deliver a defined series of secure assessments, delivered at key moments across a program of study to assure student attainment of program learning outcomes. This poster provides insight into UON’s contemporary and agile approach to TEL and assessment redesign, with potential for staff at other institutions to adopt similar responses.

Fall detection method based on spatio-temporal coordinate attention for high-resolution networks

Fall behavior is closely related to the high mortality rate of the elderly, so fall detection has become an important and urgent research area in human behavior recognition. However, the existing fall detection methods, suffer from the loss of detailed action information during feature extraction due to the downsampling operation, resulting in subpar performance when detecting falls with similar behaviors such as lying and sitting. To solve the challenges, this study proposes a high-resolution spatio-temporal feature extraction method based on a spatio-temporal coordinate attention mechanism. The method employs 3D convolutions to extract spatio-temporal features and utilizes gradual down-sampling to generate a multi-resolution sub-network, thus realizing multi-scale fusion and perception enhancement of details. In particular, this study designs a pseudo-3D basic block, which simulates the ability of 3D convolution, to ensure the running speed of the network while controlling the number of parameters. Further, a spatio-temporal coordinate attention mechanism is designed to accurately extract the spatio-temporal positional changes of key skeletal points and the interrelationships among them. Long-term dependencies in horizontal, vertical, temporal directions are captured through three one-dimensional global pooling operations. Then the long-range relationships and channel correlations among features are captured by cascading and slicing operations. Finally, the key information is effectively highlighted by performing dot-multiplication operations between the feature maps from the horizontal, vertical and temporal directions and the input feature maps. Experimental results on three typical public datasets show that the proposed method can better extract motion features and improve the accuracy of fall detection.

Gradient dynamics approach to reactive thin-film hydrodynamics

Wetting and dewetting dynamics of simple and complex liquids is described by kinetic equations in gradient dynamics form that incorporates the various coupled dissipative processes in a fully thermodynamically consistent manner. After briefly reviewing this, we also review how chemical reactions can be captured by a related gradient dynamics description, assuming detailed balanced mass action type kinetics. Then, we bring both aspects together and discuss mesoscopic reactive thin-film hydrodynamics illustrated by two examples, namely, models for reactive wetting and reactive surfactants. These models can describe the approach to equilibrium but may also be employed to study out-of-equilibrium chemo-mechanical dynamics. In the latter case, one breaks the gradient dynamics form by chemostatting to obtain active systems. In this way, for reactive wetting we recover running drops that are driven by chemically sustained wettability gradients and for drops covered by autocatalytic reactive surfactants we find complex forms of self-propulsion and self-excited oscillations.

SYNERGISTIC EFFECT OF HERBAL TEA SAMPLES WITH CIPROFLOXACIN AGAINST MRSA AND THEIR ANTIOXIDANT ACTIVITIES

OBJECTIVE: Sambucus nigra L. (elderberry), Salvia sclarea L. (clary sage), Rosmarinus officinalis L. (rosemary), and Coriandrum sativum L. (coriander) are all consumed as flavoring agents for food and are well-known in traditional medicine for the treating various diseases worldwide. These herbs are also commonly used for microbial infections, especially to relieve cough, fever, and cold symptoms. This study aims to screen and compare the content of total phenols and antioxidant activity potential of three different extracts from each commercial sample of S. nigra, S. sclarea, R. officinalis and C. sativum from Türkiye. We also investigated the (Minimum Inhibitory Concentration (MIC) values against Staphylococcus aureus ATCC 29213 (methicillin-susceptible, MSSA) and Staphylococcus aureus ATCC 43300 (methicillin-resistant, MRSA) and the synergistic activity with an antibiotic, ciprofloxacin, by checkerboard assay. MATERIAL AND METHODS: The fruits of S. nigra and C. sativum, the aerial parts of S. sclarea, and the leaves of R. officinalis were purchased from a trading company that marketed them as herbal tea in Türkiye. This study investigated the total phenolic content and antioxidant potential of extracts from commercial samples. We also determined the synergistic effect of herbal tea samples with ciprofloxacin against methicillin-resistant Staphylococcus aureus (MRSA). RESULTS: R. officinalis (rosemary) and Salvia sclarea (clary sage) extracts showed high phenolic content and antioxidant activity, whereas it was determined that C.sativum (coriander) and S. nigra (elderberry) extracts exhibited lower antioxidant activity and low phenolic compounds. Moreover, ciprofloxacin in combination with the ethanolic extract of S. sclarea showed additive antibacterial activity against S. aureus ATCC 43300. CONCLUSIONS: We conclude that herbal tea prepared from commercial R. officinalis (rosemary) and S.sclarea (clary sage) samples can support the antioxidant activity with high phenolic content and that ciprofloxacin combined with the ethanolic extract of clary sage showed additive antibacterial activity against methicillin-resistant S. aureus ATCC 43300. Further studies are needed to understand the mechanism of additive action in detail.

Visual Communication Method of Multi-Frame Film and Television Special Effects Images Based on Deep Learning

In the view of art form change, there is a perspective problem in the detail part of multi-frame film and television special effects (TSEs) images in the special effects rendering module, which leads to the greater ambiguity of multi-frame film and TSEs images. In order to advance the talent of identifying the detail structures and characteristics of multi-frame film and TSEs images, a visual communication technology of multi-frame film and TSEs images in the view of art form change grounded on deep learning is suggested. The transmission relation model of detail characteristics of multi-frame film and TSEs images in the field of artistic form change is constructed, and the attenuation treatment of detail action special effects of multi-frame film and TSEs images in the field of artistic form change is carried out with the assistance of deep learning approaches. The detailed information and color of multi-frame film and TSEs images are obtained by using prior map knowledge instead of rendering basic color. Over the technique of filtering and preserving, the multi-frame film and TSEs images are directed to screen the detailed feature quantity of the input film and TSEs images in the field of artistic form change. In addition, the Sobel operator is practiced to perceive the scrawny edge information of multi-frame film and TSEs images, and block fitting interpolation and depth filtering analysis are used in the edge area to realize the visual communication and color feature parameter identification and amplification of multi-frame film and TSEs images in the field of artistic form change, so as to improve the fuzzy enhancement of multi-frame film and TSEs images. The test results and results indicate that the average Peak signal-to-noise ratio (PSNR) of the proposed method is about 37.7166[Formula: see text]dB, which is 49.08% and 52.08% higher than the PSNRs of the Harris method and SUFR method, respectively. It has been confirmed that this scheme can successfully solve the edge blurring and distortion problems of multi-frame movies and image images in the field of art form change.

Insights into inhibitory action and interaction of bisdemethoxycurcumin on tyrosinase: Spectroscopic and docking analysis

Bisdemethoxycurcumin (BDMC), a demethoxy derivative of curcumin, has garnered interest for its potential anti-tyrosinase properties, which are crucial for applications in food preservation and cosmetic industries. Despite its recognized bioactive effects, the detailed inhibitory action and interaction of BDMC on tyrosinase and its application in anti-browning processes remain unclear. This study aims to dissect the molecular interactions of BDMC with tyrosinase, elucidate its inhibition mechanism, and assess its efficacy in preventing browning, thereby underpinning its potential as a natural anti-browning agent. Employing a battery of spectroscopic techniques, we characterized the interaction of BDMC with tyrosinase. The anti-browning properties of BDMC were evaluated on fresh-cut apples, and its effect on enzymatic activities related to browning was also investigated. The results indicate that BDMC interacts with tyrosinase in a reversible mixed-type inhibition manner with an IC50 value of 12.5 ± 0.2 μM. Surface Plasmon Resonance (SPR) results indicated that BDMC presented good binding affinity toward tyrosinase. Fluorescence quenching results showed that BDMC could quench the fluorescence of tyrosinase in a static process. Synchronous fluorescence, circular dichroism spectra, and three-dimensional fluorescence results indicated that interaction of BDMC against tyrosinase resulted in changes of tyrosinase on microenvironment and conformation, thus causing decrease of tyrosinase activity. Copper-chelating results presented that BDMC could chelate to copper with stoichiometric ratio of 1: 2. Molecular docking provided intricate details of how BDMC interacted with tyrosinase. Moreover, BDMC exhibited anti-browning capability on fresh cut apples, and could regulate PPO, POD, and APX activities. The comprehensive analysis proposed in this study consolidated the theoretical basis of BDMC as a tyrosinase inhibitor and supported its potential anti-browning application.

Diospyros lotus leaf extract and its main component myricitrin inhibit itch‑related IL‑6 and IL‑31 by suppressing microglial inflammation and microglial‑mediated astrocyte activation.

Diospyros lotus has been traditionally used in Asia for medicinal purposes, exhibiting a broad spectrum of pharmacological effects including antioxidant, neuroprotective and anti‑inflammatory properties. While the anti‑itch effect of D. lotus leaves has been reported, studies on the detailed mechanism of action in microglia and astrocytes, which are members of the central nervous system, have yet to be revealed. The present study aimed to investigate effects of D. lotus leaf extract (DLE) and its main component myricitrin (MC) on itch‑related cytokines and signaling pathways in lipopolysaccharide (LPS)‑stimulated microglia. The effect of DLE and MC on activation of astrocyte stimulated by microglia was also examined. Cytokine production was evaluated through reverse transcription PCR and western blot analysis. Signaling pathway was analyzed by performing western blotting and immunofluorescence staining. The effect of microglia on astrocytes activation was evaluated via western blotting for receptors, signaling molecules and itch mediators and confirmed through gene silencing using short interfering RNA. DLE and MC suppressed the production of itch‑related cytokine IL‑6 and IL‑31 in LPS‑stimulated microglia. These inhibitory effects were mediated through the blockade of NF‑κB, MAPK and JAK/STAT pathways. In astrocytes, stimulation by microglia promoted the expression of itch‑related molecules such as oncostatin M receptor, interleukin 31 receptor a, inositol 1,4,5‑trisphosphate receptor 1, lipocalin‑2 (LCN2), STAT3 and glial fibrillary acidic protein. However, DLE and MC significantly inhibited these receptors. Additionally, astrocytes stimulated by microglia with IL‑6, IL‑31, or both genes silenced did not show activation of LCN2 or STAT3. The findings of the present study demonstrated that DLE and MC could suppress pruritic activity in astrocytes induced by microglia‑derived IL‑6 and IL‑31. This suggested the potential of DLE and MC as functional materials capable of alleviating pruritus.

Antioxidant and anti-urease activities of Cardamine bulbifera: Insights from molecular docking and density functional theory studies

IntroductionCardamine bulbifera (L.) Crantz, commonly known as “Asian bittercress”, is a plant species widely distributed across Asia. It belongs to the Brassicaceae and has been traditionally used in medicinal applications. This study investigates the phytochemical composition, phenolic content, antioxidant properties, and anti-urease activity of C. bulbifera. MethodsIn this study, the aerial parts of the C. bulbifera were collected. The total polyphenol content of the extracts was determined using spectrophotometric methods, and its antioxidant and anti-urease activities were assessed. The chemical composition was characterised using gas chromatography-mass spectroscopic (GC-MS) analysis. Additionally, molecular docking studies explored potential interactions between the identified compounds and Helicobacter pylori CagA oncoprotein. Furthermore, Density Functional Theory (DFT) analysis provided valuable insights into the electronic properties of the main compounds. ResultThe total phenolic content of C. bulbifera extract was 225 ± 0.02 mg GAE/g extract DW, and the total flavonoid content was 62.64 ± 3.27 mg QE/g extract DW. The 2,2-Diphenyl-1-Picrylhydrazyl (DPPH) assay revealed an IC50 value of 1.01 ± 0.04 mg/mL, indicating significant antioxidant activity. The IC50 value for anti-urease activity was determined to be 2.74 ± 0.03 µg/mL, suggesting potent inhibition of urease enzyme activity. GC-MS analysis identified 15 bioactive compounds in the extract. Molecular docking studies highlighted Phenol, 3,5-bis(1,1-dimethylethyl) and 1-dodecanol as compounds with the highest binding affinity for the H. pylori CagA oncoprotein, suggesting potential therapeutic implications against H. pylori-related cancers. Additionally, DFT analysis emphasised these compounds' electronic properties and chemical reactivities, indicating their potential role in future pharmaceutical developments. ConclusionC. bulbifera exhibits rich phenolic and flavonoid content and significant antioxidant and intense urease inhibition activities. These findings suggest that C. bulbifera may offer potential therapeutic options for conditions related to H. pylori infections, including cancer. Further research is needed to explore its mechanisms of action and clinical applications in more detail.

Reinforcement learning in autonomous defense systems: Strategic applications and challenges

Reinforcement learning (RL) is one of the most progressive ways to improve the efficiency of drones and robotic systems in the context of the defense and security industries. In Anomaly Detection (AD) systems, this paper discusses the potential of RL as a Model Selection Criteria (MSC) method and its associated issues. RL algorithms enable such systems to adapt to and learn from interactions with their environment, optimizing their response to complex and dynamic threats. This way, new states may be introduced with better decision-making processes, improving the effectiveness of the operations and enabling Reinforcement learning -powered systems to learn new scenarios as well as perform detailed defensive actions in a real-time context. The importance of RL in national defense can therefore be said to lie in its capacities for changing how threats are identified, how threats are responded to, and even what strategies of defense are thought of. Self-governing systems that incorporate Reinforcement learning are capable of functioning in an unpredictable environment, evaluating threats correctly, and carrying out defensive measures with the help of people practically at all. This versatility is critical in modern warfare because a preferred option is the right response to threats that were unknown a few years ago. However, incorporating RL into autonomous defense systems is not without big challenges. Some important problem areas are improved stability and accuracy of RL algorithms in various and critical situations, the legal and practical consequences of autonomous decision-making and possible threats that can arise due to adversarial manipulation of learning algorithms. In addition, such systems have to be developed and put into practice under national and international standards to meet certain requirements and build confidence in such applications. This paper explores these strategic uses and issues and presents a detailed overview of how RL can improve independent defense functionalities, as well as the significant problems relating to this approach. Thus, by providing case studies and theoretical analysis, it aims to demonstrate that RL has the potential to define the technological development of defense and benefit national security systems in the context of a growing threat.

Applying vision-guided graph neural networks for adaptive task planning in dynamic human robot collaborative scenarios

ABSTRACT The Assemble-To-Order (ATO) strategy is increasingly becoming prevalent in the manufacturing sector due to the high demand for high-volume personalised and customised goods. The use of Human-Robot Collaborative (HRC) Systems are increasingly being investigated in order to make use of the dexterous strength of human hands while at the same time make use of the ability of robots to carry massive loads. However, current HRC systems struggle to adapt dynamically to varying human actions and cluttered workspaces. In this paper, we propose a novel neural network framework that integrates both Graph Neural Network (GNN) and Long Short-Term Memory (LSTM) for adaptive response during HRC scenarios. Our framework enables a robot to interpret human actions and generate detailed action plans while dealing with objects in a cluttered workspace thereby addressing the challenges of dynamic human-robot collaboration. Experimental results demonstrate improvements in assembly efficiency and flexibility, making our approach the first integration of iterative grasping and flexible HRC within a unified neural network architecture.

The Modulatory Effects and Therapeutic Potential of Cannabidiol in the Gut.

Cannabidiol (CBD) is a major non-psychotropic phytocannabinoid that exists in the Cannabis sativa plant. CBD has been found to act on various receptors, including both cannabinoid and non-cannabinoid receptors. In addition, CBD has antioxidant effects that are independent of receptors. CBD has demonstrated modulatory effects at different organ systems, such as the central nervous system, immune system, and the gastrointestinal system. Due to its broad effects within the body and its safety profile, CBD has become a topic of therapeutic interest. This literature review summarizes previous research findings with regard to the effect of CBD on the gastrointestinal (GI) system, including its effects at the molecular, cellular, organ, and whole-body levels. Both pre-clinical animal studies and human clinical trials are reviewed. The results of the studies included in this literature review suggest that CBD has significant impact on intestinal permeability, the microbiome, immune cells and cytokines. As a result, CBD has been shown to have therapeutic potential for GI disorders such as inflammatory bowel disease (IBD). Furthermore, through interactions with the gut, CBD may also be helpful in the treatment of disorders outside the GI system, such as non-alcoholic liver disease, postmenopausal disorders, epilepsy, and multiple sclerosis. In the future, more mechanistic studies are warranted to elucidate the detailed mechanisms of action of CBD in the gut. In addition, more well-designed clinical trials are needed to explore the full therapeutic potential of CBD on and through the gut.

Exocyclic and Linker Editing of Lys63-linked Ubiquitin Chains Modulators Specifically Inhibits Non-homologous End-joining Repair.

Despite the great advances in discovering cyclic peptides against protein targets, their reduced aqueous solubility, cell permeability, and activity of the cyclic peptide restrict its utilization in advanced biological research and therapeutic applications. Here we report on a novel approach of structural alternation of the exocyclic and linker parts that led to a new derivative with significantly improved cell activity allowing us to dissect its mode of action in detail. We have identified an effective cyclic peptide (CP7) that induces approximately a 9-fold increase in DNA damage accumulation and a remarkable increase in apoptotic cancer cell death compared to the reported molecule. Notably, treating cells with CP7 leads to a dramatic decrease in the efficiency of non-homologous end joining (NHEJ) repair of DNA double-strand breaks (DSBs), which is accompanied by an increase in homologous recombination (HR) repair. Interestingly, treating BRCA1-deficient cells with CP7 restores HR integrity, which is accompanied by increased resistance to CP7. Additionally, CP7 treatment increases the sensitivity of cancer cells to ionizing radiation. Collectively, our findings demonstrate that CP7 is a selective inhibitor of NHEJ, offering a potential strategy to enhance the effectiveness of radiation therapy.

Exocyclic and Linker Editing of Lys63‐linked Ubiquitin Chains Modulators Specifically Inhibits Non‐homologous End‐joining Repair

AbstractDespite the great advances in discovering cyclic peptides against protein targets, their reduced aqueous solubility, cell permeability, and activity of the cyclic peptide restrict its utilization in advanced biological research and therapeutic applications. Here we report on a novel approach of structural alternation of the exocyclic and linker parts that led to a new derivative with significantly improved cell activity allowing us to dissect its mode of action in detail. We have identified an effective cyclic peptide (CP7) that induces approximately a 9‐fold increase in DNA damage accumulation and a remarkable increase in apoptotic cancer cell death compared to the reported molecule. Notably, treating cells with CP7 leads to a dramatic decrease in the efficiency of non‐homologous end joining (NHEJ) repair of DNA double‐strand breaks (DSBs), which is accompanied by an increase in homologous recombination (HR) repair. Interestingly, treating BRCA1‐deficient cells with CP7 restores HR integrity, which is accompanied by increased resistance to CP7. Additionally, CP7 treatment increases the sensitivity of cancer cells to ionizing radiation. Collectively, our findings demonstrate that CP7 is a selective inhibitor of NHEJ, offering a potential strategy to enhance the effectiveness of radiation therapy.

Complex Pathophysiology of Acute Kidney Injury (AKI) in Aging: Epigenetic Regulation, Matrix Remodeling, and the Healing Effects of H2S.

The kidney is an essential excretory organ that works as a filter of toxins and metabolic by-products of the human body and maintains osmotic pressure throughout life. The kidney undergoes several physiological, morphological, and structural changes with age. As life expectancy in humans increases, cell senescence in renal aging is a growing challenge. Identifying age-related kidney disorders and their cause is one of the contemporary public health challenges. While the structural abnormalities to the extracellular matrix (ECM) occur, in part, due to changes in MMPs, EMMPRIN, and Meprin-A, a variety of epigenetic modifiers, such as DNA methylation, histone alterations, changes in small non-coding RNA, and microRNA (miRNA) expressions are proven to play pivotal roles in renal pathology. An aged kidney is vulnerable to acute injury due to ischemia-reperfusion, toxic medications, altered matrix proteins, systemic hemodynamics, etc., non-coding RNA and miRNAs play an important role in renal homeostasis, and alterations of their expressions can be considered as a good marker for AKI. Other epigenetic changes, such as histone modifications and DNA methylation, are also evident in AKI pathophysiology. The endogenous production of gaseous molecule hydrogen sulfide (H2S) was documented in the early 1980s, but its ameliorative effects, especially on kidney injury, still need further research to understand its molecular mode of action in detail. H2S donors heal fibrotic kidney tissues, attenuate oxidative stress, apoptosis, inflammation, and GFR, and also modulate the renin-angiotensin-aldosterone system (RAAS). In this review, we discuss the complex pathophysiological interplay in AKI and its available treatments along with future perspectives. The basic role of H2S in the kidney has been summarized, and recent references and knowledge gaps are also addressed. Finally, the healing effects of H2S in AKI are described with special emphasis on epigenetic regulation and matrix remodeling.

94 Associative effects of two potent anti-methanogenic Moringa oleifera accessions mixed at various proportions on in vitro rumen fermentation and methane inhibition

Abstract Moringa is an important anti-methanogenic plant with a potential to develop as multipurpose feed additives. Previous studies identified two potent accessions (accession 07633 designated as A3 and accession collected from Pretoria designated as A11) with high methane (CH4) inhibition characteristics. Two metabolite ion features (MIFs) 4.44_609.1462 and MIF 4.53_433.1112 were identified as bioactive MIFs associated with greater methane inhibition in Moringa accession A3 and A11, respectively. Two separate studies were conducted with an aim to name the MIF associated with methane inhibition and evaluate the benefit of mixing plant extract from A3 and A11 in different proportions to exploit their additive or synergistic effect in inhibiting CH4 emission. In study 1, software and online tools such as MS-DIAl, MS-FINDER, and the mass bank database were used to identify the MIF 4.44_609.1462 and MIF 4.53_433.1112, and the two MIFs were tentatively named as Hesperidin and Isovitexin, respectively (Figure 1). In study 2, the Moringa plant extracts from A3 and A11 were mixed in the following proportion A3100:A110, A380:A1120, A360:A1140, A350:A1150, A340:A1160, A320:A1180, and A30:A11100 proportions (A3:A11), and applied at a rate 50 mg/kg DM of Eragrostis curvula hay incubated in an Incoshake incubator to determine their effect on in vitro gas production and CH4, and in vitro organic matter digestibility (IVOMD) of the hay. In each incubation run, the sole or a mixture of the Moringa plant extract treatments were added to the test feed and incubated in 125 mL serum bottles with four replications per treatment, and the incubation was repeated for three runs. A Chi–square (☐2) test were used to determine the presence of an associative effect for mixtures combined at different proportion. Generally, the mixture resulted in less (P &amp;lt; 0.05) CH4 volume, slightly improved or no effect on IVOMD, propionate concentration decreased acetate while increasing propionate concentration, with higher CH4 inhibition, and % CH4 inhibition was significantly greater when the two accessions were mixed in 50% proportion (Figure 2). Specifically, associative effects were recorded when the two accessions are mixed in 50% proportion in terms of greater CH4 inhibition, propionic acid concentration and total volatile fatty acid production (TVFA), as well as reduction in CH4 per unit TVFA and C2:C3 ratio (Table 1). Therefore a 50% binary cocktail of M. oleifera accession A3 and A11 (A350:A1150) plant extracts can be used as feed additive for CH4 inhibition without affecting the feed fermentation adversely when compared with the sole accession leaf extracts or other proportions of binary cocktails. Detailed mechanisms of action, however, need to be confirmed.

Effects of zinc in podocytes and cortical collecting duct in vitro and Dahl salt-sensitive rats in vivo

Zinc is one of the essential divalent cations in the human body and a fundamental microelement involved in the regulation of many cellular and subcellular functions. Experimental studies reported that zinc deficiency is associated with renal damage and could increase blood pressure. It was proposed that zinc dietary supplementation plays a renoprotective role. Our study aimed to investigate the effects of zinc on intracellular signaling in renal cells and explore the correlation between dietary zinc and the progression of salt-induced hypertension. The impact of extracellular zinc concentrations on two different kidney epithelial cell types - podocytes and principal cells of the cortical collecting duct (CCD), was tested. In podocytes, a rise in extracellular zinc promotes TRPC6 channel-mediated calcium entry but not altered intracellular zinc levels. However, we observe the opposite effect in CCD cells with no alteration in calcium levels and steady-state elevation in intracellular zinc. Moreover, prolonged extracellular zinc exposure leads to cytotoxic insults in CCD cells but not in podocytes, characterized by increased cell death and disrupted cytoskeletal organization. Next, we tested if dietary zinc plays a role in the development of hypertension in Dahl salt-sensitive rats. Neither zinc-rich nor deficient diets impact the regular development of salt-sensitive hypertension. These results suggest specialized roles for zinc in renal function, implicating its involvement in proliferation and apoptosis in CCD cells and calcium signaling and cytoskeletal dynamics modulation in podocytes. Further research is required to elucidate the detailed mechanisms of zinc action and its implications in renal health and disease.