Search Results (255)

In response to recent regulatory guidelines, including ICH (International Council for Harmonisation) Q2 (R2) and Q14, we developed a UPLC-ELSD method to quantify Medium-Chain Triglycerides (MCTs) in Labrafac™ WL 1349 for nanoemulsion applications. This procedure, crafted using Analytical Quality by Design (AQbD) principles, addresses not only the validation of the methodology but also the lifecycle management challenges associated with the analysis of lipid-based excipients. Key parameters such as mobile phase composition, organic modifier, column type, flow rate, diluent, and column temperature were optimized to meet regulatory standards and ensure robustness in MCT quantification. Optimal conditions were achieved with a Waters Acquity HSS T3 (100 × 2.1 mm i.d., 1.8 μm) column at 33 °C, using a mixture of methanol (97.5%) and water (2.5%) containing 0.4% of formic acid at a flow rate of 0.41 mL/min. The method demonstrated an excellent fit on a cubic modelization for MCTs over a broad range of concentrations. Forced degradation studies, including hydrolytic (acidic and basic), oxidative, and thermal stress, confirmed the method’s suitability for possible stability scenarios. This validated UPLC method was successfully applied to quantitative analyses of bulk and formulation prototype samples containing MCTs. This AQbD-driven method enhances not only knowledge but also regulatory-compliant and cost-effective excipient control. Full article

Background: Therapeutic strategies for methicillin-resistant Staphylococcus aureus (MRSA) are increasingly limited due to the ability of the pathogen to evade conventional treatments such as vancomycin and daptomycin. This challenge has shifted the focus towards novel strategies, including the resensitization of β-lactams, which are still used as first-line treatments for methicillin-susceptible Staphylococcus aureus (MSSA). To achieve this, it is essential to identify the secondary resistome associated with the clinically relevant β-lactam antibiotics. Methods: Transposon-Directed Insertion Site Sequencing (TraDIS) was employed to assess conditional essentiality by analyzing the depletion of mutants from a highly saturated transposon library of MRSA USA300 JE2 exposed to ½ minimal inhibitory concentration (MIC) of oxacillin or cefazolin. Results: TraDIS analysis led to the identification of 52 shared fitness genes involved in β-lactam resistance that are primarily linked to cell wall metabolism and regulatory systems. Among these, both known resistance factors and novel conditionally essential genes were highlighted. As proof of concept, transposon mutants corresponding to nine genes (sagB, SAUSA300_0657, SAUSA300_0957, SAUSA300_1683, SAUSA300_1964, SAUSA300_1966, SAUSA300_1967, SAUSA300_1692, and mazF) were grown in the presence of β-lactam antibiotics and their MICs were determined. All mutants showed significantly reduced resistance to β-lactam antibiotics. Conclusions: This comprehensive genome-wide investigation provides novel insights into the resistance mechanisms of β-lactam antibiotics, and suggests potential therapeutic targets for combination therapies with helper drugs. Full article

The region of the Arab Gulf is marching ahead very fast toward digitalization in ways prompted by initiatives, such as Saudi Vision 2030 and the UAE’s strategy for Smart Government. Thus, both underscore the boundless movement toward the inclusion of advanced technologies into accounting practices, such as Business Intelligence and Enterprise Resource Planning systems. While these technologies enhance efficiency and facilitate informed decision-making, they also render financial data vulnerable to cybersecurity threats, such as phishing, ransomware, and insider attacks. This paper investigates the impact of cybersecurity practices, ethical accountability, regulatory frameworks, and emerging technologies on the adoption of and trust in digital accounting systems in the GCC region. A quantitative research approach was followed, wherein the responses from a randomly selected sample of 324 professionals representing the GCC nations were collected. The empirical analysis was completed using Partial Least Squares Structural Equation Modeling. Strong cybersecurity measures, AI-driven threat detection mechanisms, and custom-fit employee training programs facilitate the adoption of and faith in digital accounting information systems considerably. Ethical accountability acts as the partial mediator of those effects, and supportive regulatory frameworks enhance cybersecurity strategy effectiveness. This study examines the development of integrated cybersecurity strategies with respect to technology, ethics, and regulations. It makes several major recommendations, calling for bringing the GCC countries’ regulatory frameworks into line with international standards; encouraging workforce training programs; and utilizing AI-powered technologies for proactive threat detection and management. These findings can arm stakeholders with a holistic pathway toward developing secure, resilient, and future-oriented digital accounting infrastructures across the region. Full article

The European Union aims for climate neutrality by 2050 and has proposed the Packaging and Packing Waste Regulation (PPWR) to promote a circular economy, focusing on reducing packaging waste. In this context, a comprehensive sustainability assessment for liquid dairy product packaging, including beverage cartons, bottles and to-go cups, in the DACH region (Germany, Austria and Switzerland) was conducted. The aim was to consider various ecological aspects of environmental impacts and circularity. As the aspect of recyclability is a core aspect in the PPWR, the calculation was of central interest in this project. Here, major differences in the waste management infrastructure between countries could be identified. The majority of assessed packaging falls below the PPWR’s 70% recyclability requirement, with Switzerland showing even lower recyclability due to poor packaging collection and recycling infrastructure. Significant discrepancies in packaging efficiency exist, indicating unnecessary resource consumption, especially in the case of to-go cups. Additionally, the carbon footprint of packaging materials can vary up to ten times within certain product categories, negatively impacting the environment. Good results were identified for the use of certified renewable resources. Overall, the results of the assessment demonstrate several areas for improvement in light of forthcoming regulatory requirements, which must be met in Germany and Austria. Full article

Over the past century, numerous methods for assessing cell viability have been developed, and there are many different ways to categorize these methods accordingly. We have chosen to use the Organisation for Economic Co-operation and Development (OECD) classification due to its regulatory importance. The OECD categorizes these methods into four groups: non-invasive cell structure damage, invasive cell structure damage, cell growth, and cellular metabolism. Despite the variety of cell viability methods available, they can all be categorized within these four groups, except for two novel methods based on the cell membrane potential, which we added to the list. Each method operates on different principles and has its own advantages and disadvantages, making it essential for researchers to choose the method that best fits their experimental design. This review aims to assist researchers in making this decision by describing these methods regarding their potential use and providing direct references to the cell viability assessment methods. Additionally, we use the OECD classification to facilitate potential regulatory use and to highlight the need for adding a new category to their list. Full article

The Paris Agreement emphasizes the need to reduce greenhouse gas emissions, particularly from coal power. One suggested approach is repowering coal-fired power plants (CPPs) with small modular reactors (SMRs). South Korea plans to retire CPPs in the coming decades and requires alternative options for coal-fired energy. This study presents a scoping analysis comparing variable renewable energy (VRE) sources with SMRs for repowering CPPs in the Korean context. The analysis indicates that SMRs may be a more favorable option than VRE sources, particularly due to their load-following capabilities. In this study, two types of SMRs were investigated: high-temperature gas reactors (HTGRs) and pressurized water reactors (PWRs). HTGRs are suitable to fit the high-temperature operating conditions of steam turbines but require multiple units due to their low volumetric flow rates. PWRs, while matching the volumetric flow rate of existing CPP turbines, require additional thermal energy sources to meet the high-temperature operating conditions of steam turbines. Lastly, an analysis of necessary regulatory and legislative changes in South Korea’s nuclear framework is presented, identifying several key regulatory issues for repowering coal with nuclear energy. Full article

Background: Heart failure (HF) management increasingly relies on innovative solutions to enhance monitoring and care. Wearable devices, originally popularized for fitness tracking, show promise in clinical decision-making for HF. This study explores the application and potential for the broader integration of wearable technology in HF management, emphasizing remote monitoring and personalized care. Methods: A comprehensive literature review was performed to assess the role of wearables in HF management, focusing on functionalities like vital sign tracking, patient engagement, and clinical decision support. Clinical outcomes and barriers to adopting wearable technology in HF care were critically analyzed. Results: Wearable devices increasingly track physiological parameters relevant to HF, such as heart rate, physical activity, and sleep. They can identify at-risk patients, promote lifestyle changes, facilitate early diagnosis, and accurately detect arrhythmias that lead to decompensation. Additionally, wearables may assess fluid status, identifying early signs of decompensation to prevent hospitalization and supporting therapeutic adjustments. They also enhance physical activity and optimize cardiac rehabilitation programs, improving patient outcomes. Both wearable and implanted cardiac devices enable continuous, non-invasive monitoring through small devices. However, challenges like data integration, regulatory approval, and reimbursement impede their widespread adoption. Conclusions: Wearable technology can transform HF management through continuous monitoring and early interventions. Collaboration among involved parties is essential to overcome integration challenges and validate most of these devices in clinical practice. Full article

Flowering is initiated in response to environmental cues, with the photoperiod and ambient temperature being the main ones. The regulatory pathways underlying floral transition are well studied in Arabidopsis thaliana but remain largely unknown in legumes. Here, we first applied an in silico approach to infer the regulatory inputs of four FT-like genes of the narrow-leafed lupin Lupinus angustifolius. We studied the roles of FTc1, FTc2, FTa1, and FTa2 in the activation of meristem identity gene AGL8 in response to 8 h and 16 h photoperiods, vernalization, and the circadian rhythm. We developed a set of regression models of AGL8 regulation by the FT-like genes and fitted these models to the recently published gene expression data. The importance of the input from each FT-like gene or their combinations was estimated by comparing the performance of models with one or few FT-like genes turned off, thereby simulating loss-of-function mutations that were yet unavailable in L. angustifolius. Our results suggested that in the early flowering Ku line and intermediate Pal line, the FTc1 gene played a major role in floral transition; however, it acted through different mechanisms under short and long days. Turning off the regulatory input of FTc1 resulted in substantial changes in AGL8 expression associated with vernalization sensitivity and the circadian rhythm. In the wild ku line, we found that both FTc1 and FTa1 genes had an essential role under long days, which was associated with the vernalization response. These results could be applied both for setting up new experiments and for data analysis using the proposed modeling approach. Full article

Leaf senescence, the final stage of leaf development, is crucial for plant fitness as it enhances nutrient reutilization, supporting reproductive success and overall plant adaptation. Understanding its molecular and genetic regulation is essential to improve crop resilience and productivity, particularly in the face of global climate change. This review explores the significant contributions of natural genetic diversity to our understanding of leaf senescence, focusing on insights from model plants and major crops. We discuss the physiological and adaptive significance of senescence in plant development, environmental adaptation, and agricultural productivity. The review emphasizes the importance of natural genetic variation, including studies on natural accessions, landraces, cultivars, and artificial recombinant lines to unravel the genetic basis of senescence. Various approaches, from quantitative trait loci mapping to genome-wide association analysis and in planta functional analysis, have advanced our knowledge of senescence regulation. Current studies focusing on key regulatory genes and pathways underlying natural senescence, identified from natural or recombinant accession and cultivar populations, are highlighted. We also address the adaptive implications of abiotic and biotic stress factors triggering senescence and the genetic mechanisms underlying these responses. Finally, we discuss the challenges in translating these genetic insights into crop improvement. We propose future research directions, such as expanding studies on under-researched crops, investigating multiple stress combinations, and utilizing advanced technologies, including multiomics and gene editing, to harness natural genetic diversity for crop resilience. Full article

A robust analytical method was developed for the simultaneous detection of 504 pesticide multiresidues in various crops using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-QTOF). The method integrates both MS¹ and MS² levels through sequential window acquisition of all theoretical mass spectra (SWATH) analysis, allowing for accurate mass measurements and the construction of a spectral library to enhance pesticide residue identification. An evaluation of the method was carried out according to international standards, including the FAO guidelines and SANTE/11312/2021. Validation across five representative crops—potato, cabbage, mandarin, brown rice, and soybean—demonstrated exceptional sensitivity, with over 80% of the analytes detected at trace levels (≤2.5 μg/kg). Moreover, an impressive 96.8% to 98.8% of the compounds demonstrated LOQs of ≤10 μg/kg. Most compounds exhibited excellent linearity (r² ≥ 0.980) and satisfactory recovery rates at spiking levels of 0.01 and 0.1 mg/kg. Among 42 crop samples analyzed, pesticides were detected in 1 cabbage, 3 mandarin, and 6 rice samples, with a mass accuracy within ±5 ppm and a Fit score ≥ 70.8, confirming the method’s practical applicability and reliability. The detected residues ranged from 12.3 to 339.3 μg/kg, all below the established maximum residue limits (MRLs). This comprehensive approach offers an efficient, reliable, and scalable solution for pesticide multiresidue monitoring, supporting food safety programs and regulatory compliance. Full article

Carbon catabolite repression (CCR) is a common transcriptional regulatory mechanism that microorganisms use to efficiently utilize carbon nutrients, which is critical for the fitness of microorganisms and for pathogenic species to cause infection. Here, we characterized two CCR genes, VdCreA and VdCreC, in Verticillium dahliae that cause cotton Verticillium wilt disease. The VdCreA and VdCreC knockout mutants displayed slow growth with decreased conidiation and microsclerotium production and reduced virulence to cotton, suggesting that VdCreA and VdCreC are involved in growth and pathogenicity in V. dahliae. We further generated 36 highly reliable and stable ΔVdCreA and ΔVdCreC libraries to comprehensively explore the dynamic expression of genes and metabolites when grown under different carbon sources and CCR conditions. Based on the weighted gene co-expression network analysis (WGCNA) and correlation networks, VdCreA is co-expressed with a multitude of downregulated genes. These gene networks span multiple functional pathways, among which seven genes, including PYCR (pyrroline-5-carboxylate reductase), are potential target genes of VdCreA. Different carbon source conditions triggered entirely distinct gene regulatory networks, yet they exhibited similar changes in metabolic pathways. Six genes, including 6-phosphogluconolactonase and 2-ODGH (2-oxoglutarate dehydrogenase E1), may serve as hub genes in this process. Both VdCreA and VdCreC could comprehensively influence the expression of plant cell wall-degrading enzyme (PCWDE) genes, suggesting that they have a role in pathogenicity in V. dahliae. The integrated expression profiles of the genes and metabolites involved in the glycolysis/gluconeogenesis and pentose phosphate pathways showed that the two major sugar metabolism-related pathways were completely changed, and GADP (glyceraldehyde-3-phosphate) may be a pivotal factor for CCR under different carbon sources. All these results provide a more comprehensive perspective for further analyzing the role of Cre in CCR. Full article

This paper compares various approaches to the scalability and replicability analysis (SRA) of smart grid pilot projects, highlighting the need for a comprehensive SRA methodology as called for by the European Commission and International Energy Agency. This study addresses the need for a standardized SRA methodology and explores how three EU-funded projects—Platone, EUniversal, and IElectrix—adapted the general guidelines developed by the BRIDGE initiative. These guidelines provide recommendations for developing a comprehensive large-scale deployment analysis. The results show that while the guidelines are usable and flexible, project-specific conditions and data availability limitations—particularly in regulatory and technical analysis—can pose challenges. Some key recommendations to overcome these and facilitate future applications are identified. These include defining SRA methodologies and securing data-sharing agreements early. The lack of standardized approaches for presenting SRA results hampers cross-project comparison. Thus, creating an open-use case repository and updating the BRIDGE guidelines with more detailed examples, benchmarks, and reference networks is recommended. Additionally, linking SRA with cost–benefit analysis (CBA) is suggested in order to evaluate the commercial viability of smart grid solutions. The paper concludes that while the BRIDGE guidelines have proven to be fit for purpose, further developments are needed to facilitate their practical application in real-world projects. Full article

The first-line management of cervical dystonia (CD) symptoms is intramuscular injection of botulinum toxin type A (BoNTA). However, a comparison of safety among BoNTAs is difficult because, per regulatory authorities, units of BoNTA activity are not interchangeable. Dysphagia and muscle weakness are widely considered two key adverse events to monitor closely in the treatment of CD. This integrated analysis compared the safety of BoNTAs approved for CD in the US by evaluating relationships between the incidence of dysphagia and muscle weakness in prescribing information and the core neurotoxin content. Coefficients The coefficients of determination (R²) and trendlines were estimated via regression-based lines of best fit. Adverse drug reaction (ADR) rates were strongly correlated with core neurotoxin amounts for conventional BoNTAs (slope coefficients: dysphagia = 0.048, R² = 0.74; muscle weakness = 0.096, R² = 0.82). The published ADR rates at approved doses for conventional BoNTAs were higher compared with DaxibotulinumtoxinA (DAXI; DAXXIFY^®, Revance Therapeutics, Inc., Nashville, TN, USA) by core neurotoxin content. The use of a core neurotoxin amount was found to be an effective method for comparing the safety of BoNTA products. Current clinical trials suggest that DAXI, a novel BoNTA formulation, provides a potentially wider safety margin compared with other approved BoNTAs for CD. The lower amount of core neurotoxin administered at approved doses compared with conventional BoNTAs may explain low on-target ADRs like muscle weakness, whereas reduced diffusion from the injection site is thought to be responsible for low off-target ADRs like dysphagia. Full article

In developing nations, such as Ekiti State, Nigeria, the utilization of remotely sensed data, particularly satellite and UAV imagery, remains significantly underexploited in land administration. This limits multi-resolution imagery’s potential in land governance and socio-economic development. This study examines factors influencing UAV adoption for land administration in Nigeria, mapping seven rural, peri-urban, and urban sites with orthomosaics (2.2 cm to 3.39 cm resolution). Boundaries were manually delineated, and parcel areas were calculated. Using the 0.05 m orthomosaic as a reference, the Horizontal Radial Root Mean Square Error (RMSEr) and Normalized Parcel Area Error (NPAE) were computed. Results showed a consistent increase in error with increasing resolution (0.1 m to 1 m), with RMSEr ranging from 0.053 m (formal peri-urban) to 2.572 m (informal rural settlement). Formal settlements with physical demarcations exhibited more consistent values. A comparison with GNSS data revealed that RMSEr values conformed to the American Society for Photogrammetry and Remote Sensing (ASPRS) Class II and III standards. The research demonstrates physical demarcations’ role in facilitating cadastral mapping, with formal settlements showing the highest suitability. This study recommends context-specific imagery resolution to enhance land governance. Key implications include promoting settlement typology awareness and addressing UAV regulatory challenges. NPAE values can serve as a metric for assessing imagery resolution fitness for cadastral mapping. Full article

Understanding the interplay between genotype and fitness is a core question in evolutionary biology. Here, we address this challenge in the context of microbial adaptation to environmental stressors. This study explores the role of epistasis in bacterial adaptation by examining genetic and phenotypic changes in silver-adapted Escherichia coli populations, focusing on the role of beneficial mutations in two-component response systems (TCRS). To do this, we measured 24-hour growth assays and conducted whole-genome DNA and RNA sequencing on E. coli mutants that confer resistance to ionic silver. We showed recently that the R15L cusS mutation is central to silver resistance, primarily through upregulation of the cus efflux system. However, here we show that this mutation’s effectiveness is significantly enhanced by epistatic interactions with additional mutations in regulatory genes such as ompR, rho, and fur. These interactions reconfigure global stress response networks, resulting in robust and varied resistance strategies across different populations. This study underscores the critical role of epistasis in bacterial adaptation, illustrating how interactions between multiple mutations and how genetic backgrounds shape the resistance phenotypes of E. coli populations. This work also allowed for refinement of our model describing the role TCRS genes play in bacterial adaptation by now emphasizing that adaptation to environmental stressors is a complex, context-dependent process, driven by the dynamic interplay between genetic and environmental factors. These findings have broader implications for understanding microbial evolution and developing strategies to combat antimicrobial resistance. Full article