Search Results (523)

Since the first paper published by Susan Cole in 1990 detailing multidrug resistance mediated by ABCC1/MRP1, research into the C-subfamily of ATP-binding cassette transporters has continued to uncover a wide range of functionally divergent proteins. However, several orphan transporters remain in the C-subfamily, and the physiological function and substrates of ABCC5, ABCC11, and ABCC12 remain elusive. This review explores the emerging understanding of human ABCC5. Unlike other ABC transporters with well-defined drug export functions, ABCC5’s physiological roles remain only partially understood. While it is known for its involvement in multidrug resistance in cancers, recent studies suggest broader implications in development, metabolism, neurobiology, and male fertility. ABCC5 exports various endogenous substrates, including cyclic nucleotides (cAMP and cGMP), glutamate conjugates like NAAG, and possibly haem. Knockout models in mice, zebrafish, and sea urchins reveal ABCC5’s role in gut formation, brain function, eye development, and iron metabolism. In mice, its deletion results in lower adipose tissue mass, enhanced insulin sensitivity, and neurobehavioral changes resembling schizophrenia, highlighting its role in glutamatergic signalling and circadian regulation. Functionally, ABCC5 appears to impact adipocyte differentiation and GLP-1 release, implicating it in type 2 diabetes susceptibility in humans. Structural studies using human ABCC5 revealed a novel autoinhibitory mechanism involving a peptide segment (C46–S64) that blocks substrate binding, offering new potential for selective inhibitor development. However, this review emphasises caution in targeting ABCC5 for cancer therapy due to its underappreciated physiological function(s), particularly in the brain and male reproductive system. Understanding ABCC5’s substrate specificity, regulatory mechanisms, and functional redundancy with its paralog ABCC12 remains critical for successful therapeutic strategies in humans. Full article

Background/Objectives: Diabetic retinopathy is a leading cause of blindness in diabetic patients, with disease susceptibility influenced by both genetic and environmental factors. This study aimed to identify novel genetic variants associated with DR and evaluate interactions between polygenic risk scores (PRS) and lifestyle factors in a Korean diabetic cohort. Methods: After excluding subjects with non-diabetic retinopathy eye diseases (n = 2519), we analyzed data from 50,361 non-diabetic controls, 4873 diabetic participants without retinopathy (DM-NR), and 165 with diabetic retinopathy (DM-DR). We conducted genome-wide association studies comparing DM-NR and DM-DR groups, performed generalized multifactor dimensionality reduction (GMDR) analysis for epistatic interactions, developed unweighted PRS models, and examined PRS–lifestyle interactions using two-way analysis of covariance. Results: DM-DR prevalence showed strong associations with metabolic syndrome and its components. Five novel genetic variants were identified: ABCA4_rs17110929, MMP2-AS1_rs2576531, FOXP1_rs557869288, MRPS33_rs1533933, and DRD2_rs4936270. A significant three-way epistatic interaction among the first three variants was discovered through GMDR analysis. High-PRS individuals (scores 5–6) showed a 49-fold higher odds ratio of DM-DR compared to low-PRS individuals (scores 0–2; p < 0.0001). MAGMA analysis revealed enrichment in pathways related to protein degradation, vascular function, and neuronal signaling, with predominant upregulation in brain tissues. Significant PRS × lifestyle interactions were identified for fruit intake, coffee consumption, alcohol intake, eating duration, and physical activity, with lifestyle factors modifying genetic risk effects (all p < 0.003). Conclusions: These findings identify novel genetic variants and epistatic interactions in DM-DR pathogenesis, supporting the use of PRS-based risk stratification for intensive monitoring and personalized lifestyle interventions. The discovery of brain tissue-enriched pathways suggests DM-DR shares mechanisms with neurodegenerative diseases, expanding therapeutic targets beyond traditional vascular approaches. Full article

Background: In the current context of increasing competitiveness and complexity in markets, accurate demand forecasting has become a key element for efficient production planning. Methods: This study implements recurrent neural networks (RNNs) to predict raw material demand using historical sales data, leveraging their ability to identify complex temporal patterns by analyzing 156 historical records. Results: The findings reveal that the RNN-based model significantly outperforms traditional methods in predictive accuracy when sufficient data is available. Conclusions: Although integration with MRP systems is not explored, the results demonstrate the potential of this deep learning approach to improve decision-making in production management, offering an innovative solution for increasingly dynamic and demanding industrial environments. Full article

Background and aim: Managing the therapy of patients with chronic liver diseases and comorbidities presents significant challenges for physicians and pharmacists, particularly regarding drug-induced liver damage and polypharmacy. Given the liver’s central role in drug detoxification, polypharmacy in liver disease requires special attention. The aim of the review was to assess the prevalence of polypharmacy among patients with chronic liver diseases. Approach and Results: A literature search focused on randomized controlled trials, database reviews, and medical records. Review of PubMed, SCOPUS, and ScienceDirect databases identified 2578 manuscripts, however only 11 studies met the inclusion criteria. The results of studies showed that the prevalence of polypharmacy among patients with chronic liver disease can exceed 50%, and can lead to high prevalence of MRP and pDDI among those patients. Conclusions: Findings reveal a critical link between polypharmacy and adverse outcomes in chronic liver diseases, including cirrhosis, hepatitis, and non-alcoholic fatty liver disease. Individualized treatment plans, considering factors such as age, gender, comorbidities, and liver disease severity are essential. The interventions focused on mitigating MRP and reducing pDDI need to be implemented in order to reduce the potential harm of polypharmacy. Full article

Half of all Canadians will develop cancer at some point in their lifetimes. These rates have increased substantially over the last decade alongside increasing effectiveness and complexity of treatment options. Therefore, the need for patients to receive both an early diagnosis and ongoing care has never been so important. In Alberta, referrals to oncology specialty care have increased 18% in the last 7 years with no commensurate increase in the number of oncology health care professionals. Challenges with oncologic care access and provider recruitment are not unique to Alberta. In 2004, Cancer Care Alberta, specifically the Cross Cancer Institute (CCI), embarked on an initiative focusing on nurse practitioner (NP) care provision, aiming to address these gaps. The purpose of this article is a description of four distinct NP care models: the Assigned model, Consultative model, Partner model, and Most Responsible Provider (MRP model) significantly contributing to enhanced and expanded cancer care delivery at CCI. To the best of our knowledge, we are the first to demonstrate how NPs can significantly address the rapidly expanding demands for specialist oncology care. This work highlights roles and exemplars of NP care to meet the evolving needs of cancer patients, the multidisciplinary care team and the health system. Full article

This study investigated associations between substitutions and match running performance (MRP) under the new five-substitution rule, utilising running data from the 2022 FIFA World Cup involving all 32 participating men’s national teams, comprising elite professional football players at the highest international competitive level. A paired sample t-test compared running performance among entire match players (EMP), replaced players (RP), and substitute players (SP) per team per match. A linear mixed model (LMM) was used to analyse the association between substitutions and MRP while also considering match-related factors associated with MRP as covariates and controlling for team variations. The main finding was that substitute players exhibit superior running performance compared to RP and EMP. Running metrics related to match outcomes indicate that more substitutions are associated with increases in total running distance and the number of sprints. This study highlights the importance of substitutions on team running performance under the new rules in modern elite football. Coaches can optimise their substitution strategies and physical training according to the new rules to meet the high-intensity demands of the game. Full article

Microbial communities, as critical functional components of riverine ecosystems, play a pivotal role in biogeochemical cycles and water quality regulation. The South-to-North Water Diversion Middle Route Project (SNWD-MRP) is a major cross-basin water transfer initiative, and bacteria are essential for the stability of water quality in the project. This study employed environmental DNA (eDNA) metabarcoding targeting the 16S rRNA gene to investigate spatiotemporal variations in water quality and bacterial communities along the SNWD-MRP during summer and winter. Integrated analyses, including redundancy analysis (RDA), Mantel tests, and ecological network modeling, were applied to unravel the driving mechanisms of microbial succession. The water quality along the SNWD-MRP is generally classified as Grade I, with significant seasonal variations in water quality parameters and microbial community composition. In the summer, higher temperatures lead to an increased abundance of cyanobacteria. In contrast, during the winter, lower water temperatures and higher dissolved oxygen levels result in the dominance of Pseudomonas and Bacillota species. RDA identified the permanganate index as the primary driver of microbial composition across seasons, with total phosphorus and total nitrogen having a greater influence in winter. Mantel tests highlighted significant correlations between Cyanobacteria and total phosphorus during winter. Ecological network analysis revealed that the complexity and connectivity of the winter network increased, likely due to suitable nutrient levels rendering the microbial network more complex and stable. These findings underscore the synergistic effects of temperature and nutrient availability on microbial succession, providing actionable insights for optimizing water quality management and ecological stability in large-scale water diversion systems. Full article

The Maillard reaction (MR), a non-enzymatic interaction between reducing sugars and amino compounds, plays a pivotal role in developing the flavor, color, and aroma of thermally processed foods. Beyond its culinary relevance, the MR gives rise to a structurally diverse array of compounds, including a novel class of fluorescent nanomaterials known as carbon nanodots (CNDs). These Maillard-derived CNDs, although primarily incidental in food systems, exhibit physicochemical characteristics—such as aqueous solubility, biocompatibility, and tunable fluorescence—that are similar to engineered CNDs currently explored in biomedical fields. While CNDs synthesized through hydrothermal or pyrolytic methods are well-documented for drug delivery and imaging applications, no studies to date have demonstrated the use of Maillard-derived CNDs specifically in drug delivery. This review examines the chemistry of the Maillard reaction, the formation mechanisms and characteristics of food-based CNDs, and their potential functional applications in food safety, bioactivity, and future biomedical use. Additionally, it critically evaluates the health implications of Maillard reaction products (MRPs), including both beneficial antioxidants and harmful by-products such as advanced glycation end-products (AGEs). This integrated perspective highlights the dual role of MR in food quality and human health, while identifying key research gaps needed to harness the full potential of food-origin nanomaterials. Full article

Broth cooking is a traditional pretreatment and ripening strategy for high-commercial-value dehydrated marine food, effectively enhancing its texture and rehydration properties. In this work, we characterized the structural information of Maillard reaction products (MRPs) derived from beef scrap stock and investigated their effects on the texture and rehydration performance of dehydrated abalone. The optical and structural properties of the MRPs were analyzed using X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), transmission electron microscopy (TEM), and fluorescence spectroscopy. These MRPs showed osmosis in abalone processing including pretreatment and drying. Low-field nuclear magnetic resonance (LF-NMR) results revealed that MRP pretreatment improved the moisture migration and physicochemical properties of dehydrated abalone. These findings suggest that MRPs, owing to their high osmotic efficiency and nanoscale size, could serve as promising food additives and potential alternatives to traditional penetrating agents in the food industry, enhancing the rehydration performance of dried seafood and reducing quality deterioration. Full article

This research addresses the challenges of proactive scheduling and routing in manufacturing systems governed by the Material Requirement Planning (MRP) method. Such systems often face capacity constraints, difficulties in resource balancing, and limited traceability of component requirements. The lack of seamless integration between customer orders and production tasks, combined with the manual and time-consuming nature of schedule adjustments, highlights the need for an automated and optimized scheduling method. We propose a novel optimization-based approach that leverages mixed-integer linear programming (MILP) combined with a proprietary procedure for reducing the size of the modeled problem to generate feasible and/or optimal production schedules. The model incorporates dynamic routing, partial resource utilization, limited additional resources (e.g., tools, workers), technological breaks, and time quantization. Key results include determining order feasibility, identifying unfulfilled order components, minimizing costs, shortening deadlines, and assessing feasibility in the absence of available resources. By automating the generation of data from MRP/ERP systems, constructing an optimization model, and exporting the results back to the MRP/ERP structure, this method improves decision-making and competes with expensive Advanced Planning and Scheduling (APS) systems. The proposed innovation solution—the integration of MILP-based optimization with the proprietary PT (data transformation) and PR (model-size reduction) procedures—not only increases operational efficiency but also enables demand source tracking and offers a scalable and economical alternative for modern production environments. Experimental results demonstrate significant reductions in production costs (up to 25%) and lead times (more than 50%). Full article

Background/Objectives: Among Enterobacterales, OXA-48-like-producing Proteus mirabilis strains have been scarcely detected. Herein, we characterized a bla_OXA-48-harbouring P. mirabilis strain recovered from Greece (Pm GR-1), while phylogenomics and comparative genomics analyses with previously published bla_OXA-48 carriers were also assessed. Methods: Characterization of Pm GR-1 was performed by the Vitek^® Compact and Mass Spectrometry systems, antimicrobial susceptibility testing, detection of beta-lactamases, multilocus-sequence typing (MLST), and whole-genome sequencing (WGS). In silico prediction of mobile genetic elements (MGEs), genomic islands (GIs), antimicrobial resistance genes (ARGs) and virulence factors (VFs), and phylogenetic, core-genome SNP and comparative genomics analyses were executed using bioinformatic tools. Results: Pm GR-1 was isolated from a urine sample of an outpatient in a Greek hospital. It exhibited a multidrug-resistant phenotype, being susceptible only to amikacin and ceftazidime/avibactam. It co-carried several beta-lactamase genes on the chromosome (bla_OXA-48, bla_CTX-M-14, bla_TEM-1) and a plasmid (bla_TEM-2) and several other ARGs, but also mutations associated with quinolone resistance in the DNA gyrase and topoisomerase IV subunits. It belonged to the international clone ST135 that has also been detected among OXA-48-producing P. mirabilis strains from Germany and the USA. Pm GR-1 was genetically related to those from Germany, sharing highly similar MGEs, GIs, ARGs and VFs, including the chromosomal bla_OXA-48 genetic structure, the O-antigen locus, the flagella locus, the MR/P fimbriae operon, and the urease gene cluster. Conclusions: To our knowledge, this is the first report from Greece of a bla_OXA-48-possessing P. mirabilis strain. The emergence of bla_OXA-48 among P. mirabilis strains of the international clone ST135 in different geographical regions is worrying. Close monitoring of these strains is required in One Health settings. Full article

The pharmacological treatment of cholangiocarcinoma (CCA) is often hampered by tumor resistance. Improving our understanding of this issue is crucial for developing strategies that can overcome drug refractoriness. We have established and characterized two novel human cell sublines derived from extrahepatic CCA EGI-1 cells that are resistant to cisplatin and 5-fluorouracil (5-FU). Migration and proliferation were analyzed using holographic microscopy. The expression of genes involved in drug uptake and efflux was determined by RT-qPCR. Cross-resistance to commonly used antitumor drugs was assayed using the MTT test. EGI-1 sublines resistant to cisplatin (CR) or 5-FU (FR) exhibited more than a three-fold increase in resistance to cisplatin and 5-FU, respectively, and showed reduced proliferation, migration, and colony-formation rates, along with an altered cell cycle compared to wild-type cells, while retaining tumorigenic capacity. The analysis of the transportome showed downregulation of uptake transporters and upregulation of the export pumps MRP3/4. EGI-1 cells with acquired resistance to 5-FU demonstrated cross-resistance to irinotecan and gemcitabine, while cisplatin-resistant cells showed decreased sensitivity to 5-FU and platinum derivatives. These resistant cell lines offer valuable models for investigating the molecular basis of chemoresistance in CCA, providing a robust platform for the development and evaluation of novel therapeutic strategies. Full article

Objectives: To investigate whether a Multimodal Rehabilitation Program (MRP) affects the change in visual–spatial abilities, especially attention, information-processing speed, visual–spatial learning, the severity of depression, and strategies for coping with pain in Complex Regional Pain Syndrome (CRPS) participants. Methods: The study was conducted between October 2021 and February 2023, with a 4-week rehabilitation program that included individual physiotherapy, manual and physical therapy, and psychological intervention such as psychoeducation, relaxation, and Graded Motor Imagery therapy. Twenty participants with CRPS and twenty healthy participants, forming a control group, were enlisted. The study was a 2-arm parallel: a CRPS group with MRP intervention and a healthy control group matched to the CRPS group according to demographic variables. Before and after, the MRP participants in the CRPS group were assessed for visual–spatial learning, attention abilities, severity of depression, and pain-coping strategy. The healthy control group underwent the same assessment without intervention before two measurements. The primary outcome measure was Reproduction on Rey–Osterrieth’s Complex Figure Test assessing visual–spatial learning. Results: In the post-test compared to the pre-test, the participants with CRPS obtained a significantly high score in visual–spatial learning (p < 0.01) and visual information-processing speed (p = 0.01). They made significantly fewer omission mistakes in visual working memory (p = 0.01). After the MRP compared to the pre-test, the CRPS participants indicated a decrease in the severity of depression (p = 0.04) and used a task-oriented strategy for coping with pain more often than before the rehabilitation program (p = 0.02). Conclusions: After a 4-week MRP, the following outcomes were obtained: an increase in visual–spatial learning, visual information-processing speed, a decrease in severity of depression, and a change in the pain-coping strategies—which became more adaptive. Full article

Breast cancer is the most frequently diagnosed cancer among women. In recent years, immunotherapy, a key targeted treatment strategy, has gained prominence in the management of this disease. Immune cells within the tumor microenvironment can significantly affect treatment outcomes. Among immunotherapeutic approaches, or programmed death protein 1(PD-1) and programmed death-ligand 1(PD-L1)-targeted therapies are increasingly recognized for their role in modulating cancer–immune system interactions. This study investigated the impact of PD-1/PD-L1 pathway inhibition on the expression of drug resistance-related proteins in an in vitro breast cancer model incorporating immune cells. MDA-MB-231 and MCF-7 cell lines were used as breast cancer cells, while THP-1 and Jurkat cells represented monocytes and lymphocytes, respectively. The effects of paclitaxel (PTX), doxorubicin (Dox), and PD-1/PD-L1 inhibitors (BMS-1166 and Human PD-L1 Inhibitor IV (PI4)) on cell viability were evaluated using an MTT assay, and the IC₅₀ values were determined. Flow cytometry was used to analyze PD-1/PD-L1 expression and the drug resistance proteins ABCG2 (ATP-binding cassette sub-family G member 2, breast cancer resistance protein), MDR-1 (multidrug resistance protein 1), and MRP-1 (multidrug resistance-associated protein 1) across co-culture models. Based on the results, Dox reduced PD-L1 expression in all groups except for MDA-MB-231:THP-1, while generally lowering drug resistance protein levels, except in MDA-MB-231:Jurkat. BMS-1166 significantly decreased cell viability and enhanced chemotherapy-induced cytotoxicity. Interestingly, in the MDA-MB-231:Jurkat co-culture, both inhibitors reduced PD-L1 but increased drug resistance protein expression. Paclitaxel’s effect on PD-L1 varied depending on the immune context. These findings highlight that PD-1/PD-L1 inhibitors and chemotherapeutic agents differentially affect PD-L1 and drug resistance-related protein expression depending on the immune cell composition within the tumor microenvironment. Full article

Sustainable manufacturing is gaining attention in the scientific literature. However, it remains unclear how to effectively incorporate it within Production Planning and Control (PPC) tasks. All the choices taken in terms of PPC impact sustainability, and sustainability managers and planners or managers involved in tasks, such as scheduling or inventory management, are not conscious of what this means or implies, above all, in terms of the sustainable performance indicators on which their actions can act. While several studies have addressed both PPC and sustainability, there is still limited guidance or structured frameworks specifically aimed at systematically linking PPC tasks with sustainability indicators in a practical and operational industrial context, despite the development of numerous sustainability standards in recent years. For this reason, this research aimed to develop a first detailed framework, specifically based on the Global Reporting Initiative (GRI) standard, that associates the most relevant indicators with the PPC phases, highlighting the type of impact (direct or indirect) of each phase on them. This could help with strategic decisions and promote more informed choices. The overall framework revealed the prevalence of environmental aspects involved in PPC phases (as expected) and a challenge related to the measurability of indicators (above all, the social ones). Furthermore, the Material Requirements Planning (MRP), identified as the most significant phase in terms of its impact on sustainability, was deeply analyzed, providing details related to the decision-making processes of this phase that affect sustainable performance. Full article