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Journal of Cheminformatics Apr 2024In this paper we present a method that allows leveraging 3D electron density information to train a deep neural network pipeline to segment regions of high, medium and...
In this paper we present a method that allows leveraging 3D electron density information to train a deep neural network pipeline to segment regions of high, medium and low electronegativity and classify substances as health hazardous or non-hazardous. We show that this can be used for use-cases such as cosmetics and food products. For this purpose, we first generate 3D electron density cubes using semiempirical molecular calculations for a custom European Chemicals Agency (ECHA) subset consisting of substances labelled as hazardous and non-hazardous for cosmetic usage. Together with their 3-class electronegativity maps we train a modified 3D-UNet with electron density cubes to segment reactive sites in molecules and classify substances with an accuracy of 78.1%. We perform the same process on a custom food dataset (CompFood) consisting of hazardous and non-hazardous substances compiled from European Food Safety Authority (EFSA) OpenFoodTox, Food and Drug Administration (FDA) Generally Recognized as Safe (GRAS) and FooDB datasets to achieve a classification accuracy of 64.1%. Our results show that 3D electron densities and particularly masked electron densities, calculated by taking a product of original electron densities and regions of high and low electronegativity can be used to classify molecules for different use-cases and thus serve not only to guide safe-by-design product development but also aid in regulatory decisions. SCIENTIFIC CONTRIBUTION: We aim to contribute to the diverse 3D molecular representations used for training machine learning algorithms by showing that a deep learning network can be trained on 3D electron density representation of molecules. This approach has previously not been used to train machine learning models and it allows utilization of the true spatial domain of the molecule for prediction of properties such as their suitability for usage in cosmetics and food products and in future, to other molecular properties. The data and code used for training is accessible at https://github.com/s-singh-ivv/eDen-Substances .
PubMed: 38627862
DOI: 10.1186/s13321-024-00835-y -
BioRxiv : the Preprint Server For... Apr 2024Molecular details of genome packaging are little understood for the majority of viruses. In enteroviruses (EVs), cleavage of the structural protein VP0 into VP4 and VP2...
Molecular details of genome packaging are little understood for the majority of viruses. In enteroviruses (EVs), cleavage of the structural protein VP0 into VP4 and VP2 is initiated by the incorporation of RNA into the assembling virion and is essential for infectivity. We have applied a combination of bioinformatic, molecular and structural approaches to generate the first high-resolution structure of an intermediate in the assembly pathway, termed a provirion, which contains RNA and intact VP0. We have demonstrated an essential role of VP0 E096 in VP0 cleavage independent of RNA encapsidation and generated a new model of capsid maturation, supported by bioinformatic analysis. This provides a molecular basis for RNA-dependence, where RNA induces conformational changes required for VP0 maturation, but that RNA packaging itself is not sufficient to induce maturation. These data have implications for understanding production of infectious virions and potential relevance for future vaccine and antiviral drug design.
PubMed: 38617325
DOI: 10.1101/2024.04.06.588229 -
International Journal of Molecular... Mar 2024Antidepressant drugs play a crucial role in the treatment of mental health disorders, but their efficacy and safety can be compromised by drug degradation. Recent... (Review)
Review
Antidepressant drugs play a crucial role in the treatment of mental health disorders, but their efficacy and safety can be compromised by drug degradation. Recent reports point to several drugs found in concentrations ranging from the limit of detection (LOD) to hundreds of ng/L in wastewater plants around the globe; hence, antidepressants can be considered emerging pollutants with potential consequences for human health and wellbeing. Understanding and implementing effective degradation strategies are essential not only to ensure the stability and potency of these medications but also for their safe disposal in line with current environment remediation goals. This review provides an overview of degradation pathways for amitriptyline, a typical tricyclic antidepressant drug, by exploring chemical routes such as oxidation, hydrolysis, and photodegradation. Connex issues such as stability-enhancing approaches through formulation and packaging considerations, regulatory guidelines, and quality control measures are also briefly noted. Specific case studies of amitriptyline degradation pathways forecast the future perspectives and challenges in this field, helping researchers and pharmaceutical manufacturers to provide guidelines for the most effective degradation pathways employed for minimal environmental impact.
Topics: Humans; Amitriptyline; Antidepressive Agents, Tricyclic; Drug Packaging; Environmental Pollutants; Environmental Restoration and Remediation
PubMed: 38612638
DOI: 10.3390/ijms25073822 -
Veterinary Medicine (Auckland, N.Z.) 2024The intentional and illegal misrepresentation of fake medications involves falsely indicating their source. These fraudulent medications can include products that...
Evaluating the Knowledge, Practice, and Regulatory Situation of Veterinary Experts Regarding Counterfeit Veterinary Medications in the Selected Districts of Central Gondar Zone, Ethiopia.
BACKGROUND
The intentional and illegal misrepresentation of fake medications involves falsely indicating their source. These fraudulent medications can include products that contain either accurate or incorrect ingredients, lack proper labeling, have insufficient quantities of ingredients, and are packaged with counterfeit packaging. This unlawful activity has led to treatment failures, the development of antibiotic resistance, adverse effects, and even deaths. Hence, the objective of this study was to assess the knowledge, practice, and regulatory status of veterinary drug experts in the central Gondar zone of Ethiopia regarding counterfeit veterinary medications.
METHODS
From January 2023 to July 2023, a self-administered structured questionnaire was utilized to conduct a cross-sectional study in Central Gondar Zone, Ethiopia. The analysis of the data involved the application of descriptive and chi-square tests.
RESULTS
The study revealed that the majority of professionals possessed a work experience ranging from 5 to 9 years (23; 56.1%). Additionally, a total of 25 individuals (61.0%) who participated in the research had not undergone any kind of training. It was observed that a significant proportion of participants (82.9%) possessed knowledge about counterfeit veterinary drugs. Only about 63% and 36% of respondents had high knowledge and good practice concerning veterinary counterfeit drugs, respectively. Only 29.3% of participants have reported practices. Furthermore, a poor regulatory level of coordination was detected (85.4%). The study revealed a significant (χ2 =7.6165; p = 0.022) disparity between the respondents' practice levels and training. Respondents' regulatory levels were also significantly associated (p < 0.05) with their sex (χ2 = 13.34; p = 0.001) and work experience (χ2 = 13.64; p = 0.033). The research findings also revealed a noteworthy correlation between practice and regulatory activity (χ2 = 15.0463; p = 0.005).
CONCLUSION
The study outlines the necessity of awareness initiatives, with a focus on the significance of veterinary experts' knowledge, practice, and regulatory efforts in addressing the issue of counterfeit veterinary medications.
PubMed: 38595914
DOI: 10.2147/VMRR.S450560 -
Poultry Science Jun 2024The aim of this study was to investigate the antimicrobial effect of marination, natural antimicrobials, and packaging on the microbial population of chicken tawook...
The aim of this study was to investigate the antimicrobial effect of marination, natural antimicrobials, and packaging on the microbial population of chicken tawook during storage at 4°C. Chicken meat was cut into 10 g cubes and marinated. The chicken was then mixed individually with 0.5% or 1% (w/v) vanillin (VA), β-resorcylic acid (BR), or eugenol (EU), and stored under aerobic (AP) or vacuum (VP) packing at 4°C for 7 d. The marinade decreased microbial growth as monitored by total plate count, yeast and mold, lactic acid bacteria, and Pseudomonas spp. by about 1 log cfu/g under AP. The combination of marinade and antimicrobials under AP and VP decreased growth of spoilage-causing microorganisms by 1.5 to 4.8 and 2.3 to 4.6 log cfu/g, respectively. Change in pH in VP meat was less than 0.5 in all treated samples including the control. Marination decreased the lightness of the meat (L*) and significantly (p < 0.05) increased the redness (A*) and yellowness (B*). Overall acceptability was highest for marinated samples with 0.5% BR.
Topics: Animals; Chickens; Food Packaging; Meat; Microbiota; Anti-Infective Agents; Food Storage; Food Microbiology; Food Preservation
PubMed: 38593547
DOI: 10.1016/j.psj.2024.103687 -
Environmental Health Perspectives Apr 2024The European Food Safety Authority (EFSA) recommended lowering their estimated tolerable daily intake (TDI) for bisphenol A (BPA) 20,000-fold to . BPA is an extensively...
The Conflict between Regulatory Agencies over the 20,000-Fold Lowering of the Tolerable Daily Intake (TDI) for Bisphenol A (BPA) by the European Food Safety Authority (EFSA).
BACKGROUND
The European Food Safety Authority (EFSA) recommended lowering their estimated tolerable daily intake (TDI) for bisphenol A (BPA) 20,000-fold to . BPA is an extensively studied high production volume endocrine disrupting chemical (EDC) associated with a vast array of diseases. Prior risk assessments of BPA by EFSA as well as the US Food and Drug Administration (FDA) have relied on industry-funded studies conducted under good laboratory practice protocols (GLP) requiring guideline end points and detailed record keeping, while also claiming to examine (but rejecting) thousands of published findings by academic scientists. Guideline protocols initially formalized in the mid-twentieth century are still used by many regulatory agencies. EFSA used a 21st century approach in its reassessment of BPA and conducted a transparent, but time-limited, systematic review that included both guideline and academic research. The German Federal Institute for Risk Assessment (BfR) opposed EFSA's revision of the TDI for BPA.
OBJECTIVES
We identify the flaws in the assumptions that the German BfR, as well as the FDA, have used to justify maintaining the TDI for BPA at levels above what a vast amount of academic research shows to cause harm. We argue that regulatory agencies need to incorporate 21st century science into chemical hazard identifications using the CLARITY-BPA (Consortium Linking Academic and Regulatory Insights on BPA Toxicity) nonguideline academic studies in a collaborative government-academic program model.
DISCUSSION
We strongly endorse EFSA's revised TDI for BPA and support the European Commission's (EC) apparent acceptance of this updated BPA risk assessment. We discuss challenges to current chemical risk assessment assumptions about EDCs that need to be addressed by regulatory agencies to, in our opinion, become truly protective of public health. Addressing these challenges will hopefully result in BPA, and eventually other structurally similar bisphenols (called regrettable substitutions) for which there are known adverse effects, being eliminated from all food-related and many other uses in the EU and elsewhere. https://doi.org/10.1289/EHP13812.
Topics: Humans; Benzhydryl Compounds; Food Safety; No-Observed-Adverse-Effect Level; Phenols; Systematic Reviews as Topic
PubMed: 38592230
DOI: 10.1289/EHP13812 -
Journal of Pharmaceutical Sciences Jul 2024In the field of healthcare logistics, the reliance on conventional transport methods such as cars for the delivery of monoclonal antibodies (mAbs) is susceptible to...
In the field of healthcare logistics, the reliance on conventional transport methods such as cars for the delivery of monoclonal antibodies (mAbs) is susceptible to challenges posed by traffic and infrastructure, leading to increased and unpredictable transport times. Recognizing the potential role of drones in mitigating these challenges, we aimed to investigate the impact of medical drone transport on the stability of mAbs. Compromised stability could lead to aggregation and immunogenicity, thereby jeopardizing the efficacy and safety of mAbs. We studied the transportation of vials as well as ready-to-administer infusion bags with blinatumomab, tocilizumab, and daratumumab. The methodology involved the measurement of both temperature and mechanical shock during drone transport. Moreover, the analytical techniques High Performance Size-Exclusion Chromatography (HP-SEC), Dynamic Light Scattering (DLS), Light Obscuration (LO), Micro-Flow Imaging (MFI), and Nanoparticle Tracking Analysis (NTA) were employed to comprehensively assess the presence of aggregates and particle formation. The key findings revealed no significant differences between car and drone transport, indicating that the stability of mAbs in both vials and infusion bags was adequately maintained during drone transport. This suggests that medical drones are a viable and reliable means for the inter-hospital transport of mAbs, paving the way for more efficient and predictable logistics in healthcare delivery.
Topics: Antibodies, Monoclonal; Transportation; Drug Stability; Humans; Drug Packaging; Hospitals; Temperature
PubMed: 38582280
DOI: 10.1016/j.xphs.2024.04.002 -
Experimental & Molecular Medicine Apr 2024Extracellular vesicles (EVs), including exosomes, are increasingly recognized as potent mediators of intercellular communication due to their capacity to transport a... (Review)
Review
Extracellular vesicles (EVs), including exosomes, are increasingly recognized as potent mediators of intercellular communication due to their capacity to transport a diverse array of bioactive molecules. They assume vital roles in a wide range of physiological and pathological processes and hold significant promise as emerging disease biomarkers, therapeutic agents, and carriers for drug delivery. Exosomes encompass specific groups of membrane proteins, lipids, nucleic acids, cytosolic proteins, and other signaling molecules within their interior. These cargo molecules dictate targeting specificity and functional roles upon reaching recipient cells. Despite our growing understanding of the significance of exosomes in diverse biological processes, the molecular mechanisms governing the selective sorting and packaging of cargo within exosomes have not been fully elucidated. In this review, we summarize current insights into the molecular mechanisms that regulate the sorting of various molecules into exosomes, the resulting biological functions, and potential clinical applications, with a particular emphasis on their relevance in cancer and other diseases. A comprehensive understanding of the loading processes and mechanisms involved in exosome cargo sorting is essential for uncovering the physiological and pathological roles of exosomes, identifying therapeutic targets, and advancing the clinical development of exosome-based therapeutics.
Topics: Exosomes; Humans; Neoplasms; Animals; Cell Communication; Biological Transport
PubMed: 38580812
DOI: 10.1038/s12276-024-01209-y -
Scientific Reports Apr 2024Bisphenol-A (BPA) is widely used in food packaging and household products, leading to daily human exposure and potential health risks including metabolic diseases like...
Bisphenol-A (BPA) is widely used in food packaging and household products, leading to daily human exposure and potential health risks including metabolic diseases like type 2 diabetes mellitus (T2DM). Understanding BPA's mechanisms and developing intervention strategies is urgent. Centella asiatica, a traditional herbal medicine containing pentacyclic triterpenoids, shows promise due to its antioxidant and anti-inflammatory properties, utilized for centuries in Ayurvedic therapy. We investigated the effect of Centella asiatica (CA) ethanol extract on BPA-induced pancreatic islet toxicity in male Swiss albino mice. BPA administration (10 and 100 μg/kg body weight, twice daily) for 21 days caused glucose homeostasis disturbances, insulin resistance, and islet dysfunction, which were partially mitigated by CA supplementation (200 and 400 mg/kg body weight). Additionally, heightened oxidative stress, elevated levels of proinflammatory cytokines, loss of mitochondrial membrane potential (MMP), abnormal cell cycle, and increased apoptosis were implicated in the detrimental impact of BPA on the endocrine pancreas which were effectively counteracted by CA supplementation. In summary, CA demonstrated a significant ability to mitigate BPA-induced apoptosis, modulate redox homeostasis, alleviate inflammation, preserve MMP, and regulate the cell cycle. As a result, CA emerged as a potent agent in neutralizing the diabetogenic effects of BPA to a considerable extent.
Topics: Mice; Animals; Male; Humans; Diabetes Mellitus, Type 2; Centella; Islets of Langerhans; Antioxidants; Benzhydryl Compounds; Body Weight; Phenols
PubMed: 38580733
DOI: 10.1038/s41598-024-58545-2 -
Heliyon Apr 2024After harvesting, pathogens can infect fresh vegetables in different ways. Pathogenic bacteria associated with fresh vegetables can cause widespread epidemics associated...
After harvesting, pathogens can infect fresh vegetables in different ways. Pathogenic bacteria associated with fresh vegetables can cause widespread epidemics associated with foodborne illness. The aim of this study was to assess the microbiological quality of carrot slices after treatment with aqueous extracts of (AE) at different concentrations AE1 (10 mg/mL), AE2 (5 mg/mL), AE3 (2.5 mg/mL) and AE4 (1.25 mg/mL), and subsp. serovar Enteritidis, along with vacuum packaging and storage of carrots for 7 days at 4 °C. On days 1. and 7., total viable counts (TVC), and coliforms bacteria (CB), and count were all analysed. Microorganisms that were obtained from carrots were identified using MALDI-TOF MS Biotyper Mass Spectrometry. The total viable, coliform bacteria and counts were varied by the group of treatment. Higher counts were found in the control group on both days. The most isolated species of bacteria were and on the 1. day and on the 7. day. The current study adds useful information for a better understanding of how reacts to the effect of AE and its potential use as a sustainable washing method to eliminate bacteria from freshly cut carrots.
PubMed: 38576551
DOI: 10.1016/j.heliyon.2024.e29065