Trends in Mercury Contamination Distribution among Human and Animal Populations in the Amazon Region.

Mercury contamination in the Amazon arising from both natural sources and intensive mining activities in the region is a significant public health concern. This metal is used to separate Au from sediments. Accordingly, this study aimed to assess the impact of mining on mercury contamination in the animal and human populations of the Amazon. This overall objective was pursued through a systematic review of the existing literature to assess the impact of Hg and identify gaps in geographic coverage arising from this assessment. Herein, we employed PECO and PRISMA-ScR protocols to select articles published between 2017 and 2023 based on projected points on a map within the biogeographic boundaries of the Amazon. We found that mercury concentrations increase with trophic levels, reaching high values of 3.7 µg/g in the muscles of predatory fish and 34.9 µg/g in human hair. The mean level of mercury in human hair in the whole (Amazon) region exceeds 6 µg/g, surpassing tolerance levels. Although mining regions show high concentrations of Hg, the highest incidence was observed among populations with fish-based diets. It was concluded that continuous research and monitoring of fish in the region are required in order to accurately assess the risk associated with Hg contamination, especially since fish are the main source of protein in this region.

Metabolomic insights into phenolics-rich chestnut shells extract as a nutraceutical ingredient - A comprehensive evaluation of its impacts on oxidative stress biomarkers by an in-vivo study.

The present study attempted for the first time to explore the effects of the daily oral intake of a phenolics-rich extract from chestnut shells (CS) on the metabolomic profiling of rat tissues by liquid chromatography coupled to Orbitrap-mass spectrometry (LC-ESI-LTQ-Orbitrap-MS) targeted to polyphenolics and their metabolites and screen potential oxidative stress biomarkers, validating its use as a promising nutraceutical ingredient with outstanding antioxidant properties for the prevention and co-therapy of lifestyle-related diseases triggered by oxidative stress. The results demonstrated new insights into the metabolomic fingerprinting of polyphenols from CS, confirming their absorption and biotransformation by phase I (hydrogenation) and II (glucuronidation, methylation, and sulfation) enzymes. Phenolic acids were the main polyphenolic class, followed by hydrolyzable tannins, flavanols, and lignans. In contrast to the liver, sulfated conjugates were the principal metabolites reaching the kidneys. The multivariate data analysis predicted an exceptional contribution of polyphenols and their microbial and phase II metabolites to the in-vivo antioxidant response of the CS extract in rats, recommending its use as an appealing source of anti-aging molecules for nutraceuticals. This is the first study that explored the relation between metabolomic profiling of rat tissues and in-vivo antioxidant effects after oral treatment with a phenolics-rich CS extract.

Protecting Police Officers Against Burnout: Overcoming a Fragmented Research Field.

This study aims to identify the determinants of burnout in police officers. We considered a wide range of psychosocial risk factors, individual variables that have been previously found to be associated with burnout in police officers (affective and cognitive empathy, self-care), and variables whose unique impact on burnout of police officers needs further clarification (organizational justice and organizational identification). The study was conducted in Portugal, and the sample was constituted by 573 members of the National Republican Guard (GNR-Guarda Nacional Republicana). The participants were invited to answer an online anonymous survey, which included previously validated measures of the following variables: burnout (exhaustion and disengagement), psychosocial risk factors, self-care, empathy (cognitive and affective), organizational justice, and organizational identification. Furthermore, we controlled for the potential impact of demographic variables (age, gender, years of professional experience, religiosity, political orientation, and income). Multiple regression analysis showed that when taken together, only a few of the variables associated with burnout had a unique impact on both exhaustion and disengagement: quantitative demands and affective empathy were burnout risk factors; meaningful work, organizational justice (distributive justice, procedural justice, and interactional justice), and organizational identification were burnout protective factors. Our results highlight the importance of developing theoretical models and planning interventions to prevent burnout in police officers, focusing mainly on the above-mentioned variables.

Developing a personalised, evidence-based and inclusive learning (PEBIL) model of blended learning: A cross-sectional survey.

Whilst the use of various blended learning models preceded the COVID-19 pandemic, the abrupt shift to remote delivery served as catalyst within the sector in enhancing digital solutions to meet immediate student needs. As we emerge from the pandemic, a return to purely didactic and impersonal in-person teaching seems anticlimactic, with the return to the lecture theatre seeing many lecturers trialling various digital tools in creating more interactive in-person, synchronous, and asynchronous sessions. In evaluating students' experiences of the various tools and approaches applied by academic staff, a survey was developed by a multidisciplinary team of educators at Cardiff University's School of Medicine exploring student perceptions of e-learning resources (ELRs), as well as student experiences of various blended learning approaches. The primary aim of this study was to evaluate student experience, satisfaction, and engagement with ELRs and blended learning. A total of 179 students (undergraduate and postgraduate) completed the survey. 97% confirmed that e-learning resources were blended within the teaching they received, with 77% rating the quality of e-learning as good-to-excellent and 66% reporting a preference for asynchronous resources that enable them to learn at their own pace. A variety of platforms, tools, and approaches were identified by students as meeting their diverse learning needs. We therefore propose a personalised, evidence-based and inclusive learning (PEBIL) model enabling the application of digital technologies both on and offline.

Appraisal of a new potential antioxidants-rich nutraceutical ingredient from chestnut shells through in-vivo assays - A targeted metabolomic approach in phenolic compounds.

Chestnut (Castanea sativa) shells (CSS) are a source of bioactive compounds with well demonstrated in-vitro antioxidant properties. Nevertheless, no in-vivo studies have already evaluated this effect. This study evaluated the effects of the oral daily administration of an eco-friendly CSS extract (50 and 100 mg/kg per body weight (b.w.)) to rats regarding in-vivo antioxidant activity, glucose and lipids levels, and metabolomic profiling of polyphenols by LC-ESI-LTQ-Orbitrap-MS. The results demonstrated the in-vivo antioxidant properties in the animals liver, kidney and blood serum, as well as protective effects against hemolysis and rising of blood glucose and lipids levels. New insights on metabolomic profiling of polyphenols proved their absorption and further biotransformation by phase I (hydrogenation and hydroxylation) and II reactions (glucuronidation, methylation and sulfation). This is the first study that attempted to validate a novel nutraceutical ingredient extracted from CSS byin-vivoassays, corroborating the outcomes screened by in-vitro assays.

Insights into the 3D In Vitro Permeability and In Vivo Antioxidant Protective Effects of Kiwiberry Leaf Extract: A Step Forward to Human Nutraceutical Use.

Actinidia arguta (Siebold & Zucc.) Planch. ex Miq. (kiwiberry) leaves are a source of phenolic compounds with pro-health biological effects, such as antioxidant and anti-inflammatory activities. Despite the huge number of studies reporting the composition of A. arguta leaves, no in vitro or in vivo studies explore its potential use as nutraceutical ingredient based on these activities. Therefore, this study aims to characterize the safety profile of kiwiberry leaf extracts using in vitro and in vivo approaches through the assessment of intestinal cell viability (Caco-2 and HT29-MTX), 3D intestinal permeation, and, most important, the redox markers, biochemical profile and liver and kidney function effects after the animal assays. Briefly, wistar rats were orally treated for 7 days with kiwiberry leaf extracts (50 and 75 mg/kg bw), water (negative control), or vitamin C (positive control). The cell viability was above 90% at 1000 µg/mL for both cells. Coumaroyl quinic acid and rutin achieved a permeation higher than 25% in the 3D intestinal model. The animal studies confirmed the extracts' ability to increase superoxide dismutase, glutathione peroxidase, and catalase content in animals' livers and kidneys while simultaneously decreasing the triglycerides content. This study highlighted the antioxidant capacity of kiwiberry leaf extracts, ensuring their efficacy and safety as a nutraceutical ingredient.

Oral delivery of camptothecin-loaded multifunctional chitosan-based micelles is effective in reduce colorectal cancer.

Colorectal cancer (CRC) is a heterogeneous disease with high incidence and mortality worldwide. The efficacy of conventional CRC chemotherapy is hampered by poor drug solubility and bioavailability and suboptimal pharmacokinetic profiles. In this work, camptothecin (CPT), a potent anticancer drug, was loaded into an amphiphilic chitosan modified with PEG and oleic acid, to reduce CRC progression after oral administration. While CPT-loaded micelles presented anticancer activity against HCT116, Caco-2 and HT29 CRC cell lines in vitro, empty micelles demonstrated a safe profile when incubated with human blood cells and colorectal cancer cell lines. In a more complex 3D CRC multicellular spheroid model, CPT-loaded micelles also exhibited a significant effect on the spheroid's metabolic activity and size reduction. Remarkably, in vivo studies performed in a HCT116 xenograft model, showed a significant reduction on the tumor growth during and after treatment with CPT-loaded micelles. Moreover, in a more biological relevant in vivo model of chemically-induced CRC, orally administered CPT-loaded micelles demonstrated a significant reduction on tumor incidence and inflammation signs. The findings here reported indicate that CPT-loaded into chitosan-based micelles, by improving drug solubility, alongside its safety profile for normal tissues, may have a promising role CRC chemotherapy.

Dermoscopic classification of melasma: Concordance study and correlation with the melanophages count.

BACKGROUND: Melasma is a common hypermelanosis characterized by symmetrical brownish macules, especially on the face. Histologic analysis demonstrates increased epidermal and dermal melanin. Dermoscopy is useful to estimate the depth of the melanin and may help in the diagnosis and classification of melasma, with therapeutic importance. OBJECTIVES: To evaluate the diagnostic concordance of dermoscopic classification of epidermal or mixed subtypes of melasma and the correlation between dermoscopic and histopathological findings. METHODS: Twenty-eight women with facial melasma, phototypes III to V, ages between 30 and 61 years were selected. Based on the evaluation of clinical and dermoscopic images, two independent observers classified melasma into epidermal or mixed subtypes. The intra and interobserver concordances were calculated. Histopathological analysis of epidermal melanin extension and maximum number of melanophages per high-power field (400×; HPF) have been assessed. Association between the melanophages count and the dermoscopic classification was evaluated. RESULTS: Intraobserver agreement was 82.1%, and between observers, from 78.6% to 89.3%, according to the Kappa index. Histopathology revealed increased intraepidermal melanin and the presence of dermal melanophages in all the samples. Ten or more melanophages/HPF was significantly associated with mixed melasma. CONCLUSIONS: Moderate to substantial concordance in the dermoscopic classification of melasma was found, and the correlation between this classification and the dermal melanophages count have been suggested. Intradermal component of every case of melasma should be considered for therapeutic and prognostic purposes.

H3K36 methylation and DNA-binding both promote Ioc4 recruitment and Isw1b remodeler function.

The Isw1b chromatin-remodeling complex is specifically recruited to gene bodies to help retain pre-existing histones during transcription by RNA polymerase II. Recruitment is dependent on H3K36 methylation and the Isw1b subunit Ioc4, which contains an N-terminal PWWP domain. Here, we present the crystal structure of the Ioc4-PWWP domain, including a detailed functional characterization of the domain on its own as well as in the context of full-length Ioc4 and the Isw1b remodeler. The Ioc4-PWWP domain preferentially binds H3K36me3-containing nucleosomes. Its ability to bind DNA is required for nucleosome binding. It is also furthered by the unique insertion motif present in Ioc4-PWWP. The ability to bind H3K36me3 and DNA promotes the interaction of full-length Ioc4 with nucleosomes in vitro and they are necessary for its recruitment to gene bodies in vivo. Furthermore, a fully functional Ioc4-PWWP domain promotes efficient remodeling by Isw1b and the maintenance of ordered chromatin in vivo, thereby preventing the production of non-coding RNAs.

Dimensões profissionais do serviço social: sistematização dos documentos do CFESS e da ABEPSS em tempos de pandemia / Professional dimensions of social work: systematization of CFESS and ABEPSS documents in times of pandemic

Neste artigo, objetiva-se dar visibilidade aos mecanismos de orientação ao exercício profissional por meio da sistematização dos documentos produzidos pelo Conselho Federal de Serviço Social (CFESS) e pela Associação Brasileira de Ensino e Pesquisa em Serviço Social (ABEPSS) em decorrência da pandemia de COVID-19. O artigo apresenta resultados obtidos via pesquisa qualitativa documental, a partir de fontes de coleta de dados de domínio público. As informações foram tratadas via análise de conteúdo sob uma perspectiva dialético-crítica. Os documentos expedidos pelo CFESS e ABEPSS, durante a pandemia, demarcam a direção e a orientação ao exercício profissional, que tem como norte a análise crítica da conjuntura e da realidade ora apresentada. Clama-se para que os/as assistentes sociais se posicionem de forma crítica frente ao cenário de agravamento das expressões da questão social e que tenham o compromisso de propor e executar intervenções concatenadas com seus princípios ético-políticos, com destaque à defesa intransigente dos direitos sociais da classe trabalhadora, por ser uma parcela da sociedade que mais está exposta às múltiplas situações de desproteção social na pandemia.

In this article, the objective is to give visibility to the mechanisms for guiding professional practice, by systematizing the documents produced by the agencies - CFESS and ABEPSS, due to the pandemic of COVID-19. The article presents results obtained in qualitative documentary research, the data were treated via content analysis from a critical dialectical perspective. Documents issued by the CFESS and ABEPSS, during the pandemic, act to demarcate the direction and orientation to the professional practice, the critical analysis of the conjuncture and the reality now presented. It is claimed that Social Workers take a critical stand against the scenario of worsening expressions of the social issue and are committed to proposing and executing interventions concatenated with their ethical-political principles, with emphasis on the uncompromising defense of the social rights of the working class, as it is a part of society that is most exposed to the multiple situations of social deprotection in the pandemic.

Evaluation of drug susceptibility in nontuberculous mycobacteria using the SLOMYCO and RAPMYCO sensititre plates.

Background: Non-tuberculous Mycobacteria (NTM) cause different forms of diseases. According to recent guideline by ATS/ERS/ESCMID/IDSA, drug susceptibility test (DST) is an important requirement to choose adequate treatment. The minimum inhibitory concentration (MIC) test is the recommended method. Sensititre SLOMYCO and RAPMYCO commercial panels were developed to perform mycobacteria DST easier. However, there are only two comparative studies between SLOMYCO and the MIC method and none for the RAPMYCO panel. The present study aimed to evaluate the Sensititre SLOMYCO and RAPMYCO plates in determining drug susceptibility compared to the gold standard method (MIC). Methods: The tests were carried out with clinical isolates received in the diagnostic routine of the Tuberculosis Laboratory at Institute Adolfo Lutz from the most frequent species in the state of São Paulo, Brazil. Reference strains were tested for repeatability and reproducibility analyses. MIC and Sensititre plates readings were compared with and without resazurin stain. Agreement between results was defined as MIC within the same dilution or dilution variation resulting the same category in both tests. Results were classified by categorical errors. Results: The RAPMYCO panel had 100% agreement for the drugs amikacin, doxycycline, ciprofloxacin and trimethoprim/sulfamethoxazole, 83.3% for clarithromycin and moxifloxacin and 60% for cefoxitin. The SLOMYCO panel had 80% agreement for amikacin and moxifloxacin and 60% for clarithromycin, rifabutin, rifampicin and ciprofloxacin. The repeatability and reproducibility with RAPMYCO and SLOMYCO plates showed a high level of agreement for the drugs tested, being higher with the use of resazurin. However, an evaluation on routine condition is needed. Conclusions: The present study found that the fewer steps in the tests with Sensititre plates and reading with resazurin allow its use with greater safety and efficiency in the laboratory routine. The results presented here will facilitate the execution of a validation for complete incorporation of Sensititre plates into a diagnostic routine.

Mucus-producing 3D cell culture models.

In vitro cell-based models have been used for a long time since they are normally easily obtained and have an advantageous cost-benefit. Besides, they can serve a variety of ends, from studying drug absorption and metabolism to disease modeling. However, some in vitro models are too simplistic, not accurately representing the living tissues. It has been shown, mainly in the last years, that fully mimicking a tissue composition and architecture can be paramount for cellular behavior and, consequently, for the outcomes of the studies using such models. Because of this, 3D in vitro cell models have been gaining much attention, since they are able to better replicate the in vivo environment. In this review we focus on 3D models that contain mucus-producing cells, as mucus can play a pivotal role in drug absorption. Being frequently overlooked, this viscous fluid can have an impact on drug delivery. Thus, the aim of this review is to understand to which extent can mucus affect mucosal drug delivery and to provide a state-of-the-art report on the existing 3D cell-based mucus models.

A scale-up strategy for the synthesis of chitosan derivatives used in micellar nanomedicines.

Nanomedicines have been increasingly investigated and used by pharmaceutical industry due to their potential in solving various public health problems. However, standardizing and approving nanomedicines remains a significant challenge, as the translation from the laboratory to the market is still limited. These constraints are due to a lack of reproducibility and standardization of procedures, small batch sizes due to inability to scale-up, or the associated production costs as a result of the production methods chosen. In this work, two chitosan derivatives, methoxypolyethylene glycol-chitosan (mPEG-CS) and methoxypolyethylene glycol-chitosan-oleic acid (mPEG-CS-OA), produced at the lab scale were implemented in a pharmaceutical industry to achieve the scale-up production using cross flow filtration (CFF). The two copolymers were shown to be capable of retaining their physicochemical properties when produced in larger batch sizes, with reduced production time and increased yield. Also, both chitosan derivatives presented no in vitro cytotoxicity independent of the method of production. Furthermore, after scale-up, polymeric micelles produced from mPEG-CS-OA were tested for storage stability, demonstrating that micelles remained stable at - 20 °C for at least 6 months. This study demonstrated the feasibility of producing polymers and polymeric micelles closer to the bedside due to their suitability for GMP production.

Glycoproteome remodeling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with mixed-lineage leukemia gene rearrangement (MLL-r) is a poor-prognosis subtype for which additional therapeutic targets are urgently needed. Currently no multi-omics data set for primary MLL r patient cells exists that integrates transcriptomics, proteomics and glycomics to gain an inclusive picture of theranostic targets. Methods: We have integrated transcriptomics, proteomics and glycomics to i) obtain the first inclusive picture of primary patient BCP-ALL cells and identify molecular signatures that distinguish leukemic from normal precursor B-cells and ii) better understand the benefits and limitations of the applied technologies to deliver deep molecular sequence data across major cellular biopolymers. Results: MLL-r cells feature an extensive remodeling of their glycocalyx, with increased levels of Core 2-type O-glycans and complex N-glycans as well as significant changes in sialylation and fucosylation. Notably, glycosaminoglycan remodeling from chondroitin sulfate to heparan sulfate was observed. A survival screen, to determine if glycan remodeling enzymes are redundant, identified MGAT1 and NGLY1, essential components of the N-glycosylation/degradation pathway, as highly relevant within this in vitro screening. OGT and OGA, unique enzymes that regulate intracellular O-GlcNAcylation, were also indispensable. Transcriptomics and proteomics further identified Fes and GALNT7-mediated glycosylation as possible therapeutic targets. While there is overall good correlation between transcriptomics and proteomics data, we demonstrate that a systematic combined multi-omics approach delivers important diagnostic information that is missed when applying a single omics technology. Conclusions: Apart from confirming well-known MLL-r BCP-ALL glycoprotein markers, our integrated multi-omics workflow discovered previously unidentified diagnostic/therapeutic protein targets.

A Biophysical Insight of Camptothecin Biodistribution: Towards a Molecular Understanding of Its Pharmacokinetic Issues.

Camptothecin (CPT) is a potent anticancer drug, and its putative oral administration is envisioned although difficult due to physiological barriers that must be overcome. A comprehensive biophysical analysis of CPT interaction with biointerface models can be used to predict some pharmacokinetic issues after oral administration of this or other drugs. To that end, different models were used to mimic the phospholipid composition of normal, cancer, and blood-brain barrier endothelial cell membranes. The logD values obtained indicate that the drug is well distributed across membranes. CPT-membrane interaction studies also confirm the drug's location at the membrane cooperative and interfacial regions. The drug can also permeate membranes at more ordered phases by altering phospholipid packing. The similar logD values obtained in membrane models mimicking cancer or normal cells imply that CPT has limited selectivity to its target. Furthermore, CPT binds strongly to serum albumin, leaving only 8.05% of free drug available to be distributed to the tissues. The strong interaction with plasma proteins, allied to the large distribution (VDSS = 5.75 ± 0.932 L·Kg-1) and tendency to bioaccumulate in off-target tissues, were predicted to be pharmacokinetic issues of CPT, implying the need to develop drug delivery systems to improve its biodistribution.

p28-functionalized PLGA nanoparticles loaded with gefitinib reduce tumor burden and metastases formation on lung cancer.

Lung cancer is still the main cause of cancer-related deaths worldwide. Its treatment generally includes surgical resection, immunotherapy, radiotherapy, and chemo-targeted therapies such as the application of tyrosine kinase inhibitors. Gefitinib (GEF) is one of them, but its poor solubility in gastric fluids weakens its bioavailability and therapeutic activity. In addition, like all other chemotherapy treatments, GEF administration can cause damage to healthy tissues. Therefore, the development of novel GEF delivery systems to increase its bioavailability and distribution in tumor site is highly demanded. Herein, an innovative strategy for GEF delivery, by functionalizing PLGA nanoparticles with p28 (p28-NPs), a cell-penetrating peptide derived from the bacterial protein azurin, was developed. Our data indicated that p28 potentiates the selective interaction of these nanosystems with A549 lung cancer cells (active targeting). Further p28-NPs delivering GEF (p28-NPs-GEF) were able to selectively reduce the metabolic activity of A549 cells, while no impact was observed in non-tumor cells (16HBE14o-). In vivo studies using A549 subcutaneous xenograft showed that p28-NPs-GEF reduced A549 primary tumor burden and lung metastases formation. Overall, the design of a p28-functionalized delivery nanosystem to effectively penetrate the membranes of cancer cells while deliver GEF could provide a new strategy to improve lung cancer therapy.

3D printed systems for colon-specific delivery of camptothecin-loaded chitosan micelles.

The use of 3D printing technology in the manufacturing of drug delivery systems has expanded and benefit of a customized care. The ability to create tailor-made structures filled with drugs/delivery systems with suitable drug dosage is especially appealing in the field of nanomedicine. In this work, chitosan-based polymeric micelles loaded with camptothecin (CPT) were incorporated into 3D printing systems (printfills) sealed with an enteric layer, aiming to protect the nanosystems from the harsh environment of the gastrointestinal tract (GIT). Polymeric micelles and printfills were fully characterized and, a simulated digestion of the 3D systems upon an oral administration was performed. The printfills maintained intact at the simulated gastric pH of the stomach and, only released the micelles at the colonic pH. From there, the dissolution media was used to recreate the intestinal absorption and, chitosan micelles showed a significant increase of the CPT permeability compared to the free drug, reaching an apparent permeability coefficient (Papp) of around 9×10-6 cm/s in a 3D intestinal cell-based model. The combination of 3D printing with nanotechnology appears to have great potential for the colon-specific release of polymeric micelles, thereby increasing intestinal absorption while protecting the system/drug from degradation throughout the GIT.

Advances on colorectal cancer 3D models: The needed translational technology for nanomedicine screening.

Colorectal cancer (CRC) is a heterogeneous and molecularly complex disease, associated with high mortality worldwide, exposing the urgent need for novel therapeutic approaches. Their development and translation to the clinic have been hampered, partially due to the absence of reliable cellular models that resemble key features of the human disease. While traditional 2D models are not able to provide consistent and predictive responses about the in vivo efficiency of the formulation, animal models frequently fail to recapitulate cancer progression and to reproduce adverse effects. On its turn, multicellular 3D systems, by mimicking key genetic, physical and mechanical cues of the tumor microenvironment, constitute a promising tool in cancer research. In addition, they constitute more physiological and relevant environment for anticancer drugs screening and for predicting patient's response towards personalized approaches, bridging the gap between simplified 2D models and unrepresentative animal models. In this review, we provide an overview of CRC 3D models for translational research, with focus on their potential for nanomedicines screening.