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The objective of the study was to assess the indirect cytotoxicity of 600 ppm and 1500 ppm nano silver fluoride (NSF) compared to other commercial cariostatic agents. 56 dentin discs with 0.4 mm in thickness were obtained from intact human molars and adapted to artificial pulp chambers (APCs). The discs were divided into seven groups according to treatment (n = 8): no treatment (positive control-PC), 29% hydrogen peroxide (negative control-NC), 30% Cariestop (CS30), 38% Riva Star (RS38), 38% Advantage Arrest (AA38), 600 ppm NSF (NSF600), and 1500 ppm NSF (NSF1500). The cariostatic agents were applied on the occlusal surface of the dentin discs (facing upward), and the pulp surface (facing downward) remained in contact with the culture medium. Immediately after the treatments, the extracts (DMEM + cariostatic agent components diffused through the discs) were collected and applied to MDPC-23 cells, which were assessed for viability (CV-alamarBlue, live/dead), adhesion/spreading (F-actin), alkaline phosphatase (ALP) activity, and mineralization nodule (MN) formation. The data were statistically analyzed by ANOVA/Games-Howell (p = 0.05). CV and ALP activity in CS30, RS38, AA38, and NSF600 were similar to PC (p > 0.05). MN formation significantly decreased only in NC, CS30, RS38, and AA38 compared to PC (p < 0.001). Only NSF600 and NSF1500 did not differ from PC (p > 0.05) with mineralization nodules, and this specific cell activity significantly decreased in all other groups (p < 0.05). NSF solutions (600 ppm and 1500 ppm) did not cause transdentinal toxicity on MDPC-23 cells., (© 2024. The Author(s), under exclusive licence to The Society of The Nippon Dental University.)

Fibrous dysplasia (FD) is a mosaic skeletal disorder involving the development of benign, expansile fibro-osseous lesions during childhood that cause deformity, fractures, pain, and disability. There are no well-established treatments for FD. Fibroblast activation protein (FAPα) is a serine protease expressed in pathological fibrotic tissues that has promising clinical applications as a biomarker and local pro-drug activator in several pathological conditions. In this study, we explored the expression of FAP in FD tissue and cells through published genetic expression datasets and measured circulating FAPα in plasma samples from patients with FD and healthy donors. We found that FAP genetic expression was increased in FD tissue and cells, and present at higher concentrations in plasma from patients with FD compared to healthy donors. Moreover, FAPα levels were correlated with skeletal disease burden in patients with FD. These findings support further investigation of FAPα as a potential imaging and/or biomarker of FD, as well as a pro-drug activator specific to FD tissue.

Fibrous dysplasia (FD) is a mosaic non-inheritable genetic disorder of the skeleton in which normal bone is replaced by structurally unsound fibro-osseous tissue. There is no curative treatment for FD, partly because its pathophysiology is not yet fully known. We present a simple mathematical model of the disease incorporating its basic known biology, to gain insight on the dynamics of the involved bone-cell populations, and shed light on its pathophysiology. We develop an analytical study of the model and study its basic properties. The existence and stability of steady states are studied, an analysis of sensitivity on the model parameters is done, and different numerical simulations provide findings in agreement with the analytical results. We discuss the model dynamics match with known facts on the disease, and how some open questions could be addressed using the model., (© 2024. The Author(s), under exclusive licence to the Society for Mathematical Biology.)

Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants of GNAS encoding for Gα s and leading to excessive cyclic adenosine monophosphate signaling in bone-marrow stromal cells (BMSCs). The effect of Gα s activation in the BMSC transcriptome and how it influences FD lesion microenvironment are unclear. We analyzed changes induced by Gα s activation in the BMSC transcriptome and secretome. RNAseq analysis of differential gene expression of cultured BMSCs from patients with FD and healthy volunteers, and from an inducible mouse model of FD, was performed, and the transcriptomic profiles of both models were combined to build a robust FD BMSC genetic signature. Pathways related to Gα s activation, cytokine signaling, and extracellular matrix deposition were identified. To assess the modulation of several key secreted factors in FD pathogenesis, cytokines and other factors were measured in culture media. Cytokines were also screened in a collection of plasma samples from patients with FD, and positive correlations of several cytokines to their disease burden score, as well as to one another and bone turnover markers, were found. These data support the pro-inflammatory, pro-osteoclastic behavior of FD BMSCs and point to several cytokines and other secreted factors as possible therapeutic targets and/or circulating biomarkers for FD.

O-glycosylation is a conserved posttranslational modification that impacts many aspects of organismal viability and function. Recent studies examining the glycosyltransferase Galnt11 demonstrated that it glycosylates the endocytic receptor megalin in the kidneys, enabling proper binding and reabsorption of ligands, including vitamin D-binding protein (DBP). Galnt11-deficient mice were unable to properly reabsorb DBP from the urine. Vitamin D plays an essential role in mineral homeostasis and its deficiency is associated with bone diseases such as rickets, osteomalacia, and osteoporosis. We therefore set out to examine the effects of the loss of Galnt11 on vitamin D homeostasis and bone composition. We found significantly decreased levels of serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, consistent with decreased reabsorption of DBP. This was accompanied by a significant reduction in blood calcium levels and a physiologic increase in parathyroid hormone (PTH) in Galnt11-deficient mice. Bones in Galnt11-deficient mice were smaller and displayed a decrease in cortical bone accompanied by an increase in trabecular bone and an increase in a marker of bone formation, consistent with PTH-mediated effects on bone. These results support a unified model for the role of Galnt11 in bone and mineral homeostasis, wherein loss of Galnt11 leads to decreased reabsorption of DBP by megalin, resulting in a cascade of disrupted mineral and bone homeostasis including decreased circulating vitamin D and calcium levels, a physiological increase in PTH, an overall loss of cortical bone, and an increase in trabecular bone. Our study elucidates how defects in O-glycosylation can influence vitamin D and mineral homeostasis and the integrity of the skeletal system., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Published by Elsevier Inc.)

Background: Nutritional recommendations for patients with type 2 diabetes mellitus (T2DM) and hypertension assume high food security. However, food insecurity is estimated to affect 10% of the US population and more so patients at our student-run free clinic (SRFC). The aims of the study were to (1) assess food security in patients with a diagnosis of T2DM, hypertension, or both and (2) examine the relationship between food security and glycated hemoglobin (HbA1C) or blood pressure at an SRFC., Methods: Eligible participants completed a 10-item food security questionnaire and an item addressing perceived barriers. Most recent HbA1C and blood pressure measurements were gathered. Comparisons were made using univariate or multivariate linear regression analysis., Results: Results from 79 participants showed that 25.3% experienced high food security, 29.1% had marginal food security, 13.9% had low food security, and 30.4% had very low food security. No statistically significant association was found between food security category and HbA1C or blood pressure. However, we did find that approximately 73% of patients experienced some degree of food insecurity., Conclusions: Patients at our SRFC are ethnically and racially diverse, most have a high school education or less, and most have food insecurity. No association between food security category and HbA1C or blood pressure control was found. Providers should consider the degree of food insecurity and incorporate a culturally sensitive approach when making nutritional recommendations., Competing Interests: The authors report no funding or conflicts of interests., (Copyright © 2024 Baylor University Medical Center.)

Historically famous for their negative impact on human-built marine wood structures, mollusc shipworms play a central ecological role in marine ecosystems. Their association with bacterial symbionts, providing cellulolytic and nitrogen-fixing activities, underscores their exceptional wood-eating and wood-boring behaviours, improving energy transfer and the recycling of essential nutrients locked in the wood cellulose. Importantly, from a molecular standpoint, a minute of omic resources are available from this lineage of Bivalvia. Here, we produced and assembled a transcriptome from the globally distributed naval shipworm, Teredo navalis (family Teredinidae). The transcriptome was obtained by sequencing the total RNA from five equidistant segments of the whole body of a T. navalis specimen. The quality of the produced assembly was accessed with several statistics, revealing a highly contiguous (1194 N50) and complete (over 90% BUSCO scores for Eukaryote and Metazoan databases) transcriptome, with nearly 38,000 predicted ORF, more than half being functionally annotated. Our findings pave the way to investigate the unique evolutionary biology of these highly modified bivalves and lay the foundation for an adequate gene annotation of a full genome sequence of the species., Competing Interests: Declaration of competing interest L. Filipe. C. Castro reports financial support and equipment, drugs, or supplies were provided by University of Porto Interdisciplinary Centre of Marine and Environmental Research. L. Filipe C. Castro reports a relationship with University of Porto Interdisciplinary Centre of Marine and Environmental Research that includes: board membership, employment, funding grants, non-financial support, and travel reimbursement. Elsa Froufe reports a relationship with University of Porto Interdisciplinary Centre of Marine and Environmental Research that includes: board membership, employment, non-financial support, and travel reimbursement., (Copyright © 2024. Published by Elsevier B.V.)

Bone histomorphometry is a well-established approach to assessing skeletal pathology, providing a standard evaluation of the cellular components, architecture, mineralization, and growth of bone tissue. However, it depends in part on the subjective interpretation of cellular morphology by an expert, which introduces bias. In addition, diseases like osteogenesis imperfecta (OI) and fibrous dysplasia are accompanied by changes in the morphology and function of skeletal tissue and cells, hindering consistent evaluation of some morphometric parameters and interpretation of the results. For instance, traditional histomorphometry combined with collagen turnover markers suggested that reduced bone formation in classical OI is accompanied by increased bone resorption. In contrast, the well-documented postpubertal reduction in fractures would be easier to explain by reduced bone resorption after puberty, highlighting the need for less ambiguous measurements. Here we propose an approach to histomorphometry based on in situ mRNA hybridization, which uses Col1a1 as osteoblast and Ctsk as osteoclast markers. This approach can be fully automated and eliminates subjective identification of bone surface cells. We validate these markers based on the expression of Bglap, Ibsp, and Acp5. Comparison with traditional histological and tartrate-resistant acid phosphatase staining of the same sections suggests that mRNA-based analysis is more reliable. Unlike inconclusive traditional histomorphometry of mice with α2(I)-Gly610 to Cys substitution in the collagen triple helix, mRNA-based measurements reveal reduced osteoclastogenesis in 11-wk-old animals consistent with the postpubertal catch-up osteogenesis observed by microCT. We optimize the technique for cryosections of mineralized bone and sections of paraffin-embedded decalcified tissue, simplifying and broadening its applications. We illustrate the application of the mRNA-based approach to human samples using the example of a McCune-Albright syndrome patient. By eliminating confounding effects of altered cellular morphology and the need for subjective morphological evaluation, this approach may provide a more reproducible and accessible evaluation of bone pathology., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

This study aimed to contribute to the development of an embryo-test using the gastropod Lymnaea stagnalis , identified by the Organization for Economic Co-operation and Development (OECD) as a potential invertebrate test animal model. Together with the Potamopyrgus antipodarum , were the first mollusc models to be included in the organization testing guidelines. The focus was on validating an embryo toxicity test to cover the sensitive embryogenesis phase and on obtaining testing information on all of the model life cycle stages, contributing to close an identified gap within this context. Adhering to OECD guidelines, namely the L. stagnalis reproductive test, the study examined mortality rates, abnormality rates, development, growth, hatching rates, hearth rates, and pre-testing media suitability, during the embryogenesis, and the obtained dataset made available for further studies. Cadmium was chosen as the positive test compound due to its well-studied nature and the model's proven sensitivity to the compound, working as a reference compound for the test development. The data were collected in two 12-day assays under consistent conditions, each using 144 L. stagnalis embryos (<24 h old) from 6 egg masses (288 embryos total). Six 48-well microplates were utilized per assay, accommodating five different cadmium concentrations (32, 70, 155, 341, 750 µg/L) and a control group. Recorded parameters encompassed developmental stage, embryo position within the chorion, developmental abnormalities, hatchings, and mortality. Data analysis involved classifying embryos based on developmental stage and position, taking an exploratory approach to define the relevance of the different parameters in the compound hazard assessment during the embryogenesis. Measurements considered embryo area, perimeter, length, height, width, interocular distance, and heart rate. This dataset does not provide treated information but the raw data obtained during the proposed metodological development and toxicity testing process. The purpose of this article is to make the obtained raw data available, clearly defining the acquisition methodology to provide a comparison basis for future or existent works within this context., (© 2024 The Authors. Published by Elsevier Inc.)

Fibrous dysplasia (FD) is a rare, disabling skeletal disease for which there are no established treatments. Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand (RANKL) as a potential treatment strategy. In this study, we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre- and post-treatment in a phase 2 clinical trial of denosumab (NCT03571191) and in murine in vivo and ex vivo preclinical models. Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation, reduced cellularity, and reduced expression of the pathogenic Gα s variant in FD lesions after RANKL inhibition. RNA sequencing of human and mouse tissue supported these findings. The interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model, which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclasts. The results from this study demonstrated that, in addition to its expected antiosteoclastic effect, denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation, leading to increased bone formation within lesions. These findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.TRIAL REGISTRATION: ClinicalTrials.gov NCT03571191., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The European sardine ( Sardina pilchardus , Walbaum 1792) is indisputably a commercially important species. Previous studies using uneven sampling or a limited number of makers have presented sometimes conflicting evidence of the genetic structure of S. pilchardus populations. Here, we show that whole genome data from 108 individuals from 16 sampling areas across 5000 km of the species' distribution range (from the Eastern Mediterranean to the archipelago of Azores) support at least three genetic clusters. One includes individuals from Azores and Madeira, with evidence of substructure separating these two archipelagos in the Atlantic. Another cluster broadly corresponds to the center of the distribution, including the sampling sites around Iberia, separated by the Almeria-Oran front from the third cluster that includes all of the Mediterranean samples, except those from the Alboran Sea. Individuals from the Canary Islands appear to belong to the Mediterranean cluster. This suggests at least two important geographical barriers to gene flow, even though these do not seem complete, with many individuals from around Iberia and the Mediterranean showing some patterns compatible with admixture with other genetic clusters. Genomic regions corresponding to the top outliers of genetic differentiation are located in areas of low recombination indicative that genetic architecture also has a role in shaping population structure. These regions include genes related to otolith formation, a calcium carbonate structure in the inner ear previously used to distinguish S. pilchardus populations. Our results provide a baseline for further characterization of physical and genetic barriers that divide European sardine populations, and information for transnational stock management of this highly exploited species towards sustainable fisheries.

The validation of high-throughput toxicity tests with invertebrate species is a key priority to improve hazard assessment of new chemicals and increase the available test guidelines with organisms from a representative set of taxa. This work aimed to contribute to the validation of an embryo test with the freshwater gastropod Lymnaea stagnalis, which has been identified by Organization for Economic Co-operation and Development (OECD) as a potential invertebrate test model, and provide the basis for such an endeavor. Recently, a L. stagnalis reproductive test was standardized by the OECD. However, to encompass the entire life cycle, it is crucial to addresses embryogenic development - a phase highly susceptible to various anthropogenic chemicals, which is covered in the proposed methodology. The approach used in the present study is in line with the OECD guidelines and other published studies, namely the Detailed Review Paper (DRP) on Mollusks life-cycle toxicity testing. Here, the assay quality criteria such as basal mortality and abnormality rates, development, growth and hatching rates, the appropriated testing media, and the optimal assay duration were investigated. Cadmium was chosen as the positive test substance, due to the available data and the verified model sensitivity to this compound, namely in the OECD reproductive test validation process. The obtained data demonstrate that L. stagnalis embryogenesis using the developed methodology is highly sensitive to cadmium. High concentration-response correlation was observed using this reference compound, the EC10 and EC50 for growth are 13.57 and 21.84 μg/L, respectively, after 168 h of exposure. The development EC's 10 and 50 were 15.75 and 38.66 μg/L, respectively, after 240 h. This demonstrates the model sensitivity to this compound when compared with other embryo test models, as well as the model sensitivity during the embryogenesis, if compared with the adult stage. Further, given the determined sensitivity parameters, and incubation times, the test can be performed at 240 h as over 95 % of the control embryos were hatched and no further significant changes in the exposure groups were determined. Overall, the findings of the present study demonstrate that the embryo test with L. stagnalis has potential to high-throughput testing and the model has a high sensitivity to cadmium during this life cycle period. The background data provide by this study will be essential to foster the future standardization of this assay., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Urinary tract endometriosis (UTE), a rare manifestation, encompasses bladder and ureteral involvement. Surgical intervention is commonly recommended for UTE, though the optimal surgical approach remains a subject of debate. This study aims to report our centre's experience with UTE., Methods: We conducted a retrospective cohort study of 55 patients who underwent surgical treatment for UTE at a single tertiary centre over a 10-year period (2012-2022). Patient data, including demographics, symptoms, intraoperative findings, and complications, were collected from medical records. Data were statistically analysed, and correlations were explored., Results: The study population had a mean age of 37.11 years, with dysmenorrhea (89.1%) being the most common symptom. Bladder endometriosis was present in 27 cases, ureteral endometriosis in 25, and mixed-location in 3. Laparoscopy was the primary surgical approach, with multidisciplinary teams involving urologists. There were six patients with postoperative complications, and there were six (10.9%) recurrences of endometriosis. A positive correlation was found between age and recurrence, but no significant predictors of recurrence were identified in our analysis., Conclusions: Laparoscopic treatment of urinary endometriosis is safe and effective. Multidisciplinary collaboration plays a pivotal role in addressing this challenging condition.

The proliferation of genomic sequencing approaches has significantly impacted the field of phylogenetics. Target capture approaches provide a cost-effective, fast and easily applied strategy for phylogenetic inference of non-model organisms. However, several existing target capture processing pipelines are incapable of incorporating whole genome sequencing (WGS). Here, we develop a new pipeline for capture and de novo assembly of the targeted regions using whole genome re-sequencing reads. This new pipeline captured targeted loci accurately, and given its unbiased nature, can be used with any target capture probe set. Moreover, due to its low computational demand, this new pipeline may be ideal for users with limited resources and when high-coverage sequencing outputs are required. We demonstrate the utility of our approach by incorporating WGS data into the first comprehensive phylogenomic reconstruction of the freshwater mussel family Margaritiferidae. We also provide a catalogue of well-curated functional annotations of these previously uncharacterized freshwater mussel-specific target regions, representing a complementary tool for scrutinizing phylogenetic inferences while expanding future applications of the probe set., (© 2023 The Authors. Molecular Ecology Resources published by John Wiley & Sons Ltd.)

The highly diverse group of freshwater mussels from order Unionida is found in the world's freshwater systems due to several fascinating evolutionary adaptations, including "parental care," and most notably, an obligatory parasitic phase in their early life cycle, called glochidia, which infests and uses fish for nutrition and dispersal. Freshwater mussels play essential ecological roles in freshwater habitats, including water filtration, sediment bioturbation, and nutrient cycling. However, these species are also highly threatened, being one of the faunal groups with the highest recorded extinction rate in the wild. Genomics methods have an incredible potential to promote biodiversity conservation, allowing the characterization of population health, identification of adaptive genetic elements, delineation of conservation units, and providing a framework for predictive assessments of the impact of anthropogenic threats and climate change. Unfortunately, only six freshwater mussel species have had their whole genomes sequenced to date, and only two of these are European species. Here, we present the first genome assembly of the Painter's Mussel, Unio pictorum (Linnaeus, 1758), the type species representative of the order and the most widespread species of the genus in Europe. We used long-read PacBio Hi-Fi sequencing reads to produce a highly contiguous assembly that will pave the way for the study of European freshwater mussels in the Genome Era., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

This paper describes the design and construction of dual microfluidic paper-based analytical devices (dual-μPADs) as a lab-on-paper platform involving a "do-it-yourself" fabrication protocol. The device comprises a colorimetric and electrochemical module to obtain a dual-mode signal readout sensing strategy. A 3D pen polymeric resin was used to prepare graphite carbon-based electrodes and hydrophobic barriers on paper substrates. The proposed carbon-based ink was employed to manufacture electrodes on paper based on a stencil-printing approach, which were further characterized by electrochemical and morphological analyses. The analytical performance of the dual-μPADs was simultaneously evaluated for lactate, pH, nitrite, and salivary amylase (sAA) analysis. To demonstrate the proof-of-concept, saliva samples collected from both healthy individuals and those with periodontitis were successfully tested to demonstrate the feasibility of the proposed devices. Samples collected from individuals previously diagnosed with periodontitis showed high levels of nitrite and sAA (> 94 μmol L -1 and > 610 U mL -1 ) in comparison with healthy individuals (≤ 16 μmol L -1 and 545 U mL -1 ). Moreover, periodontitis saliva resulted in acid solution and almost null lactate levels. Notably, this protocol supplies a simple way to manufacture dual-μPADs, a versatile platform for sensitive detecting of biomarkers in saliva playing a crucial role towards the point-of-care diagnosis of periodontal disease., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

Mussels of order Unionida are a group of strictly freshwater bivalves with nearly 1,000 described species widely dispersed across world freshwater ecosystems. They are highly threatened showing the highest record of extinction events within faunal taxa. Conservation is particularly concerning in species occurring in the Mediterranean biodiversity hotspot that are exposed to multiple anthropogenic threats, possibly acting in synergy. That is the case of the dolphin freshwater mussel Unio delphinus Spengler, 1793, endemic to the western Iberian Peninsula with recently strong population declines. To date, only four genome assemblies are available for the order Unionida and only one European species. We present the first genome assembly of Unio delphinus. We used the PacBio HiFi to generate a highly contiguous genome assembly. The assembly is 2.5 Gb long, possessing 1254 contigs with a contig N50 length of 10 Mbp. This is the most contiguous freshwater mussel genome assembly to date and is an essential resource for investigating the species' biology and evolutionary history that ultimately will help to support conservation strategies., (© 2023. The Author(s).)

Contiguous assemblies are fundamental to deciphering the composition of extant genomes. In molluscs, this is considerably challenging owing to the large size of their genomes, heterozygosity, and widespread repetitive content. Consequently, long-read sequencing technologies are fundamental for high contiguity and quality. The first genome assembly of Margaritifera margaritifera (Linnaeus, 1758) (Mollusca: Bivalvia: Unionida), a culturally relevant, widespread, and highly threatened species of freshwater mussels, was recently generated. However, the resulting genome is highly fragmented since the assembly relied on short-read approaches. Here, an improved reference genome assembly was generated using a combination of PacBio CLR long reads and Illumina paired-end short reads. This genome assembly is 2.4 Gb long, organized into 1,700 scaffolds with a contig N50 length of 3.4 Mbp. The ab initio gene prediction resulted in 48,314 protein-coding genes. Our new assembly is a substantial improvement and an essential resource for studying this species' unique biological and evolutionary features, helping promote its conservation., Competing Interests: The authors declare that they have no competing interests., (© The Author(s) 2023.)

Cutaneous skeletal hypophosphatemia syndrome (CSHS) is a mosaic RASopathy characterized by the association of dysplastic skeletal lesions, congenital skin nevi of epidermal and/or melanocytic origin, and FGF23-mediated hypophosphatemia. The primary physiological source of circulating FGF23 is bone cells. However, several reports have suggested skin lesions as the source of excess FGF23 in CSHS. Consequently, without convincing evidence of efficacy, many patients with CSHS have undergone painful removal of cutaneous lesions in an effort to normalize blood phosphate levels. This study aims to elucidate whether the source of FGF23 excess in CSHS is RAS mutation-bearing bone or skin lesions. Toward this end, we analyzed the expression and activity of Fgf23 in two mouse models expressing similar HRAS/Hras activating mutations in a mosaic-like fashion in either bone or epidermal tissue. We found that HRAS hyperactivity in bone, not skin, caused excess of bioactive intact FGF23, hypophosphatemia, and osteomalacia. Our findings support RAS-mutated dysplastic bone as the primary source of physiologically active FGF23 excess in patients with CSHS. This evidence informs the care of patients with CSHS, arguing against the practice of nevi removal to decrease circulating, physiologically active FGF23.

Elucidating a basic blueprint of osteoclast-osteoblast coordination in skeletal remodeling and understanding how this coordination breaks down with age and disease is essential for addressing the growing skeletal health problem in our aging population. The paucity of simple, activatable, biologically relevant models of osteoclast-osteoblast coordination has hindered our understanding of how skeletal remolding is regulated. Here, we describe an inducible ex vivo model of osteoclast-osteoblast progenitor coordination. Induction activates the release of osteoclastogenic factors from osteoprogenitors, which elicits the differentiation and fusion of neighboring preosteoclasts. In turn, multinucleated osteoclasts release soluble coupling factors, RANK + extracellular vesicles and promote osteoprogenitor proliferation, recapitulating aspects of perturbed coordination in diseases underpinned by excessive osteoclast formation. We expect this model to expedite the investigation of cell-cell fusion, osteoclast-osteoblast progenitor coordination, and extracellular vesicle signaling during bone remodeling and offer a powerful tool for evaluating signaling cascades and novel therapeutic interventions in osteoclast-linked skeletal disease., Competing Interests: The authors declare no competing interests.

Objective: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized by its clinical variability and complexity in diagnosis and treatment. We performed both clinical and molecular descriptions of four families with MEN1 in a follow-up at a tertiary center in Brasília., Methods: From a preliminary review of approximately 500 medical records of patients with pituitary neuroendocrine tumor (PitNET) from the database of the Neuroendocrinology Outpatient Clinic of the University Hospital of Brasília, a total of 135 patients met the criteria of at least two affected family members. From this cohort, we have identified 34 families: only four with a phenotype of MEN1 and the other 30 families with the phenotype of familial isolated pituitary adenoma (FIPA). Eleven patients with a clinical diagnosis of MEN1 from these four families were selected., Results: Variants in MEN1 gene were identified in all families. One individual from each family underwent genetic testing using targeted high-throughput sequencing (HTS). All patients had primary hyperparathyroidism (PHPT), and the second most common manifestation was PitNET. One individual had well-differentiated liposarcoma, which has been previously reported in a single case of MEN1. Three variants previously described in the database and a novel variant in exon 2 have been found., Conclusions: The study allowed the genotypic and phenotypic characterization of families with MEN1 in a follow-up at a tertiary center in Brasília., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Miranda, Valadares, Barra, Mesquita, de Santana, de Castro, Rita and Naves.)

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare mosaic bone and endocrine disorder. Although most variants affect the GNAS R201 codon, obtaining a genetic diagnosis is difficult because not all cells harbor the variant, and an invasive biopsy may be required. We explored the presence of GNAS p.R201 variants in blood circulating cell free DNA (ccfDNA) using sensitive techniques of digital droplet polymerase chain reaction (PCR) (ddPCR) and competitive allele-specific TaqMan PCR (castPCR) in an effort to improve the genetic diagnosis of FD/MAS. We isolated ccfDNA from the plasma of 66 patients with a wide range of disease severity and performed both ddPCR and castPCR mutation analysis to search for GNAS p.R201H or R201C variants. We detected R201 variants in ccfDNA samples of 41 of 66 (62.1%) patients by either castPCR or ddPCR, and 45 of 66 (68.2%) of patients if the techniques were combined. Variant detection was more likely in patients with more severe disease. Skeletal disease burden score (SBS) was significantly higher in patients who had detectable variants, and SBS was a predictor of variant allele frequency. By ddPCR analysis, patients aged ≤30 years had higher detection rates, and higher variant allele frequencies, independent of disease burden. We detected variant DNA in only one patient with monostotic FD by ddPCR only. In summary, we have demonstrated that ccfDNA containing variant GNAS can be isolated from the plasma of patients with FD/MAS and that ddPCR and castPCR methods have similar variant detection rates. This methodology represents an important potential advancement in diagnosis for patients with FD/MAS, especially those younger than 30 years or with more severe disease. Published 2023. This article is a U.S. Government work and is in the public domain in the USA., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA.)

Multinucleated osteoclasts, essential for skeletal remodeling in health and disease, are formed by the fusion of osteoclast precursors, where each fusion event raises their bone-resorbing activity. Here we show that the nuclear RNA chaperone, La protein has an additional function as an osteoclast fusion regulator. Monocyte-to-osteoclast differentiation starts with a drastic decrease in La levels. As fusion begins, La reappears as a low molecular weight species at the osteoclast surface, where it promotes fusion. La's role in promoting osteoclast fusion is independent of canonical La-RNA interactions and involves direct interactions between La and Annexin A5, which anchors La to transiently exposed phosphatidylserine at the surface of fusing osteoclasts. Disappearance of cell-surface La, and the return of full length La to the nuclei of mature, multinucleated osteoclasts, acts as an off switch of their fusion activity. Targeting surface La in a novel explant model of fibrous dysplasia inhibits excessive osteoclast formation characteristic of this disease, highlighting La's potential as a therapeutic target., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Cyanobacteria produce a wealth of secondary metabolites. Since these organisms attach fatty acids into molecules in unprecedented ways, cyanobacteria can serve as a novel source for bioactive compounds acting as ligands for Peroxisome Proliferator-Activated Receptors (PPAR). PPARs (PPARα, PPARβ/δ and PPARγ) are ligand-activated nuclear receptors, involved in the regulation of various metabolic and cellular processes, thus serving as potential drug targets for a variety of pathologies. Yet, given that PPARs' agonists can have pan-, dual- or isoform-specific action, some controversy has been raised over currently approved drugs and their side effects, highlighting the need for novel molecules. Here, we expand and validate a cell-based PPAR transactivation activity biosensor, and test it in a screening campaign to guide drug discovery. Biosensor upgrades included the use of different reporter genes to increase signal intensity and stability, a different promoter to modulate reporter gene expression, and multiplexing to improve efficiency. Sensor's limit of detection (LOD) ranged from 0.36-0.89 nM in uniplex and 0.89-1.35 nM in multiplex mode. In triplex mode, the sensor's feature screening, a total of 848 fractions of 96 cyanobacteria extracts were screened. Hits were confirmed in multiplex mode and in uniplex mode, yielding one strain detected to have action on PPARα and three strains to have dual action on PPARα and -β.

This study describes the development of electrochemical paper-based analytical devices (ePADs) using carbon-based paste combining silicone glue and graphite powder. The ePADs were manufactured using the screen-printing technique, which consisted of depositing the conductive ink on a screencast on the paper surface. In addition, an alternative electrical connector was designed and 3D-printed to make the detection method cheaper, portable and reproducible. The morphological, structural, and electrochemical properties of the conductive material developed were investigated through scanning electron microscopy (SEM), Raman spectroscopy, electrochemical impedance spectroscopy (EIS), and cyclic voltammetry (CV) measurements. The ePADs combined with the alternative connector revealed high repeatability, reproducibility, and stable responses considering a well-known redox probe ([Fe(CN) 6 ] 4-/3- ). In addition, the proposed ePAD provided a linear response for standard solutions of ascorbic acid (AA) in the concentration range between 0.1 and 2.0 mmol L -1 . The achieved limit of detection was 4.0 μmol L -1 . As proof of applicability, the ePADs were evaluated for AA analysis in synthetic biofluids (blood plasma and urine), vitamin C tablets, and food (gelatine and orange juice) samples. The analytical parameters of the proposed device were compared with other reports in the literature and exhibited similar or even superior performance, highlighting its feasibility for sensing applications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Since 2011, a massive influx of pelagic brown algae Sargassum has invaded coastlines causing environmental and economic disaster. Valorizing this plentiful macroalgae can present much needed economic relief to the areas affected. Here the production of biodiesel and a high-value alginate stream using Sargassum biomass collected from the coast of Quintana Roo, Mexico is reported. Biomass was pretreated via AEA (Alginate Extraction Autohydrolysis) and enzymatic saccharification via fungal Solid State Fermentation, releasing 7 g/L total sugars. The sugar mixture was fermented using engineered Yarrowia lipolytica resulting in 0.35 g/L total lipid titer at the lab tube scale. Additionally, the capability of extracting 0.3875 g/g DW of a high-value, purified alginate stream from this material is demonstrated. The findings presented here are promising and suggest an opportunity for the optimization and scale up of a biodiesel production biorefinery for utilization of Sargassum seaweeds during seasons of high invasion., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Stomach loss has occurred independently multiple times during gnathostome evolution with notable frequency within the Teleostei. Significantly, this loss of acid-peptic digestion has been found to correlate with the secondary genomic loss of the gastric proton pump subunits (atp4a, atp4b) and pepsinogens/pepsins (pga, pgc). Gastric glands produce gastric juice containing the acid and pepsin and thus their presence is a hallmark feature of a digestive system capable of acid-peptic digestion. However, in gobiid fishes although oesogaster and gastric glands have been identified histologically, their functional significance has been questioned. In the present study we address whether the gastric proton pump is present and expressed in gastric glands of the goby Neogobius species (Gobiidae) and in members of the family Oxudercidae, a group of amphibious gobiid fishes commonly known as mudskippers (genera: Periophthalmus, Boleophthalmus, Periophthalmodon and Scartelaos). We confirmed the presence of gastric glands and have immunohistochemically localized gastric proton pump expression to these glands in Neogobius fluviatilis and Periophthalmus novemradiatus, Periophthalmus barbarus and Boleophthalmus boddarti. Genome analysis in Neogobius melanostomus, Periophthalmus magnuspinnatus, Scartelaos histophorus, Boleophthalmus pectinirostris, and Periophthalmodon schlosseri revealed the presence of both atp4a and atp4b subunit orthologues in all species in a conserved genomic loci organization. Moreover, it was possible to deduce that the complete open reading frame and the key functional amino acid residues are present. The conserved expression of the gastric proton pump provides clear evidence of the potential for gastric acid secretion indicating that acid digestion is retained in these gobiid fishes and not lost., Competing Interests: Declaration of Competing Interest No conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: To analyze and compare, in vitro, the microhardness, sorption, solubility, color stability, and cytotoxicity of three types of resin composites: self-adhesive (SARC) (Dyad Flow (DF)/Kerr), bulk-fill (Filtek Bulk Fill Flow (FBF)/3 M ESPE), and conventional (Filtek Z350XT Flow (Z350)/3 M ESPE)., Materials and Methods: Thirty cylindrical specimens were prepared using a split metal mold (15 mm × 1 mm), divided into 3 groups (n = 10) according to the material used. Vickers hardness (VH) was calculated from three indentations (300gf/15 s) per specimen. The sorption and solubility were measured according to the ISO 4049:2009 specification after storing in distilled water for 7 days. The color of each resin composite was measured using a portable digital spectrophotometer according to the CIELAB system. After a 7-day immersion in coffee, the color variation (∆E) was calculated. Following the ISO 10993:2012, the cytotoxicity in Vero cells was evaluated through the MTT assay. The results were analyzed using the Kruskal-Wallis test to compare the studied groups. The Wilcoxon test was used to compare the assessments in each studied group. For cytotoxicity analysis, the data were compared by the ANOVA test (α = 0.05)., Results: DF showed the lowest VH (28.67), highest sorption (0.543 µg/mm 3 ) and solubility (1.700 µg/mm 3 ), and higher ∆E after 7 days of coffee immersion (p = 0.008). The resin composites studied were considered non-cytotoxic., Conclusions: The SARC presented inferior mechanical and physical-chemical properties than bulk-fill and conventional resin composites, with comparable cytotoxicity against Vero cells., Clinical Relevance: The simplification of the clinical protocol of SARC can minimize the number of possible failures during the restorative technique. However, considering their inferior physical and mechanical properties, their coverage with materials of higher mechanical properties and physical-chemical stability should be considered., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Fibroblast growth factor-23 (FGF23) measurement is a critical tool in the evaluation of patients with disordered phosphate homeostasis. Available laboratory reference ranges for blood FGF23 were developed using samples from normophosphatemic individuals. Reliance on such values can lead to misdiagnosis in patients with FGF23-mediated hypophosphatemia, such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO), in whom pathology-driving FGF23 levels can be in the "normal range." To determine FGF23 levels that are diagnostic for the identification of patients with FGF23-mediated hypophosphatemic disorders, we studied 149 patients with various disorders of FGF23-mediated and FGF23-independent hypophosphatemia and defined cut-off levels for both intact FGF23 (iFGF23) and C-terminal FGF23 (cFGF23) that can accurately distinguish between FGF23-mediated and FGF23-independent hypophosphatemia. In addition, to demonstrate the relationship between FGF23 and phosphate across the spectrum of human physiology, we assessed blood levels of FGF23 and phosphate in 434 patients with various forms of hypophosphatemia, hyperphosphatemia, and normophosphatemia. An intact FGF23 cut point of 27 pg/mL was 100% sensitive and specific in distinguishing FGF23-mediated from FGF23-independent hypophosphatemia, and a cFGF23 cut point of 90 RU/mL was 100% sensitive and specific in distinguishing specifically TIO from FGF23-independent hypophosphatemia. There was overlap in the cFGF23 range of 45-90 RU/mL between genetic forms of FGF23 excess and FGF23-independent hypophosphatemia, substantiating the superiority of iFGF23 over cFGF23 in making the diagnosis of FGF23-mediated hypophosphatemia. In this cohort, using the laboratory upper limit of normal for cFGF23 (180 RU/mL) would result in a misdiagnosis in more than half of patients with FGF23-mediated hypophosphatemia. In this, the largest study of FGF23 in chronic hypophosphatemia to date, we established iFGF23 and cFGF23 cut-off values to assist in the evaluation and diagnosis of hypophosphatemic conditions. © 2022 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA., (© 2022 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Studies have consistently shown a significant increase in the risk of congenital heart defects in the offspring of diabetic mothers compared with those of nondiabetic pregnancies. Evidence points that all types of pregestational diabetes have the capacity of generating cardiac malformations in a more accentuated manner than in gestational diabetes, and there seems to be an increased risk for all congenital heart defects phenotypes in the presence of maternal diabetes. Currently, the application of some therapies is under study in an attempt to reduce the risks inherent to diabetic pregnancies; however, it has not yet been possible to fully prove their effectiveness. The present review aims to better understand the mechanisms that govern the association between pregestational diabetes and congenital heart defects and how maternal diabetes interferes with fetal cardiac development, as there is still a long way to go in the investigation of this complex process., Competing Interests: The authors have no conflict of interests to declare., (Federação Brasileira de Ginecologia e Obstetrícia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Background: Fibrous dysplasia (FD) is an uncommon bone disease characterized by the replacement of normal bone architecture with abnormal fibro-osseous connective tissue. Here, we discuss 2 cases of craniofacial FD, with malignant sarcomatous degeneration - a rare and morbid complication of the disease., Case History: Two cases of craniofacial FD with malignant degeneration are presented. In the first, a 68-year-old male with a history of FD presented with acutely worsening left-sided facial pain and V2 and V3 hypoesthesia. Imaging findings suggested a large infratemporal fossa mass with biopsy demonstrating sarcomatous degeneration. Radical craniofacial resection achieved a gross total resection with likely microscopic disease. The patient was unable to tolerate adjuvant chemotherapy or radiation and succumbed to his disease 13 months following surgery.In the second case, a 36-year-old male with McCune-Albright Syndrome and craniofacial FD presented with acutely worsening left-sided headaches and midface hypoesthesia. Imaging revealed a heterogenous and expansile lesion with erosive changes in the left nasal cavity and infratemporal fossa. Pathology was suggestive of low grade sarcomatous degeneration. Given the extensive involvement of the skull base, the tumor was deemed unresectable, and the patient soon died following initiation of chemotherapy., Clinical Relevance: Malignant sarcomatous transformation is a rare and challenging complication of craniofacial FD. Indolent onset, advanced spread at time of presentation, and close relationship with vital neurovascular structures are all hurdles for the treating clinician. The entity poses a diagnostic dilemma, as pathological analysis can be equivocal and may mimic nonmalignant processes, such as locally aggressive FD., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by Mutaz B. Habal, MD.)

Background: Fibrous dysplasia (FD) is a rare genetic bone disorder resulting in an overproduction of cAMP leading to a structurally unsound tissue, caused by a genetic mutation in the guanine nucleotide-binding protein gene (GNAS). In order to better understand this disease, several animal models have been developed with different strategies and features., Objective: Conduct a systematic review to analyze and compare animal models with the causative mutation and features of FD., Methods: A PRISMA search was conducted in Scopus, PubMed, and Web of Science. Studies reporting an in vivo model of FD that expressed the causative mutation were included for analysis. Models without the causative mutation, but developed an FD phenotype and models of FD cell implantation were included for subanalysis., Results: Seven unique models were identified. The models were assessed and compared for their face validity, construct validity, mosaicism, and induction methods. This was based on the features of clinical FD that were reported within the categories of: macroscopic features, imaging, histology and histomorphometry, histochemical and cellular markers, and blood/urine markers., Limitations: None of the models reported all features of FD and some features were only reported in one model. This made comparing models a challenge, but indicates areas where further research is necessary., Conclusion: The benefits and disadvantages of every model were assessed from a practical and scientific standpoint. While all published reports lacked complete data, the models have nonetheless informed our understanding of FD and provided meaningful information to guide researchers in bench and clinical research., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

High-fat diets seem to have a negative influence on the development of obesity and the processes associated with low-grade chronic systemic inflammation. In recent years, partial hydrogenated oil, rich in trans isomers, has been associated with deleterious health effects. It has been replaced by interesterified fat (IF). However, there is no evidence whether IF ingestion can exert adverse effects on the intestinal mucosa. Thus, this study aimed to evaluate the effect of IF on the intestinal mucosa of male Swiss mice fed a normal or high-fat diet, focusing on its effects on intestinal permeability and bacterial translocation and its possible damage to the intestinal epithelium. The animals were divided into 4 groups: Control (C) and Interesterified Control (IC) groups (10 En% lipids from unmodified fat or interesterified fat, respectively) and High Fat (HF) and Interesterified High Fat (IHF) groups (45 En% lipids from unmodified fat or interesterified fat, respectively). Compare to C, the IC, HF, and IHF groups presented flattened epithelium, a shorter villi length and a lower percentage of goblet cells, less mucin 2, an increased oxidative stress and more inflammatory cells, higher IL-1β, IL-17, and IL-23 levels. These groups also presented increased intestinal permeability and gene expression of the protein claudin 2, while JAM-A and claudin 1 gene expression was reduced. IC and IHF increased IL-6 levels while reducing occludin expression. In addition, the IC group also presented a mucosa with lesions of low intensity in the ileum, an increased mucin 5ac, TNF-α levels, and reduced occludin expression in the distal jejunum. Moreover, there was a significant increase in bacterial translocation in the IC group to blood, liver, and lungs, while HF and IHF groups presented bacterial translocation which was restricted to the mesenteric lymph nodes. In summary, our results supported the hypothesis that IF added to a normolipidic diet can be considered harmful or even worse when compared to a HF., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Shedding synchrotron light on microfluidic systems, exploring several contrasts in situ/operando at the nanoscale, like X-ray fluorescence, diffraction, luminescence, and absorption, has the potential to reveal new properties and functionalities of materials across diverse areas, such as green energy, photonics, and nanomedicine. In this work, we present the micro-fabrication and characterization of a multifunctional polyester/glass sealed microfluidic device well-suited to combine with analytical X-ray techniques. The device consists of smooth microchannels patterned on glass, where three gold electrodes are deposited into the channels to serve in situ electrochemistry analysis or standard electrical measurements. It has been efficiently sealed through an ultraviolet-sensitive sticker-like layer based on a polyester film, and The burst pressure determined by pumping water through the microchannel(up to 0.22 MPa). Overall, the device has demonstrated exquisite chemical resistance to organic solvents, and its efficiency in the presence of biological samples (proteins) is remarkable. The device potentialities, and its high transparency to X-rays, have been demonstrated by taking advantage of the X-ray nanoprobe Carnaúba/Sirius/LNLS, by obtaining 2D X-ray nanofluorescence maps on the microchannel filled with water and after an electrochemical nucleation reaction. To wrap up, the microfluidic device characterized here has the potential to be employed in standard laboratory experiments as well as in in situ and in vivo analytical experiments using a wide electromagnetic window, from infrared to X-rays, which could serve experiments in many branches of science., (© 2021. The Author(s).)

In a previous transcriptomic study of human bone marrow stromal cells (BMSCs, also known as bone marrow-derived "mesenchymal stem cells"), SFRP2 was highly over-represented in a subset of multipotent BMSCs (skeletal stem cells, SSCs), which recreate a bone/marrow organ in an in vivo ectopic bone formation assay. SFRPs modulate WNT signaling, which is essential to maintain skeletal homeostasis, but the specific role of SFRP2 in BMSCs/SSCs is unclear. Here, we evaluated Sfrp2 deficiency on BMSC/SSC function in models of skeletal organogenesis and regeneration. The skeleton of Sfrp2-deficient (KO) mice is overtly normal; but their BMSCs/SSCs exhibit reduced colony-forming efficiency, reflecting low SSC self-renewal/abundancy. Sfrp2 KO BMSCs/SSCs formed less trabecular bone than those from WT littermates in the ectopic bone formation assay. Moreover, regeneration of a cortical drilled hole defect was dramatically impaired in Sfrp2 KO mice. Sfrp2-deficient BMSCs/SSCs exhibited poor in vitro osteogenic differentiation as measured by Runx2 and Osterix expression and calcium accumulation. Interestingly, activation of the Wnt co-receptor, Lrp6, and expression of Wnt target genes, Axin2, C-myc and Cyclin D1, were reduced in Sfrp2-deficient BMSCs/SSCs. Addition of recombinant Sfrp2 restored most of these activities, suggesting that Sfrp2 acts as a Wnt agonist. We demonstrate that Sfrp2 plays a role in self-renewal of SSCs and in the recruitment and differentiation of adult SSCs during bone healing. SFRP2 is also a useful marker of BMSC/SSC multipotency, and a factor to potentially improve the quality of ex vivo expanded BMSC/SSC products., (© 2021. The Author(s).)

Introduction: Xanthones are metabolites with a variety of biological properties. The Clusiaceae family, which until recently included the genus Calophyllum, is recognised for its production of monohydroxylated and polyhydroxylated xanthones. Presently, C. brasiliense is the only Calophyllum spp. known to occur in the Yucatan peninsula., Objective: To use a combination of traditional phytochemical methods and carbon-13 nuclear magnetic resonance ( 13 C-NMR) dereplication analysis to identify xanthones in the stem bark of C. brasiliense., Material and Methods: Initial fractionation and purification of the stem bark extract of C. brasiliense produced macluraxanthone (1). Additional xanthones, together with chromanones and terpenoids, were identified using 13 C-NMR dereplication analysis in different semipurified fractions obtained from the low and medium polarity fractions of the stem bark extract of C. brasiliense., Results: Initial identification of macluraxanthone (1) was confirmed by 13 C-NMR dereplication analysis; additionally, 13 C-NMR dereplication analysis allowed the identification of a number of monohydroxylated and polyhydroxylated xanthones, together with chromanones and terpenoids., Conclusion: This study confirms C. brasiliense as a rich source of xanthones and the 13 C-NMR dereplication analysis as a suitable method to quickly identify the presence of different families of secondary metabolites in semipurified fractions., (© 2021 John Wiley & Sons, Ltd.)

When the World Health Organization declared Covid-19 as a public health emergency of international concern, the Spanish Ministry of Health called the health, labor, social security authorities, Labor and Social Security Inspection, National Institute of Security and Occupational Health, employers, unions, occupational risk prevention services, mutual societies and scientific societies of occupational medicine and nursing, to collaborate in the control of the transmission of SARS-CoV-2 in companies. The Occupational Health Group of the Public Health Commission of the Interterritorial Council of the National Health System, developed the Procedure for the prevention of occupational risks in the face of exposure to SARS-CoV-2, which has been updated 15 times until the date. It contains the prevention measures to be implemented in the workplaces: organizational and collective protection, personal protection, especially vulnerable worker and risk level, study and management of cases and contacts that occurred in the company, collaboration in the management of temporary disability and, more recently, reincorporation and management of vaccinated workers. As a result of these cooperation and collaboration frameworks, a series of activities were deployed in the workplace, which are described in this article.

Background: Telemedicine is a resource to provide health care to patients social distancing and prevent their exposure to the risk of contamination by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in medical-hospital settings. This study evaluated a virtual model of care in acromegalic patients. Methods: We recruited 78 acromegalic patients, 65% female, median age 63 years. Outpatient management was remodeled to simplify access to care by (1) adoption of virtual meetings; (2) collection of blood samples at home; (3) abolishment of printed prescription and provision of electronic files directly to central pharmacy; and (4) drugs delivered to patients' home. Patients and physicians filled electronic surveys 48 h after each consultation. Results: The patients expressed satisfaction with convenience (91.1%), decreased wait time (85.1%), and saving money (79.2%) compared to face-to-face visits. Most patients felt supported by the medical team (89.1%) and kept the prescriptions updated (84.8%). The physicians reported resolutive appointments in 92.2% of cases, despite longer time to reach the patients and subsequent calls to complement missing information. Satisfaction and patient-provider relationship were maintained during the study, but the choice for virtual appointment for the next appointment fell from 78.7% to 34.8% after 6 months. Coronavirus disease 2019 (COVID-19) was confirmed in 13% of patients, mostly mild and moderate manifestations. Conclusion: Telemedicine is a tool for medical care in underserved populations, feasible even in low-income countries. This study suggests that it is difficult to sustain exclusive remote care for more than 6 months. The method could be adopted interchangeably with in-person consultations in acromegalic patients with stable disease.