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Hepatocyte polyploidy and maturity are critical to acquiring specialized liver functions. Multiple intra- and extracellular factors influence ploidy, but how they cooperate temporally to steer liver polyploidization and maturation or how post-transcriptional mechanisms integrate into these paradigms is unknown. Here, we identified an important regulatory hierarchy in which postnatal activation of Epithelial-Splicing-Regulatory-Protein-2 (ESRP2) stimulates biogenesis of liver-specific microRNA (miR-122), thereby facilitating polyploidization, maturation, and functional competence of hepatocytes. By determining transcriptome-wide protein-RNA interactions in vivo and integrating them with single-cell and bulk hepatocyte RNA-seq datasets, we delineate an ESRP2-driven RNA processing program that drives sequential replacement of fetal-to-adult transcript isoforms. Specifically, ESRP2 binds the primary miR-122 host gene transcript to promote its processing/biogenesis. Combining constitutive and inducible ESRP2 gain- and loss-of-function mice models with miR-122 rescue experiments, we demonstrate that timed activation of ESRP2 augments miR-122-driven program of cytokinesis failure, ensuring proper onset and extent of hepatocyte polyploidization.
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BACKGROUND: The aim of the How Farm Vets Cope project was to co-design, with farm veterinary surgeons, a set of web-based resources to help them and others deal with the different situations that they can face. As part of the wider project, participants were recruited for one-to-one semi-structured phone interviews. These interviews focused on elements of job satisfaction and how the participants coped during periods of poor mental wellbeing or with setbacks and failure. METHODS: Transcripts of these interviews were analysed using both quantitative methods of sentiment analysis and text mining, including term frequency/inverse document frequency and rapid automated keyword extraction, and qualitative content analysis. The twin aims of the analysis were identifying the important themes discussed by the participants and comparing the results of the two methods to see what differences, if any, arose. RESULTS: Analysis using the afinn and nrc sentiment lexicons identified emotional themes of anticipation and trust. Rapid automated keyword extraction highlighted issues around age of vets and support, whilst using term frequency/inverse document frequency allowed for individual themes, such as religion, not present across all responses, to be identified. Content analysis supported these findings, pinpointing examples of trust around relationships with farmers and more experienced vets, along with some examples of the difference good support networks can make, particularly to younger vets. FINDINGS: This work has confirmed previous results in identifying the themes of trust, communication and support to be integral to the experience of practicing farm veterinary surgeons. Younger or less experienced vets recognised themselves as benefiting from further support and signposting, leading to a discussion around the preparation of veterinary students for entry into a farm animal vet practice. The two different approaches taken showed very good agreement in their results. The quantitative approaches can be scaled to allow a larger number of interviews to be utilised in studies whilst still allowing the important qualitative results to be identified.
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Minería de Datos , Ganado , Salud Mental , Veterinarios , Humanos , Minería de Datos/métodos , Animales , Veterinarios/psicología , Masculino , Femenino , Adulto , Satisfacción en el Trabajo , Agricultores/psicología , Persona de Mediana Edad , Entrevistas como Asunto , GranjasRESUMEN
MOTIVATION: Supervised deep learning is used to model the complex relationship between genomic sequence and regulatory function. Understanding how these models make predictions can provide biological insight into regulatory functions. Given the complexity of the sequence to regulatory function mapping (the cis-regulatory code), it has been suggested that the genome contains insufficient sequence variation to train models with suitable complexity. Data augmentation is a widely used approach to increase the data variation available for model training, however current data augmentation methods for genomic sequence data are limited. RESULTS: Inspired by the success of comparative genomics, we show that augmenting genomic sequences with evolutionarily related sequences from other species, which we term phylogenetic augmentation, improves the performance of deep learning models trained on regulatory genomic sequences to predict high-throughput functional assay measurements. Additionally, we show that phylogenetic augmentation can rescue model performance when the training set is down-sampled and permits deep learning on a real-world small dataset, demonstrating that this approach improves data efficiency. Overall, this data augmentation method represents a solution for improving model performance that is applicable to many supervised deep-learning problems in genomics. AVAILABILITY AND IMPLEMENTATION: The open-source GitHub repository agduncan94/phylogenetic_augmentation_paper includes the code for rerunning the analyses here and recreating the figures.
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Aprendizaje Profundo , Genómica , Filogenia , Genómica/métodos , Aprendizaje Automático Supervisado , HumanosRESUMEN
The liver's unique chromosomal variations, including polyploidy and aneuploidy, influence hepatocyte identity and function. Among the most well-studied mammalian polyploid cells, hepatocytes exhibit a dynamic interplay between diploid and polyploid states. The ploidy state is dynamic as hepatocytes move through the "ploidy conveyor," undergoing ploidy reversal and re-polyploidization during proliferation. Both diploid and polyploid hepatocytes actively contribute to proliferation, with diploids demonstrating an enhanced proliferative capacity. This enhanced potential positions diploid hepatocytes as primary drivers of liver proliferation in multiple contexts, including homeostasis, regeneration and repopulation, compensatory proliferation following injury, and oncogenic proliferation. This review discusses the influence of ploidy variations on cellular activity. It presents a model for ploidy-associated hepatocyte proliferation, offering a deeper understanding of liver health and disease with the potential to uncover novel treatment approaches.
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Regeneración Hepática , Hígado , Animales , Humanos , Regeneración Hepática/genética , Hepatocitos , Proliferación Celular , Poliploidía , MamíferosRESUMEN
Rift Valley fever virus (RVFV) causes mild to severe disease in humans and livestock. Outbreaks of RVFV have been reported throughout Africa and have spread outside Africa since 2000, calling for urgent worldwide attention to this emerging virus. RVFV directly infects the liver, and elevated transaminases are a hallmark of severe RVFV infection. However, the specific contribution of viral replication in hepatocytes to pathogenesis of RVFV remains undefined. To address this, we generated a recombinant miRNA-targeted virus, RVFVmiR-122, to limit hepatocellular replication. MicroRNAs are evolutionarily conserved non-coding RNAs that regulate mRNA expression by targeting them for degradation. RVFVmiR-122 includes an insertion of four target sequences of the liver-specific miR-122. In contrast to control RVFVmiR-184, which contains four target sequences of mosquito-specific miR-184, RVFVmiR-122 has restricted replication in vitro in primary mouse hepatocytes. RVFVmiR-122-infected C57BL/6 mice survived acute hepatitis and instead developed late-onset encephalitis. This difference in clinical outcome was eliminated in Mir-122 KO mice, confirming the specificity of the finding. Interestingly, C57BL/6 mice infected with higher doses of RVFVmiR-122 had a higher survival rate which was correlated with faster clearance of virus from the liver, suggesting a role for activation of host immunity in the phenotype. Together, our data demonstrate that miR-122 can specifically restrict the replication of RVFVmiR-122 in liver tissue both in vitro and in vivo, and this restriction alters the clinical course of disease following RVFVmiR-122 infection. IMPORTANCE Rift Valley fever virus (RVFV) is a hemorrhagic fever virus that causes outbreaks in humans and livestock throughout Africa and has spread to continents outside Africa since 2000. However, no commercial vaccine or treatment is currently available for human use against RVFV. Although the liver has been demonstrated as a key target of RVFV, the contribution of viral replication in hepatocytes to overall RVFV pathogenesis is less well defined. In this study we addressed this question by using a recombinant miRNA-targeted virus with restricted replication in hepatocytes. We gained a better understanding of how this individual cell type contributes to the development of disease caused by RVFV. Techniques used in this study provide an innovative tool to the RVFV field that could be applied to study the consequences of limited RVFV replication in other target cells.
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Hepatocitos , Fiebre del Valle del Rift , Virus de la Fiebre del Valle del Rift , Replicación Viral , Animales , Humanos , Ratones , Hepatocitos/patología , Hepatocitos/virología , Ratones Endogámicos C57BL , MicroARNs/genética , Fiebre del Valle del Rift/virología , Virus de la Fiebre del Valle del Rift/fisiologíaRESUMEN
Sterile α-motif domain-14 (Samd14) protein expression increases the regenerative capacity of the erythroid system. Samd14 is transcriptionally upregulated and promotes cell signaling via the receptor tyrosine kinase Kit in a critical window of acute erythroid regeneration. We generated a hematopoietic-specific conditional Samd14 knockout mouse model (Samd14-CKO) to study the role of Samd14 in hematopoiesis. The Samd14-CKO mouse was viable and exhibited no steady-state hematopoietic phenotype. Samd14-CKO mice were hypersensitive to 5-fluorouracil, resulting in more severe anemia during recovery and impaired erythroid progenitor colony formation. Ex vivo, Samd14-CKO hematopoietic progenitors were defective in their ability to form mast cells. Samd14-CKO mast cells exhibited altered Kit/stem cell factor (SCF), IL-3/IL-3R signaling, and less granularity than Samd14-FL/FL cells. Our findings indicate that Samd14 promotes both erythroid and mast cell functions. The Samd14-CKO mouse phenotype exhibits striking similarities to the KitW/W-v mice, which carry Kit mutations resulting in reduced tyrosine kinase-dependent signaling, causing mast cell and erythroid abnormalities. The Samd14-CKO mouse model is a new tool for studying hematologic pathologies involving Kit signaling.
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Anemia , Proteínas del Citoesqueleto , Hematopoyesis , Animales , Ratones , Anemia/metabolismo , Hematopoyesis/genética , Proteínas , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Transducción de Señal , Factor de Células Madre/genética , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismoRESUMEN
[This corrects the article DOI: 10.3389/fvets.2023.1099057.].
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We present JBrowse 2, a general-purpose genome annotation browser offering enhanced visualization of complex structural variation and evolutionary relationships. It retains core features of JBrowse while adding new views for synteny, dotplots, breakpoints, gene fusions, and whole-genome overviews. It allows users to share sessions, open multiple genomes, and navigate between views. It can be embedded in a web page, used as a standalone application, or run from Jupyter notebooks or R sessions. These improvements are enabled by a ground-up redesign using modern web technology. We describe application functionality, use cases, performance benchmarks, and implementation notes for web administrators and developers.
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Genómica , Programas Informáticos , Sintenía , Genoma , Evolución Biológica , Navegador Web , InternetRESUMEN
AIMS: Copper deficiency resulting from prescribing zinc in high doses is a rare but life-changing diagnosis that is frequently overlooked. The aim of this study is to gauge how often zinc-induced copper deficiency is missed, to raise awareness of the condition and to stress the need for guidelines for prescribing zinc. METHODS: Suspected cases of zinc-induced copper deficiency were retrospectively obtained by selecting those patients with hyperzincaemia and hypocupraemia from the database of the Scottish Trace Element Laboratory. Case records were reviewed to determine the validity of the suspected diagnosis. RESULTS: After exclusions, 23 instances of high serum zinc and low serum copper concentrations were found. A positive diagnosis of zinc-induced copper deficiency was made in 14 patients, of which 7 (50%) were previously undiagnosed. CONCLUSION: Serum zinc and copper concentrations are rarely measured in patients prescribed zinc and so the vast majority of cases of zinc-induced copper deficiency are likely to be undiagnosed. We recommend the current official advice on the dose and frequency of zinc administration is revised in order to limit, and potentially eradicate, the condition.
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Cobre , Zinc , Humanos , Cobre/efectos adversos , Zinc/efectos adversos , Estudios Retrospectivos , Enfermedad IatrogénicaRESUMEN
Regular evaluation is a prerequisite for systems that provide surveillance of animal populations. Scotland's Rural College Veterinary Services' Disease Surveillance Centre (DSC) network plays an integral part in surveillance to detect new and re-emerging threats within animal populations, predominantly livestock. In response to surveillance reviews and proposed changes to the network, an initial evaluation of diagnostic submissions data in 2010 to mid-2012 established a baseline "footprint," while highlighting challenges with the data. In this recent evaluation for the period 20132018, we developed a new denominator using a combination of agricultural census and movement data, to identify relevant holdings more accurately. Iterative discussions between those processing submissions data and those involved in collection at source took place to understand the intricacies of the data, establish the most appropriate dataset, and develop the processes required to optimise the data extraction and cleansing. The subsequent descriptive analysis identifies the number of diagnostic submissions, the number of unique holdings making submissions to the network and shows that both the surrounding geographic region of, and maximum distance to the closest DSC vary greatly between centres. Analysis of those submissions classed as farm animal post-mortems also highlights the effect of distance to the closest DSC. Whether specific differences between the time periods are due to changes in the behavior of the submitting holdings or the data extraction and cleaning processes was difficult to disentangle. However, with the improved techniques producing better data to work with, a new baseline footprint for the network has been created. This provides information that can help policy makers and surveillance providers make decisions about service provision and evaluate the impact of future changes. Additionally, the outputs of these analyses can provide feedback to those employed in the service, providing evidence of what they are achieving and why changes to data collection processes and ways of working are being made. In a different setting, other data will be available and different challenges may arise. However, the fundamental principles highlighted in these evaluations and the solutions developed should be of interest to any surveillance providers generating similar diagnostic data.
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We report the case of a 44-year-old gentleman who underwent coarctation repair at the age of 7 years. He was lost to follow-up and represented. Computed tomography scan demonstrated a 9.8-cm diameter aortic aneurysm involving the distal aortic arch and proximal descending aorta. Open surgery was performed to repair the aneurysm. The patient made an unremarkable recovery. He was followed up 12 weeks later, and significant improvement in preoperative symptoms was observed. This case demonstrates the importance of long-term follow-up.
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The rate that people are bitten by ticks is critical in determining the risk of tick-borne infections but is rarely quantified accurately. Often tick abundance in the environment is used as a proxy for tick bite risk, but the relationship with risk is poorly understood. We used a novel citizen science approach to measure tick bite rate in orienteers, to assess the relationship between tick abundance and tick bite risk and to identify risk factors for tick bites. Eleven orienteering events were attended in Scotland between August 2018 and September 2019. The number of tick bites in orienteers, and the time and distance of activity were collected using an online questionnaire. Tick abundance in the same areas used for the orienteering events was estimated by surveying ticks on ground vegetation using blanket drags. Among orienteers, mean incidence was 409 tick bites per 1,000 person-hours. Tick abundance and tick bite rate were strongly correlated, indicating that data from questing tick surveys is a useful proxy for the risk of human tick bites. Tick bite rate was better explained by the activity duration than distance covered and was higher in orienteers that ran earlier in the day, exposed to higher temperatures and in woodland habitats. This study highlights the value of the citizen science approach used, which crucially included submission of activity reports both with and without ticks, to generate robust data on tick bite rate. Accurately measuring tick bite rate and understanding environmental factors that influence it are essential in mitigating the risk of tick-borne diseases.
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Ixodes , Mordeduras de Garrapatas , Enfermedades por Picaduras de Garrapatas , Animales , Humanos , Mordeduras de Garrapatas/epidemiología , Enfermedades por Picaduras de Garrapatas/epidemiología , Ecosistema , Escocia/epidemiologíaRESUMEN
OBJECTIVES: To describe the incidence of adverse events (AEs), reactogenicity symptoms, menstrual changes and overall self-rated improvement in health and well-being after COVID-19 vaccination. DESIGN: VAC4COVID is an ongoing prospective, active observational, post-authorisation cohort safety study (PASS) of UK-approved vaccines for COVID-19 disease. SETTING: The study is conducted through a secure website (www.vac4covid.com) by MEMO Research, University of Dundee, UK. PARTICIPANTS: 16 265 adult (18 years or older) UK residents with a valid email address and internet access. INTERVENTIONS: Any UK-authorised COVID-19 vaccination. MAIN OUTCOME MEASURES: The outcomes reported in this interim analysis include AEs, reactogenicity-type AEs (headache, fatigue, muscle or joint pain, fever, nausea, dizziness or local vaccine reaction), menstrual changes and reported improvement in overall health and well-being. RESULTS: 11 475 consented participants (mean age 54.8 years) provided follow-up data between 2 February and 5 October 2021 (mean follow-up duration 184 days), by which date 89.2% of participants had received two vaccine doses. 89.8% of 5222 participants who completed a follow-up questionnaire in the 7 days after any COVID-19 vaccination reported no AEs. The risk of experiencing any event (not necessarily vaccine-related) requiring hospitalisation was less than 0.2%. 43.7% of post-vaccination follow-up records reported improvement in health and well-being. Reactogenicity-type reactions were more common in the week after the first dose of ChAdOx1 than BNT162b2 (7.8% vs 1.6%), but this relationship was reversed after the second dose (1.3% vs 3.1%). 0.3% of women reported menstrual symptoms after vaccination; no differences between vaccine type or dose order were detected. CONCLUSIONS: The study provides reassuring data on low rates of AEs after COVID-19 vaccination. Differences in reactogenicity-type AE profiles between ChAdOx1 and BNT162b2 and between first and second doses of these vaccines were observed. TRIAL REGISTRATION NUMBER: ISRCTN95881792; Pre-results.
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Vacunas contra la COVID-19 , COVID-19 , Adulto , Vacuna BNT162 , COVID-19/epidemiología , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Vacunación/efectos adversosRESUMEN
Autoimmune encephalitis (AE) is a neurological disorder caused by autoimmune attack on cerebral proteins. Experts currently recommend staged immunotherapeutic management, with first-line immunotherapy followed by second-line immunotherapy if response to first-line therapy is inadequate. Meta-analysis of the evidence base may provide higher quality evidence to support this recommendation. We undertook a systematic review of observational cohort studies reporting AE patients treated with either second-line immunotherapy or first-line immunotherapy alone, and outcomes reported using the modified Rankin Scale (mRS; search date: April 22, 2020). We performed several one-stage multilevel individual patient data (IPD) meta-analyses to examine the association between second-line immunotherapy and final mRS scores (PROSPERO ID CRD42020181805). IPD were obtained for 356 patients from 25 studies. Most studies were rated as moderate to high risk of bias. Seventy-one patients (71/356, 19%) were treated with second-line immunotherapy. We did not find a statistically significant association between treatment with second-line immunotherapy and final mRS score for the cohort overall (odds ratio [OR] = 1.74, 95% confidence interval [CI] = .98-3.08, p = .057), or subgroups with anti-N-methyl-D-aspartate receptor encephalitis (OR = 1.03, 95% CI = .45-2.38, p = .944) or severe AE (maximum mRS score > 2; OR = 1.673, 95% CI = .93-3.00, p = .085). Treatment with second-line immunotherapy was associated with higher final mRS scores in subgroups with anti-leucine-rich glioma-inactivated 1 AE (OR = 6.70, 95% CI = 1.28-35.1, p = .024) and long-term (at least 12 months) follow-up (OR = 3.94, 95% CI = 1.67-9.27, p = .002). We did not observe an association between treatment with second-line immunotherapy and lower final mRS scores in patients with AE. This result should be interpreted with caution, given the risk of bias, limited adjustment for disease severity, and insensitivity of the mRS in estimating psychiatric and cognitive disability.
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Encefalitis Antirreceptor N-Metil-D-Aspartato , Enfermedad de Hashimoto , Encefalitis , Enfermedad de Hashimoto/terapia , Humanos , Factores Inmunológicos , Inmunoterapia , Estudios RetrospectivosRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is an epidemic affecting 30% of the US population. It is characterized by insulin resistance, and by defective lipid metabolism and mitochondrial dysfunction in the liver. SLC25A34 is a major repressive target of miR-122, a miR that has a central role in NAFLD and liver cancer. However, little is known about the function of SLC25A34. To investigate SLC25A34 in vitro, mitochondrial respiration and bioenergetics were examined using hepatocytes depleted of Slc25a34 or overexpressing Slc25a34. To test the function of SLC25A34 in vivo, a hepatocyte-specific knockout mouse was generated, and loss of SLC25A34 was assessed in mice maintained on a chow diet and a fast-food diet (FFD), a model for NAFLD. Hepatocytes depleted of Slc25a34 displayed increased mitochondrial biogenesis, lipid synthesis, and ADP/ATP ratio; Slc25a34 overexpression had the opposite effect. In the knockout model on chow diet, SLC25A34 loss modestly affected liver function (altered glucose metabolism was the most pronounced defect). RNA-sequencing revealed changes in metabolic processes, especially fatty acid metabolism. After 2 months on FFD, knockouts had a more severe phenotype, with increased lipid content and impaired glucose tolerance, which was attenuated after longer FFD feeding (6 months). This work thus presents a novel model for studying SLC25A34 in vivo in which SLC25A34 plays a role in mitochondrial respiration and bioenergetics during NAFLD.
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MicroARNs , Enfermedad del Hígado Graso no Alcohólico , Animales , Dieta Alta en Grasa , Glucosa/metabolismo , Hepatocitos/metabolismo , Homeostasis , Metabolismo de los Lípidos , Lípidos , Hígado/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , MicroARNs/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismoRESUMEN
Facial expressions are subtle cues, central for communication and conveying emotions in mammals. Traditionally, facial expressions have been classified as a whole (e.g. happy, angry, bared-teeth), due to automatic face processing in the human brain, i.e., humans categorise emotions globally, but are not aware of subtle or isolated cues such as an eyebrow raise. Moreover, the same facial configuration (e.g. lip corners pulled backwards exposing teeth) can convey widely different information depending on the species (e.g. humans: happiness; chimpanzees: fear). The Facial Action Coding System (FACS) is considered the gold standard for investigating human facial behaviour and avoids subjective interpretations of meaning by objectively measuring independent movements linked to facial muscles, called Action Units (AUs). Following a similar methodology, we developed the CalliFACS for the common marmoset. First, we determined the facial muscular plan of the common marmoset by examining dissections from the literature. Second, we recorded common marmosets in a variety of contexts (e.g. grooming, feeding, play, human interaction, veterinary procedures), and selected clips from online databases (e.g. YouTube) to identify their facial movements. Individual facial movements were classified according to appearance changes produced by the corresponding underlying musculature. A diverse repertoire of 33 facial movements was identified in the common marmoset (15 Action Units, 15 Action Descriptors and 3 Ear Action Descriptors). Although we observed a reduced range of facial movement when compared to the HumanFACS, the common marmoset's range of facial movements was larger than predicted according to their socio-ecology and facial morphology, which indicates their importance for social interactions. CalliFACS is a scientific tool to measure facial movements, and thus, allows us to better understand the common marmoset's expressions and communication. As common marmosets have become increasingly popular laboratory animal models, from neuroscience to cognition, CalliFACS can be used as an important tool to evaluate their welfare, particularly in captivity.
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Callithrix , Reconocimiento Facial , Animales , Emociones/fisiología , Expresión Facial , Músculos Faciales/fisiología , MamíferosRESUMEN
BACKGROUND & AIMS: Interpretation of blood micronutrient levels requires age-appropriate reference intervals. This study developed age-dependent micronutrient centiles for healthy children (HC) and explored their utility in sick children. METHODS: 244 blood samples were collected from normal HC who underwent tests for acute illness. Age-dependent, centile charts were fitted for zinc, copper, magnesium and selenium in plasma and erythrocytes (RBC), and for vitamins B1, B2 and B6 in RBC. For 34 children with Crohn's disease (CrD) and 55 with coeliac disease (CoeD), Z-scores for the levels of these micronutrients were computed, using the new charts. Associations were explored between plasma and RBC micronutrient Z-scores, and in CrD with CRP and serum albumin. RESULTS: In HC, plasma zinc and selenium increased and plasma copper, magnesium and RBC vitamins B1, B2 and B6 decreased with age. In HC and in CrD, plasma and RBC Z-scores for copper, selenium and magnesium (all p < 0.001) were positively correlated, but not for zinc. In CrD, albumin was related with plasma zinc (rho = 0.62; p < 0.001) and selenium Z-scores (rho = 0.65; p < 0.001) and plasma copper Z-score with CRP (rho = 0.45; p = 0.02). A higher proportion of CrD children had low levels for B2 (21% vs 0%; p = 0.01) and B6 (18% vs 0%; p = 0.02) using the new centile charts than the local laboratory references. CONCLUSION: Age-dependent micronutrient centile charts enable tracking of micronutrient status, Z-score calculation and may prevent misdiagnosis and inappropriate treatment of deficiencies. In systemic inflammatory conditions, RBC measurements of certain micronutrients may be more reliable to use than measurements in plasma.
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Selenio , Oligoelementos , Niño , Cobre , Humanos , Micronutrientes , Albúmina Sérica , ZincRESUMEN
BACKGROUND & AIMS: The c-Myc (Myc) Basic helix-loop-helix leucine zipper (bHLH-ZIP) transcription factor is deregulated in most cancers. In association with Max, Myc controls target genes that supervise metabolism, ribosome biogenesis, translation, and proliferation. This Myc network crosstalks with the Mlx network, which consists of the Myc-like proteins MondoA and ChREBP, and Max-like Mlx. Together, this extended Myc network regulates both common and distinct gene targets. Here, we studied the consequence of Myc and/or Mlx ablation in the liver, particularly those pertaining to hepatocyte proliferation, metabolism, and spontaneous tumorigenesis. METHODS: We examined the ability of hepatocytes lacking Mlx (MlxKO) or Myc+Mlx (double KO [DKO]) to repopulate the liver over an extended period of time in a murine model of type I tyrosinemia. We also compared this and other relevant behaviors, phenotypes, and transcriptomes of the livers with those from previously characterized MycKO, ChrebpKO, and MycKO × ChrebpKO mice. RESULTS: Hepatocyte regenerative potential deteriorated as the Extended Myc Network was progressively dismantled. Genes and pathways dysregulated in MlxKO and DKO hepatocytes included those pertaining to translation, mitochondrial function, and hepatic steatosis resembling nonalcoholic fatty liver disease. The Myc and Mlx Networks were shown to crosstalk, with the latter playing a disproportionate role in target gene regulation. All cohorts also developed steatosis and molecular evidence of early steatohepatitis. Finally, MlxKO and DKO mice showed extensive hepatic adenomatosis. CONCLUSIONS: In addition to showing cooperation between the Myc and Mlx Networks, this study showed the latter to be more important in maintaining proliferative, metabolic, and translational homeostasis, while concurrently serving as a suppressor of benign tumorigenesis. GEO accession numbers: GSE181371, GSE130178, and GSE114634.