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We built a reference panel with 342 million autosomal variants using 78,195 individuals from the Genomics England (GEL) dataset, achieving a phasing switch error rate of 0.18% for European samples and imputation quality of r2 = 0.75 for variants with minor allele frequencies as low as 2 × 10-4 in white British samples. The GEL-imputed UK Biobank genome-wide association analysis identified 70% of associations found by direct exome sequencing (P < 2.18 × 10-11), while extending testing of rare variants to the entire genome. Coding variants dominated the rare-variant genome-wide association results, implying less disruptive effects of rare non-coding variants.
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Traditional activators such as sodium hydroxide and sodium silicate are commonly used in the preparation of alkali-activated materials; however, their significant environmental impact, high cost, and operational risks limit their sustainable use in treating solid waste. This study explores the innovative use of carbide slag (CS) and sodium metasilicate (NS) as alternative activators in the production of sewage sludge ash-based alkali-activated materials (SSAM) with the aim of reducing the carbon footprint of the preparation process. The results demonstrate that CS effectively activates the sewage sludge ash, enhancing the compressive strength of the SSAM to 40 MPa after curing for 28 d. When used in conjunction with NS, it synergistically improves the mechanical properties. Furthermore, the microstructure and phase composition of the SSAM are characterized. Increasing the quantities of CS and NS accelerates the dissolution of the precursor materials, promoting the formation of a higher quantity of hydration products. This significantly reduces the number of voids and defects within the samples, further enhancing the densification of the microstructure. Environmental assessments reveal that CS and NS offer substantial sustainability benefits, confirming the feasibility of activating SSAM using these materials. This approach provides a less energy-intensive and more environmentally friendly alternative to conventional activation methods and presents an effective strategy for managing large volumes of sewage sludge ash and CS.
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Aguas del Alcantarillado , Silicatos , Silicatos/química , Aguas del Alcantarillado/química , Álcalis/química , Residuos SólidosRESUMEN
BACKGROUND: Under fasting conditions, the pathway converting gluconeogenesis precursors into muscle glycogen becomes crucial due to reduced glycogen reserves. However, there is limited research on skeletal muscle gluconeogenesis and the impact of fasting on gluconeogenic gene expression. METHODS: Sheep fetal skeletal muscle cells cultured in vitro were used to study the effects of varying lactic acid concentrations (0 to 30 mM) and 2.5 mM glucose on the expression of gluconeogenesis-related genes after 6 h of fasting. The effects on mRNA and protein expression of key genes involved in skeletal muscle gluconeogenesis were measured by quantitative real time polymerase chain reaction (qRT-PCR), immunofluorescence, and western blotting at 48 h. RESULTS: Fasting increased the expression of key gluconeogenic genes, fructose-1,6-bisphosphatase 2 (FBP2), glucose-6-phosphatase 3 (G6PC3), pyruvate kinase M (PKM), monocarboxylate transporter1 (MCTS1), glucose transporter type 4 (GLUT4), pyruvate carboxylase (PC), and lactate dehydrogenase A (LDHA). The mRNA levels of FBP2, G6PC3, and MCTS1 significantly decreased with glucose addition. Additionally, 10 mM lactic acid significantly promoted the expression of FBP2, PC, MCTS1, LDHA, GLUT4, and PKM while inhibiting phosphoenolpyruvate carboxykinase (PEPCK) expression. At the protein level, 10 mM lactic acid significantly increased FBP2 and PKM protein expression. CONCLUSIONS: This study shows that fasting regulates key gluconeogenic gene expression in sheep skeletal muscle cells and highlights the role of lactic acid in inducing these gene expressions.
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Regulación de la Expresión Génica , Gluconeogénesis , Músculo Esquelético , Animales , Gluconeogénesis/genética , Gluconeogénesis/efectos de los fármacos , Ovinos , Músculo Esquelético/metabolismo , Músculo Esquelético/citología , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/metabolismo , Células Cultivadas , Ácido Láctico/metabolismo , Fructosa-Bifosfatasa/genética , Fructosa-Bifosfatasa/metabolismoRESUMEN
Constructed wetlands (CWs) are pivotal for wastewater treatment due to their high efficiency and numerous advantages. The impact of plant species and diversity on greenhouse gas (GHG) emissions from CWs requires a more comprehensive evaluation. Moreover, controversial perspectives persist about whether CWs function as carbon sinks or sources. In this study, horizontal subsurface flow (HSSF) CWs vegetated with Cyperus alternifolius, Typhae latifolia, Acorus calamus, and the mixture of these three species were constructed to evaluate pollutant removal efficiencies and GHG emissions, and estimate carbon budgets. Polyculture CWs can stably remove COD (86.79 %), NH4+-N (97.41 %), NO3--N (98.55 %), and TP (98.48 %). They also mitigated global warming potential (GWP) by suppressing N2O emissions compared with monoculture CWs. The highest abundance of the Pseudogulbenkiania genus, crucial for denitrification, was observed in polyculture CWs, indicating that denitrification dominated in nitrogen removal. While the highest nosZ copy numbers were observed in CWs vegetated with Cyperus alternifolius, suggesting its facilitation of denitrification-related microbes. Selecting Cyperus alternifolius to increase species diversity is proposed for simultaneously maintaining the water purification capacity and reducing GHG emissions. Carbon budget estimations revealed that all four types of HSSF CWs were carbon sinks after six months of operation, with carbon accumulation capacity of 4.90 ± 1.50 (Cyperus alternifolius), 3.31 ± 2.01 (Typhae latifola), 1.78 ± 1.30 (Acorus calamus), and 2.12 ± 0.88 (polyculture) kg C/m2/yr. This study implies that under these operation conditions, CWs function as carbon sinks rather than sources, aligning with carbon peak and neutrality objectives and presenting significant potential for carbon reduction efforts.
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Gases de Efecto Invernadero , Eliminación de Residuos Líquidos , Humedales , Gases de Efecto Invernadero/análisis , Eliminación de Residuos Líquidos/métodos , Cyperus/metabolismo , Carbono/metabolismo , Aguas Residuales , Typhaceae/metabolismo , Acorus/metabolismoRESUMEN
Aim: The present study was designed to investigate the coregulatory effects of multiple histone modifications (HMs) on gene expression in lung adenocarcinoma (LUAD). Materials & methods: Ten histones for LUAD were analyzed using ChIP-seq and RNA-seq data. An innovative computational method is proposed to quantify the coregulatory effects of multiple HMs on gene expression to identify strong coregulatory genes and regions. This method was applied to explore the coregulatory mechanisms of key ferroptosis-related genes in LUAD. Results: Nine strong coregulatory regions were identified for six ferroptosis-related genes with diverse coregulatory patterns (CA9, PGD, CDKN2A, PML, OTUB1 and NFE2L2). Conclusion: This quantitative method could be used to identify important HM coregulatory genes and regions that may be epigenetic regulatory targets in cancers.
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Chiral halide perovskite materials promise both superior light response and the capability to distinguish circularly polarized emissions, which are especially common in the fluorescence spectra of organic chiral materials. Herein, thin-film field-effect transistors (FETs) based on chiral quasi-two-dimensional perovskites are explored, and the temperature dependence of the charge carrier transport mechanism over the broad temperature range (80-300 K) is revealed. A typical p-type charge transport behavior is observed for both left-handed (S-C6H5(CN2)2NH3)2(CH3NH3)n-1PbnI3n+1 and right-handed (R-C6H5(CN2)2NH3)2(CH3NH3)n-1PbnI3n+1 chiral perovskites, with maximum carrier mobilities of 1.7 × 10-5 cm2 V-1 s-1 and 2.5 × 10-5 cm2 V-1 s-1 at around 280 K, respectively. The shallow traps with smaller activation energy (0.03 eV) hinder the carrier transport over the lower temperature regime (80-180 K), while deep traps with 1 order of magnitude larger activation energy than the shallow traps moderate the charge carrier transport in the temperature range of 180-300 K. From the charge carrier mechanism point of view, impurity scattering is established as the dominant factor from 80 K until around 280 K, while phonon scattering becomes predominant up to room temperature. Responsivities of 0.15 A W-1 and 0.14 A W-1 for left-handed and right-handed chiral perovskite FET devices are obtained.
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BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 25% of the population and currently has no effective treatments. Plasma proteins with causal evidence may represent promising drug targets. We aimed to identify plasma proteins in the causal pathway of MASLD and explore their interaction with obesity. METHODS: We analysed 2,941 plasma proteins in 43,978 European participants from UK Biobank. We performed genome-wide association study (GWAS) for all MASLD-associated proteins and created the largest MASLD GWAS (109,885 cases/1,014,923 controls). We performed Mendelian Randomization (MR) and integrated proteins and their encoding genes in MASLD ranges to identify candidate causal proteins. We then validated them through independent replication, exome sequencing, liver imaging, bulk and single-cell gene expression, liver biopsies, pathway, and phenome-wide data. We explored the role of obesity by MR and multivariable MR across proteins, body mass index, and MASLD. RESULTS: We found 929 proteins associated with MASLD, reported five novel genetic loci associated with MASLD, and identified 17 candidate MASLD protein targets. We identified four novel targets for MASLD (CD33, GRHPR, HMOX2, and SCG3), provided protein evidence supporting roles of AHCY, FCGR2B, ORM1, and RBKS in MASLD, and validated nine previously known targets. We found that CD33, FCGR2B, ORM1, RBKS, and SCG3 mediated the association of obesity and MASLD, and HMOX2, ORM1, and RBKS had effect on MASLD independent of obesity. CONCLUSIONS: This study identified new protein targets in the causal pathway of MASLD, providing new insights into the multi-omics architecture and pathophysiology of MASLD. These findings advise further therapeutic interventions for MASLD.
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Dkks have inhibitory effects on the Wnt signaling pathway, which is involved in the development of skin and its appendages and the regulation of hair growth. The nucleotide sequences were compared and analyzed to further investigate the relationship between the structure and function of the Dkk gene family and vertebrate epidermal hair. The analysis of the molecular evolution of the Dkk family revealed that the evolution rate of the genes changed significantly after speciation, with the Aves and Reptilia branches showing accelerated evolution. Additionally, positive selection was observed at specific sites. The tertiary structure of the protein was also predicted. The analysis of the functional divergence of the Dkk family revealed that the functional divergence coefficient of each gene was greater than 0, with most of the functional divergence sites were located in the Cys-2 domain and a few in the Cys-1 domain. This suggests that the amino acid and functional divergence sites may play a role in regulating the binding of the Dkk family to LRP5/6, and thus affect the inhibition of Wnt signaling, leading to different functions of Dkk1, Dkk2, and Dkk4 in the development of skin hair follicles. In addition, the Dkk families of Aves and Reptilia may have undergone adaptive evolution and functional divergence.
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Péptidos y Proteínas de Señalización Intercelular , Vía de Señalización Wnt , Péptidos y Proteínas de Señalización Intercelular/genética , Vía de Señalización Wnt/genética , Secuencia de Bases , Evolución MolecularRESUMEN
The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into trans pQTLs across multiple biological domains, highlight genetic influences on ligand-receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public-private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics1.
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Bancos de Muestras Biológicas , Proteínas Sanguíneas , Bases de Datos Factuales , Genómica , Salud , Proteoma , Proteómica , Humanos , Sistema del Grupo Sanguíneo ABO/genética , Proteínas Sanguíneas/análisis , Proteínas Sanguíneas/genética , COVID-19/genética , Descubrimiento de Drogas , Epistasis Genética , Fucosiltransferasas/metabolismo , Predisposición Genética a la Enfermedad , Plasma/química , Proproteína Convertasa 9/metabolismo , Proteoma/análisis , Proteoma/genética , Asociación entre el Sector Público-Privado , Sitios de Carácter Cuantitativo , Reino Unido , Galactósido 2-alfa-L-FucosiltransferasaRESUMEN
A large volume, scalable synthesis procedure of HgTe quantum dots (QDs) capped initially with short-chain conductive ligands ensures ligand exchange-free and simple device fabrication. An effective n- or p-type self-doping of HgTe QDs is achieved by varying cation-anion ratio, as well as shifting the Fermi level position by introducing single- or double-cyclic thiol ligands, that is, 2-furanmethanethiol (FMT) or 2,5-dimercapto-3,4-thiadiasole (DMTD) in the synthesis. This allows for preserving the intact surface of the HgTe QDs, thus ensuring a one order of magnitude reduced surface trap density compared with HgTe subjected to solid-state ligand exchange. The charge carrier diffusion length can be extended from 50 to 90 nm when the device active area consists of a bi-layer of cation-rich HgTe QDs capped with DMTD and FMT, respectively. As a result, the responsivity under 1340 nm illumination is boosted to 1 AW-1 at zero bias and up to 40 AW-1 under -1 V bias at room temperature. Due to high noise current density, the specific detectivity of these photodetectors reaches up to 1010 Jones at room temperature and under an inert atmosphere. Meanwhile, high photoconductive gain ensures a rise in the external quantum efficiency of up to 1000% under reverse bias.
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Background & Aims: Non-alcoholic fatty liver disease (NAFLD) has a prevalence of â¼25% worldwide, with significant public health consequences yet few effective treatments. Human genetics can help elucidate novel biology and identify targets for new therapeutics. Genetic variants in mitochondrial amidoxime-reducing component 1 (MTARC1) have been associated with NAFLD and liver-related mortality; however, its pathophysiological role and the cell type(s) mediating these effects remain unclear. We aimed to investigate how MTARC1 exerts its effects on NAFLD by integrating human genetics with in vitro and in vivo studies of mARC1 knockdown. Methods: Analyses including multi-trait colocalisation and Mendelian randomisation were used to assess the genetic associations of MTARC1. In addition, we established an in vitro long-term primary human hepatocyte model with metabolic readouts and used the Gubra Amylin NASH (GAN)-diet non-alcoholic steatohepatitis mouse model treated with hepatocyte-specific N-acetylgalactosamine (GalNAc)-siRNA to understand the in vivo impacts of MTARC1. Results: We showed that genetic variants within the MTARC1 locus are associated with liver enzymes, liver fat, plasma lipids, and body composition, and these associations are attributable to the same causal variant (p.A165T, rs2642438 G>A), suggesting a shared mechanism. We demonstrated that increased MTARC1 mRNA had an adverse effect on these traits using Mendelian randomisation, implying therapeutic inhibition of mARC1 could be beneficial. In vitro mARC1 knockdown decreased lipid accumulation and increased triglyceride secretion, and in vivo GalNAc-siRNA-mediated knockdown of mARC1 lowered hepatic but increased plasma triglycerides. We found alterations in pathways regulating lipid metabolism and decreased secretion of 3-hydroxybutyrate upon mARC1 knockdown in vitro and in vivo. Conclusions: Collectively, our findings from human genetics, and in vitro and in vivo hepatocyte-specific mARC1 knockdown support the potential efficacy of hepatocyte-specific targeting of mARC1 for treatment of NAFLD. Impact and implications: We report that genetically predicted increases in MTARC1 mRNA associate with poor liver health. Furthermore, knockdown of mARC1 reduces hepatic steatosis in primary human hepatocytes and a murine NASH model. Together, these findings further underscore the therapeutic potential of targeting hepatocyte MTARC1 for NAFLD.
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Organic-inorganic (hybrid) metal halide perovskites (MHPs) incorporating chiral organic ligand molecules are naturally sensitive to left- and right-handed circular polarized light, potentially enabling selective circular polarized photodetection. Here, the photoresponses in chiral MHP polycrystalline thin films made of ((S)-(-)-α-methyl benzylamine)2PbI4 and ((R)-(+)-α-methyl benzylamine)2PbI4, denoted as (S-MBA)2 PbI4 and (R-MBA)2PbI4, respectively, are investigated by employing a thin-film field-effect transistor (FET) configuration. The left-hand-sensitive films made of (S-MBA)2PbI4 perovskite show higher photocurrent under left-handed circularly polarized (LCP) light than under right-handed circularly polarized (RCP) illumination under otherwise identical conditions. Conversely, the right-hand-sensitive films made of (R-MBA)2PbI4 are more sensitive to RCP than LCP illumination over a wide temperature range of 77-300 K. Furthermore, based on FET measurements, we found evidence of two different carrier transport mechanisms with two distinct activation energies in the 77-260 and 280-300 K temperature ranges, respectively. In the former temperature range, shallow traps are dominant in the perovskite film, which are filled by thermally activated carriers with increasing temperature; in the latter temperature range, deep traps with one order of magnitude larger activation energy dominate. Both types of chiral MHPs show intrinsic p-type carrier transport behavior regardless of the handedness (S or R) of these materials. The optimal carrier mobility for both handedness of material is around (2.7 ± 0.2) × 10-7 cm2 V-1 s-1 at 270-280 K, which is two magnitudes larger than those reported in nonchiral perovskite MAPbI3 polycrystalline thin films. These findings suggest that chiral MHPs can be an excellent candidate for selective circular polarized photodetection applications, without additional polarizing optical components, enabling simplified construction of detection systems.
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Constructed wetlands (CWs) are an eco-technology for wastewater treatment and are applied worldwide. Due to the regular influx of pollutants, CWs can release considerable quantities of greenhouse gases (GHGs), ammonia (NH3), and other atmospheric pollutants, such as volatile organic compounds (VOCs) and hydrogen sulfide (H2S), etc., which will aggravate global warming, degrade air quality and even threaten human health. However, there is a lack of systematic understanding of factors affecting the emission of these gases in CWs. In this study, we applied meta-analysis to quantitatively review the main influencing factors of GHG emission from CWs; meanwhile, the emissions of NH3, VOCs, and H2S were qualitatively assessed. Meta-analysis indicates that horizontal subsurface flow (HSSF) CWs emit less CH4 and N2O than free water surface flow (FWS) CWs. The addition of biochar can mitigate N2O emission compared to gravel-based CWs but has the risk of increasing CH4 emission. Polyculture CWs stimulate CH4 emission but pose no influence on N2O emission compared to monoculture CWs. The influent wastewater characteristics (e.g., C/N ratio, salinity) and environmental conditions (e.g., temperature) can also impact GHG emission. The NH3 volatilization from CWs is positively related to the influent nitrogen concentration and pH value. High plant species richness tends to reduce NH3 volatilization and plant composition showed greater effects than species richness. Though VOCs and H2S emissions from CWs do not always occur, it should be a concern when using CWs to treat wastewater containing hydrocarbon and acid. This study provides solid references for simultaneously achieving pollutant removal and reducing gaseous emission from CWs, which avoids the transformation of water pollution into air contamination.
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Gases , Gases de Efecto Invernadero , Humanos , Gases/análisis , Gases de Efecto Invernadero/análisis , Metano/análisis , Óxido Nitroso/análisis , Aguas Residuales , HumedalesRESUMEN
Chronic pain is characterized by discrete pain episodes of unpredictable frequency and duration. This hinders the study of pain mechanisms and contributes to the use of pharmacological treatments associated with side effects, addiction and drug tolerance. Here, we show that a closed-loop brain-machine interface (BMI) can modulate sensory-affective experiences in real time in freely behaving rats by coupling neural codes for nociception directly with therapeutic cortical stimulation. The BMI decodes the onset of nociception via a state-space model on the basis of the analysis of online-sorted spikes recorded from the anterior cingulate cortex (which is critical for pain processing) and couples real-time pain detection with optogenetic activation of the prelimbic prefrontal cortex (which exerts top-down nociceptive regulation). In rats, the BMI effectively inhibited sensory and affective behaviours caused by acute mechanical or thermal pain, and by chronic inflammatory or neuropathic pain. The approach provides a blueprint for demand-based neuromodulation to treat sensory-affective disorders, and could be further leveraged for nociceptive control and to study pain mechanisms.
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Interfaces Cerebro-Computador , Ratas , Animales , Ratas Sprague-Dawley , Dolor/psicología , Giro del CínguloRESUMEN
DNA methylation is an important epigenetic regulatory form that regulates gene expression and tissue development. This study compared the effects of high fiber, low protein (HFLP) and low fiber, high protein (LFHP) diets on the DNA methylation profile of twin lambs' muscles, their effect on glycolysis/gluconeogenesis and related pathways by transcriptome and deep whole-genome bisulfite sequencing (WGBS). Results identified 1,945 differentially methylated regions (DMRs) and 1,471 differentially methylated genes (DMGs). Also, 487 differentially expressed transcripts belonging to 368 differentially expressed genes (DEGs) were discovered between the twin lambs under different diets. Eleven overlapped genes were detected between the DEGs and the DMGs. FKBP5 and FOXO1 were detected to be significantly different. The FOXO1 regulated cAMP and the glycolysis/gluconeogenesis pathways. The glycolysis/gluconeogenesis, and the FOXO pathways were significantly enriched. The expressions of HOMER1 and FOXO1 in the HFLP group were significantly higher than those in the LFHP group. There is a significant correlation between the upregulated gene expression and hypomethylation of HOMER1 and FOXO1 gene in HFLP group. The results showed that FOXO1 induces PDK4 expression in muscle while regulating FKBP5 activity, which stimulates glucose production by activating specific gluconeogenesis target genes. The FOXO1 was able to regulate the glucose metabolism, the cAMP and the occurrence of glycolysis/gluconeogenesis pathways. This study showed that feed type can affect the methylation levels of the glycolysis related gluconeogenesis genes and interaction pathways, providing new ideas for a better understanding of the regulation of muscle energy metabolism and feed development.
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Metilación de ADN , Gluconeogénesis , Animales , Ovinos/genética , Metilación de ADN/genética , Gluconeogénesis/genética , Transducción de Señal/genética , Transcriptoma , Músculos , Glucólisis/genéticaRESUMEN
BACKGROUND: Exacerbation-prone asthma is a feature of severe disease. However, the basis for its persistency remains unclear. OBJECTIVES: To determine the clinical and transcriptomic features of frequent exacerbators (FEs) and persistent FEs (PFEs) in the U-BIOPRED cohort. METHODS: We compared features of FE (≥2 exacerbations in past year) to infrequent exacerbators (IE, <2 exacerbations) and of PFE with repeat ≥2 exacerbations during the following year to persistent IE (PIE). Transcriptomic data in blood, bronchial and nasal epithelial brushings, bronchial biopsies and sputum cells were analysed by gene set variation analysis for 103 gene signatures. RESULTS: Of 317 patients, 62.4% had FE, of whom 63.6% had PFE, while 37.6% had IE, of whom 61.3% had PIE. Using multivariate analysis, FE was associated with short-acting beta-agonist use, sinusitis and daily oral corticosteroid use, while PFE was associated with eczema, short-acting beta-agonist use and asthma control index. CEA cell adhesion molecule 5 (CEACAM5) was the only differentially expressed transcript in bronchial biopsies between PE and IE. There were no differentially expressed genes in the other four compartments. There were higher expression scores for type 2, T-helper type-17 and type 1 pathway signatures together with those associated with viral infections in bronchial biopsies from FE compared to IE, while there were higher expression scores of type 2, type 1 and steroid insensitivity pathway signatures in bronchial biopsies of PFE compared to PIE. CONCLUSION: The FE group and its PFE subgroup are associated with poor asthma control while expressing higher type 1 and type 2 activation pathways compared to IE and PIE, respectively.
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Asma , Transcriptoma , Asma/genética , Asma/metabolismo , Asma/patología , Bronquios/patología , Estudios de Cohortes , Humanos , Esputo/metabolismo , Transcriptoma/genéticaRESUMEN
OBJECTIVES: To investigate the incidence of extrauterine growth retardation (EUGR) and its risk factors in very preterm infants (VPIs) during hospitalization in China. METHODS: A prospective multicenter study was performed on the medical data of 2 514 VPIs who were hospitalized in the department of neonatology in 28 hospitals from 7 areas of China between September 2019 and December 2020. According to the presence or absence of EUGR based on the evaluation of body weight at the corrected gestational age of 36 weeks or at discharge, the VPIs were classified to two groups: EUGR group (n=1 189) and non-EUGR (n=1 325). The clinical features were compared between the two groups, and the incidence of EUGR and risk factors for EUGR were examined. RESULTS: The incidence of EUGR was 47.30% (1 189/2 514) evaluated by weight. The multivariate logistic regression analysis showed that higher weight growth velocity after regaining birth weight and higher cumulative calorie intake during the first week of hospitalization were protective factors against EUGR (P<0.05), while small-for-gestational-age birth, prolonged time to the initiation of total enteral feeding, prolonged cumulative fasting time, lower breast milk intake before starting human milk fortifiers, prolonged time to the initiation of full fortified feeding, and moderate-to-severe bronchopulmonary dysplasia were risk factors for EUGR (P<0.05). CONCLUSIONS: It is crucial to reduce the incidence of EUGR by achieving total enteral feeding as early as possible, strengthening breastfeeding, increasing calorie intake in the first week after birth, improving the velocity of weight gain, and preventing moderate-severe bronchopulmonary dysplasia in VPIs.
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Recien Nacido Prematuro , Recién Nacido de muy Bajo Peso , Femenino , Retardo del Crecimiento Fetal , Edad Gestacional , Hospitalización , Humanos , Incidencia , Lactante , Recién Nacido , Estudios Prospectivos , Factores de RiesgoRESUMEN
INTRODUCTION: Asthma is a heterogeneous disease with poorly defined phenotypes. Patients with severe asthma often receive multiple treatments including oral corticosteroids (OCS). Treatment may modify the observed metabotype, rendering it challenging to investigate underlying disease mechanisms. Here, we aimed to identify dysregulated metabolic processes in relation to asthma severity and medication. METHODS: Baseline urine was collected prospectively from healthy participants (n=100), patients with mild-to-moderate asthma (n=87) and patients with severe asthma (n=418) in the cross-sectional U-BIOPRED cohort; 12-18-month longitudinal samples were collected from patients with severe asthma (n=305). Metabolomics data were acquired using high-resolution mass spectrometry and analysed using univariate and multivariate methods. RESULTS: A total of 90 metabolites were identified, with 40 significantly altered (p<0.05, false discovery rate <0.05) in severe asthma and 23 by OCS use. Multivariate modelling showed that observed metabotypes in healthy participants and patients with mild-to-moderate asthma differed significantly from those in patients with severe asthma (p=2.6×10-20), OCS-treated asthmatic patients differed significantly from non-treated patients (p=9.5×10-4), and longitudinal metabotypes demonstrated temporal stability. Carnitine levels evidenced the strongest OCS-independent decrease in severe asthma. Reduced carnitine levels were associated with mitochondrial dysfunction via decreases in pathway enrichment scores of fatty acid metabolism and reduced expression of the carnitine transporter SLC22A5 in sputum and bronchial brushings. CONCLUSIONS: This is the first large-scale study to delineate disease- and OCS-associated metabolic differences in asthma. The widespread associations with different therapies upon the observed metabotypes demonstrate the need to evaluate potential modulating effects on a treatment- and metabolite-specific basis. Altered carnitine metabolism is a potentially actionable therapeutic target that is independent of OCS treatment, highlighting the role of mitochondrial dysfunction in severe asthma.
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Antiasmáticos , Asma , Corticoesteroides/uso terapéutico , Antiasmáticos/uso terapéutico , Asma/genética , Carnitina/uso terapéutico , Estudios Transversales , Humanos , Índice de Severidad de la Enfermedad , Miembro 5 de la Familia 22 de Transportadores de SolutosRESUMEN
The Cashmere goat (Capra hircus) is renowned for its high-quality fiber production trait. The hair cycle in Cashmere goat has an annual rhythm. To deepen the understanding of the molecular foundation of annual rhythm in the skin of Cashmere goat, we did a comparative analysis of the Cashmere goat skin transcriptome all year round. 4002 Differentially expressed genes (DEGs) were identified with seasonal variations. 12 months transcriptome were divided into four developmental stages: Jan-Mar, Apr-Jul, Aug-Oct, and Nov-Dec based on gene expression patterns. 13 modules of highly correlated genes in skin were identified using WGCNA. Ten of these modules were consistent with the development stages. The gene function of those genes in each module was analyzed by functional enrichment. The results indicated that Wnt and Hedgehog signaling pathways were inhibited from January to March and activated from April to July. The cutaneous immune system of Cashmere goats has high activity from August to October. Fatty acid metabolism dominates goat skin from November to December. This study provides new information related to the annual skin development cycle, which could provide molecular biological significance for understanding the seasonal development and response to the annual rhythm of skin.