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The homeodomain (HD) protein Bicoid (Bcd) is thought to function as a gradient morphogen that positions boundaries of target genes via threshold-dependent activation mechanisms. Here, we analyze 66 Bcd-dependent regulatory elements and show that their boundaries are positioned primarily by repressive gradients that antagonize Bcd-mediated activation. A major repressor is the pair-rule protein Runt (Run), which is expressed in an opposing gradient and is necessary and sufficient for limiting Bcd-dependent activation. Evidence is presented that Run functions with the maternal repressor Capicua and the gap protein Kruppel as the principal components of a repression system that correctly orders boundaries throughout the anterior half of the embryo. These results put conceptual limits on the Bcd morphogen hypothesis and demonstrate how the Bcd gradient functions within the gene network that patterns the embryo.
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Drosophila melanogaster/embriología , Drosophila melanogaster/genética , Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Transactivadores/metabolismo , Animales , Tipificación del Cuerpo , Proteínas de Unión al ADN/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Elementos de Facilitación Genéticos , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Neurodegeneration is becoming one of the leading causes of death worldwide as the population expands and grows older. There is a growing desire to understand the mechanisms behind prion proteins as well as the prion-like proteins that make up neurodegenerative diseases (NDs), including Alzheimer's disease (AD) and Parkinson's disease (PD). Both amyloid-ß (Aß) and hyperphosphorylated tau (p-tau) proteins behave in ways similar to those of the infectious form of the prion protein, PrPSc, such as aggregating, seeding, and replicating under not yet fully understood mechanisms, thus the designation of prion-like. This review aims to highlight the shared mechanisms between prion-like proteins and prion proteins in the structural variations associated with aggregation and disease development. These mechanisms largely focus on the dysregulation of protein homeostasis, self-replication, and protein aggregation, and this knowledge could contribute to diagnoses and treatments for the given NDs.
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In the process of repairing the surface of products in aviation, aerospace, and other fields by spraying, accurate 3D cumulative-coating modeling is an important research issue in spraying-process simulation. The approach to this issue is a 3D cumulative-coating model based on inclined spraying. Firstly, an oblique spraying layer cumulative model was established, which could quickly collect the coating thickness distribution data of different spray distances. Secondly, 3D cumulative-coating modeling was conducted with the distance between the measuring point and the axis of the spray gun and the spraying distance between the measuring points as the input parameters, and the coating thickness of the measuring point as the output parameter. The experimental results show that the mean relative error of the cumulative model of the oblique spraying layer is less than 4.1% in the case of a 170~290 mm spraying distance and that the model is applicable in the range of -80~80 mm, indicating that the data on the oblique spraying coating proposed in this paper is accurate and fast. The accuracy of the 3D cumulative-coating model proposed in this paper is 1.2% and 21.5% higher than that of the two similar models, respectively. Therefore, the approach of 3D cumulative-coating modeling based on inclined distance spraying is discovered, demonstrating the advantages of fast and accurate modeling and enabling accurate 3D cumulative-coating modeling for spraying process simulation.
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In vivo cross-linking studies suggest that the Drosophila transcription factor Bicoid (Bcd) binds to several thousand sites during early embryogenesis, but it is not clear how many of these binding events are functionally important. In contrast, reporter gene studies have identified >60 Bcd-dependent enhancers, all of which contain clusters of the consensus binding sequence TAATCC. These studies also identified clusters of TAATCC motifs (inactive fragments) that failed to drive Bcd-dependent activation. In general, active fragments showed higher levels of Bcd binding in vivo and were enriched in predicted binding sites for the ubiquitous maternal protein Zelda (Zld). Here we tested the role of Zld in Bcd-mediated binding and transcription. Removal of Zld function and mutations in Zld sites caused significant reductions in Bcd binding to known enhancers and variable effects on the activation and spatial positioning of Bcd-dependent expression patterns. Also, insertion of Zld sites converted one of six inactive fragments into a Bcd-responsive enhancer. Genome-wide binding experiments in zld mutants showed variable effects on Bcd-binding peaks, ranging from strong reductions to significantly enhanced levels of binding. Increases in Bcd binding caused the precocious Bcd-dependent activation of genes that are normally not expressed in early embryos, suggesting that Zld controls the genome-wide binding profile of Bcd at the qualitative level and is critical for selecting target genes for activation in the early embryo. These results underscore the importance of combinatorial binding in enhancer function and provide data that will help predict regulatory activities based on DNA sequence.
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Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Secuencias de Aminoácidos , Animales , Proteínas de Drosophila/genética , Embrión no Mamífero , Elementos de Facilitación Genéticos/genética , Proteínas de Homeodominio/genética , Mutación , Proteínas Nucleares , Unión Proteica , Transactivadores/genética , Factores de Transcripción/genéticaRESUMEN
People with HIV (PWH) taking antiretroviral therapy (ART) have persistent cognitive impairment. The prevalence of cognitive impairment is higher in women with HIV (WWH) compared to men with HIV (MWH), possibly due to sex differences in immune function. Here we report sex differences in cerebrospinal fluid (CSF) immune markers in relation to cognitive performance. A subset of 83 PWH on ART (52% WWH; mean age = 37.6 years, SD = 7.9) from the Rakai community cohort study Cohort and Rakai Health Sciences Program supported clinics in rural Uganda completed a neuropsychological (NP) assessment and a lumbar puncture. CSF was used to measure 16 cytokines/chemokines. Individual NP test z-scores were generated based on local normative data. A series of least absolute shrinkage and selection operator (lasso) regressions examined associations between CSF inflammatory markers and NP outcomes. Overall, there were no sex differences in CSF inflammatory marker levels. However, MWH displayed more associations between inflammatory markers and cognitive performance than WWH. Among MWH, inflammatory markers were associated with a number of cognitive domains, including attention, processing speed, fluency, executive function, learning and memory. MIP-1ß, INF-γ, GM-CSF, IL-7 and IL-12p70 were associated with multiple domains. Among WWH, few inflammatory markers were associated cognition. Degree of associations between CSF inflammatory biomarkers and cognitive performance varied by sex in this young, ART-treated, Ugandan cohort. Further investigation into sex-specific inflammatory mechanisms of cognitive impairment among PWH is warranted to inform sex-specific management strategies.
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Cognición , Infecciones por VIH , Adulto , Biomarcadores , Estudios de Cohortes , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Masculino , Pruebas Neuropsicológicas , UgandaRESUMEN
Developing efficient oxygen evolution reaction (OER) electrocatalysts is important for enhancing the water splitting efficiency. However, with the current catalysts containing one kind of active sites, it is challenging to achieve low overpotentials because of the four-electron transfer process. Herein is reported HZIF-2-CoMo, a new metal-organic framework with well-defined Co-Mo dual sites that can promote the OER process through an unconventional Mo6+/Co2+ dual-site relay mechanism. Theoretical calculations suggested that the Mo and Co sites stabilize the HO* and HOO* intermediates, respectively, and that the unique Co-O-Mo configuration induces the formation of a Co-O*-Mo transition intermediate, remarkably reducing the reaction free energy. As a result, HZIF-2-CoMo shows an overpotential of 277 mV at 10 mA cm-2 and a low Tafel slope of 70 mV dec-1 in alkaline solution, making it one of the best OER electrocatalysts reported to date.
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Porous carbon materials rich in defects are promising candidates in energy storage and conversion applications. Herein, a facile template-free approach is reported for the synthesis of a two-dimensional (2 D) mesoporous carbon material derived from fullerene (C60 ) microsheets (FMSs) through simple heat treatment. The sample obtained at 1000 °C (FMS1000) shows a large surface area of 1507.6â m2 g-1 owing to the presence of mesopores and rich defects, which promote electron and mass transfer in the electrocatalytic process of the oxygen reduction reaction (ORR), showing an excellent performance with an onset potential of 0.95â V, a half-wave potential of 0.85â V, and long-term durability of 2000â cycles, comparable to the performance of commercial Pt/C. Moreover, FMS1000 displays a remarkable supercapacitive property with a specific capacitance of 330.7â F g-1 at 0.2â A g-1 and good long-term stability with a capacitance retention of 97 % over 50 000 cycles. Thus, a practical strategy for the production of mesoporous carbon materials with different morphological structures and porous defects as high-performance energy materials is advanced.
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OBJECTIVE: As the most prevalent internal modification in mammalian messenger RNA, N6methyladenosine (m6A) plays an important role in posttranscriptional gene regulation. METTL3 is a key component of the m6A methyltransferase complex and has recently been shown to play important roles in cancer development and progression. The current study was aimed to explore the function and underlying mechanism of METTL3 in ovarian cancer. METHODS: METTL3 expression was assessed by immunohistochemistry in 162 ovarian carcinoma patients. Stable cell lines with METTL3 gene overexpression or knockdown were established to investigate the function of METTL3 in ovarian cancer in vitro and in vivo. RESULTS: METTL3 was frequently upregulated in ovarian carcinoma and that a high level of METTL3 was significantly associated with tumor grade (Pâ¯=â¯0.001), pT status (Pâ¯=â¯0.002), pN/pM status (Pâ¯<â¯0.001), FIGO stage (Pâ¯<â¯0.001), and overall survival rate (Pâ¯<â¯0.001). Stable overexpression of METTL3 in the OVCAR3 and COV504 cell lines significantly increased cellular proliferation, focus formation, motility, invasion, and tumor formation in nude mice. Silencing METTL3 expression in the SKOV3 and HO-8910 cell lines with short hairpin RNA effectively inhibited its oncogenic function. Further study found that METTL3 promoted epithelial-mesenchymal transition (EMT) by upregulating the receptor tyrosine kinase AXL. CONCLUSION: Our findings suggest that METTL3 plays very important oncogenic roles in ovarian carcinoma development and/or aggressiveness by stimulating AXL translation and EMT and that METTL3 may serve as a novel prognostic and/or therapeutic target of interest in ovarian cancer.
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Metiltransferasas/metabolismo , Neoplasias Ováricas/enzimología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Animales , Procesos de Crecimiento Celular/fisiología , Línea Celular Tumoral , Movimiento Celular/fisiología , Transición Epitelial-Mesenquimal , Femenino , Técnicas de Silenciamiento del Gen , Xenoinjertos , Humanos , Metiltransferasas/biosíntesis , Metiltransferasas/genética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Regulación hacia Arriba , Tirosina Quinasa del Receptor AxlRESUMEN
Despite years of study, the precise mechanisms that control position-specific gene expression during development are not understood. Here, we analyze an enhancer element from the even skipped (eve) gene, which activates and positions two stripes of expression (stripes 3 and 7) in blastoderm stage Drosophila embryos. Previous genetic studies showed that the JAK-STAT pathway is required for full activation of the enhancer, whereas the gap genes hunchback (hb) and knirps (kni) are required for placement of the boundaries of both stripes. We show that the maternal zinc-finger protein Zelda (Zld) is absolutely required for activation, and present evidence that Zld binds to multiple non-canonical sites. We also use a combination of in vitro binding experiments and bioinformatics analysis to redefine the Kni-binding motif, and mutational analysis and in vivo tests to show that Kni and Hb are dedicated repressors that function by direct DNA binding. These experiments significantly extend our understanding of how the eve enhancer integrates positive and negative transcriptional activities to generate sharp boundaries in the early embryo.
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Proteínas de Drosophila/genética , Elementos de Facilitación Genéticos , Regulación del Desarrollo de la Expresión Génica , Proteínas de Homeodominio/genética , Factores de Transcripción/genética , Animales , Secuencia de Bases , Cruzamientos Genéticos , Análisis Mutacional de ADN , Proteínas de Unión al ADN/metabolismo , Drosophila , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/fisiología , Genes Reporteros , Proteínas de Homeodominio/fisiología , Modelos Biológicos , Datos de Secuencia Molecular , Proteínas Nucleares , Proteínas Represoras/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/fisiología , Transgenes , Técnicas del Sistema de Dos HíbridosRESUMEN
It has been more than three decades since the discovery of multifunctional factors, the Non-POU-Domain-Containing Octamer-Binding Protein, NonO, and the Splicing Factor Proline- and Glutamine-Rich, SFPQ. Some of their functions, including their participation in transcriptional and posttranscriptional regulation as well as their contribution to paraspeckle subnuclear body organization, have been well documented. In this review, we focus on several other established roles of NonO and SFPQ, including their participation in the cell cycle, nonhomologous end-joining (NHEJ), homologous recombination (HR), telomere stability, childhood birth defects and cancer. In each of these contexts, the absence or malfunction of either or both NonO and SFPQ leads to either genome instability, tumor development or mental impairment.
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Large differences in projected future annual precipitation increases in North America exists across 27 CMIP6 models under four emission scenarios. These differences partly arise from weak representations of land-atmosphere interactions. Here we demonstrate an emergent constraint relationship between annual growth rates of future precipitation and growth rates of historical temperature. The original CMIP6 projections show 0.49% (SSP126), 0.98% (SSP245), 1.45% (SSP370) and 1.92% (SSP585) increases in precipitation per decade. Combining observed warming trends, the constrained results show that the best estimates of future precipitation increases are more likely to reach 0.40-0.48%, 0.83-0.93%, 1.29-1.45% and 1.70-1.87% respectively, implying an overestimated future precipitation increases across North America. The constrained results also are narrow the corresponding uncertainties (standard deviations) by 13.8-31.1%. The overestimated precipitation growth rates also reveal an overvalued annual growth rates in temperature (6.0-13.2% or 0.12-0.37°C) and in total evaporation (4.8-14.5%) by the original models' predictions. These findings highlight the important role of temperature for accurate climate predictions, which is important as temperature from current climate models' simulations often still have systematic errors.
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Lluvia , América del Norte , Incertidumbre , Temperatura , Modelos Teóricos , Cambio Climático , Predicción/métodosRESUMEN
Iron-loaded zeolite (Fe-zeolite) has shown great potential as an efficient catalyst for degrading organic pollutants with high concentrations in the catalytic wet peroxide oxidation (CWPO) process under mild conditions. Here, 0.4 wt% Lanthanum (La) was added in the 1.0 wt% Fe-ZSM-5 by two-step impregnation method for an enhanced H2O2 utilization efficiency. For a systematical comparison, the CWPO process at 55 °C, where m-cresol with a high concentration of 1000 mg/L as a substrate, was studied over Fe-ZSM-5 and Fe-La-ZSM-5 catalysts. Compared with Fe-ZSM-5, Fe-La-ZSM-5 showed 15% higher H2O2 utilization efficiency with comparable total organic carbon (TOC) removal at around 40%, meanwhile with a 15% reduced metal leaching. Transmission electron microscopy (TEM) with elemental mapping (EDS), surface acidity analysis by Fourier transform infrared (FT-IR) and NH3-temperature programmed desorption (NH3-TPD), redox property analysis by Raman spectroscopy and H2-temperature-programmed reduction (H2-TPR) of both catalysts revealed, that the La doped Fe-ZSM-5 can provide an altered surface acidity, a more uniform and evenly dispersed surface Fe species with a promoted reducibility, which effectively promoted the accurate decomposition of H2O2 into the reactive â¢OH radicals, enhanced the H2O2 utilization efficiency, and increased the catalyst stability. Also, more than 90% conversion was maintained during the continuous experiment for more than 10 consecutive test days under 55 °C without pH adjustment, showing a promising possibility of the Fe-La-ZSM-5 for a practical wastewater treatment process.
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Peróxidos , Zeolitas , Peróxido de Hidrógeno/química , Lantano , Zeolitas/química , Espectroscopía Infrarroja por Transformada de Fourier , Catálisis , Oxidación-ReducciónRESUMEN
The treatment of high-salinity and high-organic wastewater is a tough task, with the removal of organic matter and the separation of salts often mutually restricting. Catalytic wet air oxidation (CWAO) coupled desalination technology (membrane distillation (MD), membrane bioreactor (MBR), ultrafiltration (UF), nanofiltration (NF), etc.) provides an effective method to simultaneously degrade the high-salinity (via desalination) and high-organic matters (via CWAO) in wastewater. In this work, five kinds of RuO2/TiO2 catalysts with different calcination temperatures were prepared for CWAO of maleic acid wastewater with a theoretical chemical oxygen demand (COD) value of 20,000 mg L-1. RuO2/TiO2 series catalysts demonstrated prominent salt resistance, with more than 80% TOC removal rates in the CWAO system containing 5 wt% Na2SO4; while RuO2/TiO2-350 showed the best degradation performance in both non-salinity and Na2SO4-containing conditions. Multiple characterization techniques, such as XRD, BET, XPS, NH3-TPD and TEM etc., verified the physicochemical structure of RuO2/TiO2 catalysts, and their influence on the degradation of pollutants. The calcination temperature was found to have a direct impact on the specific surface area, pore volume, oxygen vacancies and acid sites of catalysts, which in turn affected the ultimate catalytic activity. Furthermore, we also investigated the performance of the RuO2/TiO2-350 catalyst for the treatment of acids, alcohols and aromatic compounds with the addition of NaCl or Na2SO4, proving its good universality and excellent salt resistance in saline wastewater. Meanwhile, the relationship between the structure of three types of organic compounds and the degradation effect in the CWAO system was also explored.
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Contaminantes Ambientales , Contaminantes Químicos del Agua , Aguas Residuales , Cloruro de Sodio , Contaminantes Químicos del Agua/análisis , Catálisis , Oxidación-ReducciónRESUMEN
The type VI secretion system (T6SS) is a widespread protein secretion apparatus deployed by many Gram-negative bacterial species to interact with competitor bacteria, host organisms, and the environment. Yersinia pseudotuberculosis T6SS4 was recently reported to be involved in manganese acquisition; however, the underlying regulatory mechanism still remains unclear. In this study, we discovered that T6SS4 is regulated by ferric uptake regulator (Fur) in response to manganese ions (Mn2+), and this negative regulation of Fur was proceeded by specifically recognizing the promoter region of T6SS4 in Y. pseudotuberculosis. Furthermore, T6SS4 is induced by low Mn2+ and oxidative stress conditions via Fur, acting as a Mn2+-responsive transcriptional regulator to maintain intracellular manganese homeostasis, which plays important role in the transport of Mn2+ for survival under oxidative stress. Our results provide evidence that T6SS4 can enhance the oxidative stress resistance and virulence for Y. pseudotuberculosis. This study provides new insights into the regulation of T6SS4 via the Mn2+-dependent transcriptional regulator Fur, and expands our knowledge of the regulatory mechanisms and functions of T6SS from Y. pseudotuberculosis.
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Purpose: To quantify the morphology of eyeballs with posterior staphyloma (PS) with Zernike decomposition and to explore the association between Zernike coefficients with existing PS classification. Methods: Fifty-three eyes with high myopia (HM, ≤-6.00D) and 30 with PS were included. PS was classified with traditional methods based on OCT findings. Eyeballs' morphology was obtained with 3D MRI, from which the height map of the posterior surface was extracted. Zernike decomposition was performed to derive the coefficients of the 1st-27th items, which were compared between HM and PS eyes with the Mann-Whitney-U test. Receiver operating characteristics (ROC) analysis was used to test the effectiveness of using Zernike coefficients to discriminate PS from HM. Results: Compared to HM eyeballs, PS eyeballs had significantly increased vertical and horizontal tilt, oblique astigmatism, defocus, vertical and horizontal coma, and higher order aberrations (HOA) (all Ps < 0.05). HOA was the most effective in PS classification with an area under the ROC curve (AUROC) value of 0.977. Among the 30 PS, 19 were the wide macular type with large defocus and negative spherical aberration; 4 were the narrow macular type with positive spherical aberration; 3 were inferior PS with greater vertical tilt, and 4were peripapillary PS with larger horizontal tilt. Conclusion: PS eyes have significantly increased Zernike coefficients, and HOA is the most effective parameter to differentiate PS from HM. The geometrical meaning of the Zernike components showed great accordance with PS classification.
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The Bicoid (Bcd) transcription factor is distributed as a long-range concentration gradient along the anterior posterior (AP) axis of the Drosophila embryo. Bcd is required for the activation of a series of target genes, which are expressed at specific positions within the gradient. Here we directly tested whether different concentration thresholds within the Bcd gradient establish the relative positions of its target genes by flattening the gradient and systematically varying expression levels. Genome-wide expression profiles were used to estimate the total number of Bcd target genes, and a general correlation was found between the Bcd concentration required for activation and the positions where target genes are expressed in wild-type embryos. However, concentrations required for target gene activation in embryos with flattened Bcd were consistently lower than those present at each target gene's position in the wild-type gradient, suggesting that Bcd is in excess at every position along the AP axis. Also, several Bcd target genes were positioned in correctly ordered stripes in embryos with flattened Bcd, and we suggest that these stripes are normally regulated by interactions between Bcd and the terminal patterning system. Our findings argue strongly against the strict interpretation of the Bcd morphogen hypothesis, and support the idea that target gene positioning involves combinatorial interactions that are mediated by the binding site architecture of each gene's cis-regulatory elements.
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Tipificación del Cuerpo , Drosophila melanogaster/embriología , Proteínas de Homeodominio/metabolismo , Transactivadores/metabolismo , Animales , Proteínas de Drosophila , Drosophila melanogaster/genética , Embrión no Mamífero/metabolismo , Regulación del Desarrollo de la Expresión Génica , Genoma de los Insectos/genética , Proteínas de Homeodominio/genética , Modelos Biológicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Transactivadores/genéticaRESUMEN
BACKGROUND: HIV infection results in immunometabolic reprogramming. While we are beginning to understand how this metabolic reprogramming regulates the immune response to HIV infection, we do not currently understand the impact of ART on immunometabolism in people with HIV (PWH). METHODS: Serum obtained from HIV-infected (n = 278) and geographically matched HIV seronegative control subjects (n = 300) from Rakai Uganda were used in this study. Serum was obtained before and ~2 years following the initiation of ART from HIV-infected individuals. We conducted metabolomics profiling of the serum and focused our analysis on metabolic substrates and pathways assocaited with immunometabolism. RESULTS: HIV infection was associated with metabolic adaptations that implicated hyperactive glycolysis, enhanced formation of lactate, increased activity of the pentose phosphate pathway (PPP), decreased ß-oxidation of long-chain fatty acids, increased utilization of medium-chain fatty acids, and enhanced amino acid catabolism. Following ART, serum levels of ketone bodies, carnitine, and amino acid metabolism were normalized, however glycolysis, PPP, lactate production, and ß-oxidation of long-chain fatty acids remained abnormal. CONCLUSION: Our findings suggest that HIV infection is associated with an increased immunometabolic demand that is satisfied through the utilization of alternative energetic substrates, including fatty acids and amino acids. ART alone was insufficient to completely restore this metabolic reprogramming to HIV infection, suggesting that a sustained impairment of immunometabolism may contribute to chronic immune activation and comorbid conditions in virally suppressed PWH.
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Infecciones por VIH , Aminoácidos , Ácidos Grasos/metabolismo , Humanos , Lactatos , UgandaRESUMEN
Neuropsychiatric complications are common among women with HIV (WWH). The pathophysiological mechanisms underlying these complications are not fully known but likely driven in part by immune modulation. We examined associations between T-cell activation states which are required to mount an effective immune response (activation, co-stimulation/normal function, exhaustion, senescence) and neuropsychiatric complications in WWH. 369 WWH (78% HIV RNA undetectable/<20cp/mL) enrolled in the Women's Interagency HIV Study completed neuropsychological testing and measures of depression (Center for Epidemiological Studies Depression Scale-CES-D), self-reported stress levels (Perceived Stress Scale-10), and post-traumatic stress (PTSD Checklist-Civilian Scale). Multiparametric flow cytometry evaluated T-cell activation state. Partial least squares regressions were used to examine T-cell phenotypes and neuropsychiatric outcome associations after confounder adjustment. In the total sample and among virally suppressed (VS)-WWH, CD4+ T-cell exhaustion was associated with poorer learning and attention/working memory (P's < 0.05). In the total sample, CD4+ T-cell activation was associated with better attention/working memory and CD8+ T-cell co-stimulation and senescence was associated with poorer executive function (P's < 0.05). For mental health outcomes, in the total sample, CD4+ T-cell activation was associated with more perceived stress and CD4+ T-cell exhaustion was associated with less depressive symptoms (P's < 0.05). Among VS-WWH, CD4+ senescence was associated with less perceive stress and CD8+ T-cell co-stimulation and senescence was associated with higher depression (P's < 0.05). Together, results suggest the contribution of peripheral CD4+ and CD8+ T-cell activation status to neuropsychiatric complications in WWH.
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BACKGROUND: Morphogen gradients are thought to create concentration thresholds that differentially position the expression boundaries of multiple target genes. Despite intensive study, it is still unclear how the concentration profiles within gradients are spatially related to the critical patterning thresholds they generate. RESULTS: Here we use a combination of quantitative measurements and ectopic-misexpression experiments to examine the transcriptional-repression activities of the Hunchback (Hb) protein gradient in Drosophila embryos. Our results define five expression boundaries that are set primarily by differences in Hb concentration and two boundaries that are set by combinatorial mechanisms involving Hb and at least one other repressor. CONCLUSIONS: Hb functions as a repressive morphogen, but only within a specific range of concentrations ( approximately 40% to approximately 4.4% of maximum Hb concentration), within which there are at least four distinct concentration thresholds. The lower limit of the range reflects a position where the slope of the gradient becomes too shallow for resolution by specific target genes. Concentrations above the upper limit do not contribute directly to differential-repression mechanisms, but they provide a robust source that permits proper functioning of the gradient in heterozygous embryos that contain only one functional hb gene.
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Proteínas de Unión al ADN/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila/embriología , Regulación del Desarrollo de la Expresión Génica , Morfogénesis/genética , Factores de Transcripción/metabolismo , Animales , Proteínas de Unión al ADN/genética , Drosophila/genética , Drosophila/metabolismo , Drosophila/ultraestructura , Proteínas de Drosophila/genética , Procesamiento de Imagen Asistido por Computador , Inmunohistoquímica , Hibridación Fluorescente in Situ , Microscopía Confocal , Morfogénesis/fisiología , Factores de Transcripción/genéticaRESUMEN
In this study, the contents of heavy metals and Cd and Pb isotope ratios of agricultural soil and potential source samples collected from farmland receiving sewage irrigation in Wuqing District, Tianjin, China were determined. Multiple methods were used for source analysis, including positive matrix factorization (PMF), correlation analysis, principal component analysis (PCA), and the Cd and Pb isotope ratio method. The results showed that agricultural soil was slightly contaminated by heavy metals in the research area, with relatively higher Cd and Pb accumulation levels compared to those of other heavy metals. Four types of pollution sources, including the soil parent material sources, industrial emission sources, agricultural practice sources, and mixed sources of sewage irrigation and transportation were apportioned and quantified by PMF, combined with the results of PCA and correlation analysis. The contribution rates quantified by the Cd and Pb isotope ratio method were similar, suggesting that no single source dominates Pb and Cd pollution. The contribution rates of Pb analyzed by the isotope ratio method were almost identical to those of the PMF model, indicating the rationality of the PMF result. Our results suggested that correlation analysis and PCA should be utilized to provide information for obtaining reasonable results and defining source categories for PMF, whereas the isotope ratio method should be applied to verify the accuracy of source contributions analyzed by PMF.