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1.
Biochem Pharmacol ; 225: 116271, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38723722

RESUMO

Cardiac fibrosis is characterized by abnormal proliferation of cardiac fibroblasts (CFs) and ventricular remodeling, which finally leads to heart failure. Inflammation and oxidative stress play a central role in the development of cardiac fibrosis. CyPA (Cyclophilin A) is a main proinflammatory cytokine secreted under the conditions of oxidative stress. The mechanisms by which intracellular and extracellular CyPA interact with CFs are unclear. Male C57BL/6 J mice received angiotensin Ⅱ (Ang Ⅱ) or vehicle for 4 weeks. Inhibition of CyPA significantly reversed Ang Ⅱ-induced cardiac hypertrophy and fibrosis. Mechanically, TGF-ß (Transforming growth factor-ß) signaling was found to be an indispensable downstream factor of CyPA-mediated myofibroblast differentiation and proliferation. Furthermore, intracellular CyPA and extracellular CyPA activate TGF-ß signaling through NOD-like receptor protein 3 (NLRP3) inflammasome and nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, respectively. Pharmacological inhibition of CyPA and its receptor CD147 implemented by Triptolide also attenuated the expression of TGF-ß signaling and cardiac fibrosis in Ang Ⅱ-model. These studies elucidate a novel mechanism by which CyPA promotes TGF-ß and its downstream signaling in CFs and identify CyPA (both intracellular and extracellular) as plausible therapeutic targets for preventing or treating cardiac fibrosis induced by chronic Ang Ⅱ stimulation.

2.
Plant Cell Environ ; 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38712996

RESUMO

For trees originating from boreal and temperate regions, the dormancy-to-active transition, also known as bud dormancy release and bud break, are crucial processes that allow trees to reactive growth in the spring. The molecular mechanisms underlying these two processes remain poorly understood. Here, through integrative multiomics analysis of the transcriptome, DNA methylome, and proteome, we gained insights into the reprogrammed cellular processes associated with bud dormancy release and bud break. Our findings revealed multilayer regulatory landscapes governing bud dormancy release and bud break regulation, providing a valuable reference framework for future functional studies. Based on the multiomics analysis, we have determined a novel long intergenic noncoding RNA named Phenology Responsive Intergenic lncRNA 1 (PRIR1) plays a role in the activation of bud break. that the molecular mechanism of PRIR1 has been preliminary explored, and it may partially promote bud break by activating its neighbouring gene, EXORDIUM LIKE 5 (PtEXL5), which has also been genetically confirmed as an activator for bud break. This study has revealed a lncRNA-mediated regulatory mechanism for the control of bud break in Populus, operating independently of known regulatory pathways.

3.
Mol Psychiatry ; 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38724566

RESUMO

Psychiatric disorders are highly heritable yet polygenic, potentially involving hundreds of risk genes. Genome-wide association studies have identified hundreds of genomic susceptibility loci with susceptibility to psychiatric disorders; however, the contribution of these loci to the underlying psychopathology and etiology remains elusive. Here we generated deep human brain proteomics data by quantifying 11,608 proteins across 268 subjects using 11-plex tandem mass tag coupled with two-dimensional liquid chromatography-tandem mass spectrometry. Our analysis revealed 788 cis-acting protein quantitative trait loci associated with the expression of 883 proteins at a genome-wide false discovery rate <5%. In contrast to expression at the transcript level and complex diseases that are found to be mainly influenced by noncoding variants, we found protein expression level tends to be regulated by non-synonymous variants. We also provided evidence of 76 shared regulatory signals between gene expression and protein abundance. Mediation analysis revealed that for most (88%) of the colocalized genes, the expression levels of their corresponding proteins are regulated by cis-pQTLs via gene transcription. Using summary data-based Mendelian randomization analysis, we identified 4 proteins and 19 genes that are causally associated with schizophrenia. We further integrated multiple omics data with network analysis to prioritize candidate genes for schizophrenia risk loci. Collectively, our findings underscore the potential of proteome-wide linkage analysis in gaining mechanistic insights into the pathogenesis of psychiatric disorders.

4.
Cell Rep Med ; : 101547, 2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38703764

RESUMO

Non-clear cell renal cell carcinomas (non-ccRCCs) encompass diverse malignant and benign tumors. Refinement of differential diagnosis biomarkers, markers for early prognosis of aggressive disease, and therapeutic targets to complement immunotherapy are current clinical needs. Multi-omics analyses of 48 non-ccRCCs compared with 103 ccRCCs reveal proteogenomic, phosphorylation, glycosylation, and metabolic aberrations in RCC subtypes. RCCs with high genome instability display overexpression of IGF2BP3 and PYCR1. Integration of single-cell and bulk transcriptome data predicts diverse cell-of-origin and clarifies RCC subtype-specific proteogenomic signatures. Expression of biomarkers MAPRE3, ADGRF5, and GPNMB differentiates renal oncocytoma from chromophobe RCC, and PIGR and SOSTDC1 distinguish papillary RCC from MTSCC. This study expands our knowledge of proteogenomic signatures, biomarkers, and potential therapeutic targets in non-ccRCC.

5.
Foods ; 13(9)2024 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-38731730

RESUMO

This study aimed to investigate the changes in proteins and volatile flavor compounds that occur in bacon during low-temperature smoking (LTS) and identify potential correlations between these changes. To achieve this, a combination of gas chromatography-mass spectrometry and proteomics was employed. A total of 42 volatile flavor compounds were identified in the bacon samples, and, during LTS, 11 key volatile flavor compounds with variable importance were found at a projection value of >1, including 2',4'-dihydroxyacetophenone, 4-methyl-2H-furan-5-one, Nonanal, etc. In total, 2017 proteins were quantified at different stages of LTS; correlation coefficients and KEGG analyses identified 27 down-regulated flavor-related proteins. Of these, seven were involved in the tricarboxylic acid (TCA) cycle, metabolic pathways, or amino acid metabolism, and they may be associated with the process of flavor formation. Furthermore, correlation coefficient analysis indicated that certain chemical parameters, such as the contents of free amino acids, carbonyl compounds, and TCA cycle components, were closely and positively correlated with the formation of key volatile flavor compounds. Combined with bioinformatic analysis, the results of this study provide insights into the proteins present in bacon at various stages of LTS. This study demonstrates the changes in proteins and the formation of volatile flavor compounds in bacon during LTS, along with their potential correlations, providing a theoretical basis for the development of green processing methods for Hunan bacon.

6.
Technol Cancer Res Treat ; 23: 15330338241248576, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38693824

RESUMO

Background: Acute myeloid leukemia (AML) is a type of blood cancer characterized by excessive growth of immature myeloid cells. Unfortunately, the prognosis of pediatric AML remains unfavorable. It is imperative to further our understanding of the mechanisms underlying leukemogenesis and explore innovative therapeutic approaches to enhance overall disease outcomes for patients with this condition. Methods: Quantitative reverse-transcription PCR was used to quantify the expression levels of microRNA (miR)-133a and miR-135a in 68 samples from 59 pediatric patients with AML. Dual-luciferase reporter transfection assay, Cell Counting Kit-8 assay, and western blot analysis were used to investigate the functions of miR-133a and miR-135a. Results: Our study found that all-trans-retinoic acid (ATRA) promoted the expression of miR-133a and miR-135a in AML cells, inhibited caudal type homeobox 2 (CDX2) expression, and subsequently inhibited the proliferation of AML cells. Additionally, miR-133a and miR-135a were highly expressed in patients with complete remission and those with better survival. Conclusions: miR-133a and miR-135a may play an antioncogenic role in pediatric AML through the ATRA-miRNA133a/135a-CDX2 pathway. They hold promise as potentially favorable prognostic indicators and novel therapeutic targets for pediatric AML.


Assuntos
Biomarcadores Tumorais , Leucemia Mieloide Aguda , MicroRNAs , Tretinoína , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Biomarcadores Tumorais/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/metabolismo , MicroRNAs/genética , Prognóstico , Tretinoína/farmacologia , Tretinoína/uso terapêutico
7.
bioRxiv ; 2024 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-38586029

RESUMO

Prostate cancer is an exemplar of an enhancer-binding transcription factor-driven disease. The androgen receptor (AR) enhanceosome complex comprised of chromatin and epigenetic coregulators assembles at enhancer elements to drive disease progression. The paralog lysine acetyltransferases p300 and CBP deposit histone marks that are associated with enhancer activation. Here, we demonstrate that p300/CBP are determinant cofactors of the active AR enhanceosome in prostate cancer. Histone H2B N-terminus multisite lysine acetylation (H2BNTac), which was exclusively reliant on p300/CBP catalytic function, marked active enhancers and was notably elevated in prostate cancer lesions relative to the adjacent benign epithelia. Degradation of p300/CBP rapidly depleted acetylation marks associated with the active AR enhanceosome, which was only partially phenocopied by inhibition of their reader bromodomains. Notably, H2BNTac was effectively abrogated only upon p300/CBP degradation, which led to a stronger suppression of p300/CBP-dependent oncogenic gene programs relative to bromodomain inhibition. In vivo experiments using a novel, orally active p300/CBP proteolysis targeting chimera (PROTAC) degrader (CBPD-409) showed that p300/CBP degradation potently inhibited tumor growth in preclinical models of castration-resistant prostate cancer and synergized with AR antagonists. While mouse p300/CBP orthologs were effectively degraded in host tissues, prolonged treatment with the PROTAC degrader was well tolerated with no significant signs of toxicity. Taken together, our study highlights the pivotal role of p300/CBP in maintaining the active AR enhanceosome and demonstrates how target degradation may have functionally distinct effects relative to target inhibition, thus supporting the development of p300/CBP degraders for the treatment of advanced prostate cancer.

8.
Environ Geochem Health ; 46(5): 147, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38578456

RESUMO

The Qinghai-Tibet Plateau, located at the Third Pole and known as the "Asian water tower," serves as a crucial ecological barrier for China. Grasping the soil quality on the Qinghai-Tibet Plateau holds paramount importance for the rational and scientific exploitation of soil resources within the region and is essential for vegetation restoration and ecological reconstruction. This study, conducted in Maqin County, Qinghai Province, collected 1647 soil samples (0-20 cm) within a study area of 6300 km2. Sixteen soil indicators were selected that were split into beneficial (N, P, S, and B), harmful (Cr, Hg, As, Pb, Ni, and Cd), and essential (Cu, Zn, Se, Ga, K, and Ca) elements. The Soil Quality Index (SQI) was computed to assess soil quality across diverse geological contexts, land cover classifications, and soil profiles. The results indicate that the overall SQI in the study area was comparatively high, with most regions having an SQI between 0.4 and 0.6, categorized as moderately to highly satisfactory. Among the different geological backgrounds, the highest SQI was found in the Quaternary alluvium (0.555) and the lowest in the Precambrian Jinshuikou Formation (0.481). Regarding different land-use types, the highest SQI was observed in glacier- and snow-covered areas (0.582) and the lowest in other types of grassland (0.461). The highest SQI was recorded in typical alpine meadow soil (0.521) and the lowest in leached brown soil (0.460). The evaluation results have significant reference value for the sustainable utilization and management of soil in Maqin County, Qinghai Province, China.


Assuntos
Mercúrio , Solo , Humanos , Tibet , China , Atividades Humanas
9.
Sensors (Basel) ; 24(7)2024 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-38610450

RESUMO

Convolutional neural networks (CNNs) have significantly advanced various fields; however, their computational demands and power consumption have escalated, posing challenges for deployment in low-power scenarios. To address this issue and facilitate the application of CNNs in power constrained environments, the development of dedicated CNN accelerators is crucial. Prior research has predominantly concentrated on developing low precision CNN accelerators using code generated from high-level synthesis (HLS) tools. Unfortunately, these approaches often fail to efficiently utilize the computational resources of field-programmable gate arrays (FPGAs) and do not extend well to full precision scenarios. To overcome these limitations, we integrate vector dot products to unify the convolution and fully connected layers. By treating the row vector of input feature maps as the fundamental processing unit, we balance processing latency and resource consumption while eliminating data rearrangement time. Furthermore, an accurate design space exploration (DSE) model is established to identify the optimal design points for each CNN layer, and dynamic partial reconfiguration is employed to maximize each layer's access to computational resources. Our approach is validated through the implementation of AlexNet and VGG16 on 7A100T and ZU15EG platforms, respectively. We achieve an average convolutional layer throughput of 28.985 GOP/s and 246.711 GOP/s for full precision. Notably, the proposed accelerator demonstrates remarkable power efficiency, with a maximum improvement of 23.989 and 15.376 times compared to current state-of-the-art FPGA implementations.

10.
J Behav Addict ; 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38662450

RESUMO

Background and aims: Nomophobia (NMP) is a contemporary digital ailment referring to the improper utilization of smartphones which can have significant impacts on the physical and mental health of college students. However, as a result of unclear cutoff points, the proportion of people with NMP may be exaggerated. This study therefore aimed to determine the critical value of NMP and assess the extent to which Chinese college students are impacted by NMP using the Nomophobia Questionnaire (NMP-Q). Methods: Latent profile analysis (LPA) and the receiver operating characteristic curve (ROC) were combined to determine the critical value based on NMP-Q scores using a large sample of 3,998 college students (Mage = 20.58; SD = 1.87). Results: Based on latent profile (i.e., at-risk NMP group), ROC revealed an optimal cut-off point of 73 (Sensitivity = 0.965, Specificity = 0.970, Accuracy = 0.968, AUC = 99.60%, Youden's index = 0.935), and the percentage of NMP students being 28.04%, with 1,121 participants identified as positive cases (probable cases). Positive cases were found to exhibit more severe depression and anxiety symptoms, with a higher proportion of females were observed in the positive group (N = 829; 73.95%). Conclusions: These findings provide evidence that the proportion of NMP individuals may have been overestimated in the past. Furthermore, this study helps to validate the NMP-Q as a valid tool to identify NMP in college-aged individuals.

11.
Sci Rep ; 14(1): 9040, 2024 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-38641637

RESUMO

Immune thrombocytopenia (ITP), an acquired autoimmune disease, is characterized by immune-mediated platelet destruction. A biomarker is a biological entity that contributes to disease pathogenesis and reflects disease activity. Metabolic alterations are reported to be associated with the occurrence of various diseases. As metabolic biomarkers for ITP have not been identified. This study aimed to identify metabolism-related differentially expressed genes as potential biomarkers for pathogenesis of ITP using bioinformatic analyses.The microarray expression data of the peripheral blood mononuclear cells were downloaded from the Gene Expression Omnibus database (GSE112278 download link: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE112278 ). Key module genes were intersected with metabolism-related genes to obtain the metabolism-related key candidate genes. The hub genes were screened based on the degree function in the coytoscape sofware. The key ITP-related genes were subjected to functional enrichment analysis. Immune infiltration analysis was performed using a single-sample gene set enrichment analysis algorithm to evaluate the differential infiltration levels of immune cell types between ITP patient and control. Molecular subtypes were identified based on the expression of hub genes. The expression of hub genes in the ITP patients was validated using quantitative real-time polymerase chain reaction analysis. This study identified five hub genes (ADH4, CYP7A1, CYP1A2, CYP8B1, and NR1H4), which were be associated with the pathogenesis of ITP, and two molecular subtypes of ITP. Among these hub genes, CYP7A1 and CYP8B1 involved in cholesterol metabolism,were further verified in clinical samples.


Assuntos
Púrpura Trombocitopênica Idiopática , Trombocitopenia , Humanos , Púrpura Trombocitopênica Idiopática/genética , Leucócitos Mononucleares , Esteroide 12-alfa-Hidroxilase , Biomarcadores , Biologia Computacional
12.
BMC Psychiatry ; 24(1): 297, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38641813

RESUMO

BACKGROUND: This study aimed to investigate the interplay between anxiety and depressive symptoms in Chinese college freshmen using the causal system perspective (CSP), which differs from the traditional common cause perspective (CCP) by providing an alternative explanation by attributing comorbidity to direct interactions among symptoms. METHODS: A convenience sample of 2,082 Chinese college freshmen (39.51% male, Mage = 18.61) from a normal university completed the Generalized Anxiety Disorder 7-Item Scale (GAD-7) and the Patient Health Questionnaire (PHQ-9). Network analysis was conducted and evaluated as to centrality, stability, node predictability, and bridging features. Moreover, the moderated network model (MNM) was utilized to detect the moderation effects of gender in the comorbidity network. RESULTS: The network of anxiety and depressive symptoms exhibited stability, characterized by the core symptoms of "restlessness", "lack of energy", and "excessive worry about control", as well as the bridging symptoms of "fearfulness", "sad mood", and "irritability". Notably, the nodes representing "uncontrollable worry" and "difficulty in relaxation" demonstrated the highest predictive power. Gender did not exert any moderating effects on the anxiety and depressive symptom network. CONCLUSION: These results reinforce that certain anxiety or depressive symptoms are more central than others, and thus play a more vital role in the comorbid network. These findings highlight underlying potential targeting symptoms to consider in future interventions.


Assuntos
Ansiedade , Depressão , Masculino , Humanos , Adolescente , Feminino , Depressão/diagnóstico , Depressão/epidemiologia , Universidades , Ansiedade/epidemiologia , Ansiedade/diagnóstico , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/epidemiologia , Comorbidade
13.
Elife ; 132024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38602170

RESUMO

Stains are known to be anti-inflammatory, but the mechanism remains poorly understood. Here we show that macrophages, either treated with statin in vitro or from statin-treated mice, have reduced cholesterol levels and higher expression of Jmjd3, a H3K27me3 demethylase. We provide evidence that lowering cholesterol levels in macrophages suppresses the ATP synthase in the inner mitochondrial membrane (IMM) and changes the proton gradient in the mitochondria. This activates NFkB and Jmjd3 expression to remove the repressive marker H3K27me3. Accordingly, the epigenome is altered by the cholesterol reduction. When subsequently challenged by the inflammatory stimulus LPS (M1), both macrophages treated with statins in vitro or isolated from statin-treated mice in vivo, express lower levels pro-inflammatory cytokines than controls, while augmenting anti-inflammatory Il10 expression. On the other hand, when macrophages are alternatively activated by IL4 (M2), statins promote the expression of Arg1, Ym1, and Mrc1. The enhanced expression is correlated with the statin-induced removal of H3K27me3 from these genes prior to activation. In addition, Jmjd3 and its demethylase activity are necessary for cholesterol to modulate both M1 and M2 activation. We conclude that upregulation of Jmjd3 is a key event for the anti-inflammatory function of statins on macrophages.

14.
Cancer Lett ; 591: 216892, 2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38621459

RESUMO

Non-small cell lung cancer (NSCLC) is a leading cause of mortality worldwide and requires effective treatment strategies. Recently, the development of a novel multiple-target tyrosine kinase inhibitor, anlotinib, has drawn increasing attention, especially it shows advantages when combined with PD-1/PD-L1 blockade. However, the mechanism by which anlotinib improves immunotherapy and remodeling of the tumor microenvironment remains unclear. In this study, we found that anlotinib combined with PD-1 blockade significantly inhibited tumor growth and reduced tumor weight in a lung cancer xenograft model compared to any single treatment. Both immunofluorescence and flow cytometry analyses revealed that anlotinib induced a CD8+ T cell dominated tumor microenvironment, which might account for its improved role in immunotherapy. Further investigations showed that CCL5-mediated CD8+ T cell recruitment plays a critical role in anlotinib and PD-1 blockade strategies. The depletion of CD8+ T cells abrogated this process. In conclusion, our findings showed that the combination of anlotinib and PD-1 blockade produced promising effects in the treatment of lung cancer, and that the induction of CCL5-mediced CD8+ T cell recruitment by anlotinib provided a novel mechanism of action.

15.
ACS Omega ; 9(12): 14297-14309, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38559961

RESUMO

Numerical simulations of a 600 t/day waste incinerator was carried out using the fluid dynamic incinerator code and Fluent to evaluate the effect of biomass blending on furnace temperature, pollutant generation, and selective noncatalytic-reduction (SNCR) denitrification when treating low calorific-value waste. The results show that as the biomass blending ratio increases, the water content gradually decreases, the calorific value increases, and the maximum temperature of the incinerator gradually increases from 1227 to 1408 K, while the content of exported NOx increases from 579 to 793 mg/Nm3; during the combustion of low-quality waste, the residence time of the flue gas in the high-temperature region (above 1123 K) is 1.62 s. When the biomass blending ratio exceeds 20%, the residence time of the flue gas in the high-temperature region is more than 2 s, which can effectively curb the generation of dioxin. When the biomass blending ratio is 20%, and the normalized stoichiometric ratio (2nurea/nNO) of urea injected into the SNCR is 1.1, the NOx concentration at the outlet is 230.08 mg/Nm3, which satisfies the NOx emission standard of less than 250 mg/Nm3.

16.
J Neurosurg ; : 1-10, 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38579358

RESUMO

OBJECTIVE: CT and MRI are synergistic in the information provided for neurosurgical planning. While obtaining both types of images lends unique data from each, doing so adds to cost and exposes patients to additional ionizing radiation after MRI has been performed. Cross-modal synthesis of high-resolution CT images from MRI sequences offers an appealing solution. The authors therefore sought to develop a deep learning conditional generative adversarial network (cGAN) which performs this synthesis. METHODS: Preoperative paired CT and contrast-enhanced MR images were collected for patients with meningioma, pituitary tumor, vestibular schwannoma, and cerebrovascular disease. CT and MR images were denoised, field corrected, and coregistered. MR images were fed to a cGAN that exported a "synthetic" CT scan. The accuracy of synthetic CT images was assessed objectively using the quantitative similarity metrics as well as by clinical features such as sella and internal auditory canal (IAC) dimensions and mastoid/clinoid/sphenoid aeration. RESULTS: A total of 92,981 paired CT/MR images obtained in 80 patients were used for training/testing, and 10,068 paired images from 10 patients were used for external validation. Synthetic CT images reconstructed the bony skull base and convexity with relatively high accuracy. Measurements of the sella and IAC showed a median relative error between synthetic CT scans and ground truth images of 6%, with greater variability in IAC reconstruction compared with the sella. Aerations in the mastoid, clinoid, and sphenoid regions were generally captured, although there was heterogeneity in finer air cell septations. Performance varied based on pathology studied, with the highest limitation observed in evaluating meningiomas with intratumoral calcifications or calvarial invasion. CONCLUSIONS: The generation of high-resolution CT scans from MR images through cGAN offers promise for a wide range of applications in cranial and spinal neurosurgery, especially as an adjunct for preoperative evaluation. Optimizing cGAN performance on specific anatomical regions may increase its clinical viability.

17.
Sci Rep ; 14(1): 7638, 2024 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561452

RESUMO

Hypomyelinating leukodystrophy (HLD) is a rare genetic heterogeneous disease that can affect myelin development in the central nervous system. This study aims to analyze the clinical phenotype and genetic function of a family with HLD-7 caused by POLR3A mutation. The proband (IV6) in this family mainly showed progressive cognitive decline, dentin dysplasia, and hypogonadotropic hypogonadism. Her three old brothers (IV1, IV2, and IV4) also had different degrees of ataxia, dystonia, or dysarthria besides the aforementioned manifestations. Their brain magnetic resonance imaging showed bilateral periventricular white matter atrophy, brain atrophy, and corpus callosum atrophy and thinning. The proband and her two living brothers (IV2 and IV4) were detected to carry a homozygous mutation of the POLR3A (NM_007055.4) gene c. 2300G > T (p.Cys767Phe), and her consanguineous married parents (III1 and III2) were p.Cys767Phe heterozygous carriers. In the constructed POLR3A wild-type and p.Cys767Phe mutant cells, it was seen that overexpression of wild-type POLR3A protein significantly enhanced Pol III transcription of 5S rRNA and tRNA Leu-CAA. However, although the mutant POLR3A protein overexpression was increased compared to the wild-type protein overexpression, it did not show the expected further enhancement of Pol III function. On the contrary, Pol III transcription function was frustrated (POLR3A, BC200, and tRNA Leu-CAA expression decreased), and MBP and 18S rRNA expressions were decreased. This study indicates that the POLR3A p.Cys767Phe variant caused increased expression of mutated POLR3A protein and abnormal expression of Pol III transcripts, and the mutant POLR3A protein function was abnormal.


Assuntos
Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central , Masculino , Feminino , Humanos , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Mutação , Fenótipo , Atrofia , RNA de Transferência , RNA Polimerase III/genética , RNA Polimerase III/metabolismo
18.
Oecologia ; 2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38683388

RESUMO

Hard limestone substrates, which are extensively distributed, are believed to exacerbate drought and increase the difficulty of restoration in vulnerable karst regions. Fissures in such substrates may alleviate the negative effect of drought on plants, but the underlying mechanisms remain poorly understood. In a two-way factorial block design, the growth and photosynthesis of 2-year-old Phoebe zhennan seedlings were investigated in two water availabilities (high versus low) and three stimulated fissure habitat groups (soil, soil-filled fissure and non-soil-filled fissure). Moreover, the fissure treatments included both small and big fissures. Compared to the soil group, the non-soil-filled fissure group had decreased the total biomass, root biomass, total root length, and the root length of fine roots in the soil layer at both water availabilities, but increased net photosynthetic rate (Pn) and retained stable water use efficiency (WUE) at low water availability. However, there were no significant differences between the soil-filled fissure group and soil group in the biomass accumulation and allocation as well as Pn. Nevertheless, the SF group decreased the root distribution in total and in the soil layer, and also increased WUE at low water availability. Across all treatments, fissure size had no effect on plant growth or photosynthesis. Karst fissures filled with soil can alleviate drought impacts on plant root growth, which involves adjusting root distribution strategies and increasing water use efficiency. These results suggest that rock fissures can be involved in long-term plant responses to drought stress and vegetation restoration in rocky mountain environments under global climate change.

19.
Biomedicines ; 12(4)2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38672222

RESUMO

Retinal structural and functional changes in humans can be manifestations of different physiological or pathological conditions. Retinal imaging is the only way to directly inspect blood vessels and their pathological changes throughout the whole body non-invasively. Various quantitative analysis metrics have been used to measure the abnormalities of retinal microvasculature in the context of different retinal, cerebral and systemic disorders. Recently developed optical coherence tomography angiography (OCTA) is a non-invasive imaging tool that allows high-resolution three-dimensional mapping of the retinal microvasculature. The identification of retinal biomarkers from OCTA images could facilitate clinical investigation in various scenarios. We provide a framework for extracting computational retinal microvasculature biomarkers (CRMBs) from OCTA images through a knowledge-driven computerized automatic analytical system. Our method allows for improved identification of the foveal avascular zone (FAZ) and introduces a novel definition of vessel dispersion in the macular region. Furthermore, retinal large vessels and capillaries of the superficial and deep plexus can be differentiated, correlating with retinal pathology. The diagnostic value of OCTA CRMBs was demonstrated by a cross-sectional study with 30 healthy subjects and 43 retinal vein occlusion (RVO) patients, which identified strong correlations between OCTA CRMBs and retinal function in RVO patients. These OCTA CRMBs generated through this "all-in-one" pipeline may provide clinicians with insights about disease severity, treatment response and prognosis, aiding in the management and early detection of various disorders.

20.
Foods ; 13(8)2024 Apr 18.
Artigo em Inglês | MEDLINE | ID: mdl-38672908

RESUMO

To investigate the gelation process of direct ultra-high-temperature (UHT) milk, a pilot-scale steam infusion heat treatment was used to process milk samples over a wide temperature of 142-157 °C for 0.116-6 s, followed by storage at 4 °C, 25 °C, and 37 °C. The results of the physicochemical properties of milk showed that the particle sizes and plasmin activities of all milk samples increased during storage at 25 °C, but age gelation only occurred in three treated samples, 147 °C/6 s, 142 °C/6 s, and 142 °C/3 s, which all had lower plasmin activities. Furthermore, the properties of formed gels were further compared and analyzed by the measures of structure and intermolecular interaction. The results showed that the gel formed in the 147 °C/6 s-treated milk with a higher C* value had a denser network structure and higher gel strength, while the 142 °C/6 s-treated milk had the highest porosity. Furthermore, disulfide bonds were the largest contributor to the gel structure, and there were significant differences in disulfide bonds, hydrophobic interaction forces, hydrogen bonds, and electrostatic force among the gels. Our results showed that the occurrence of gel was not related to the thermal load, and the different direct UHT treatments produced different age gels in the milk.

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