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1.
FASEB J ; 38(5): e23523, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38457275

RESUMEN

Zinc and ring finger 3 (ZNRF3) is a negative suppressor of Wnt signal and newly identified as an important regulator in tumorigenesis and development. However, the pan-cancer analysis of ZNRF3 has not been reported. We found that ZNRF3 was significantly decreased in six tumors including CESC, KIRP, KIRC, SKCM, OV, and ACC, but increased in twelve tumors, namely LGG, ESCA, STES, COAD, STAD, LUSC, LIHC, THCA, READ, PAAD, TGCT, and LAML. Clinical outcomes of cancer patients were closely related to ZNRF3 expression in ESCA, GBM, KIRC, LUAD, STAD, UCEC, LGG, and SARC. The highest genetic alteration frequency of ZNRF3 occurred in ACC. Abnormal expression of ZNRF3 could be attributed to the differences of copy number variation (CNV) and DNA methylation as well as ZNRF3-interacting proteins. Besides, ZNRF3 were strongly associated with tumor heterogeneity, tumor stemness, immune score, stromal score and ESTIMATE score in certain cancers. In terms of immune cell infiltration, ZNRF3 was positively correlated to infiltration of cancer-associated fibroblasts in CESC, HNSC, OV, PAAD, PRAD, and THYM, but negatively associated with infiltration of CD8 T cells in HNSC, KIRC, KIRP and THYM. Moreover, ZNRF3 expression was correlated with most immune checkpoint genes in SARC, LUSC, LUAD, PRAD, THCA, UVM, TGCT, and OV, and associated with overwhelming majority of immunoregulatory genes in almost all cancers. Most RNA modification genes were also remarkably related to ZNRF3 level in KIRP, LUAD, LUSC, THYM, UVM, PRAD, and UCEC, indicating that ZNRF3 might have an important effect on cancer epigenetic regulation. Finally, we verified the expression and role of ZNRF3 in clinical specimens and cell lines of renal cancer and liver cancer. This study provides a comprehensive pan-cancer analysis of ZNRF3 and reveals the complexity of its carcinogenic effect.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Variaciones en el Número de Copia de ADN , Epigénesis Genética , Pronóstico , Zinc
2.
J Am Chem Soc ; 146(13): 9230-9240, 2024 Apr 03.
Artículo en Inglés | MEDLINE | ID: mdl-38494637

RESUMEN

Keratan sulfate (KS) is a proteoglycan that is widely expressed in the extracellular matrix of various tissue types, where it performs multiple biological functions. KS is the least understood proteoglycan, which in part is due to a lack of panels of well-defined KS oligosaccharides that are needed for structure-binding studies, as analytical standards, to examine substrate specificities of keratinases, and for drug development. Here, we report a biomimetic approach that makes it possible to install, in a regioselective manner, sulfates and fucosides on oligo-N-acetyllactosamine (LacNAc) chains to provide any structural element of KS by using specific enzyme modules. It is based on the observation that α1,3-fucosides, α2,6-sialosides and C-6 sulfation of galactose (Gal6S) are mutually exclusive and cannot occur on the same LacNAc moiety. As a result, the pattern of sulfation on galactosides can be controlled by installing α1,3-fucosides or α2,6-sialosides to temporarily block certain LacNAc moieties from sulfation by keratan sulfate galactose 6-sulfotransferase (CHST1). The patterns of α1,3-fucosylation and α2,6-sialylation can be controlled by exploiting the mutual exclusivity of these modifications, which in turn controls the sites of sulfation by CHST1. Late-stage treatment with a fucosidase or sialidase to remove blocking fucosides or sialosides provides selectively sulfated KS oligosaccharides. These treatments also unmasked specific galactosides for further modification by CHST1. To showcase the potential of the enzymatic strategy, we have prepared a range of poly-LacNAc derivatives having different patterns of fucosylation and sulfation and several N-glycans decorated by specific arrangements of sulfates.


Asunto(s)
Galactosa , Sulfato de Queratano , Sulfato de Queratano/química , Biomimética , Oligosacáridos , Carbohidrato Sulfotransferasas , Proteoglicanos , Galactósidos , Sulfatos
3.
Biochem Genet ; 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38833082

RESUMEN

Targeting protein for Xenopus kinesin-like protein 2 (TPX2), a well-known mitotic protein, has been linked to carcinogenesis in several cancers. This study investigated the role of TPX2 in hepatocellular carcinoma (HCC) from various aspects using bioinformatic analyses. TPX2 expression and its prognostic value in pan-cancers were analyzed using SangerBox. TPX2 expression and its association with prognosis, immune infiltration, tumor mutations, and signaling pathways in HCC were analyzed using UALCAN, BoxKaplan-Meier Plotter, GEPIA, Human Protein Atlas, TIMER 2.0, and SangerBox. Genes co-expressed with TPX2 in HCC were analyzed using the HCCDB database, followed by functional enrichment using SangerBox. Clinical predictive models were established based on TPX2 and its co-expressed genes using the ACLBI database. TPX2 expression significantly increased in pan-cancers and was associated with survival in nearly half of the cancer types. High TPX2 expression has been linked to poor survival outcomes in patients with HCC. TPX2 expression was positively correlated with abundant infiltration of immune cells (including B cells, CD4 + /CD8 + T cells, macrophages, neutrophils, and dendritic cells), TP53 mutation, and carcinogenesis-related pathways, such as the PI3K/AKT/mTOR pathway, cellular response to hypoxia, and tumor proliferation signature. Nineteen genes were found to be co-expressed with TPX2 in HCC, and these genes showed close positive correlations and were mainly implicated in cell cycle-related functions. A prognostic model established using TPX2 and its expressed genes could stratify HCC patients into high- and low-risk groups, with a significantly shorter survival time in high-risk groups. The prognostic model performed well in predicting 1-, 3-, and 5-year survival of patients with HCC, with areas under the curve of 0.801, 0.725, and 0.711, respectively. TPX2 functions as an oncogene in HCC, and its high expression is detrimental to the survival of patients with HCC. Thus, TPX2 may be a prognostic biomarker and potential therapeutic target for HCC.

4.
Sensors (Basel) ; 24(9)2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38732862

RESUMEN

Online monitoring and real-time feedback on inclusions in molten metal are essential for metal quality control. However, existing methods for detecting aluminum melt inclusions face challenges, including interference, prolonged processing times, and latency. This paper presents the design and development of an online monitoring system for molten metal inclusions. Initially, the system facilitates real-time adjustment of signal acquisition parameters through a multiplexer. Subsequently, it employs a detection algorithm capable of swiftly extracting pulse peaks, with this task integrated into our proprietary host computer software to ensure timely detection and data visualization. Ultimately, we developed a monitoring device integrated with this online monitoring system, enabling the online monitoring of the aluminum alloy filtration process. Our findings indicate that the system can accurately measure the size and concentration of inclusions during the filtration process in real time, offering enhanced detection speed and stability compared to the industrial LiMCA CM (liquid metal cleanliness analyzer continuous monitoring) standard. Furthermore, our evaluation of the filtration process demonstrates that the effectiveness of filtration significantly improves with the increase in inclusion sizes, and the synergistic effect of combining CFF (ceramic foam filter) and MCF (metallics cartridge filter) filtration methods exceeds the performance of the CFF method alone. This system thus provides valuable technical support for optimizing filtration processes and controlling inclusion quality.

5.
Sensors (Basel) ; 24(9)2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38732873

RESUMEN

Traditional methods for assessing the cleanliness of liquid metal are characterized by prolonged detection times, delays, and susceptibility to variations in sampling conditions. To address these limitations, an online cleanliness-analyzing system grounded in the method of the electrical sensing zone has been developed. This system facilitates real-time, in situ, and quantitative analysis of inclusion size and amount in liquid metal. Comprising pneumatic, embedded, and host computer modules, the system supports the continuous, online evaluation of metal cleanliness across various metallurgical processes in high-temperature environments. Tests conducted with gallium liquid at 90 °C and aluminum melt at 800 °C have validated the system's ability to precisely and quantitatively detect inclusions in molten metal in real time. The detection procedure is stable and reliable, offering immediate data feedback that effectively captures fluctuations in inclusion amount, thereby meeting the metallurgical industry's demand for real-time analyzing and control of inclusion cleanliness in liquid metal. Additionally, the system was used to analyze inclusion size distribution during the hot-dip galvanizing process. At a zinc melt temperature of 500 °C, it achieved a detection limit of 21 µm, simultaneously providing real-time data on the size and amount distribution of inclusions. This represents a novel strategy for the online monitoring and quality control of zinc slag throughout the hot-dip galvanizing process.

6.
Surgery ; 176(3): 785-797, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38851900

RESUMEN

BACKGROUND: Advanced clear cell renal cell carcinoma still lacks reliable diagnostic and prognostic biomarkers. Recently, tumor vaccines targeting specific molecules have been proposed as a promising treatment in mitigating tumor progression, which was rekindled under the background of the COVID-19 pandemic. However, the application of messenger RNA vaccine against advanced clear cell renal cell carcinoma antigens remains stagnant, and no subgroup of patients deemed suitable for vaccination has been extensively studied or validated. Our study aims to explore novel advanced clear cell renal cell carcinoma antigen signatures to select suitable patients for vaccination. METHODS: Gene expression profiles of advanced clear cell renal cell carcinoma samples and their corresponding clinical data were retrieved from The Cancer Genome Atlas. The least absolute shrinkage and selection operator model was applied to develop signatures to stratify patients with advanced clear cell renal cell carcinoma. Receiver operating characteristic analysis was used to compare the prognostic accuracy of each factor. Tumor Immune Estimation Resource was used to visualize the relationship between the proportion of antigen-presenting cells and the expression of filtered genes. The "CIBERSORT" and "WGCNA" R Packages were employed to ascertain disparities in immune infiltration levels between advanced clear cell renal cell carcinoma subgroups. The Search Tools for the Retrieval of Interacting Genes database and Cytoscape were used to construct the protein-protein interaction network. CCK-8 and colony formation assays were included in the invitro experiment. RESULTS: In total, 244 potential tumor antigens were identified. Using the least absolute shrinkage and selection operator Cox regression, 21 tumor antigens were selected for developing a risk evaluation signature. The risk score signature can be a useful tool to predict the outcome of advanced clear cell renal cell carcinoma patients. According to the differential clinical, molecular, and immune-related genes, we divided advanced clear cell renal cell carcinoma patients into the immune "cold" subtype and immune "hot" subtype. By developing a logistic score, the immune subtype signature can better distinguish a patient more likely to be immune "cold" subtype or immune "hot" subtype. Interestingly, patients with high risk scores had a higher proportion of immune "hot" subtype than those with a low risk score. Furthermore, the prognostic value was significantly improved when combining risk score and immune subtype. Distinct immune landscapes and signal pathways were observed between different tumor subtypes. Finally, novel tumor antigens related to oxidative stress were identified. CONCLUSION: The tumor-antigens-based risk score and immune subtype signatures identified potentially effective neo-antigens for advanced clear cell renal cell carcinoma messenger RNA vaccine development, and patients with low risk scores and immune "cold" subtype tumors are more prone to benefit from messenger RNA vaccination. Furthermore, our study highlights the significant role of oxidative stress in determining the efficacy of the messenger RNA vaccine.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Vacunas de ARNm , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/inmunología , Neoplasias Renales/genética , Neoplasias Renales/inmunología , Vacunas contra el Cáncer/uso terapéutico , Vacunas contra el Cáncer/inmunología , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/genética , Pronóstico , COVID-19/inmunología , COVID-19/prevención & control , Masculino , Femenino , Perfilación de la Expresión Génica , Transcriptoma , Persona de Mediana Edad , Biomarcadores de Tumor/genética
7.
Front Biosci (Landmark Ed) ; 29(3): 91, 2024 Feb 29.
Artículo en Inglés | MEDLINE | ID: mdl-38538254

RESUMEN

OBJECTIVE: The morphology and functions of the human trabecular meshwork (HTM) are dysregulated in glaucoma, and the molecular mechanisms of this dysregulation remain unknown. According to an established in vitro model, whose function was to study the regulatory networks sustaining the response of HTM cells to the increased substrate stiffness, we systematically analyzed the expression pattern of long noncoding RNAs (lncRNAs), the important regulatory RNAs in cells. METHODS: Bioinformatics analysis was performed to identify the dysregulated lncRNAs in response to increased substrate stiffness using transcriptome sequencing data (RNA-seq). Then we interfered with the expression of several dysregulated lncRNAs in HTM cells to explore their molecular targets. The cross-linking immunoprecipitation and sequencing method (CLIP-seq) was used to identify enhancer of zeste homolog 2 (EZH2)-targeted RNAs in HTM cells. The chromatin IP and sequencing method (ChIP-seq) was used to identify the targets of EZH2 and histone H3 at lysine 27 (H3K27me3). RESULTS: The response of thousands of dysregulated lncRNAs to increased substrate stiffness was identified through RNA-seq. Functional prediction of these lncRNAs revealed that they potentially regulated key biological processes, including extracellular matrix (ECM) organization. By interfering with the expression of lncRNA SHNG8, ZFHX4-AS1, and RP11-552M11.4, the results demonstrated that those lncRNAs extensively regulated the expression levels of ECM-associated genes. Moreover, we found that EZH2 expression was significantly decreased at high substrate stiffness. Using CLIP-seq to identify EZH2-targeted RNAs in HTM cells, we found that SNHG8 was bound by EZH2. According to the CLIP-seq data of EZH2, we found that EZH2 binding sites were observed in the transcripts of SNHG8-regulated genes, but not in the ChIP-seq results of EZH2 and H3K27me3. CONCLUSION: Our results suggest that SNHG8 and EZH2 may cooperate to regulate the expression of a subset of genes by influencing their RNA abundance, explaining how they support HTM cell morphology and high density. This study contributes to the understanding of the alteration of HTM during the progression of glaucoma by identifying functional lncRNAs, especially SNHG8, and suggests novel therapeutic targets to treat glaucoma.


Asunto(s)
Glaucoma , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Histonas/metabolismo , Transcriptoma , Malla Trabecular/metabolismo , Cromatina/metabolismo , Biología Computacional/métodos , Glaucoma/genética , Glaucoma/metabolismo
8.
Front Biosci (Landmark Ed) ; 29(2): 57, 2024 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-38420795

RESUMEN

BACKGROUND: Colocasia esculenta L. Schott is a main traditional root crop in China, serving as an important vegetable and staple food. Drought stress plays vital role on the growth and development of taro corm. METHODS: Two different varieties of taro in Jiangsu were selected: Xiangsha taro and Longxiang taro. The accumulation characteristics, morphological structure, and physicochemical properties of taro corm starch were studied by microscopic observation, particle size analysis, and X-ray diffractometer (XRD) analysis. Transcriptome analyses were used to identify the related genes of taro corm under drought stress. RESULTS: During the growth of taro, the number of amyloplasts showed an obvious increasing trend and shifted from being dispersed throughout the cells to being gathered on one side of the cells, and morphological observations showed that smaller granular distribution gradually changed to a larger lumpy distribution. The particle size of Longxiang taro is smaller than that of Xiangsha taro. Under drought stress conditions, the occurrence of starch grains and corm size were inhibited in Xiangsha taro. Transcriptome sequencing of drought-stressed taro corms showed that the enzymes related to starch synthesis were differentially expressed. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of drought-stressed taro corms showed that drought affected hormone signal transduction, material metabolism, drought stress tolerance, plant growth and development, and stress resistance, which triggered the plant drought adaptive response. CONCLUSIONS: Drought stress inhibits starch accumulation in taro.


Asunto(s)
Colocasia , Almidón , Almidón/química , Colocasia/genética , Colocasia/química , Sequías , Alimentos , China
9.
Transl Oncol ; 44: 101942, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38555741

RESUMEN

Cisplatin resistance plays a significant role in the dismal prognosis and progression of muscle-invasive bladder cancer (MIBC). However, the strategies to predict prognosis and cisplatin resistance are inefficient, and it remains unclear whether cisplatin resistance is associated with tumor immunity. In this study, we integrated the transcriptional data from cisplatin-resistant cell lines and a TCGA-MIBC cohort to establish cisplatin-resistance-related cluster classification and a cisplatin-resistance-related gene risk score (CRRGRS). Kaplan-Meier survival curves showed that compared with those in low CRRGRS group, MIBC patients belonging to high CRRGRS group had worse prognosis in TCGA-MIBC cohort and external GEO cohorts. Meanwhile, CRRGRS was able to help forecast chemotherapy and immunotherapy response of MIBC patients in the TGCA cohort and IMvigor210 cohort. Moreover, compared with the low CRRGRS group, the high CRRGS group possessed a relatively immunosuppressive "cold tumor" phenotype with a higher tumor immune dysfunction and exclusion (TIDE) score, ESTIMATE score, stromal score and immune score and a lower immunophenoscore (IPS) score. The upregulated expression levels of immune checkpoint genes, including PD-1, PD-L1 and CTLA4, in the high CRRGRS group also further indicated that a relative immunosuppressive tumor microenvironment may exist in MIBC patients belonging to high CRRGRS group. In addition, we integrated CRRGRS and clinical characteristics with prognostic value to develop a nomogram, which could help forecast overall survival of MIBC patients. Furthermore, DIAPH3 was identified as a regulator of proliferation and cisplatin resistance in MIBC. The expression of DIAPH3 was increased in cisplatin-resistant cell lines and chemotherapy-unsensitive people. Further mechanism exploration revealed that DIAPH3 facilitated tumor proliferation and cisplatin resistance by regulating the NF-kB and epithelial-mesenchymal transition (EMT) pathways. In conclusion, the comprehensive investigations of CRRGRS increased the understanding of cisplatin resistance and provided promising insights to restrain tumor growth and overcome chemoresistance by targeting DIAPH3.

10.
J Econ Entomol ; 117(2): 564-577, 2024 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-38289982

RESUMEN

Tomostethus sinofraxini Wang & Wei (a new name is proposed for Tomostethus fraxini Niu & Wei, 2022: Tomostethus sinofraxini Wang & Wei, nom. nov.), an emerging sawfly pest of the Chinese ash, Fraxinus chinensis, is now endemic to Beijing, Tianjin, Hebei, and Shandong provinces. Given the severity of its infestation and the speed of its range expansion, we studied the phylogenetic relationship of T. sinofraxini with other sawfly species and its life history to be better informed for the management strategies. The nearly complete T. sinofraxini mitogenome is 16,169 bp in length and encodes 2 ribosomal RNAs (rrnL and rrnS), 22 transfer RNAs (tRNAs), and 13 protein-coding genes. The nucleotide composition is biased toward adenine and thymine (A + T = 81.7%). In comparison to the architecture of the ancestral insect mitogenome, 2 transposition events occur on the IQM tRNA cluster, rearranging it from IQM to MQI. Our phylogenetic analysis suggests that T. sinofraxini belongs to a group composed of paraphyletic subfamilies Blennocampinae and Heterarthrinae. In addition, to document its life history, we observed T. sinofraxini development at 2 geographical locations in Beijing, China, with different altitudes. At Jiulong Mountain, with a higher altitude and a lower average temperature, the developmental time of egg, larval, and adult stages was 19%-31% longer than that observed at the Chinese Academy of Forestry. A basic understanding of biological traits and molecular signatures is the critical first step to develop an integrated pest management framework for this emerging pest of the Chinese ash.


Asunto(s)
Fraxinus , Genoma Mitocondrial , Himenópteros , Animales , Filogenia , ARN Ribosómico/genética , ARN de Transferencia/genética
11.
Biology (Basel) ; 13(5)2024 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-38785787

RESUMEN

The assassin bug Sycanus bifidus has a wide distribution across southern China. This study explored its distribution and evolution by analyzing mitochondrial and nuclear ribosomal RNA genes, revealing how Pleistocene climate and geological changes shaped its phylogeography. We identified two main clades, A and B, that diverged in the Middle Pleistocene. Hainan Island's populations form a unique group within Clade A, suggesting that the Qiongzhou Strait served as a dispersal corridor during glaciation. Rising sea levels likely separated the Hainan population afterward. Ecological niche modeling showed that both populations have been viable since the last interglacial period, with demographic analyses indicating possible expansions during the Middle and Late Pleistocene, driven by favorable climates. This study highlights the significant effects of Pleistocene sea-level and climatic changes on the distribution and evolution of S. bifidus in China.

12.
Mitochondrial DNA B Resour ; 9(5): 631-635, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38751733

RESUMEN

In the present study, the complete mitochondrial genome (mitogenome) of the Papilio macilentus (Lepidoptera: Papilionoidea: Papilionidae) was sequenced by next-generation sequencing method. The mitochondrial genome is a circular DNA molecule of 15,264 bp in size with 80.7% AT content, including 37 genes (13 protein-coding genes, 2 rRNA genes, and 22 tRNA genes), and a long non-coding region (Control region). All protein-coding genes are initiated by ATN codons, and terminated with TAA, TAG, or single T. All tRNAs can be folded into common clover leaf secondary structure, except trn-S1. Phylogenetic analyses based on 13 protein-coding genes and 2 rRNA genes using maximum likelihood and Bayesian inference confirmed that P. macilentus and Papilio memnon are clustered into a clade, and revealed the relationships between Papilionini, Troidini, Teinopaippini and Leptocircini.

13.
Ambio ; 53(9): 1323-1335, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38653867

RESUMEN

Protected areas (PAs) are effective in mitigating human pressures, yet their future pressure alleviating effects remain unclear. In this study, we employed the ConvLSTM model to forecast the future human footprint and analyzed human pressure trends using Theil-Sen median and Mann-Kendall tests. We further evaluated the mitigating effects of PAs within their buffer zones (1-10 km) and the contributions of different IUCN categories of PAs to mitigating human pressure using linear regression models. The results indicate that by 2035, the average human pressure value is expected to increase by 11%, with trends exhibiting a polarized pattern. Furthermore, PAs also effectively mitigate human pressure within their 1 km buffer zones. Different categories of PAs vary in their effectiveness in mitigating human pressure, and stricter conservation areas are not always the most effective. This study can offer insights for evaluating the effectiveness of PAs in reducing human pressure and advocate for their targeted management in urban areas.


Asunto(s)
Conservación de los Recursos Naturales , Humanos , Conservación de los Recursos Naturales/métodos , Modelos Teóricos
14.
Front Pharmacol ; 15: 1411642, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39139632

RESUMEN

Background: Chronic intestinal pseudo-obstruction (CIPO) is a type of intestinal dysfunction with symptoms of intestinal blockage but without the actual mechanical obstruction. Currently, there are no drugs available to treat this disease. Herein, we report the characterization of the PrP-SCA7-92Q transgenic (Tg) line as a valuable CIPO mouse model and investigated the tolerability and efficacy of the 5-hydroxytryptamine type-4 receptor (5HT4R) agonist velusetrag as a promising pharmacological treatment for CIPO. Methods: To test the pharmacodynamics of velusetrag, 8-week-old SCA7 Tg mice, which express human mutated Ataxin-7 gene containing 92 CAG repeats under the mouse prion protein promoter, were treated for 5 weeks by oral route with velusetrag at 1 and 3 mg/kg doses or vehicle. Body weight was monitored throughout the treatment. After sacrifice, the small intestine and proximal colon were collected for whole-mount immunostaining. Untreated, age-matched, C57BL/6J mice were also used as controls in comparison with the other experimental groups. Results: Analysis of SCA7 Tg mice showed tissue damage and alterations, mucosal abnormalities, and ulcers in the distal small intestine and proximal colon. Morphological changes were associated with significant neuronal loss, as shown by decreased staining of pan-neuronal markers, and with accumulation of ataxin-7-positive inclusions in cholinergic neurons. Administration of velusetrag reversed intestinal abnormalities, by normalizing tissue damage and re-establishing the normal level of glia/neuron's count in both the small and large intestines. Conclusion: We demonstrated that the PrP-SCA7-92Q Tg line, a model originally developed to mimic spinocerebellar ataxia, is suitable to study CIPO pathology and can be useful in establishing new therapeutic strategies, such as in the case of velusetrag. Our results suggest that velusetrag is a promising compound to treat patients affected by CIPO or intestinal dysmotility disease.

15.
Nat Nanotechnol ; 19(5): 652-659, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38351230

RESUMEN

Proteins are the primary functional actors of the cell. While proteoform diversity is known to be highly biologically relevant, current protein analysis methods are of limited use for distinguishing proteoforms. Mass spectrometric methods, in particular, often provide only ambiguous information on post-translational modification sites, and sequences of co-existing modifications may not be resolved. Here we demonstrate fluorescence resonance energy transfer (FRET)-based single-molecule protein fingerprinting to map the location of individual amino acids and post-translational modifications within single full-length protein molecules. Our data show that both intrinsically disordered proteins and folded globular proteins can be fingerprinted with a subnanometer resolution, achieved by probing the amino acids one by one using single-molecule FRET via DNA exchange. This capability was demonstrated through the analysis of alpha-synuclein, an intrinsically disordered protein, by accurately quantifying isoforms in mixtures using a machine learning classifier, and by determining the locations of two O-GlcNAc moieties. Furthermore, we demonstrate fingerprinting of the globular proteins Bcl-2-like protein 1, procalcitonin and S100A9. We anticipate that our ability to perform proteoform identification with the ultimate sensitivity may unlock exciting new venues in proteomics research and biomarker-based diagnosis.


Asunto(s)
Transferencia Resonante de Energía de Fluorescencia , Transferencia Resonante de Energía de Fluorescencia/métodos , Humanos , alfa-Sinucleína/química , alfa-Sinucleína/metabolismo , Procesamiento Proteico-Postraduccional , Proteínas Intrínsecamente Desordenadas/química , Imagen Individual de Molécula/métodos , Aprendizaje Automático , Mapeo Peptídico/métodos
16.
iScience ; 27(8): 110411, 2024 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-39108731

RESUMEN

Genetic basis underlying the biodiversity and phenotypic plasticity are fascinating questions in evolutionary biology. Such molecular diversity can be achieved at multi-omics levels. Here, we sequenced the first chromosome-level genome of assassin bug Rhynocoris fuscipes, a polyphagous generalist predator for biological control of agroecosystems. Compared to non-predatory true bugs Apolygus lucorum and Riptortus pedestris, the R. fuscipes-specific genes were enriched in diet-related genes (e.g., serine proteinase, cytochrome P450) which had higher expression level and more exons than non-diet genes. Extensive A-to-I RNA editing was identified in all three species and showed enrichment in genes associated with diet in R. fuscipes, diversifying the transcriptome. An extended analysis between five predaceous and 27 phytophagous hemipteran species revealed an expansion of diet-related genes in R. fuscipes. Our findings bridge the gap between genotype and phenotype, and also advance our understanding on genetic and epigenetic bases governing the diet shifts in ture bugs.

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