Altered Protein
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2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Guiming Hu ◽  
Fei Gao ◽  
Guanzhe Wang ◽  
Yan Fang ◽  
Yuanyuan Guo ◽  
...  

Abstract Background Although an association between the cytochrome P4502D6 (CYP2D6) *10 (100C>T) polymorphism and hepatocellular carcinoma (HCC) is known, the mechanism remains unclear. Here we aimed to explore mechanisms of CYP2D6*10 (100C>T) polymorphism conferring to HCC, and screen markers for HCC. Methods Label-free global proteome profiling with 34 normal livers and peritumor tissue from 61 HCC patients was performed, and angiopoietin-like protein-6 (ANGPTL6) was evaluated in 2 liver samples validation cohorts and 2 blood specimens validation cohorts. Results We found a significantly decreased frequency of TT in HCC patients which reduced HCC susceptibility by 69.2% and was accompanied by lowered enzymatic activity for CYP2D6. Proteomic analysis revealed 1342 differentially expressed proteins (DEPs) that were associated with HCC and 88 DEPs were identified as 100 TT-related proteins, likely underlying the susceptibility to HCC. Twenty-two upregulated DEPs and 66 downregulated DEPs were mainly related to lipid metabolism and the extracellular matrix, respectively. High ANGPTL6 was associated with a higher risk to HCC and worse prognosis. ANGPTL6 was both an independent risk factor and an independent prognostic factor for HCC and exhibited strong potential for predicting HCC occurrence, with comparable AUC values and higher sensitivity compared with alpha-fetoprotein. Conclusions The TT genotype-associated decreased risk of HCC appears to be related to lowered CYP2D6 activity and altered protein expression in the tumor microenvironment, and ANGPTL6 is a promising new diagnostic and prognostic biomarker for HCC. Our findings reveal new mechanistic insights for polymorphisms related to HCC risk and provide avenues for screening for HCC.


2021 ◽  
Vol 22 (16) ◽  
pp. 8597
Author(s):  
Ilka Wilhelmi ◽  
Alexander Neumann ◽  
Markus Jähnert ◽  
Meriem Ouni ◽  
Annette Schürmann

Dysfunctional islets of Langerhans are a hallmark of type 2 diabetes (T2D). We hypothesize that differences in islet gene expression alternative splicing which can contribute to altered protein function also participate in islet dysfunction. RNA sequencing (RNAseq) data from islets of obese diabetes-resistant and diabetes-susceptible mice were analyzed for alternative splicing and its putative genetic and epigenetic modulators. We focused on the expression levels of chromatin modifiers and SNPs in regulatory sequences. We identified alternative splicing events in islets of diabetes-susceptible mice amongst others in genes linked to insulin secretion, endocytosis or ubiquitin-mediated proteolysis pathways. The expression pattern of 54 histones and chromatin modifiers, which may modulate splicing, were markedly downregulated in islets of diabetic animals. Furthermore, diabetes-susceptible mice carry SNPs in RNA-binding protein motifs and in splice sites potentially responsible for alternative splicing events. They also exhibit a larger exon skipping rate, e.g., in the diabetes gene Abcc8, which might affect protein function. Expression of the neuronal splicing factor Srrm4 which mediates inclusion of microexons in mRNA transcripts was markedly lower in islets of diabetes-prone compared to diabetes-resistant mice, correlating with a preferential skipping of SRRM4 target exons. The repression of Srrm4 expression is presumably mediated via a higher expression of miR-326-3p and miR-3547-3p in islets of diabetic mice. Thus, our study suggests that an altered splicing pattern in islets of diabetes-susceptible mice may contribute to an elevated T2D risk.


2021 ◽  
Vol 2021 ◽  
pp. 1-4
Author(s):  
Katarzyna Noras ◽  
Ewa Rusak ◽  
Przemysława Jarosz-Chobot

Diabetes is a disease that affects many people around the world. Its complications are the cause of cardiovascular diseases (CVD) and increased mortality. That is why the search for predictive biomarkers is so important. The aim of the study was to show the prevalence of the problem and risk factors in children and adolescents with type 1 diabetes. These patients are often overweight and obese, and the percentage of lipid disorders is particularly high. The discussed markers of CVD risk in type 1 diabetes include apolipoproteins (apo-B and apo-C3), modified forms of LDL, and the role of high-density lipoprotein (HDL). Recently, a new look at the vasoprotective effect of HDL has appeared, which due to its dysfunctional form in type 1 diabetes may not protect against cardiovascular risk. The HDL proteome in type 1 diabetes has an altered protein composition compared to the healthy population. Another direction of research is determining the importance of trace elements (mainly Mg) in the development of diabetes complications.


2021 ◽  
pp. 167219
Author(s):  
Adi Ulman ◽  
Tal Levin ◽  
Bareket Dassa ◽  
Aaron Javitt ◽  
Assaf Kacen ◽  
...  

Agronomy ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1481
Author(s):  
Aurora Ghirardelli ◽  
Michela Schiavon ◽  
Giuseppe Zanin ◽  
Piotr Ostapczuk ◽  
Roberta Masin

Weeds account for losses in crop yields, and this event might be exacerbated by salinity. Therefore, we investigated the responses of Chenopodium album L. and soybean (Glycine max (L.) Merr.) to salt stress, as well as interferences between species. Ten-day old plants were grown for 1 week in a single- or mixed-species set-up, either with or without 100 mM of NaCl. C. album reduced the biomass of soybean similarly to salt stress, while its growth was unaffected under any condition. C. album decreased the crop protein content when salinity was applied. This effect was ascribed to altered protein metabolism and/or N usage to produce other N metabolites, including osmolytes. The two species did not reciprocally affect the capacity to accumulate Na+, but the weed contained two-fold more Na+ in the leaves. Elevated initial K+ concentration and high K+ delivery to the shoot likely explained the better acclimation of C. album to salinity. C. album produced more phenolics and proline and exhibited greater antioxidant activity, but low lipid peroxidation, in the mixed set-up under salinity. Thus, it is possible that the weed could become more resilient to salinity when growing in a soybean field. In the long term, this might cause significant losses in soybean productivity as expected by the dramatic decline in crop protein content.


2021 ◽  
Author(s):  
Kimberlee P Giffen ◽  
Yi Li ◽  
Huizhan Liu ◽  
Xiao-Chang Zhao ◽  
Chang-Jun Zhang ◽  
...  

Lysosomes contribute to cellular homeostasis via processes including phagocytosis, macromolecule catabolism, secretion, and nutrient sensing mechanisms. Defective proteins related to lysosomal macromolecule catabolism are known to cause a broad range of lysosomal storage diseases. It is unclear, however, if mutations in genes in the autophagy-lysosomal pathway can cause syndromic disease. Here we show that SLC7A14, a transporter protein mediating lysosomal uptake of cationic amino acids, is evolutionarily conserved in vertebrate mechanosensitive hair cells and highly expressed in lysosomes of mammalian cochlear inner hair cells (IHCs) and retinal photoreceptors. Autosomal recessive mutation of SLC7A14 caused loss of IHCs and photoreceptors, leading to pre-synaptic auditory neuropathy and retinitis pigmentosa in mice and humans. Loss of function mutation altered protein trafficking and disrupted lysosomal homeostasis, resulting in dysregulation of basal autophagy and progressive cell degeneration. This study is the first to implicate autophagy-lysosomal dysfunction in syndromic hearing and vision loss in mice and humans. 


2021 ◽  
Vol 22 (12) ◽  
pp. 6360
Author(s):  
Giulia Di Donato ◽  
Debora Mariarita d’Angelo ◽  
Luciana Breda ◽  
Francesco Chiarelli

Systemic autoinflammatory diseases are a heterogeneous family of disorders characterized by a dysregulation of the innate immune system, in which sterile inflammation primarily develops through antigen-independent hyperactivation of immune pathways. In most cases, they have a strong genetic background, with mutations in single genes involved in inflammation. Therefore, they can derive from different pathogenic mechanisms at any level, such as dysregulated inflammasome-mediated production of cytokines, intracellular stress, defective regulatory pathways, altered protein folding, enhanced NF-kappaB signalling, ubiquitination disorders, interferon pathway upregulation and complement activation. Since the discover of pathogenic mutations of the pyrin-encoding gene MEFV in Familial Mediterranean Fever, more than 50 monogenic autoinflammatory diseases have been discovered thanks to the advances in genetic sequencing: the advent of new genetic analysis techniques and the discovery of genes involved in autoinflammatory diseases have allowed a better understanding of the underlying innate immunologic pathways and pathogenetic mechanisms, thus opening new perspectives in targeted therapies. Moreover, this field of research has become of great interest, since more than a hundred clinical trials for autoinflammatory diseases are currently active or recently concluded, allowing us to hope for considerable acquisitions for the next few years. General paediatricians need to be aware of the importance of this group of diseases and they should consider autoinflammatory diseases in patients with clinical hallmarks, in order to guide further examinations and refer the patient to a specialist rheumatologist. Here we resume the pathogenesis, clinical aspects and diagnosis of the most important autoinflammatory diseases in children.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sebnem Garip Ustaoglu ◽  
Mohamed H. M. Ali ◽  
Fazle Rakib ◽  
Erwin L. A. Blezer ◽  
Caroline L. Van Heijningen ◽  
...  

AbstractTraumatic brain injury (TBI) is the main cause of disability and mortality in individuals under the age of 45 years. Elucidation of the molecular and structural alterations in brain tissue due to TBI is crucial to understand secondary and long-term effects after traumatic brain injury, and to develop and apply the correct therapies. In the current study, the molecular effects of TBI were investigated in rat brain at 24 h and 1 month after the injury to determine acute and chronic effects, respectively by Fourier transform infrared imaging. This study reports the time-dependent contextual and structural effects of TBI on hippocampal brain tissue. A mild form of TBI was induced in 11-week old male Sprague Dawley rats by weight drop. Band area and intensity ratios, band frequency and bandwidth values of specific spectral bands showed that TBI causes significant structural and contextual global changes including decrease in carbonyl content, unsaturated lipid content, lipid acyl chain length, membrane lipid order, total protein content, lipid/protein ratio, besides increase in membrane fluidity with an altered protein secondary structure and metabolic activity in hippocampus 24 h after injury. However, improvement and/or recovery effects in these parameters were observed at one month after TBI.


2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Andrea Schenkmayerova ◽  
Gaspar P. Pinto ◽  
Martin Toul ◽  
Martin Marek ◽  
Lenka Hernychova ◽  
...  

AbstractProtein dynamics are often invoked in explanations of enzyme catalysis, but their design has proven elusive. Here we track the role of dynamics in evolution, starting from the evolvable and thermostable ancestral protein AncHLD-RLuc which catalyses both dehalogenase and luciferase reactions. Insertion-deletion (InDel) backbone mutagenesis of AncHLD-RLuc challenged the scaffold dynamics. Screening for both activities reveals InDel mutations localized in three distinct regions that lead to altered protein dynamics (based on crystallographic B-factors, hydrogen exchange, and molecular dynamics simulations). An anisotropic network model highlights the importance of the conformational flexibility of a loop-helix fragment of Renilla luciferases for ligand binding. Transplantation of this dynamic fragment leads to lower product inhibition and highly stable glow-type bioluminescence. The success of our approach suggests that a strategy comprising (i) constructing a stable and evolvable template, (ii) mapping functional regions by backbone mutagenesis, and (iii) transplantation of dynamic features, can lead to functionally innovative proteins.


2021 ◽  
Vol 12 ◽  
Author(s):  
Song Li ◽  
Jing Gao ◽  
Qian Xu ◽  
Xue Zhang ◽  
Miao Huang ◽  
...  

Gastric cancer is a leading cause of cancer-related deaths with considerable heterogeneity among patients. Appropriate classifications are essential for prognosis prediction and individualized treatment. Although immunotherapy showed potential efficacy in a portion of patients with gastric cancer, few studies have tried to classify gastric cancer specifically based on immune signatures. In this study, we established a 3-subtype cluster with low (CLIM), medium (CMIM), and high (CHIM) enrichment of immune signatures based on immunogenomic profiling. We validated the classification in multiple independent datasets. The CHIM subtype exhibited a relatively better prognosis and showed features of “hot tumors”, including low tumor purity, high stromal components, overexpression of immune checkpoint molecules, and enriched tumor-infiltrated immune cells (activated T cells and macrophages). In addition, CHIM tumors were also characterized by frequent ARID1A mutation, rare TP53 mutation, hypermethylation status, and altered protein expression (HER2, β-catenin, Cyclin E1, PREX1, LCK, PD-L1, Transglutaminase, and cleaved Caspase 7). By Gene Set Variation Analysis, “TGFβ signaling pathway” and “GAP junction” were enriched in CLIM tumors and inversely correlated with CD8+ and CD4+ T cell infiltration. Of note, the CHIM patients showed a higher response rate to immunotherapy (44.4% vs. 11.1% and 16.7%) and a more prolonged progression-free survival (4.83 vs. 1.86 and 2.75 months) than CMIM and CLIM patients in a microsatellite-independent manner. In conclusion, the new immune signature-based subtypes have potential therapeutic and prognostic implications for gastric cancer management, especially immunotherapy.


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