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1.
Sci Rep ; 13(1): 1483, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36707625

RESUMO

Alkaliptosis is a recently discovered type of pH-dependent cell death used for tumor therapy. However, its underlying molecular mechanisms and regulatory networks are largely unknown. Here, we report that the acetate-activating enzyme acetyl-CoA short-chain synthase family member 2 (ACSS2) is a positive regulator of alkaliptosis in human pancreatic ductal adenocarcinoma (PDAC) cells. Using qPCR and western blot analysis, we found that the mRNA and protein expression of ACSS2 was upregulated in human PDAC cell lines (PANC1 and MiaPaCa2) in response to the classic alkaliptosis activator JTC801. Consequently, the knockdown of ACSS2 by shRNAs inhibited JTC801-induced cell death in PDAC cells, and was accompanied by an increase in cell clone formation and a decrease in intracellular pH. Mechanically, ACSS2-mediated acetyl-coenzyme A production and subsequent histone acetylation contributed to NF-κB-dependent CA9 downregulation, and this effect was enhanced by the histone deacetylase inhibitor trichostatin A. These findings may provide new insights for understanding the metabolic basis of alkaliptosis and establish a potential strategy for PDAC treatment.

2.
Food Chem ; 411: 135499, 2023 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-36696717

RESUMO

Shrimp meat is prone to autolysis and decay due to the abundance of endogenous enzymes and contamination from microorganisms. HVEF freezing can slow the spoilage of shrimp, producing small and uniform ice crystals, resulting in less damage to muscle tissue. In this study, HVEF technique was used to freeze the shrimp (Solenocera melantho), and the UPLC-MS metabolic technique was used to investigate the metabolites of frozen shrimp meat. Compared with the control group, 367 differential metabolites were identified in the HVEF group. Mapping them to the KEGG database, there were 108 with KEGG ID. Purine metabolism and pyrimidine metabolism were the most enriched pathways. In addition, phosphatidylcholines (PCs), inosine (HxR), and l-valine were identified as potential biomarkers associated with lipid, nucleotide, and organic acid metabolism, respectively. Overall, HVEF can improve freezing quality of shrimp meat by slowing down the metabolism of substances in the muscle of S. melantho.

3.
Biofabrication ; 15(2)2023 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-36608336

RESUMO

Tendon injuries are common debilitating musculoskeletal diseases with high treatment expenditure in sports medicine. The development of tendon-biomimetic scaffolds may be promising for improving the unsatisfactory clinical outcomes of traditional therapies. In this study, we combined an advanced electrospun nanofiber yarn-generating technique with a traditional textile manufacturing strategy to fabricate innovative nano-micro fibrous woven scaffolds with tendon-like anisotropic structure and high-strength mechanical properties for the treatment of large-size tendon injury. Electrospun nanofiber yarns made from pure poly L-lactic acid (PLLA) or silk fibroin (SF)/PLLA blend were fabricated, and their mechanical properties matched and even exceeded those of commercial PLLA microfiber yarns. The PLLA or SF/PLLA nanofiber yarns were then employed as weft yarns interlaced with commercial PLLA microfiber yarns as warp yarns to generate two new types of nanofibrous scaffolds (nmPLLA and nmSF/PLLA) with a plain-weaving structure. Woven scaffolds made from pure PLLA microfiber yarns (both weft and warp directions) (mmPLLA) were used as controls.In vitroexperiments showed that the nmSF/PLLA woven scaffold with aligned fibrous topography significantly promoted cell adhesion, elongation, proliferation, and phenotypic maintenance of tenocytes compared with mmPLLA and nmPLLA woven scaffolds. Moreover, the nmSF/PLLA woven scaffold exhibited the strongest immunoregulatory functions and effectively modulated macrophages towards the M2 phenotype.In vivoexperiments revealed that the nmSF/PLLA woven scaffold notably facilitated Achilles tendon regeneration with improved structure by macroscopic, histological, and ultrastructural observations six months after surgery, compared with the other two groups. More importantly, the regenerated tissue in the nmSF/PLLA group had excellent biomechanical properties comparable to those of the native tendon. Overall, our study provides an innovative biological-free strategy with ready-to-use features, which presents great potential for clinical translation for damaged tendon repair.


Assuntos
Fibroínas , Nanofibras , Tecidos Suporte/química , Engenharia Tecidual/métodos , Poliésteres/química , Tendões , Nanofibras/química , Fibroínas/química , Regeneração
4.
Neural Regen Res ; 18(7): 1542-1547, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36571360

RESUMO

Acquired immune deficiency syndrome infection can lead to cognitive dysfunction represented by changes in the default mode network. Most recent studies have been cross-sectional and thus have not revealed dynamic changes in the default mode network following acquired immune deficiency syndrome infection and antiretroviral therapy. Specifically, when brain imaging data at only one time point are analyzed, determining the duration at which the default mode network is the most effective following antiretroviral therapy after the occurrence of acquired immune deficiency syndrome. However, because infection times and other factors are often uncertain, longitudinal studies cannot be conducted directly in the clinic. Therefore, in this study, we performed a longitudinal study on the dynamic changes in the default mode network over time in a rhesus monkey model of simian immunodeficiency virus infection. We found marked changes in default mode network connectivity in 11 pairs of regions of interest at baseline and 10 days and 4 weeks after virus inoculation. Significant interactions between treatment and time were observed in the default mode network connectivity of regions of interest pairs area 31/V6.R and area 8/frontal eye field (FEF). L, area 8/FEF.L and caudal temporal parietal occipital area (TPOC).R, and area 31/V6.R and TPOC.L. ART administered 4 weeks after infection not only interrupted the progress of simian immunodeficiency virus infection but also preserved brain function to a large extent. These findings suggest that the default mode network is affected in the early stage of simian immunodeficiency virus infection and that it may serve as a potential biomarker for early changes in brain function and an objective indicator for making early clinical intervention decisions.

5.
Biosens Bioelectron ; 222: 115004, 2023 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-36516630

RESUMO

Whole-cell biosensors based on transcriptional regulators are powerful tools for rapid measurement, high-throughput screening, dynamic metabolic regulation, etc. To optimize the biosensing performance of transcriptional regulator, its effector-binding domain is commonly engineered. However, this strategy is encumbered by the limitation of diversifying such a large domain and the risk of affecting effector specificity. Molecular dynamics simulation of effector binding of LysG (an LysR-type transcriptional regulator, LTTR) suggests the crucial role of the short linker helix (LH) connecting effector- and DNA-binding domains in protein conformational change. Directed evolution of LH efficiently produced LysG variants with extended operational range and unaltered effector specificity. The whole-cell biosensor based on the best LysGE58V variant outperformed the wild-type LysG in enzyme high-throughput screening and dynamic regulation of l-lysine biosynthetic pathway. LH mutations are suggested to affect DNA binding and facilitate transcriptional activation upon effector binding. LH engineering was also successfully applied to optimize another LTTR BenM for biosensing. Since LTTRs represent the largest family of prokaryotic transcriptional regulators with highly conserved structures, LH engineering is an efficient and universal strategy for development and optimization of whole-cell biosensors.


Assuntos
Técnicas Biossensoriais , Fatores de Transcrição , Fatores de Transcrição/genética , Fatores de Transcrição/química , Proteínas de Bactérias/genética , Domínios Proteicos , DNA/genética
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 40(1): 76-80, 2023 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-36585006

RESUMO

OBJECTIVE: To explore the clinical and genetic characteristics of a child with spinocerebellar ataxia type 29 (SCA29) due to novel variant of the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) gene. METHODS: The child was subjected high-throughput sequencing, and candidate variant was verified by Sanger sequencing of his family members. RESULTS: The child was found to harbor a c.800C>T (p.T267M) variant of the ITPR1 gene, which was not found in his parents and their fetus. The variant has occurred in a hotspot of the ITPR1 gene variants and was unreported before in China. Based on his clinical and genetic characteristics, the child was diagnosed with SCA29. CONCLUSION: The novel heterozygous c.800C>T (p.T267M) of the ITPR1 gene probably underlay the SCA29 in this child.


Assuntos
Ataxias Espinocerebelares , Degenerações Espinocerebelares , Criança , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Família , Ataxias Espinocerebelares/diagnóstico , Ataxias Espinocerebelares/genética , Mutação
7.
J Med Genet ; 59(9): 840-849, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-34544842

RESUMO

BACKGROUND: A large number of new causative and risk genes for amyotrophic lateral sclerosis (ALS) have been identified mostly in patients of European ancestry. In contrast, we know relatively little regarding the genetics of ALS in other ethnic populations. This study aims to provide a comprehensive analysis of the genetics of ALS in an unprecedented large cohort of Chinese mainland population and correlate with the clinical features of rare variants carriers. METHODS: A total of 1587 patients, including 64 familial ALS (FALS) and 1523 sporadic ALS (SALS), and 1866 in-house controls were analysed by whole-exome sequencing and/or testing for G4C2 repeats in C9orf72. Forty-one ALS-associated genes were analysed. FINDINGS: 155 patients, including 26 (40.6%) FALS and 129 (8.5%) SALS, carrying rare pathogenic/likely pathogenic (P/LP) variants of ALS causative genes were identified. SOD1 was the most common mutated gene, followed by C9orf72, FUS, NEK1, TARDBP and TBK1. By burden analysis, rare variants in SOD1, FUS and TARDBP contributed to the collective risk for ALS (p<2.5e-6) at the gene level, but at the allelic level TARDBP p.Gly294Val and FUS p.Arg521Cys and p.Arg521His were the most important single variants causing ALS. Clinically, P/LP variants in TARDBP and C9orf72 were associated with poor prognosis, in FUS linked with younger age of onset, and C9orf72 repeats tended to affect cognition. CONCLUSIONS: Our data provide essential information for understanding the genetic and clinical features of ALS in China and for optimal design of genetic testing and evaluation of disease prognosis.


Assuntos
Esclerose Amiotrófica Lateral , Esclerose Amiotrófica Lateral/epidemiologia , Esclerose Amiotrófica Lateral/genética , Proteína C9orf72/genética , Estudos de Coortes , Predisposição Genética para Doença , Humanos , Mutação/genética , Superóxido Dismutase-1/genética
8.
Food Res Int ; 162(Pt B): 112098, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36461404

RESUMO

Yellow pigments in the water-extract of safflower (Carthamus tinctorius L.) belong to quinochalcone flavonoid family and are widely used as food colourants. The aim of the study was to characterize the main quinochalcone compounds in safflower water-extract during blooming period when floret changed colour. Mass-spectrometry results showed that hydroxysafflor yellow A (HSYA) and anhydrosafflor yellow B (AHSYB) were the most abundant. Based on 370 florets samples collected from 144 cultivars, the contents of HSYA and AHSYB were determined, which showed that only AHSYB content had relatively strong positive association with colour indexes. The ratio of HSYA/AHSYB and visual colour exhibited certain patterns: yellow = 2, orange = 3-4, red = more dispersed, mostly falling 5-6. Most of the florets had HSYA increased first and decreased, while AHSYB decreased all the time when floret changed colour as yellow â†’ orange â†’ red. Regardless of the composition of HSYA/AHSYB in florets, the antioxidant capacities of safflower petal water-extracts were the same.


Assuntos
Carthamus tinctorius , Antioxidantes , Cor , Excipientes , Água , Extratos Vegetais
9.
Front Genet ; 13: 1038274, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36468023

RESUMO

Prenatal imaging phenotypes and genotypes were analyzed in 13 cases prenatally diagnosed with Joubert syndrome (JS), all of which underwent magnetic resonance imaging (MRI), ultrasound, and genetic testing. Prenatal MRI diagnosed 10 cases as JS with a typical molar tooth sign (MTS), while prenatal ultrasound diagnosed or suspiciously diagnosed 11 cases as JS with typical or mild MTS in 10 cases. Mutations in JS-related genes and other prenatal JS imaging phenotypes were identified in 10 cases, including OFD1 in two cases [cerebellar vermis (CV) absence, posterior fossa dilation, ventriculomegaly, polydactyly, malformations of cortical development (MCD), and persistent left superior vena cava], TMEM67 in two cases (CV absence, polydactyly, hyperechoic kidneys or polycystic kidneys, posterior fossa dilation, and ventriculomegaly), CC2D2A in two cases (CV absence, polydactyly, MCD, agenesis of the corpus callosum, encephalocele and hydrocephalus, ventriculomegaly, and posterior fossa dilation), RPGRIP1L in one case (CV absence), TCTN3 in one case (CV absence, polydactyly, MCD, and posterior fossa dilation), CEP290 in one case (CV absence and polycystic kidney), and NPHP1 in one case (CV absence). The prenatal diagnosis of JS presents a number of challenges, including the variants of unknown significance, the lack of functional assessment in prenatal imaging, unclear phenotype-genotype relationships in prenatal evaluation, and the incorrect identification of the JS hallmark, the MTS, in prenatal imaging, especially on ultrasound. Although combined MRI, ultrasound, and exome sequencing could help improve the prenatal diagnosis of JS, there still exist significant challenges.

10.
Chin Med J (Engl) ; 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36469355

RESUMO

BACKGROUND: Gut-resident macrophages (gMacs) supplemented by monocytes-to-gMacs differentiation play a critical role in maintaining intestinal homeostasis. Activating transcription factor 4 (ATF4) is involved in immune cell differentiation. We therefore set out to investigate the role of ATF4-regulated monocytes-to-gMacs differentiation in sepsis-induced intestinal injury. METHODS: Sepsis was induced in C57BL/6 wild type (WT) mice and Atf4-knockdown (Atf4+/-) mice by cecal ligation and puncture or administration of lipopolysaccharide (LPS). Colon, peripheral blood mononuclear cells, sera, lung, liver, and mesenteric lymph nodes were collected for flow cytometry, hematoxylin and eosin staining, immunohistochemistry, quantitative reverse transcription polymerase chain reaction, and enzyme-linked immunosorbent assay, respectively. RESULTS: CD64, CD11b, Ly6C, major histocompatibility complex-II (MHC-II), CX3CR1, Ly6G, and SSC were identified as optimal primary markers for detecting the process of monocytes-to-gMacs differentiation in the colon of WT mice. Monocytes-to-gMacs differentiation was impaired in the colon during sepsis and was associated with decreased expression of ATF4 in P1 (Ly6Chi monocytes), the precursor cells of gMacs. Atf4 knockdown exacerbated the impairment of monocytes-to-gMacs differentiation in response to LPS, resulting in a significant reduction of gMacs in the colon. Furthermore, compared with WT mice, Atf4+/- mice exhibited higher pathology scores, increased expression of inflammatory factor genes (TNF-α, IL-1ß), suppressed expression of CD31 and vascular endothelial-cadherin in the colon, and increased translocation of intestinal bacteria to lymph nodes and lungs following exposure to LPS. However, the aggravation of sepsis-induced intestinal injury resulting from Atf4 knockdown was not caused by the enhanced inflammatory effect of Ly6Chi monocytes and gMacs. CONCLUSION: ATF4, as a novel regulator of monocytes-to-gMacs differentiation, plays a critical role in protecting mice against sepsis-induced intestinal injury, suggesting that ATF4 might be a potential therapeutic target for sepsis treatment.

11.
Front Plant Sci ; 13: 1071657, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36531388

RESUMO

Sorghum has recently attracted much attention for its tolerance in high salt environment. However, the effect and regulatory mechanism of the gibberellic acid (GA3)-mediated alleviation of salt stress in sorghum remains unclear. Herein, we reported that a GA3 concentration of 50 mg/L is optimal for sorghum ("Jitian 3") development under salt stress. We conducted a whole-transcriptome analysis between GA3-treated and control sorghum leaves under salt stress, and we identified 1002 differentially expressed (DE)-messenger RNAs (mRNAs), 81 DE-long non-coding RNAs (lncRNAs), 7 DE-circular RNAs (circRNAs), and 26 DE-microRNA (miRNAs) in sorghum following GA3 treatment. We also identified a majority of DE-mRNAs and non-coding RNAs (ncRNAs) targets that serve essential roles in phenylpropanoid biosynthesis and plant hormone networks. In addition, we generated a competitive endogenous RNA (ceRNA)-miRNA-target gene network, and 3 circRNAs (circRNA_2746, circRNA_6515, circRNA_5622), 4 lncRNAs (XR_002450182.1, XR_002452422.1, XR_002448510.1, XR_002448296.1) and 4 genes (LOC8056546, LOC8062245, LOC8061469, LOC8071960) probably act as valuable candidates for the regulation of the GA3-mediated alleviation of salt stress in sorghum. Our findings uncovered potential mRNA and non-coding RNAs that contribute to GA3 regulation, thus offering a basis for the future investigation of underlying mechanisms of salt stress in sorghum.

12.
J Ethnopharmacol ; 304: 116046, 2022 Dec 22.
Artigo em Inglês | MEDLINE | ID: mdl-36567042

RESUMO

ETHNOPHARMACOLOGICAL RELEVANT: Erxian Decoction (EXD) has been used empirically for more than 70 years to treat premature ovarian failure (POF), but more research is needed to understand how it works. AIM OF THE RESEARCH: The study aims to ascertain both in vivo and in vitro rewards of EXD. MATERIALS AND METHODS: EXD is composed of Curculiginis Rhizoma, Epimedii Folium, Morindae Officinalis, Angelicae Sinensis, Anemarrhenae Rhizoma, and Phellodendri Chinensis Cortex. UPLC/MS analysis was used to investigate the components of EXD. Using a POF model created by administering cisplatin to rats intraperitoneally, the pharmacodynamic effects of EXD were investigated. Three dose groups of EXD were garaged into rats: high (15.6 g/kg), medium (7.8 g/kg), and low (3.9 g/kg). By using a vaginal smear, the impact of EXD on the rat estrous cycle was evaluated. An ELISA test was used to measure the anti-Mullerian hormone (AMH), estradiol (E2), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels in the serum of rats. By using HE stains, pathological alterations in the ovaries may be seen. MDA and SOD levels in ovarian samples were used to measure the degree of ovarian oxidation. TUNEL labeling of ovarian sections was used to find apoptosis levels. By using ATP, energy production was evaluated. The relative expression of proteins connected to aging and the RAGE pathway was assessed using Western blot. Then, using H2O2, a model of senescent human ovarian granulosa cells (KGN) was created in vitro. The impact of EXD and H2O2 on cellular senescence was discovered using-galactosidase staining. Cell apoptosis levels were found using PI/Hoechest33342. By using DCFH-DA, intracellular ROS was examined. MDA and SOD concentrations were used to measure the degree of cellular oxidation. RAGE-related mRNA and protein expression were evaluated using RT-qPCR and western blotting. RESULTS: Using UPLC/MS analysis, 39 chemicals in EXD were found. Rats' estrous cycles were enhanced by EXD, which increased ovarian index and follicle count and reduced the proportion of atretic follicles in the rats. EXD reduced LH and FSH output while restoring AMH and E2 secretion. In ovarian tissues, EXD reduced the amount of apoptosis and MDA while raising SOD activity and ATP levels. The protein levels of p16, p21, p53, and Lamin A/C were among the senescence-related proteins that EXD lowered, along with the levels of RAGE, PI3K, BAX, and CASPASE 3. Anti-apoptotic protein BCL-2 was also raised in the RAGE pathway. Senescence, apoptosis, ROS, and MDA levels in the KGN cells were lowered in vitro by EXD. Additionally, EXD increased the anti-apoptotic potential by changing the expression of CAT, SOD2, and SIRT1. RAGE, BAX, BCL-2, CASPASE 3, and p38 expression levels were altered by EXD, enhancing its anti-apoptotic capability. CONCLUSION: EXD boosted the ovary's antioxidant and anti-apoptotic capabilities while enhancing the estrous cycle and hormone output. These findings strongly suggested that EXD may contribute to the alleviation of POF and ovarian granulosa cells senescence.

13.
Nat Commun ; 13(1): 7965, 2022 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-36575162

RESUMO

Ferroptosis is a type of regulated necrosis caused by unrestricted lipid peroxidation and subsequent plasma membrane rupture. However, the lipid remodeling mechanism that determines sensitivity to ferroptosis remains poorly understood. Here, we report a previously unrecognized role for the lipid flippase solute carrier family 47 member 1 (SLC47A1) as a regulator of lipid remodeling and survival during ferroptosis. Among 49 phospholipid scramblases, flippases, and floppases we analyzed, only SLC47A1 had mRNA that was selectively upregulated in multiple cancer cells exposed to ferroptotic inducers. Large-scale lipidomics and functional analyses revealed that the silencing of SLC47A1 increased RSL3- or erastin-induced ferroptosis by favoring ACSL4-SOAT1-mediated production of polyunsaturated fatty acid cholesterol esters. We identified peroxisome proliferator activated receptor alpha (PPARA) as a transcription factor that transactivates SLC47A1. The depletion of PPARA and SLC47A1 similarly sensitized cells to ferroptosis induction, whereas transfection-enforced re-expression of SLC47A1 restored resistance to ferroptosis in PPARA-deficient cells. Pharmacological or genetic blockade of the PPARA-SLC47A1 pathway increased the anticancer activity of a ferroptosis inducer in mice. These findings establish a direct molecular link between ferroptosis and lipid transporters, which may provide metabolic targets for overcoming drug resistance.


Assuntos
Ferroptose , Animais , Camundongos , Apoptose/genética , Necrose , Peroxidação de Lipídeos/fisiologia , Lipídeos
14.
Front Immunol ; 13: 888891, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389695

RESUMO

Sepsis is a disease with a high morbidity and mortality rate. At present, there is a lack of ideal biomarker prognostic models for sepsis and promising studies using prognostic models to predict and guide the clinical use of medications. In this study, 71 differentially expressed genes (DEGs) were obtained by analyzing single-cell RNA sequencing (scRNA-seq) and transcriptome RNA-seq data, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analyses were performed on these genes. Then, a prognosis model with CCL5, HBD, IFR2BP2, LTB, and WFDC1 as prognostic signatures was successfully constructed after univariate LASSO regression analysis and multivariate Cox regression analysis. Kaplan-Meier (K-M) survival analysis, receiver operating characteristic (ROC) time curve analysis, internal validation, and principal component analysis (PCA) further validated the model for its high stability and predictive power. Furthermore, based on a risk prediction model, gene set enrichment analysis (GSEA) showed that multiple cellular functions and immune function signaling pathways were significantly different between the high- and low-risk groups. In-depth analysis of the distribution of immune cells in healthy individuals and sepsis patients using scRNA-seq data revealed immunosuppression in sepsis patients and differences in the abundance of immune cells between the high- and low-risk groups. Finally, the genetic targets of immunosuppression-related drugs were used to accurately predict the potential use of clinical agents in high-risk patients with sepsis.


Assuntos
Sepse , Análise de Célula Única , Humanos , RNA-Seq , Prognóstico , Sepse/tratamento farmacológico , Sepse/genética , Proteínas
15.
Front Microbiol ; 13: 1003623, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36386657

RESUMO

Unraveling the mechanisms structuring microbial community is a central goal in microbial ecology, but a detailed understanding of how community assembly processes relate to living habitats is still lacking. Here, via 16S rRNA gene amplicon sequencing, we investigated the assembly process of microbial communities in different habitats [water verse sediment, free-living (FL) verse particle-associated (PA)] and their impacts on the inter-taxa association patterns in the coastal Bohai Sea, China. The results showed clear differences in the composition and diversity of microbial communities among habitats, with greater dissimilarities between water column and sediment than between FL and PA communities. The microbial community assembly was dominated by dispersal limitation, ecological drift, and homogeneous selection, but their relative importance varied in different habitats. The planktonic communities were mainly shaped by dispersal limitation and ecological drift, whereas homogeneous selection played a more important role in structuring the benthic communities. Furthermore, the assembly mechanisms differed between FL and PA communities, especially in the bottom water with a greater effect of ecological drift and dispersal limitation on the FL and PA fractions, respectively. Linking assembly process to co-occurrence pattern showed that the relative contribution of deterministic processes (mainly homogeneous selection) increased under closer co-occurrence relationships. By contrast, stochastic processes exerted a higher effect when there were less inter-taxa connections. Overall, our findings demonstrate contrasting ecological processes underpinning microbial community distribution in different habitats including different lifestyles, which indicate complex microbial dynamic patterns in coastal systems with high anthropogenic perturbations.

16.
Geroscience ; 2022 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-36401740

RESUMO

Age-related cognitive slowing is a prominent precursor of cognitive decline. Functional neuroimaging studies found that cognitive processing speed is associated with activation and coupling among frontal, parietal and cerebellar brain networks. However, how the reciprocal influences of inter- and intra-network coupling mediate age-related decline in processing speed remains insufficiently studied. This study examined how inter- and intra-brain network influences mediate age-related slowing. We were interested in the fronto-insular salience network (SN), frontoparietal dorsal attention network (DAN), cerebellar network (CN) and default mode network (DMN). Reaction time (RT) and functional MRI data from 84 participants (aged 18-75) were collected while they were performing the Arrow Task in visual or audial forms. At the subject level, effective connectivities (ECs) were estimated with regression dynamic causal modelling. At the group level, structural equation models (SEMs) were used to model latent speed based on age and the EC mediators. Age was associated with decreased speed and increased inter-network effective connectivity. The CN exerting influence on the DAN (CN → DAN EC) mediated, while the SN → DAN EC suppressed age-related slowing. The DMN and intra-network ECs did not seem to play significant roles in slowing due to ageing. Inter-network connectivity from the CN and SN to the DAN contributes to age-related slowing. The seemingly antagonizing influences of the CN and SN indicate that increased task-related automaticity and decreased effortful control on top-down attention would promote greater speed in older individuals.

17.
Microbiol Spectr ; : e0317322, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36416550

RESUMO

Porcine reproductive and respiratory syndrome virus (PRRSV) is an Arterivirus that has been devastating the swine industry worldwide since the late 1980s. Severe interstitial pneumonia is the typical pathological characteristic of PRRSV-infected swine. Accumulating evidence has suggested that hypoxia-inducible factor 1α (HIF-1α) plays vital roles in the development of inflammation and the viral life cycle. However, the role and the underlying mechanism of HIF-1α in PRRSV infection remain elusive. Here, we found that PRRSV infection elevated HIF-1α expression. Furthermore, overexpression of HIF-1α increased PRRSV replication, whereas knockdown of HIF-1α inhibited PRRSV infection. Our further mechanistic analysis revealed that PRRSV-encoded nonstructural protein 1ß (nsp1ß) promoted HIF-1α transcription via its N-terminal nuclease activity and degraded the polyubiquitin chain of HIF-1α via its C-terminal deubiquitylation (DUB) enzyme activity, collectively stabilizing HIF-1α. Meanwhile, nsp1ß interacted with both HIF-1α and von Hippel-Lindau tumor suppressor (pVHL) to form a ternary complex, which may have hindered pVHL-mediated ubiquitination degradation of HIF-1α by impairing the interaction between HIF-1α and pVHL. Interestingly, pVHL also stabilized nsp1ß via K63-linked ubiquitination, forming a positive feedback loop to stabilize HIF-1α. Taken together, these results indicate that PRRSV infection stabilizes HIF-1α to facilitate viral proliferation and that viral nsp1ß plays a vital role in enhancing the expression and stabilization of HIF-1α. The regulation of HIF-1α may have great therapeutic potential for the development of novel drugs against PRRSV. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) has devastated the swine industry worldwide for over 30 years and shows no signs of slowing down. In this study, we found that PRRSV infection elevated hypoxia-inducible factor 1α (HIF-1α) expression. In addition, overexpressed HIF-1α contributed to PRRSV replication, whereas knockdown of HIF-1α reduced PRRSV growth. The PRRSV-encoded nonstructural protein 1ß (nsp1ß) exerted a stabilizing effect on HIF-1α through its nuclease protease and papain-like cysteine protease enzymatic domains. PRRSV nsp1ß also interacted with von Hippel-Lindau tumor suppressor (pVHL) and HIF-1α, whereby nsp1ß impaired the interaction between HIF-1α and pVHL. This work deepens our understanding of the molecular mechanisms involved in PRRSV infection and provides new insights for the development of HIF-1α-based anti-PRRSV therapies.

18.
ACS Nano ; 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36375012

RESUMO

The extensive spread of multidrug resistance to Gram-negative bacteria has become a huge threat to human health, where peptide-based antibacterial agents have emerged as a powerful star weapon. Here we report a lipopeptide (LP-20) constructed nanomicelle with a different antibacterial mechanism of membrane curvature modulation, which induced dynamic membrane fission resulting in acceleration and enhancement of antibacterial activity to clinically isolated ESKAPE strains, including multidrug-resistant (MDR) pathogens. The minimum inhibitory concentration was reduced to 2-10 µM, and the minimum duration for killing was shortened to less than an hour by LP-20. This is an improvement over antimicrobial peptides and traditional antibiotics, such as ciprofloxacin and tetracycline, significantly enhancing antibacterial activity for MDR, and we observed no acquisition of resistance for one month. This accelerated germicidal mechanism was attributed to multitargeting with lipopolysaccharides, phosphoethanolamine, phosphatidylglycerol, and cardiolipin, and the synergetic interactions induced a high curvature of the bacterial membrane, which facilitated simultaneously efficient damage to both inner and outer membrane. The LP-20 effectively prolonged the lifetime of myositis mice with Escherichia coli MDR and pneumonia mice with Klebsiella pneumoniae through a hepatic metabolism with ignorable toxicity. This study provides critical information for the fabrication of lipopeptide-based nano-antibiotics for the efficient control of intractable MDR caused by Gram-negative pathogens.

19.
Chin Med J (Engl) ; 2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36355867

RESUMO

BACKGROUND: Advances in organoid culture technology have provided a greater understanding of disease pathogenesis, which has been rarely studied in sepsis before. We aim to establish a suitable organoids-based intestinal injury model for sepsis. METHODS: Stable passaged organoids were constructed and pre-treated with lipopolysaccharide (LPS) to mimic sepsis-induced intestinal injury. The LPS-induced sepsis model was used as a reference. We used quantitative real-time polymerase chain reaction to evaluate the RNA levels of inflammatory factors and antimicrobial peptides. Enzyme-linked immunosorbent assay was used to evaluate the protein levels, hematoxylin and eosin staining was used to evaluate the pathology of the small intestine of mice, and immunohistochemistry and immunofluorescence were used to evaluate the intestinal epithelial barrier function. Perkin Elmer Operetta™ was used to obtain high-resolution images of three-dimensional organoids. RESULTS: An LPS concentration >150 µg/mL after 24 h was identified to cause organoid growth restriction. The fluorescence intensity of zonula occludens-1 and occludins at LPS concentrations >100 µg/mL decreased significantly after 24 h. After LPS stimulation for 8 h, the RNA expression levels of interleukin (IL)-1α, tumor necrosis factor alpha, granulocyte-macrophage colony-stimulating factor, IL-6, and regenerating islet-derived protein 3 alpha, beta, and gamma increased. These results resembled those of intestinal epithelial layer alterations in a mouse sepsis model. For IL-10, the RNA expression level increased only when the LPS level >200 µg/mL for 24 h. CONCLUSIONS: This study provides the primary intestinal in vitro model to study the effects of LPS-induced intestinal injury resembling sepsis. This model provides a platform for immune associated mechanism exploration and effective drug screening.

20.
Virology ; 577: 84-90, 2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36323047

RESUMO

Itaconate, a metabolite of the tricarboxylic acid (TCA) cycle produced by immunoresponsive gene 1 (IRG1) via catalyzation of cis-aconitate, plays important roles in metabolism and immunity. Porcine reproductive and respiratory syndrome virus (PRRSV) is an Arterivirus that has devastated the swine industry worldwide for over 30 years. Here, we found that 4-octyl itaconate (4-OI), a cell-permeable itaconate derivative, dose-dependently inhibited PRRSV proliferation by interfering with viral attachment, replication, and release. Furthermore, 4-OI suppressed the PRRSV-induced inflammatory response by enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Interestingly, PRRSV infection caused a reduction in itaconate abundance and simultaneously led to an accumulation of cis-aconitate, the upstream metabolite of itaconate, and both of these effects were accomplished by downregulating IRG1 expression. Taken together, these results demonstrate that 4-OI not only inhibits PRRSV replication but also suppresses PRRSV-induced inflammatory responses, indicating that 4-OI is a promising drug candidate for combating PRRSV.

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