Constitutive hyperproduction of sorbicillinoids in Trichoderma reesei ZC121

Abstract Background In addition to its outstanding cellulase production ability, Trichoderma reesei produces a wide variety of valuable secondary metabolites, the production of which has not received much attention to date. Among them, sorbicillinoids, a large group of hexaketide secondary metabolites derived from polyketides, are drawing a growing interest from researchers because they exhibit a variety of important biological functions, including anticancer, antioxidant, antiviral, and antimicrobial properties. The development of fungi strains with constitutive, hyperproduction of sorbicillinoids is thus desired for future industry application but is not well-studied. Moreover, although T. reesei has been demonstrated to produce sorbicillinoids with the corresponding gene cluster and biosynthesis pathway proposed, the underlying molecular mechanism governing sorbicillinoid biosynthesis remains unknown. Results Recombinant T. reesei ZC121 was constructed from strain RUT-C30 by the insertion of the gene 12121-knockout cassette at the telomere of T. reesei chromosome IV in consideration of the off-target mutagenesis encountered during the unsuccessful deletion of gene 121121. Strain ZC121, when grown on cellulose, showed a sharp reduction of cellulase production, but yet a remarkable enhancement of sorbicillinoids production as compared to strain RUT-C30. The hyperproduction of sorbicillinoids is a constitutive process, independent of culture conditions such as carbon source, light, pH, and temperature. To the best of our knowledge, strain ZC121 displays record sorbicillinoid production levels when grown on both glucose and cellulose. Sorbicillinol and bisvertinolone are the two major sorbicillinoid compounds produced. ZC121 displayed a different morphology and markedly reduced sporulation compared to RUT-C30 but had a similar growth rate and biomass. Transcriptome analysis showed that most genes involved in cellulase production were downregulated significantly in ZC121 grown on cellulose, whereas remarkably all genes in the sorbicillinoid gene cluster were upregulated on both cellulose and glucose. Conclusion A constitutive sorbicillinoid-hyperproduction strain T. reesei ZC121 was obtained by off-target mutagenesis, displaying an overwhelming shift from cellulase production to sorbicillinoid production on cellulose, leading to a record for sorbicillinoid production. For the first time, T. reesei degraded cellulose to produce platform chemical compounds other than protein in high yield. We propose that the off-target mutagenesis occurring at the telomere region might cause chromosome remodeling and subsequently alter the cell structure and the global gene expression pattern of strain ZC121, as shown by phenotype profiling and comparative transcriptome analysis of ZC121. Overall, T. reesei ZC121 holds great promise for the industrial production of sorbicillinoids and serves as a good model to explore the regulation mechanism of sorbicillinoids’ biosynthesis.https://deepblue.lib.umich.edu/bitstream/2027.42/146139/1/13068_2018_Article_1296.pd

Gastrointestinal Spatiotemporal mRNA Expression of Ghrelin vs Growth Hormone Receptor and New Growth Yield Machine Learning Model Based on Perturbation Theory

[Abstract] The management of ruminant growth yield has economic importance. The current work presents a study of the spatiotemporal dynamic expression of Ghrelin and GHR at mRNA levels throughout the gastrointestinal tract (GIT) of kid goats under housing and grazing systems. The experiments show that the feeding system and age affected the expression of either Ghrelin or GHR with different mechanisms. Furthermore, the experimental data are used to build new Machine Learning models based on the Perturbation Theory, which can predict the effects of perturbations of Ghrelin and GHR mRNA expression on the growth yield. The models consider eight longitudinal GIT segments (rumen, abomasum, duodenum, jejunum, ileum, cecum, colon and rectum), seven time points (0, 7, 14, 28, 42, 56 and 70 d) and two feeding systems (Supplemental and Grazing feeding) as perturbations from the expected values of the growth yield. The best regression model was obtained using Random Forest, with the coefficient of determination R2 of 0.781 for the test subset. The current results indicate that the non-linear regression model can accurately predict the growth yield and the key nodes during gastrointestinal development, which is helpful to optimize the feeding management strategies in ruminant production system.National Natural Science Foundation of China; 31320103917State of California; XDA05020700National Space Science Center (China); 2010T2S13National Space Science Center (China); 2012T1S0009Hunan Provincial People's Government (China); 2013TF3006Xunta de Galicia; GRC2014/04

Sex differences in the structure and function of rat middle cerebral arteries

Wang S, Zhang H, Liu Y, Li L, Guo Y, Jiao F, Fang X, Jefferson JR, Li M, Gao W, Gonzalez-Fernandez E, Maranon RO, Pabbidi MR, Liu R, Alexander BT, Roman RJ, Fan F. Sex differences in the structure and function of rat middle cerebral arteries. Am J Physiol Heart Circ Physiol 318: H1219 –H1232, 2020. First published March 27, 2020; doi:10.1152/ajpheart.00722.2019.—Epidemiological studies demonstrate that there are sex differences in the incidence, prevalence, and outcomes of cerebrovascular disease (CVD). The present study compared the structure and composition of the middle cerebral artery (MCA), neurovascular coupling, and cerebrovascular function and cognition in young Sprague-Dawley (SD) rats. Wall thickness and the inner diameter of the MCA were smaller in females than males. Female MCA exhibited less vascular smooth muscle cells (VSMCs), diminished contractile capability, and more collagen in the media, and a thicker internal elastic lamina with fewer fenestrae compared with males. Female MCA had elevated myogenic tone, lower distensibility, and higher wall stress. The stress/strain curves shifted to the left in female vessels compared with males. The MCA of females failed to constrict compared with a decrease of 15.5 ± 1.9% in males when perfusion pressure was increased from 40 to 180 mmHg. Cerebral blood flow (CBF) rose by 57.4 ± 4.4 and 30.1 ± 3.1% in females and males, respectively, when perfusion pressure increased from 100 to 180 mmHg. The removal of endothelia did not alter the myogenic response in both sexes. Functional hyperemia responses to whisker-barrel stimulation and cognition examined with an eight-arm water maze were similar in both sexes. These results demonstrate that there are intrinsic structural differences in the MCA between sexes, which are associated with diminished myogenic response and CBF autoregulation in females. The structural differences do not alter neurovascular coupling and cognition at a young age; however, they might play a role in the development of CVD after menopause. NEW & NOTEWORTHY Using perfusion fixation of the middle cerebral artery (MCA) in calcium-free solution at physiological pressure and systematically randomly sampling the sections prepared from the same M2 segments of MCA, we found that there are structural differences that are associated with altered cerebral blood flow (CBF) autoregulation but not neurovascular coupling and cognition in young, healthy Sprague-Dawley (SD) rats. Understanding the intrinsic differences in cerebrovascular structure and function in males and females is essential to develop new pharmaceutical treatments for cerebrovascular disease (CVD).Fil: Wang, Shaoxun. University Of Mississippi Medical Center; Estados UnidosFil: Zhang, Huawei. University Of Mississippi Medical Center; Estados UnidosFil: Liu, Yedan. University Of Mississippi Medical Center; Estados UnidosFil: Li, Longyang. University Of Mississippi Medical Center; Estados UnidosFil: Guo, Ya. University Of Mississippi Medical Center; Estados UnidosFil: Jiao, Feng. Peking University People's Hospital; China. University Of Mississippi Medical Center; Estados UnidosFil: Fang, Xing. University Of Mississippi Medical Center; Estados UnidosFil: Jefferson, Joshua R.. University Of Mississippi Medical Center; Estados UnidosFil: Li, Man. University Of Mississippi Medical Center; Estados UnidosFil: Gao, Wenjun. University Of Mississippi Medical Center; Estados UnidosFil: Gonzalez Fernandez, Ezekiel. University Of Mississippi Medical Center; Estados UnidosFil: Marañón, Rodrigo Oscar. University Of Mississippi Medical Center; Estados Unidos. Universidad Nacional de Tucumán. Facultad de Medicina; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán; ArgentinaFil: Pabbidi, Mallikarjuna R.. University Of Mississippi Medical Center; Estados UnidosFil: Liu, Ruen. Peking University People's Hospital; ChinaFil: Alexander, Barbara T.. University Of Mississippi Medical Center; Estados UnidosFil: Roman, Richard J.. University Of Mississippi Medical Center; Estados UnidosFil: Fan, Fan. University Of Mississippi Medical Center; Estados Unido

Radiogenomics analysis reveals the associations of dynamic contrast-enhanced–MRI features with gene expression characteristics, PAM50 subtypes, and prognosis of breast cancer

BackgroundTo investigate reliable associations between dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) features and gene expression characteristics in breast cancer (BC) and to develop and validate classifiers for predicting PAM50 subtypes and prognosis from DCE-MRI non-invasively.MethodsTwo radiogenomics cohorts with paired DCE-MRI and RNA-sequencing (RNA-seq) data were collected from local and public databases and divided into discovery (n = 174) and validation cohorts (n = 72). Six external datasets (n = 1,443) were used for prognostic validation. Spatial–temporal features of DCE-MRI were extracted, normalized properly, and associated with gene expression to identify the imaging features that can indicate subtypes and prognosis.ResultsExpression of genes including RBP4, MYBL2, and LINC00993 correlated significantly with DCE-MRI features (q-value < 0.05). Importantly, genes in the cell cycle pathway exhibited a significant association with imaging features (p-value < 0.001). With eight imaging-associated genes (CHEK1, TTK, CDC45, BUB1B, PLK1, E2F1, CDC20, and CDC25A), we developed a radiogenomics prognostic signature that can distinguish BC outcomes in multiple datasets well. High expression of the signature indicated a poor prognosis (p-values < 0.01). Based on DCE-MRI features, we established classifiers to predict BC clinical receptors, PAM50 subtypes, and prognostic gene sets. The imaging-based machine learning classifiers performed well in the independent dataset (areas under the receiver operating characteristic curve (AUCs) of 0.8361, 0.809, 0.7742, and 0.7277 for estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2)-enriched, basal-like, and obtained radiogenomics signature). Furthermore, we developed a prognostic model directly using DCE-MRI features (p-value < 0.0001).ConclusionsOur results identified the DCE-MRI features that are robust and associated with the gene expression in BC and displayed the possibility of using the features to predict clinical receptors and PAM50 subtypes and to indicate BC prognosis

MafB, a target of microRNA-155, regulates dendritic cell maturation

MafB is a member of bZip transcription factors that share similar basic region/leucine zipper DNA binding motifs and N-terminal activation domains. It is well known that MafB is highly expressed in macrophages and promotes differentiation of myeloid progenitors into macrophage. However, little is known about its function in dendritic cells. Here, we report that MafB, as a target of miR-155, which had been reported to be required for dendritic cell maturation and function, regulated dendritic cell maturation. MafB and miR-155were reversely correlated during DC maturation induced by LPS and forced expression of miR-155 reduced MafB expression. The luciferase reporter assay showed that MafB 3’UTR was directly targeted bymiR-155. In addition, knockdown of MafB promoted the phenotypic maturation of DC2.4 cells. Forced expression of MafB could significantly attenuate the phenotypic maturation of DC2.4 cells caused by overexpression of miR-155. Overall, our data demonstrates that MafB, inhibited by miR-155, was a negative regulator of DC maturation

Quantitative Trait Module-Based Genetic Analysis of Alzheimer’s Disease

The pathological features of Alzheimer’s Disease (AD) first appear in the medial temporal lobe and then in other brain structures with the development of the disease. In this work, we investigated the association between genetic loci and subcortical structure volumes of AD on 393 samples in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Brain subcortical structures were clustered into modules using Pearson’s correlation coefficient of volumes across all samples. Module volumes were used as quantitative traits to identify not only the main effect loci but also the interactive effect loci for each module. Thirty-five subcortical structures were clustered into five modules, each corresponding to a particular brain structure/area, including the limbic system (module I), the corpus callosum (module II), thalamus–cerebellum–brainstem–pallidum (module III), the basal ganglia neostriatum (module IV), and the ventricular system (module V). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment results indicate that the gene annotations of the five modules were distinct, with few overlaps between different modules. We identified several main effect loci and interactive effect loci for each module. All these loci are related to the function of module structures and basic biological processes such as material transport and signal transduction

Alteration of Mevalonate Pathway in Rat Splenic Lymphocytes: Possible Role in Cytokines Secretion Regulated by L-Theanine

L-Theanine is a nonprotein amino acid in tea, and its immunomodulatory function has been confirmed. This study aimed to investigate the effect of L-theanine addition on cytokines secretion in rat splenic lymphocytes and explore its potential immunomodulatory effects on the mevalonate biosynthetic pathway. Our results showed that L-theanine treatment did not influence the proliferation and division indexes of the splenic lymphocytes subsets. Interestingly, L-theanine treatment had regulated the contents of IFN-γ, IL-2, IL-4, IL-10, IL-12, and TNF-α  (P<0.001) except IL-6 and upregulated the mRNA and protein expression of Ras-related protein Rap-1A (Rap1A), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), and farnesyl diphosphate synthase (FDPs) (P<0.001). Additionally, there was a positive correlation between Rap1A and HMGCR proteins expression and IFN-γ, IL-4, and IL-6 levels. In conclusion, L-theanine regulated the secretion of cytokines probably by activating expression of Rap1A and HMGCR proteins involved in the mevalonate biosynthetic pathway in rat splenic lymphocytes. Therefore, L-theanine might be a promising potential drug candidate as immunopotentiator

Association of hysterectomy with nonalcoholic fatty liver disease among US women

Abstract Background A postmenopausal rise in the rates of nonalcoholic fatty liver disease (NAFLD) has been reported in women. This study thus sought to further probe the association of hysterectomy with NAFLD. Methods The data utilized in this investigation were attained from the 2017-March 2020 cycle of the National Health and Nutrition Examination Survey (NHANES), reflecting a strategic utilization of comprehensive health and nutrition information in the US population, to conduct a cross-sectional examination of the relationship between self-reported hysterectomy and NAFLD. Subjects included in this study were women aged 20 years or older. The multivariable logistic regression methodologies were utilized to determine the pertinent odds ratios (ORs) and their associated 95% confidence intervals (CIs). Results Of the 2,868 subjects enrolled in this study (mean age: 51.3 years, 95%CI: 50.0-52.6 years), 22.1% (95%CI: 19.7–24.7%) reported having undergone a hysterectomy, while 31.1% (95%CI: 28.1–34.1%) exhibited elastographic evidence of NAFLD, and 3.8% (95%CI: 2.6–5.6%) exhibited clinically significant fibrosis (CSF). Relative to women with no history of hysterectomy, those that had undergone hysterectomy exhibited a higher odd of NAFLD (OR:1.66, 95%CI: 1.24–2.21) in a multivariable model fully adjusted for age, ethnicity, body mass index, female hormone use, oophorectomy, diabetes, hyperlipidemia, and smoking status. Subgroup analyses revealed a stronger association among women who were not obese (OR:2.23, 95%CI:1.61–3.11), women who were not affected by diabetes (OR:1.76, 95%CI: 1.25–2.46), and without hyperlipidemia (OR: 1.87, 95%CI: 1.10–3.16). No significant association of hysterectomy with NAFLD encompassing CSF was identified. Conclusions The results of the present nationally representative analysis suggested an association between hysterectomy and increased NAFLD prevalence among US women. Knowledge of this relationship may better aid clinical efforts to screen for and manage NAFLD

The Importance of M1-and M2-Polarized Macrophages in Glioma and as Potential Treatment Targets

Glioma is the most common and malignant tumor of the central nervous system. Glioblastoma (GBM) is the most aggressive glioma, with a poor prognosis and no effective treatment because of its high invasiveness, metabolic rate, and heterogeneity. The tumor microenvironment (TME) contains many tumor-associated macrophages (TAMs), which play a critical role in tumor proliferation, invasion, metastasis, and angiogenesis and indirectly promote an immunosuppressive microenvironment. TAM is divided into tumor-suppressive M1-like (classic activation of macrophages) and tumor-supportive M2-like (alternatively activated macrophages) polarized cells. TAMs exhibit an M1-like phenotype in the initial stages of tumor progression, and along with the promotion of lysing tumors and the functions of T cells and NK cells, tumor growth is suppressed, and they rapidly transform into M2-like polarized macrophages, which promote tumor progression. In this review, we discuss the mechanism by which M1- and M2-polarized macrophages promote or inhibit the growth of glioblastoma and indicate the future directions for treatment