Overexpression of candidate tumor suppressor ECRG4 inhibits glioma proliferation and invasion

<p>Abstract</p> <p>Background</p> <p>ECRG4 has been shown to be a candidate tumor suppressor in several tumors, but its role in glioma remains poorly understood. In this study, we examined the mRNA expression of ECRG4 and investigated its biological role in glioma cells.</p> <p>Methods</p> <p>Real-time PCR was used to examine expression of ECRG4 in gliomas and their matched brain tissues. The effect of ECRG4 expression on cell proliferation, invasion, and migration was investigated in human U251 glioma cells. Finally, the regulation of transcription factor NF-kB by ECRG4 was evaluated by western blotting.</p> <p>Results</p> <p>Of the 10 paired samples analyzed, 9 glioma tissues displayed the decreased expression of ECRG4 compared to matched normal brain tissues. Cells transfected with ECRG4 showed significantly decreased cell proliferation as evaluated by MTT and colony formation assays. Furthermore, overexpression inhibited cell migration and invasion in transwell and Boyden chamber experiments and retarded the cell cycle progression from G1 to S phase by FACSCaliber cytometry. Protein levels of nuclear transcription factor NF-kB, which is involved in cell proliferation, inversely correlated with ECRG4 expression.</p> <p>Conclusion</p> <p>Our data suggest that ECRG4 serves as a tumor suppressor in glioma.</p

Mendelian randomization analyses support causal relationship between gut microbiota and childhood obesity

BackgroundChildhood obesity (CO) is an increasing public health issue. Mounting evidence has shown that gut microbiota (GM) is closely related to CO. However, the causal association needs to be treated with caution due to confounding factors and reverse causation.MethodsData were obtained from the Microbiome Genome Consortium for GM as well as the Early Growth Genetics Consortium for childhood obesity and childhood body mass index (CBMI). Inverse variance weighted, maximum likelihood, weighted median, and MR.RAPS methods were applied to examine the causal association. Then replication dataset was used to validate the results and reverse Mendelian randomization analysis was performed to confirm the causal direction. Additionally, sensitivity analyses including Cochran's Q statistics, MR-Egger intercept, MR-PRESSO global test, and the leave-one-out analysis were conducted to detect the potential heterogeneity and horizontal pleiotropy.ResultsOur study found suggestive causal relationships between eight bacterial genera and the risk of childhood obesity (five for CO and four for CBMI). After validating the results in the replication dataset, we finally identified three childhood obesity-related GM including the genera Akkermansia, Intestinibacter, and Butyricimonas. Amongst these, the genus Akkermansia was both negatively associated with the risk of CO (OR = 0.574; 95% CI: 0.417, 0.789) and CBMI (β = −0.172; 95% CI: −0.306, −0.039).ConclusionsIn this study, we employed the MR approach to investigate the causal relationship between GM and CO, and discovered that the genus Akkermansia has a protective effect on both childhood obesity and BMI. Our findings may provide a potential strategy for preventing and intervening in CO, while also offering novel insights into the pathogenesis of CO from the perspective of GM

NLRP6 Serves as a Negative Regulator of Neutrophil Recruitment and Function During Streptococcus pneumoniae Infection

Streptococcus pneumoniae is an invasive pathogen with high morbidity and mortality in the immunocompromised children and elderly. NOD-like receptor family pyrin domain containing 6 (NLRP6) plays an important role in the host innate immune response against pathogen infections. Our previous studies have shown that NLRP6 plays a negative regulatory role in host defense against S. pneumoniae, but the underlying mechanism is still unclear. The further negative regulatory role of NLRP6 in the host was investigated in this study. Our results showed that NLRP6(-/-) mice in the lung had lower bacterial burdens after S. pneumoniae infection and expressed higher level of tight junction (TJ) protein occludin compared to WT mice, indicating the detrimental role of NLRP6 in the host defense against S. pneumoniae infection. Transcriptome analysis showed that genes related to leukocytes migration and recruitment were differentially expressed between wild-type (WT) and NLRP6 knockout (NLRP6(-/-)) mice during S. pneumoniae infection. Also, NLRP6(-/-) mice showed higher expression of chemokines including C-X-C motif chemokine ligand 1 (CXCL1) and 2 (CXCL2) and lower gene expression of complement C3a receptor 1 (C3aR1) and P-selectin glycoprotein ligand-1 (PSGL-1) which are the factors that inhibit the recruitment of neutrophils. Furthermore, NLRP6(-/-) neutrophils showed increased intracellular bactericidal ability and the formation of neutrophil extracellular traps (NETs) during S. pneumoniae infection. Taken together, our study suggests that NLRP6 is a negative regulator of neutrophil recruitment and function during S. pneumoniae infection. Our study provides a new insight to develop novel strategies to treat invasive pneumococcal infection

Heat increases the editing efficiency of human papillomavirus E2 gene by inducing upregulation of APOBEC3A and 3G

Apolipoprotein B mRNA-editing catalytic polypeptide (APOBEC) 3 proteins have been identified as potent viral DNA mutators and have broad antiviral activity. In this study, we demonstrated that apolipoprotein B mRNA-editing catalytic polypeptide 3A (A3A) and A3G expression levels were significantly upregulated in human papillomavirus (HPV)-infected cell lines and tissues. Heat treatment resulted in elevated expression of A3A and A3G in a temperature-dependent manner in HPV-infected cells. Correspondingly, HPV-infected cells heat-treated at 44 °C showed accumulated G-to-A or C-to-T mutation in HPV E2 gene. Knockdown of A3A or A3G could promote cell viability, along with the lower frequency of A/T in HPV E2 gene. In addition, regressing genital viral warts also harbored high G-to-A or C-to-T mutation in HPV E2 gene. Taken together, we demonstrate that apolipoprotein B mRNA-editing catalytic polypeptide 3 expression and editing function was heat sensitive to a certain degree, partly explaining the mechanism of action of local hyperthermia to treat viral warts

Soybean Breeding on Seed Composition Trait

Soybean is a most important crop providing edible oil and plant protein source for human beings, in addition to animal feed because of high protein and oil content. This review summarized the progresses in the QTL mapping, candidate gene cloning and functional analysis and also the regulation of soybean oil and seed storage protein accumulation. Furthermore, as soybean genome has been sequenced and released, prospects of multiple omics and advanced biotechnology should be combined and applied for further refine research and high-quality breeding

Direct Conversion of Mouse Astrocytes Into Neural Progenitor Cells and Specific Lineages of Neurons

Background: Cell replacement therapy has been envisioned as a promising treatment for neurodegenerative diseases. Due to the ethical concerns of ESCs-derived neural progenitor cells (NPCs) and tumorigenic potential of iPSCs, reprogramming of somatic cells directly into multipotent NPCs has emerged as a preferred approach for cell transplantation. Methods: Mouse astrocytes were reprogrammed into NPCs by the overexpression of transcription factors (TFs) Foxg1, Sox2, and Brn2. The generation of subtypes of neurons was directed by the force expression of cell-type specific TFs Lhx8 or Foxa2/Lmx1a. Results: Astrocyte-derived induced NPCs (AiNPCs) share high similarities, including the expression of NPC-specific genes, DNA methylation patterns, the ability to proliferate and differentiate, with the wild type NPCs. The AiNPCs are committed to the forebrain identity and predominantly differentiated into glutamatergic and GABAergic neuronal subtypes. Interestingly, additional overexpression of TFs Lhx8 and Foxa2/Lmx1a in AiNPCs promoted cholinergic and dopaminergic neuronal differentiation, respectively. Conclusions: Our studies suggest that astrocytes can be converted into AiNPCs and lineage-committed AiNPCs can acquire differentiation potential of other lineages through forced expression of specific TFs. Understanding the impact of the TF sets on the reprogramming and differentiation into specific lineages of neurons will provide valuable strategies for astrocyte-based cell therapy in neurodegenerative diseases

Selective Generation of Dopaminergic Precursors from Mouse Fibroblasts by Direct Lineage Conversion.

Degeneration of midbrain dopaminergic (DA) neurons is a key pathological event of Parkinson\u27s disease (PD). Limited adult dopaminergic neurogenesis has led to novel therapeutic strategies such as transplantation of dopaminergic precursors (DPs). However, this strategy is currently restrained by a lack of cell source, the tendency for the DPs to become a glial-restricted state, and the tumor formation after transplantation. Here, we demonstrate the direct conversion of mouse fibroblasts into induced DPs (iDPs) by ectopic expression of Brn2, Sox2 and Foxa2. Besides expression with neural progenitor markers and midbrain genes including Corin, Otx2 and Lmx1a, the iDPs were restricted to dopaminergic neuronal lineage upon differentiation. After transplantation into MPTP-lesioned mice, iDPs differentiated into DA neurons, functionally alleviated the motor deficits, and reduced the loss of striatal DA neuronal axonal termini. Importantly, no iDPs-derived astrocytes and neoplasia were detected in mouse brains after transplantation. We propose that the iDPs from direct reprogramming provides a safe and efficient cell source for PD treatment

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Research on Influence Factors of Pig Farmers’ Ecological Farming Behavior：Based on the TPB and SEM

China’s extensive development model of pig industry gives rise to serious resource and environment bottleneck restriction, it is urgent to transform the existing development model into ecological farming model. In this process, farmers’ behavior will play a key role. On the basis of summarizing development connotation and characteristics of ecological agriculture, using survey data of 323 pig farmers in 6 provinces, based on the Theory of Planned Behavior (TPB) it introduced individual characteristics and external environment constraint variables, and made an empirical analysis on factors influencing intention and behavior of pig farmers’ ecological farming using the Structural Equation Model (SEM). Results indicate: (i) ecological farming intention of pig farmers has the largest direct effect on their ecological farming behavior; (ii) ecological farming cognition of pig farmers has significant positive effect on their ecological farming behavior; (iii) external environment has the largest indirect effect on their ecological farming behavior, followed by the overall effect, and external environment has significant positive effect on ecological farming attitude and cognition of pig farmers; (iv) individual characteristics (educational level and income level) of pig farmers influence ecological farming behavior of pig farmers through their ecological farming attitude and intention, but the degree of influence is limited

Research on Fractional-Order Global Fast Terminal Sliding Mode Control of MDF Continuous Hot-Pressing Position Servo System Based on Adaptive RBF Neural Network

In this paper, a novel fractional-order global fast terminal sliding mode control (FGFTSMC) strategy based on an adaptive radial basis function (RBF) neural network is proposed to improve the performance of a medium density fiberboard (MDF) continuous hot-pressing position servo system with parameter perturbation and external load disturbance. Primarily, the mathematical model of the MDF continuous hot-pressing position servo system is constructed based on the dynamic equation of the hydraulic system. Then, a FGFTSMC is designed to speed up the convergence rate of the system, in which an adaptive law is used to estimate the upper bound of the unknown parameters to overcome the existing parameter perturbation of the system. In addition, an RBF neural network is introduced to approximate the external load disturbance of the system. The stability of MDF continuous hot-pressing position servo system based on the control scheme developed in this paper is proven using the Lyapunov theory. Finally, the simulation results show that the presented control scheme can effectively ensure the tracking accuracy of the system and enhance the robustness of the system