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Abstract Background Mammographic density has been associated with breast cancer risk, and is modulated by established breast cancer risk factors, such as reproductive and hormonal history, as well as lifestyle. Recent epidemiological and biological findings underscore the recognized benefits of breastfeeding in reducing breast cancer risk, especially for aggressive subtypes. Current research exploring the association among mammographic density, breastfeeding, and breast cancer is sparse. Main findings Changes occur in the breasts during pregnancy in preparation for lactation, characterized by the proliferation of mammary gland tissues and the development of mammary alveoli. During lactation, the alveoli fill with milk, and subsequent weaning triggers the involution and remodeling of these tissues. Breastfeeding influences the breast microenvironment, potentially altering mammographic density. When breastfeeding is not initiated after birth, or is abruptly discontinued shortly after, the breast tissue undergoes forced and abrupt involution. Conversely, when breastfeeding is sustained over an extended period and concludes gradually, the breast tissue undergoes slow remodeling process known as gradual involution. Breast tissue undergoing abrupt involution displays denser stroma, altered collagen composition, heightened inflammation and proliferation, along with increased expression of estrogen receptor α (ERα) and progesterone receptor. Furthermore, elevated levels of pregnancy-associated plasma protein-A (PAPP-A) surpass those of its inhibitors during abrupt involution, enhancing insulin-like growth factor (IGF) signaling and collagen deposition. Prolactin and small molecules in breast milk may also modulate DNA methylation levels. Drawing insights from contemporary epidemiological and molecular biology studies, our review sheds light on how breastfeeding impacts mammographic density and explores its role in influencing breast cancer. Conclusion This review highlights a clear protective link between breastfeeding and reduced breast cancer risk via changes in mammographic density. Future research should investigate the effects of breastfeeding on mammographic density and breast cancer risk among various ethnic groups and elucidate the molecular mechanisms underlying these associations. Such comprehensive research will enhance our understanding and facilitate the development of targeted breast cancer prevention and treatment strategies.

Abstract Background Nintedanib is a primary antifibrosing medication available for idiopathic pulmonary fibrosis, systemic sclerosis-interstitial lung disease, and progressive pulmonary fibrosis, with scattered report of drug-induced thrombocytopenia. Case report A 60-year-old Asian male with no history of thrombocytopenia was administered with nintedanib to treat progressive pulmonary fibrosis. The platelet count dropped rapidly after introduction of nintedanib and resolved gradually by withdrawal of the medication along with thrombopoietin receptor agonist. Conclusion Based on experience from the limited reports, nintedanib-induced thrombocytopenia is typically reversible and manageable. Close monitoring of platelet counts in patients receiving this medication should be warranted.

High‐producing dairy cows are susceptible to altered redox balance owing to their high secretion and strong metabolism during transition to lactation. Previously reports demonstrated that pterostilbene (PTE) alleviate hydrogen peroxide (H2O2)-induced oxidative damage. However, molecular mechanism underlying protective role of PTE in H2O2-elicited oxidative stress in bovine mammary epithelial cells (MAC-T cells) remains unclear. The aims of our research is to clarify the potential molecular mechanisms of PTE in H2O2-triggered oxidative damage. MAC-T cells were pre-treated with PTE (0, 10, 25 and 50 μM) for 12 h and then cultured with H2O2 (0, 100, 200, 400, 600, 800 and 1000 μM) for another 24 h. The results were interpreted by CCK8, western blot, and immunofluorescence assay. Results showed that PTE significantly attenuated H2O2-mediated reduction in T-AOC, SOD and GSH-Px activity. Mechanistic studies found that PTE restricted the H2O2-induced protein expression of HO-1, GPX4 and SOD1, and PTE reversed intracellular MDA and ROS generation and decreased the MMP in MAC-T cells. Moreover, H2O2 exposure markedly inhibited mitophagy, whereas PTE pre-treatment activated PINK1/Parkin-mediated mitophagy pathway, which further limited ROS production. Overall, PTE can be used to improve oxidative stress and as a novel antioxidant agent in dairy cows. Highlights PTE restored the levels of H2O2-induced oxidative stress markers (T-AOC, SOD, GSH-Px and MDA) in MAC-T cells. PTE effectively blocked the increase of protein expression (HO-1, SOD1 and GPX4) in H2O2-induced MAC-T cells. PTE remarkably decreased the accumulation of ROS and improved MMP in H2O2-induced MAC-T cells. PTE exerted a significant protective effect against oxidative stress injury by reducing the inhibition of H2O2 on mitophagy.

Abstract Triple negative breast cancer (TNBC) is a type of cancer that lacks receptor expression and has complex molecular mechanisms. Recent evidence shows that the ubiquitin-protease system is closely related to TNBC. In this study, we obtain a key ubiquitination regulatory substrate-ABI2 protein by bioinformatics methods, which is also closely related to the survival and prognosis of TNBC. Further, through a series of experiments, we demonstrated that ABI2 expressed at a low level in TNBC tumors, and it has the ability to control cell cycle and inhibit TNBC cell migration, invasion and proliferation. Molecular mechanism studies proved E3 ligase CBLC could increase the ubiquitination degradation of ABI2 protein. Meanwhile, RNA-seq and IP experiments indicated that ABI2, acting as a crucial factor of tumor suppression, can significantly inhibit PI3K/Akt signaling pathway via the interaction with Rho GTPase RAC1. Finally, based on TNBC drug target ABI2, we screened and found that FDA-approved drug Colistimethate sodium(CS) has significant potential in suppressing the proliferation of TNBC cells and inducing cell apoptosis, making it a promising candidate for impeding the progression of TNBC.

Abstract Background Telomeres consist of repetitive DNA sequences at the chromosome ends to protect chromosomal stability, and primarily maintained by telomerase or occasionally by alternative telomere lengthening of telomeres (ALT) through recombination-based mechanisms. Additional mechanisms that may regulate telomere maintenance remain to be explored. Simultaneous measurement of telomere length and transcriptome in the same human embryonic stem cell (hESC) revealed that mRNA expression levels of UBQLN1 exhibit linear relationship with telomere length. Methods In this study, we first generated UBQLN1-deficient hESCs and compared with the wild-type (WT) hESCs the telomere length and molecular change at RNA and protein level by RNA-seq and proteomics. Then we identified the potential interacting proteins with UBQLN1 using immunoprecipitation-mass spectrometry (IP-MS). Furthermore, the potential mechanisms underlying the shortened telomeres in UBQLN1-deficient hESCs were analyzed. Results We show that Ubiquilin1 (UBQLN1) is critical for telomere maintenance in human embryonic stem cells (hESCs) via promoting mitochondrial function. UBQLN1 deficiency leads to oxidative stress, loss of proteostasis, mitochondria dysfunction, DNA damage, and telomere attrition. Reducing oxidative damage and promoting mitochondria function by culture under hypoxia condition or supplementation with N-acetylcysteine partly attenuate the telomere attrition induced by UBQLN1 deficiency. Moreover, UBQLN1 deficiency/telomere shortening downregulates genes for neuro-ectoderm lineage differentiation. Conclusions Altogether, UBQLN1 functions to scavenge ubiquitinated proteins, preventing their overloading mitochondria and elevated mitophagy. UBQLN1 maintains mitochondria and telomeres by regulating proteostasis and plays critical role in neuro-ectoderm differentiation.

Abstract GATA-binding protein 4 (GATA4) is recognized for its significant roles in embryogenesis and various cancers. Through bioinformatics and clinical data, it appears that GATA4 plays a role in breast cancer development. Yet, the specific roles and mechanisms of GATA4 in breast cancer progression remain elusive. In this study, we identify GATA4 as a tumor suppressor in the invasion and migration of breast cancer. Functionally, GATA4 significantly reduces the transcription of MMP9. On a mechanistic level, GATA4 diminishes MMP9 transcription by interacting with p65 at the NF-κB binding site on the MMP9 promoter. Additionally, GATA4 promotes the recruitment of HDAC1, amplifying the bond between p65 and HDAC1. This leads to decreased acetylation of p65, thus inhibiting p65’s transcriptional activity on the MMP9 promoter. Moreover, GATA4 hampers the metastasis of breast cancer in vivo mouse model. In summary, our research unveils a novel mechanism wherein GATA4 curtails breast cancer cell metastasis by downregulating MMP9 expression, suggesting a potential therapeutic avenue for breast cancer metastasis.

Background: Neurotransmitter deficits and spatial associations among neurotransmitter distribution, brain activity, and clinical features in Parkinson's disease (PD) remain unclear. Better understanding of neurotransmitter impairments in PD may provide potential therapeutic targets. Therefore, we aimed to investigate the spatial relationship between PD-related patterns and neurotransmitter deficits. Methods: We included 59 patients with PD and 41 age- and sex-matched healthy controls (HCs). The voxel-wise mean amplitude of the low-frequency fluctuation (mALFF) was calculated and compared between the two groups. The JuSpace toolbox was used to test whether spatial patterns of mALFF alterations in patients with PD were associated with specific neurotransmitter receptor/transporter densities. Results: Compared to HCs, patients with PD showed reduced mALFF in the sensorimotor- and visual-related regions. In addition, mALFF alteration patterns were significantly associated with the spatial distribution of the serotonergic, dopaminergic, noradrenergic, glutamatergic, cannabinoid, and acetylcholinergic neurotransmitter systems (p

The potential role of peroxisome proliferator-activated receptor (PPAR) in regulating the biosynthesis of long-chain polyunsaturated fatty acids (LCPUFA) has not been explored in marine gastropod. In this study, we identified and characterized a PPAR gene from the abalone species Haliotis discus hannai Ino. This gene encodes a peptide consisting of 469 amino acids and comprises typical four domains: A/B domain, DNA-binding domain, D domain, and ligand-binding domain. Highest homology with that of the Patella depressa (51.08 %) from multiple alignments and phylogenetic tree analyses revealed it is a direct orthologue of the vertebrate PPAR. Tissue distribution analysis demonstrated that PPAR was highly expressed in muscle and gill, with lower expression observed in the kidney, female gonad, and hepatopancreas. Dual-luciferase reporter assays indicated that abalone PPAR significantly up-regulated the promoter activity of Δ5 fatty acyl desaturase (Δ5fad), a crucial enzyme in LCPUFA biosynthesis. Furthermore, C18PUFA significantly increased the expressions of Δ5fad and PPAR in the hepatopancreas of abalone compared to the control group fed with an LCPUFA-rich diet. These findings suggest that PPAR acts as a positive transcription factor for the fad gene, contributing to the transcriptional regulation of LCPUFA biosynthesis in abalone.

The current computer-aided diagnosis for cervical cancer screening encounters issues with missing detailed information during colposcopic image segmentation and incomplete edge delineation. To overcome these challenges, this study introduces the RUC-U2Net architecture, which enhances image segmentation through feature refinement and upsampling connections. Two variants are developed: RUC-U2Net and the lightweight RUC+-U2Net. Initially, a feature refinement module that leverages an attention mechanism is proposed to improve detail capture by the model’s fundamental unit during downsampling. Subsequently, the integration of diagonal attention in connecting peer-level encoders and decoders supplements finer semantic details to the decoder’s feature maps, addressing the problem of incomplete edge segmentation. Finally, the application of the Focal Tversky loss function allows the model to concentrate on difficult samples, mitigating the challenges posed by imbalanced distributions of positive and negative samples in training datasets. Experimental evaluations on three publicly available datasets demonstrate that the proposed models significantly outperform existing methods across seven performance metrics, evidencing their superior segmentation accuracy.

IntroductionBTBD8 has been identified as a susceptible gene for inflammatory bowel diseases (IBD). However, the function of BTBD8 in normal development and IBD pathogenesis remains unknown.MethodsWe administered drinking water with 3% dextran sodium sulfate (DSS) to wild-type (WT) and Btbd8 knockout (KO) mice for seven consecutive days to induce IBD. Subsequently, we further examined whether Btbd8 KO affects intestinal barrier and inflammation.ResultsWe demonstrated that Btbd8 deficiency partially protects mice from DSS-induced IBD, even though no obvious phenotypes were observed in Btbd8 KO mice. Btbd8 deletion leads to strengthened tight junctions between intestinal epithelial cells, elevated intestinal stem cell activity, and enhanced mucus layer. All these three mechanisms work together to improve the intestinal barrier integrity in Btbd8 KO mice. In addition, Btbd8 deficiency mitigates inflammation by reducing the expression of IL-1β and IL-6 by macrophages.DiscussionOur studies validate the crucial role of Btbd8 in IBD pathogenesis, and reveal that Btbd8 deficiency may ameliorate DSS-induced IBD through improving the intestinal barrier integrity, as well as suppressing inflammatory response mediated by macrophages. These findings suggest that Btbd8 could be a promising therapeutic target for the treatment of IBD.

Abstract Background Glioblastoma (GBM) is a type of highly malignant brain tumor that is known for its significant intratumoral heterogeneity, meaning that there can be a high degree of variability within the tumor tissue. Despite the identification of several subtypes of GBM in recent years, there remains to explore a classification based on genes related to proliferation and growth. Methods The growth-related genes of GBM were identified by CRISPR-Cas9 and univariate Cox regression analysis. The expression of these genes in the Cancer Genome Atlas cohort (TCGA) was used to construct growth-related genes subtypes (GGSs) via consensus clustering. Validation of this subtyping was performed using the nearest template prediction (NTP) algorithm in two independent Gene Expression Omnibus (GEO) cohorts and the ZZ cohort. Additionally, copy number variations, biological functions, and potential drugs were analyzed for each of the different subtypes separately. Results Our research established multicenter-validated GGSs. GGS1 exhibits the poorest prognosis, with the highest frequency of chr 7 gain & chr 10 loss, and the lowest frequency of chr 19 & 20 co-gain. Additionally, GGS1 displays the highest expression of EGFR. Furthermore, it is significantly enriched in metabolic, stemness, proliferation, and signaling pathways. Besides we showed that Foretinib may be a potential therapeutic agent for GGS1, the worst prognostic subtype, through data screening and in vitro experiments. GGS2 has a moderate prognosis, with a slightly higher proportion of chr 7 gain & chr 10 loss, and the highest proportion of chr 19 & 20 co-gain. The prognosis of GGS3 is the best, with the least chr 7 gain & 10 loss and EGFR expression. Conclusions These results enhance our understanding of the heterogeneity of GBM and offer insights for stratified management and precise treatment of GBM patients.

Abstract Sepsis is the uncontrolled reaction of the body to infection-induced inflammation, which results in life-threatening multiple-organ dysfunction (MODS). Although the research on sepsis has advanced significantly in recent years, its pathophysiology remains entirely unknown. Ferroptosis is a new-fashioned type of programmed cell death that may have an impact on sepsis development. However, the precise mechanism still needs to be explored. In this paper, Four pediatric sepsis datasets [training datasets (GSE26378 and GSE26440) and validation datasets (GSE11755 and GSE11281)] were chosen through the GEO (Gene Expression Omnibus) database, and 63 differentially expressions of ferroptosis-relation-genes (DE-FRGs) were eventually discovered using bioinformatics investigation. Functional annotation was performed using GO and KEGG pathway enrichment analysis. Then, four Core-FRGs (FTH1, GPX4, ACSL1, and ACSL6) were extracted after the construction of the protein–protein interaction (PPI) network and the research of the MCODE module. Consequently, Hub-FRG (GPX4) was found using the validation datasets, and correlation exploration of immunity populations (neutrophils, r = − 0.52; CD8 T-cells, r = 0.43) and immunity checkpoints (CD274, r = − 0.42) was implemented. The usefulness of GPX4 as a marker in sepsis was assessed in a mouse model of sepsis. The findings demonstrate that GPX4 is a crucial biomarker and a new latent immunotherapy target for the prediction and therapy of pediatric sepsis.

Abstract This article utilizes an online job recruitment dataset of more than 4.6 million jobs in China to examine the urban scaling patterns of explicit and tacit knowledge. Knowledge complexity is considered essential for economic development and innovation, and recent studies find complex economic activities of many fields concentrate more in large cities. However, it remains unclear whether the urban concentration tendency would differ by explicit and tacit knowledge, given the latter is often argued as the hard core knowledge more difficult to transfer. We measure explicit/tacit knowledge in job descriptions regarding education/experience requirements. Our analysis reveals that knowledge of different natures differs to a great extent in their property of urban concentration. Specifically, jobs requiring greater explicit knowledge show higher urban scaling rates. This, however, is not true for tacit knowledge, as it demonstrates the exact opposite pattern. Our findings suggest that while cities are centers of knowledge and innovation, the engines of continued growth tend to become more biased towards explicit rather than know-how knowledge.

Abstract Telomeres, at the ends of chromosomes, protect chromosomes from fusion and preserve genomic stability. However, the molecular mechanisms underlying telomere attrition-induced genome instability remain to be understood. We systematically analyzed the expression of retrotransposons and performed genomic sequencing of different cell and tissue types with telomeres of varying lengths due to telomerase deficiency. We found that critically short telomeres altered retrotransposon activity to promote genomic instability in mouse embryonic stem cells, as evidenced by elevated numbers of single nucleotide variants, indels and copy number variations (CNVs). Transpositions of retrotransposons such as LINE1 resulting from the short telomeres can also be found in these genomes with elevated number of mutations and CNVs. Retrotransposon activation is linked to increased chromatin accessibility, and reduced heterochromatin abundance correlates with short telomeres. Re-elongation of telomeres upon recovery of telomerase partly represses retrotransposons and heterochromatin accumulation. Together, our findings suggest a potential mechanism by which telomeres maintain genomic stability by suppressing chromatin accessibility and retrotransposon activity.

Bovine mastitis is among the most serious disease in the dairy industry and brings huge economic losses due to the decrease in milk quality and quantity. Betaine, a naturally occurring compound, possesses several pharmacological activities including anti-inflammatory and anti-oxidant ability, but whether betaine has protective effects on bovine mastitis is unknown. The aim of this study is to investigate the effect of betaine on mastitis and further discover its feasible molecular mechanism in lipopolysaccharide (LPS)-stimulated bovine mammary epithelial cells (BMECs). BMECs were pre-treated with or without betaine or LPS. Cell viability was measured with CCK-8 to examine the cytotoxicity. The levels of pro-inflammatory cytokines were measured by ELISA kits. Western blotting was used to explore the regulation of genes associated with inflammatory and oxidative stress genes. The results showed that LPS treatment significantly increased the production of pro-inflammation (IL-1β, IL-6 and TNFα), enhanced malondialdehyde (MDA) content, reduced superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity, and markedly up-regulated the protein expression of COX2 and iNOS (p

In electrolytic capacitorless permanent magnet synchronous motor (PMSM) drives, the DC-link voltage will fluctuate in a wide range due to the use of slim film capacitor. When the flux-weakening current is lower than −ψf/Ld during the high speed operation, the flux-weakening control loop will transform to a positive feedback mode, which means the reduction of flux-weakening current will lead to the acceleration of the voltage saturation, thus the whole system will be unstable. In order to solve this issue, this paper proposes a novel flux-weakening method for electrolytic capacitorless motor drives to maintain a negative feedback characteristic of the control loop during high speed operation. Based on the analysis of the instability mechanism in flux-weakening region, a quadrature voltage constrain mechanism is constructed to stabilize the system. Meanwhile, the parameters of the controller are theoretically designed for easier industrial application. The proposed algorithm is implemented on a 1.5kW electrolytic capacitorless PMSM drive to verify the effectiveness of the flux-weakening performance.

Summary: Various culture conditions by small molecules have been explored to extend pluripotency of stem cells, but their impacts on cell fate in vivo remain elusive. We systematically compared the effects of various culture conditions on the pluripotency and cell fate in vivo of mouse embryonic stem cells (ESCs) by tetraploid embryo complementation assay. Conventional ESC cultures in serum/LIF-based condition produced complete ESC mice and also the survival to adulthood at the highest rates of all other chemical-based cultures. Moreover, long-term examination of the survived ESC mice demonstrated that conventional ESC cultures did not lead to visible abnormality for up to 1.5–2 years, whereas the prolonged chemical-based cultures developed retroperitoneal atypical teratomas or leiomyomas. The chemical-based cultures exhibited transcriptomes and epigenomes that typically differed from those of conventional ESC cultures. Our results warrant further refinement of culture conditions in promoting the pluripotency and safety of ESCs in future applications.

Abstract Background The contribution of autophagy to cancer therapy resistance remains complex, mainly owing to the discrepancy of autophagy mechanisms in different therapy. However, the potential mechanisms of autophagy-mediated resistance to icotinib have yet to be elucidated. Methods The effect of autophagy in icotinib resistance was examined using a series of in vitro and in vivo assays. The results above were further verified in biopsy specimens of lung cancer patients before and after icotinib or gefitinib treatment. Results Icotinib increased ATG3, ATG5, and ATG7 expression, but without affecting Beclin-1, VPS34 and ATBG14 levels in icotinib-resistant lung cancer cells. Autophagy blockade by 3-MA or silencing Beclin-1 had no effects on resistance to icotinib. CQ effectively restored lung cancer cell sensitivity to icotinib in vitro and in vivo. Notably, aberrantly activated STAT3 and highly expressed FOXM1 were required for autophagy induced by icotinib, without the involvement of AMPK/mTOR pathway in this process. Alterations of STAT3 activity using genetic and/or pharmacological methods effectively affected FOXM1 and ATG7 levels increased by icotinib, with altering autophagy and icotinib-mediated apoptosis in resistant cells. Furthermore, silencing FOXM1 impaired up-regulated ATG7 induced by STAT3-CA and icotinib. STAT3/FOXM1 signalling blockade also reversed resistance to icotinib in vivo. Finally, we found a negative correlation between STAT3/FOXM1/ATG7 signalling activity and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) treatment efficacy in patients undergoing EGFR-TKIs treatment. Conclusions Our findings support that STAT3/FOXM1/ATG7 signalling-induced autophagy is a novel mechanism of resistance to icotinib, and provide insights into potential clinical values of ATG7-dependent autophagy in icotinib treatment. Graphical abstract

Argon injection is usually applied in the continuous casting mold to prevent submerged entry nozzle (SEN) clogging. However, the stability of the slag–steel interface is affected by the injected gas, even leading to the formation of the slag eye. A computational fluid dynamics–discrete bubble model–volume of fluid (CFD-DBM-VOF) model is established to predict the argon–slag–steel–air four-phase flow in the continuous casting mold. The bubble behavior is treated with the Lagrangian approach considering bubble coalescence and breakup. The movement behavior of the slag–steel interface is analyzed with and without argon blowing, validated with the water model. The results show that the large bubble tends to float up into the slag–steel interface near the SEN with argon injection, resulting in fluctuations in the slag–steel interface near the SEN. The bubble distribution, flow field, fluctuation height of the slag–steel interface and configuration of the slag eye in the mold are analyzed. Furthermore, the effect on the casting speed, gas flow rate and thickness of the slag layer is obtained based on the result. The mathematical prediction results showcase a combination of well-established phenomena and newly generated predictions.

In this work, we introduce an extended gradient method that employs the gradients of the preceding two iterates to construct the search direction for the purpose of solving the centralized and decentralized smooth and strongly convex functions. Additionally, we establish the linear convergence for iterate sequences in both the centralized and decentralized manners. Furthermore, the numerical experiments demonstrate that the centralized extended gradient method can achieve faster acceleration than the compared algorithms, and the search direction also exhibits the capability to improve the convergence of the existing algorithms in both two manners.

BackgroundEwing’s sarcoma (ES) is one of the most prevalent malignant bone tumors worldwide. However, the molecular mechanisms of the genes and signaling pathways of ES are still not well sufficiently comprehended. To identify candidate genes involved in the development and progression of ES, the study screened for key genes and biological pathways related to ES using bioinformatics methods.MethodsThe GSE45544 and GSE17618 microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified, and functional enrichment analysis was performed. A protein–protein interaction (PPI) network was built, and key module analysis was performed using STRING and Cytoscape. A core-gene was gained and was validated by the validation dataset GSE67886 and immunohistochemistry (IHC). The diagnostic value and prognosis evaluation of ES were executed using, respectively, the ROC approach and Cox Regression.ResultsA total of 187 DEGs, consisting of 56 downregulated genes and 131 upregulated genes, were identified by comparing the tumor samples to normal samples. The enriched functions and pathways of the DEGs, including cell division, mitotic nuclear division, cell proliferation, cell cycle, oocyte meiosis, and progesterone-mediated oocyte maturation, were analyzed. There were 149 nodes and 1246 edges in the PPI network, and 15 hub genes were identified according to the degree levels. The core gene (UBE2T) showed high expression in ES, validated by using GSE67886 and IHC. The ROC analysis revealed UBE2T had outstanding diagnostic value in ES (AUC = 0.75 in the training set, AUC = 0.90 in the validation set). Kaplan-Meier (analysis of survival rate) and Cox Regression analyses indicated that UBE2T was a sign of adverse results for sufferers with ES.ConlusionUBE2T was a significant value biomarker for diagnosis and treatment of ES, thereby presenting a novel potential therapeutic target for ES as well as a new perspective for assessing the effect of treatment and prognostic prediction.

The increasing prominence of urban scaling laws highlights the importance of a systematic understanding of the variational scaling rates for different economic activities. In this article, we utilize several datasets to provide the first systematic investigation of the urban scaling of manufacturing industries in China. Most existing literature assumes that the divergence in urban scaling can be explained by returns to agglomeration, with a few exceptions instead highlighting the role of knowledge complexity or a mixture of both. Our main purpose in this paper is to explain the inter-sector variation of urban scaling rates. In doing this, we provide a clearer approach to demonstrating the relations between urban scaling, returns to agglomeration, and knowledge complexity. Our findings are twofold. First, after uncovering the scaling rates (denoted as urban concentration) and returns to agglomeration (denoted as urban productivity) for each sub-manufacturing sector, we prove that, rather than being a positive predictor, returns to agglomeration is slightly negatively associated with urban scaling rates. This finding reveals that urban concentration of manufacturing may not simply be a natural consequence driven by the maximization of performance. We also show that this result of the manufacturing system contrasts with what would be found in other pure knowledge systems such as patents. Secondly, we measure the complexity for each sector and demonstrate that the variation of urban concentration can be largely explained by their complexity, consistent with the knowledge complexity perspective. Specifically, complex manufacturing sectors are found to concentrate more in large cities than less complex sectors in China. This result provides support for the view that the growth of complex activities hinges more on diversity than on efficiency. The findings above can greatly reduce the current level of ambiguity associated with urban scaling, returns to agglomeration and complexity, and have important policy implications for urban planners, highlighting the significance of a more balanced and diversified configuration of urban productive activities for the growth of innovation economy.

PurposeThis study aims to investigate values of intra- and peri-tumoral regions in the mammography and magnetic resonance imaging (MRI) image for prediction of sentinel lymph node metastasis (SLNM) in invasive breast cancer (BC).MethodsThis study included 208 patients with invasive BC between Spe. 2017 and Apr. 2021. All patients underwent preoperative digital mammography (DM), digital breast tomosynthesis (DBT), dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DWI) scans. Radiomics features were extracted from manually outlined intratumoral regions, and automatically dilated peritumoral tumor regions in each modality. The least absolute shrinkage and selection operator (LASSO) regression was used to select key features from each region to develop radiomics signatures (RSs). Area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity and negative predictive value (NPV) were calculated to evaluate performance of the RSs.ResultsIntra- and peri-tumoral regions of BC can provide complementary information on the SLN status. In each modality, the Com-RSs derived from combined intra- and peri-tumoral regions always yielded higher AUCs than the Intra-RSs or Peri-RSs. A total of 10 and 11 features were identified as the most important predictors from mammography (DM plus DBT) and MRI (DCE-MRI plus DWI), respectively. The DCE-MRI plus DWI generated higher AUCs compared with DM plus DBT in the training (AUCs, DCE-MRI plus DWI vs. DM plus DBT, 0.897 vs. 0.846) and validation (AUCs, DCE-MRI plus DWI vs. DM plus DBT, 0.826 vs. 0.786) cohort.ConclusionsRadiomics features from intra- and peri-tumoral regions can provide complementary information to identify the SLNM in both mammography and MRI. The DCE-MRI plus DWI generated lower specificity, but higher AUC, accuracy, sensitivity and negative predictive value compared with DM plus DBT.

Samples of pure titanium with a purity of 99.99 wt.% were successfully processed by equal channel angular pressing (ECAP) at cryogenic temperature. Deformed microstructures of ECAPed samples were characterized by electron backscattering diffraction (EBSD), and its homogeneity was studied by color-coded contour mapping of microhardness distribution. EBSD results indicate the original coarse grains with an average grain size of 196 μm were significantly refined to 0.56 μm after four passes, and that the prism slip systems were activated in the whole deformation process and with increasing passes number more slip systems were activated. The hardness mapping reveals that the microstructure of samples prior to ECAP is basically homogeneous but becomes inhomogeneous after one pass and then gradually homogeneous with additional passes. In addition, the grain refinement of ECAPed titanium at cryogenic temperature was discussed and confirmed by CDRX. Also, the factors of influence on the homogeneity of microstructure were analyzed.

Remediation of environmental toxic pollutants has attracted extensive attention in recent years. Microbial bioremediation has been an important technology for removing toxic pollutants. However, microbial activity is also susceptible to toxicity stress in the process of intracellular detoxification, which significantly reduces microbial activity. Electroactive microorganisms (EAMs) can detoxify toxic pollutants extracellularly to a certain extent, which is related to their unique extracellular electron transfer (EET) function. In this review, the extracellular and intracellular aspects of the EAMs’ detoxification mechanisms are explored separately. Additionally, various strategies for enhancing the effect of extracellular detoxification are discussed. Finally, future research directions are proposed based on the bottlenecks encountered in the current studies. This review can contribute to the development of toxic pollutants remediation technologies based on EAMs, and provide theoretical and technical support for future practical engineering applications.

The leopard coral trout generally exhibited numerous round, minute blue spots covering its head (about the size of nostril) and body (except ventral side). This is a characteristic that distinguishes them from similar species. Recently, however, we found the leopard coral trout with black spots. Here, the distribution and ultrastructure of chromatophores in the blue and black spots were investigated with light and transmission electron microscopies. The results showed that in the blue spots, two types of chromatophores are present in the dermis, with the light-reflecting iridophores located in the upper layer and the aggregated light-absorbing melanophores in the lower layer. Black spots have a similar chromatophore composition, except that the melanosomes within the melanophores disperse their dendritic processes to encircle the iridophores. Interestingly, after the treatment of forskolin, a potent adenylate cyclase activator, the blue spots on the body surface turned black. On the other hand, using the skin preparations in vitro, the electrical stimulation and norepinephrine treatment returned the spots to blue color again, indicating the sympathetic nerves were involved in regulating the coloration of blue spots. Taken together, our results revealed that the blue spots of the leopard coral trout can change color to black and vice versa, resulting from the differences in the distribution of melanosomes, which enriches our understanding of the body color and color changes of fishes.

Abstract Background The activation of T cells and imbalanced redox metabolism enhances the development of graft-versus-host disease (GVHD). Human placenta-derived mesenchymal stromal cells (hPMSCs) can improve GVHD through regulating T cell responses. However, whether hPMSCs balance the redox metabolism of CD4+IL-10+ T cells and liver tissue and alleviate GVHD remains unclear. This study aimed to investigate the effect of hPMSC-mediated treatment of GVHD associated with CD4+IL-10+ T cell generation via control of redox metabolism and PD-1 expression and whether the Nrf2 and NF-κB signaling pathways were both involved in the process. Methods A GVHD mouse model was induced using 6–8-week-old C57BL/6 and Balb/c mice, which were treated with hPMSCs. In order to observe whether hPMSCs affect the generation of CD4+IL-10+ T cells via control of redox metabolism and PD-1 expression, a CD4+IL-10+ T cell culture system was induced using human naive CD4+ T cells. The percentage of CD4+IL-10+ T cells and their PD-1 expression levels were determined in vivo and in vitro using flow cytometry, and Nrf2, HO-1, NQO1, GCLC, GCLM, and NF-κB levels were determined by western blotting, qRT-PCR, and immunofluorescence, respectively. Hematoxylin-eosin, Masson’s trichrome, and periodic acid-Schiff staining methods were employed to analyze the changes in hepatic tissue. Results A decreased activity of superoxide dismutase (SOD) and a proportion of CD4+IL-10+ T cells with increased PD-1 expression were observed in GVHD patients and the mouse model. Treatment with hPMSCs increased SOD activity and GCL and GSH levels in the GVHD mouse model. The percentage of CD4+IL-10+ T cells with decreased PD-1 expression, as well as Nrf2, HO-1, NQO1, GCLC, and GCLM levels, both in the GVHD mouse model and in the process of CD4+IL-10+ T cell generation, were also increased, but NF-κB phosphorylation and nuclear translocation were inhibited after treatment with hPMSCs, which was accompanied by improvement of hepatic histopathological changes. Conclusions The findings suggested that hPMSC-mediated redox metabolism balance and decreased PD-1 expression in CD4+IL-10+ T cells were achieved by controlling the crosstalk between Nrf2 and NF-κB, which further provided evidence for the application of hPMSC-mediated treatment of GVHD.

PurposeThe aim of this study is to investigate radiomics features extracted from the optimal peritumoral region and the intratumoral area on the early phase of dynamic contrast-enhanced MRI (DCE-MRI) for predicting molecular subtypes of invasive ductal breast carcinoma (IDBC).MethodsA total of 422 IDBC patients with immunohistochemical and fluorescence in situ hybridization results from two hospitals (Center 1: 327 cases, Center 2: 95 cases) who underwent preoperative DCE-MRI were retrospectively enrolled. After image preprocessing, radiomic features were extracted from the intratumoral area and four peritumoral regions on DCE-MRI from two centers, and selected the optimal peritumoral region. Based on the intratumoral, peritumoral radiomics features, and clinical–radiological characteristics, five radiomics models were constructed through support vector machine (SVM) in multiple classification tasks related to molecular subtypes and visualized by nomogram. The performance of radiomics models was evaluated by receiver operating characteristic curves, confusion matrix, calibration curves, and decision curve analysis.ResultsA 6-mm peritumoral size was defined the optimal peritumoral region in classification tasks of hormone receptor (HR)-positive vs others, triple-negative breast cancer (TNBC) vs others, and HR-positive vs human epidermal growth factor receptor 2 (HER2)-enriched vs TNBC, and 8 mm was applied in HER2-enriched vs others. The combined clinical–radiological and radiomics models in three binary classification tasks (HR-positive vs others, HER2-enriched vs others, TNBC vs others) obtained optimal performance with AUCs of 0.838, 0.848, and 0.930 in the training cohort, respectively; 0.827, 0.813, and 0.879 in the internal test cohort, respectively; and 0.791, 0.707, and 0.852 in the external test cohort, respectively.ConclusionRadiomics features in the intratumoral and peritumoral regions of IDBC on DCE-MRI had a potential to predict the HR-positive, HER2-enriched, and TNBC molecular subtypes preoperatively.

The aggregation of alpha-synuclein (α-Syn) is closely related to the occurrence of some neurodegenerative diseases such as Parkinson’s disease. The misfolding of α-Syn monomer plays a key role in the formation of aggregates and extension of fibril. However, the misfolding mechanism of α-Syn remains elusive. Here, three different α-Syn fibrils (isolated from a diseased human brain, generated by in vitro cofactor-tau induction, and obtained by in vitro cofactor-free induction) were selected for the study. The misfolding mechanisms of α-Syn were uncovered by studying the dissociation of the boundary chains based on the conventional molecular dynamics (MD) and Steered MD simulations. The results showed that the dissociation paths of the boundary chains in the three systems were different. According to the reverse process of dissociation, we concluded that in the human brain system, the binding of the monomer and template starts from the C-terminal and gradually misfolds toward the N-terminal. In the cofactor-tau system, the monomer binding starts from residues 58–66 (contain β3), followed by the C-terminal coil (residues 67–79). Then, the N-terminal coil (residues 36–41) and residues 50–57 (contain β2) bind to the template, followed by residues 42–49 (contain β1). In the cofactor-free system, two misfolding paths were found. One is that the monomer binds to the N/C-terminal (β1/β6) and then binds to the remaining residues. The other one is that the monomer binds sequentially from the C- to N-terminal, similar to the human brain system. Furthermore, in the human brain and cofactor-tau systems, electrostatic interactions (especially from residues 58–66) are the main driving force during the misfolding process, whereas in the cofactor-free system, the contributions of electrostatic and van der Waals interactions are comparable. These results may provide a deeper understanding for the misfolding and aggregation mechanism of α-Syn.

Suspended sediment load (SSL) estimation is essential for both short- and long-term water resources management. Suspended sediments are taken into account as an important factor of the service life of hydraulic structures such as dams. The aim of this research is to estimat SSL by coupling intrinsic time-scale decomposition (ITD) and two kinds of DDM, namely evolutionary polynomial regression (EPR) and model tree (MT) DDMs, at the Sarighamish and Varand Stations in Iran. Measured data based on their lag times are decomposed into several proper rotation components (PRCs) and a residual, which are then considered as inputs for the proposed model. Results indicate that the prediction accuracy of ITD-EPR is the best for both the Sarighamish (R2 = 0.92 and WI = 0.96) and Varand (R2 = 0.92 and WI = 0.93) Stations (WI is the Willmott index of agreement), while a standalone MT model performs poorly for these stations compared with other approaches (EPR, ITD-EPR and ITD-MT) although peak SSL values are approximately equal to those by ITD-EPR. Results of the proposed models are also compared with those of the sediment rating curve (SRC) method. The ITD-EPR predictions are remarkably superior to those by the SRC method with respect to several conventional performance evaluation metrics.

Abstract Background Mesenchymal stem cells (MSCs) were considered a regenerative therapeutic approach in both acute and chronic diseases. However, whether MSCs regulate the antioxidant metabolism of CD4+ T cells and weaken immunosenescence remains unclear. Here, we reported the protective effects of hPMSCs in aging-related CD4+ T cell senescence and identified the underlying mechanisms using a d-gal-induced mouse aging model. Methods In vivo study, 40 male C57BL/6 mice (8 weeks) were randomly divided into four groups: control group, d-gal group, hPMSC group, and PBS group. In in vitro experiment, human naive CD4+ T (CD4CD45RA) cells were prepared using a naive CD4+ T cell isolation kit II and pretreated with the Akt inhibitor LY294002 and Nrf2 inhibitor ML385. Then, isolated naive CD4+ T cell were co-cultured with hPMSCs for 72 h in the absence or presence of anti-CD3/CD28 Dynabeads and IL-2 as a mitogenic stimulus. Intracellular ROS changes were detected by flow cytometry. The activities of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase were measured by colorimetric analysis. The senescent T cells were detected SA-β-gal stain. The expression of aging-related proteins was detected by Western blotting, RT-PCR, and confocal microscopy. Results We found that hPMSC treatment markedly decreased the ROS level, SA-β-gal-positive cells number, senescence-associated secretory phenotype (IL-6 and OPN) expression, and aging-related protein (P16 and P21) expression in senescent CD4+ T cells. Furthermore, hPMSC treatment effectively upregulated Nrf2 nuclear translocation and the expression of downstream target genes (HO-1, CAT, GCLC, and NQO1) in senescent CD4+ T cells. Moreover, in vitro studies revealed that hPMSCs attenuated CD4+ T cell senescence by upregulating the Akt/GSK-3β/Fyn pathway to activate Nrf2 functions. Conversely, the antioxidant effects of hPMSCs were blocked by the Akt inhibitor LY294002 and Nrf2 inhibitor ML385 in senescent CD4+ T cells. Conclusions Our results indicate that hPMSCs attenuate d-gal-induced CD4+ T cell senescence by activating Nrf2-mediated antioxidant defenses and that upregulation of Nrf2 by hPMSCs is regulated via the Akt/GSK-3β/Fyn pathway.

Synchronous reluctance machines (SynRMs) have drawn increasing attention in recent years owing to their advantages such as low cost, simple structure, ease of manufacture, and high robustness. The main obstacle to the promotion of SynRMs is severe parameter nonlinearity, which deteriorates drive performance. Sensorless control methods for SynRMs are critical technologies that can broaden the industrial applications of SynRMs. Various methods of parameter identification and sensorless control strategies are reviewed and discussed, including self-commissioning, which is analyzed in detail. Furthermore, sensorless control strategies that can improve the industrial application of SynRMs are described. Finally, future research trends concerning SynRMs are analyzed and discussed.

Since mid-December 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has outbroken in Wuhan, Hubei Province, China, and spread rapidly to other provinces in China and dozens of countries and regions around the world, becoming the Public Health Emergency of International Concern (Public Health Emergency of International Concern). SARS-CoV-2 can mainly transmit by droplets or close contact, and is generally susceptible in the crowd. Tumor patients are at high risk of this pathogen because of their impaired immune function. Identifying tumor patients with 2019 novel coronavirus disease (COVID-19) early, and understanding its distribution characteristics can help to improve the cure rate of patients, and better control the epidemic and development of SARS-CoV-2 much better. With comprehensive analysis of relevant literature, this paper reviews the clinical characteristics of neoplastic patients with COVID-19, and puts forward some suggestions on how to deal with this epidemic.

Abstract Background Growth hormone inducible transmembrane protein (GHITM) is a highly conserved transmembrane protein. This study was conducted to investigate the role of GHITM gene in the apoptosis and growth of the golden apple snail Pomacea canaliculate. Results The complete cDNA of this gene was cloned using the rapid amplification of cDNA ends (RACE) method and subjected to bioinformatics analysis. The full-length cDNA was 2242 bp, including an open reading frame of 1021 bp that encoded a protein of 342 amino acid residues. The mRNA expression profiles of GHITM gene in different tissues (liver, kidney, gonad and foot) and different growth phases (6-months old and 2-years old) showed that it was expressed in various tissues and different growth phases. Silencing of the GHITM gene by RNAi (RNA interference) experiments revealed that the GHITM gene possibly plays a role in inhibiting apoptosis through detecting the Caspase (Cysteine-requiring Aspartate Protease)-3 activity. In addition, the aperture width and body whorl length of the snail was significantly affected by RNAi, suggesting that this gene plays a significant role in promoting the growth of the organism. Conclusions These results demonstrated that the GHITM gene was involved in apoptosis and growth in golden apple snail.

The display of recombinant proteins on the surfaces of bacteria is a research topic with many possible biotechnology applications—among which, the choice of host cell and anchoring motif is the key for efficient display. Corynebacterium glutamicum is a promising host for surface display due to its natural advantages, while single screening methods and fewer anchor proteins restrict its application. In this study, the subcellular localization (SCL) predictor LocateP and tied-mixture hidden Markov models were used to analyze all five known endogenous anchor proteins of C. glutamicum and test the accuracy of the predictions. Using these two tools, the SCLs of all proteins encoded by the genome of C. glutamicum 13032 were predicted, and 14 potential anchor proteins were screened. Compared with the positive controls NCgl1221 and NCgl1337, three anchoring proteins—NCgl1307, NCgl2775, and NCgl0717—performed better. This study also discussed the applicability of the anchor protein screening method used in this experiment to other bacteria.

In the genus Corynebacterium, AmtR is a key component of the nitrogen regulatory system, and it belongs to the TetR family of transcription regulators. There has been much research on AmtR structure, functions, and regulons in the type strain C. glutamicum ATCC 13032, but little research in other C. glutamicum strains. In this study, chromatin immunoprecipitation and massively parallel DNA sequencing (ChIP-seq) was performed to identify the AmtR regulon in C. glutamicum ATCC 14067. Ten peaks were obtained in the C. glutamicum ATCC 14067 genome including two new peaks related to three operons (RS_01910-RS_01915, RS_15995, and RS_16000). The interactions between AmtR and the promoter regions of the three operons were confirmed by electrophoretic mobility shift assays (EMSAs). The RS_01910, RS_01915, RS_15995, and RS_16000 are not present in the type strain C. glutamicum ATCC 13032. Sequence analysis indicates that RS_01910, RS_01915, RS_15995, and RS_16000, are related to the degradation of creatine and creatinine; RS_01910 may encode a protein related to creatine transport. The genes RS_01910, RS_01915, RS_15995, and RS_16000 were given the names crnA, creT, cshA, and hyuB, respectively. Real-time quantitative PCR (RT-qPCR) analysis and sfGFP (superfolder green fluorescent protein) analysis reveal that AmtR directly and negatively regulates the transcription and expression of crnA, creT, cshA, and hyuB. A growth test shows that C. glutamicum ATCC 14067 can use creatine or creatinine as a sole nitrogen source. In comparison, a creT deletion mutant strain is able to grow on creatinine but loses the ability to grow on creatine. This study provides the first genome-wide captures of the dynamics of in vivo AmtR binding events and the regulatory network they define. These elements provide more options for synthetic biology by extending the scope of the AmtR regulon.

Aquaporins (AQPs) are integral membrane proteins that facilitate the transport of water and small solutes across cell membranes. These proteins are vital for maintaining water homeostasis in living organisms. In mammals, thirteen aquaporins have been characterized, but in crustaceans, especially penaeid shrimp, the diversity, structure, and substrate specificity of these membrane channel proteins are largely unknown. We here presented the three types of AQPs from Litopenaeus vannamei based on genome and transcriptome sequencing. Phylogenetic analysis showed that each AQP separately represented members of aquaglyceroporins, classical aquaporins, and unorthodox aquaporins, thus they were named as LvAQP3, LvAQP4, and LvAQP11. The LvAqp4 was mostly expressed in hepatopancreas, stomach, and gill, meanwhile LvAqp3 and LvAqp11 were separately predominantly expressed in intestine and muscle, respectively. To investigate possible roles of aquaporins in osmoregulation, mRNA expression changes in mainly expressed tissues were analyzed after acute exposure or long-term acclimation to different salinities. The results revealed that the expression levels of aquaporins genes were significantly decreased in most tissues (except hepatopancreas) under salinity stress, though the expression patterns were variable among isoforms and tissues. Moreover, comparative transcriptome analysis indicated the combination roles of aquaglyceroporin and amino acid metabolism related genes and pathways in response to acute salinity changes in the intestine. This study opened new windows for future investigations and provided new insights into the role of aquaporins in osmoregulation in L. vannamei.

Summary: The maintenance of healthy and resilient gut microbiota is critical for the life quality and healthspan of the elderly. Fecal microbiota transplantation (FMT) has been increasingly used to restore healthy gut microbiota. We systemically studied the establishment and resilience of transplanted microbiota after autologous versus heterologous FMT in aged recipients. Gut microbiota of aged mice (20 months old) failed to restore their original diversity and composition over 8 weeks via spontaneous recovery after antibiotics treatment; in contrast, FMT using either autologous or heterologous (2 months old from a different vendor) donors facilitated the recovery successfully, established donor-like microbiota states, and affected host gene expression profile. Furthermore, the transplanted microbiota established by heterologous FMT is not resilient during chemical-induced colonic inflammation, in contrast to that of autologous FMT. Our findings highlighted the need to monitor the long-term stability of transplanted gut microbiota and to perform multiple FMT when necessary.

Drawing the engineering sections automatically and efficiently is significant for the investigation results of geotechnical engineering to provide the scientific and detailed geological basis for urban planning and construction, but it is still difficult to draw the engineering geological sections automatically without manual edit. A method, taking the engineering strata in Quaternary loose sedimentary as the research object, was proposed to automatically draw multiscale engineering geological sections of engineering layers including lenses and strata pinch-out based on the investigation results and borehole data of geotechnical (geological) engineering. Firstly, the spatial information of the top and bottom boundaries of any borehole layer were extracted, and then based on the stratigraphical column, the borehole layer was studied by a step-by-step coarsen from the finest stratigraphical column to the coarsest stratigraphical column, and the occupation relationship among layers was distinguished; secondly, from the coarsest stratigraphical column to the finest level stratigraphical column step-by-step and taking the radial basis function (RBF) interpolation as an example, top and bottom boundaries were interpolated, respectively, by following the order of current stratigraphical column; next, topological relationship among engineering layers was processed according to contact relationship of strata, and strata boundaries with 0 thickness were deleted; and finally, auxiliary information such as scaler and legend were added in section to complete the drawing of multiscale sections. Studies of one site case and one region case demonstrate that the method can perfectly and automatically draw the engineering geological section of engineering layers including lenses and strata pinch-out.

Corynebacterium glutamicum is regarded as an industrially important microbial cell factory and is widely used to produce various value-added chemicals. Because of the importance of C. glutamicum applications, current research is increasingly focusing on developing C. glutamicum synthetic biology platforms. Because of its ability to condense with adipic acid to synthesize the industrial plastic nylon-46, putrescine is an important platform compound of industrial interest. Developing a high-throughput putrescine biosensor can aid in accelerating the design–build–test cycle of cell factories (production strains) to achieve high putrescine-generating strain production in C. glutamicum. This study developed a putrescine-specific biosensor (pSenPuuR) in C. glutamicum using Escherichia coli-derived transcriptional factor PuuR. The response characteristics of the biosensor to putrescine were further improved by optimizing the genetic components of pSenPuuR, such as the response promoter, reporter protein, and promoter for controlling PuuR expression. According to the findings of the study, pSenPuuR has the potential to be used to assess putrescine production in C. glutamicum and is suitable for high-throughput genetic variant screening.

Background: There has been a recent appreciation that some metabolic enzymes can profoundly influence the nature of the immune response produced in macrophages. However, the role of mitochondrial phosphoenolpyruvate carboxykinase (PCK2) in immune response remains unknown. This study aims to investigate the role of PCK2 in lipopolysaccharides (LPS)-induced activation in Kupffer cells.Methods: Inflammatory cytokines were determined by real-time quantitative reverse transcription-polymerase chain action (qRT-PCR) and flow cytometric analysis using a cytometric bead array. Western blotting and immunofluorescence staining were used to determine PCK2 expression and subcellular distribution under confocal laser microscopy. qRT-PCR, flow cytometry, and high-performance liquid chromatography (HPLC) were used to determine mitochondrial function. Pharmacological inhibition, knockdown, and overexpression of PCK2 were used to confirm its function. Co-immunoprecipitation (Co-IP) was performed to determine MAPK/NF-κB phosphorylation.Results: Inflammatory response was significantly increased in LPS-treated mice and Kupffer cells. During the inflammatory process, the protein level of PCK2 was significantly upregulated in Kupffer cells. Interestingly, the localization of PCK2 was mainly in cytosol rather than mitochondria after LPS stimulation. Gain-of-function and loss-of-function analyses found that PCK2 overexpression significantly upregulated the levels of inflammation markers, whereas PCK2 knockdown or inhibition significantly mitigated LPS-induced inflammatory response in Kupffer cells. Furthermore, PCK2 promoted protein phosphorylation of NF-κB and AKT/MAPK, the major signaling pathways, controlling inflammatory cascade activation.Conclusion: We identified a novel function of PCK2 in mediating LPS-induced inflammation and provided mechanistic insights into the regulation of inflammatory response in Kupffer cells. Therefore, PCK2 may serve as a novel therapeutic target for the regulation of Kupffer cells-mediated inflammatory responses.

ObjectivesThis study aims to evaluate digital mammography (DM), digital breast tomosynthesis (DBT), dynamic contrast-enhanced (DCE), and diffusion-weighted (DW) MRI, individually and combined, for the values in the diagnosis of breast cancer, and propose a visualized clinical-radiomics nomogram for potential clinical uses.MethodsA total of 120 patients were enrolled between September 2017 and July 2018, all underwent preoperative DM, DBT, DCE, and DWI scans. Radiomics features were extracted and selected using the least absolute shrinkage and selection operator (LASSO) regression. A radiomics nomogram was constructed integrating the radiomics signature and important clinical predictors, and assessed with the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA).ResultsThe radiomics signature derived from DBT plus DM generated a lower area under the ROC curve (AUC) and sensitivity, but a higher specificity compared with that from DCE plus DWI. The nomogram integrating the combined radiomics signature, age, and menstruation status achieved the best diagnostic performance in the training (AUCs, nomogram vs. combined radiomics signature vs. clinical model, 0.975 vs. 0.964 vs. 0.782) and validation (AUCs, nomogram vs. combined radiomics signature vs. clinical model, 0.983 vs. 0.978 vs. 0.680) cohorts. DCA confirmed the potential clinical usefulness of the nomogram.ConclusionsThe DBT plus DM provided a lower AUC and sensitivity, but a higher specificity than DCE plus DWI for detecting breast cancer. The proposed clinical-radiomics nomogram has diagnostic advantages over each modality, and can be considered as an efficient tool for breast cancer screening.

In this study, after 30 days of long-time exposure to high salinity (36‰ and 44‰), we explored the combined effects of high salinity and ammonia nitrogen (15 mg/L ammonia-N) stresses on the energy metabolism, immune response, oxidative resistance, and ammonia metabolism of Litopenaeus vannamei during the 48 h of ammonia exposure. The results showed increased glucose levels in the hemolymph and accelerated anaerobic metabolism with higher lactate levels in the muscle of all experimental groups. The combined action of the stressors decreased the non-specific immune responses of shrimp by decreasing the activities of alkaline phosphatase (AKP) and acid phosphatase (ACP), and the expression levels of phenol oxidase (PO), immune deficiency (IMD), and arginine kinase (AK) genes at the end of the exposure. In addition, the antioxidant defense system that L. vannamei employs via the total antioxidant capacity (T-AOC), superoxide dismutase (T-SOD) and catalase (CAT) enzymes, and the heat shock protein70 (HSP70) and thioredoxin (TRX) proteins was affected by exposure to high salinity and amminoa-N when exposed to ammonia-N with different high salinity stress. Furthermore, the expression levels of ammonia metabolism-related genes glutamate dehydrogenase (GDH) and glutamine synthetase (GS) were initially significantly upregulated and then declined in the hepatopancreas of the high salinity treatment groups. The study revealed that variations in high salinity and ammonia beyond the optimal range significantly influence glycometabolism, non-specific immunity, antioxidation, and ammonia metabolism, and that these two factors can have significant synergistic effects.

Background/Aims: Although red blood cells (RBCs) transfusions can be lifesaving, they are not without risk. RBCs storage is associated with the abnormal metabolism of glutathione (GSH), which may increase the risk of the oxidative damage of RBCs after transfusion. The responsible mechanisms remain unknown. Methods: We determined the L-cysteine efflux and influx by evaluating the changes of free -SH concentrations in stored RBCs. The glutamate cysteine ligase (GCL) activities and protein content in stored RBCs was determined by fluorescence assay and western blotting. In addition, the glucose metabolism enzyme activity of RBCs was measured by spectrophotometric assay under in vitro incubation conditions. Results: We found that both L-cysteine transport and GCL activity significantly declined, thereby inducing the dysfunction of GSH synthesis during blood storage, which could be attenuated by ATP supplement and DTT treatment. In addition, the glycometabolic enzyme (G6PDH, HK, PK and LDH) activity significantly decreased after 6 weeks storage. Oxidant stress-induced dysfunction in glucose metabolism was the driving force for decreased GSH synthesis during storage. Conclusion: These experimental findings reflect an underlying molecular mechanism that oxidant stress induced glucose metabolism dysfunction contribute to decreased GSH synthesis in stored RBCs.

Drought is one of the major abiotic stress factors limiting peanut production. It causes the loss of pod yield during the pod formation stage. Here, one previously identified drought-tolerant cultivar, “L422” of peanut, was stressed by drought (35 ± 5%) at pod formation stage for 5, 7, and 9 days. To analyze the drought effects on peanut, we conducted physiological and transcriptome analysis in leaves under well-watered (CK1, CK2, and CK3) and drought-stress conditions (T1, T2, and T3). By transcriptome analysis, 3,586, 6,730, and 8,054 differentially expressed genes (DEGs) were identified in “L422” at 5 days (CK1 vs T1), 7 days (CK2 vs T2), and 9 days (CK3 vs T3) of drought stress, respectively, and 2,846 genes were common DEGs among the three-time points. Furthermore, the result of weighted gene co-expression network analysis (WGCNA) revealed one significant module that was closely correlated between drought stress and physiological data. A total of 1,313 significantly up-/down-regulated genes, including 61 transcription factors, were identified in the module at three-time points throughout the drought stress stage. Additionally, six vital metabolic pathways, namely, “MAPK signaling pathway-plant,” “flavonoid biosynthesis,” “starch and sucrose metabolism,” “phenylpropanoid biosynthesis,” “glutathione metabolism,” and “plant hormone signal transduction” were enriched in “L422” under severe drought stress. Nine genes responding to drought tolerance were selected for quantitative real-time PCR (qRT-PCR) verification and the results agreed with transcriptional profile data, which reveals the reliability and accuracy of transcriptome data. Taken together, these findings could lead to a better understanding of drought tolerance and facilitate the breeding of drought-resistant peanut cultivars.

To manipulate nasal microbiota for respiratory health, we need to better understand how this microbial community is assembled and maintained. Previous work has demonstrated that the pH in the nasal passage experiences temporal fluctuations. Yet, the impact of such pH fluctuations on nasal microbiota is not fully understood. Here, we examine how temporal fluctuations in pH might affect the coexistence of nasal bacteria in in silico communities. We take advantage of the cultivability of nasal bacteria to experimentally assess their responses to pH and the presence of other species. Based on experimentally observed responses, we formulate a mathematical model to numerically investigate the impact of temporal pH fluctuations on species coexistence. We assemble in silico nasal communities using up to 20 strains that resemble the isolates that we have experimentally characterized. We then subject these in silico communities to pH fluctuations and assess how the community composition and coexistence is impacted. Using this model, we then simulate pH fluctuations—varying in amplitude or frequency—to identify conditions that best support species coexistence. We find that the composition of nasal communities is generally robust against pH fluctuations within the expected range of amplitudes and frequencies. Our results also show that cooperative communities and communities with lower niche overlap have significantly lower composition deviations when exposed to temporal pH fluctuations. Overall, our data suggest that nasal microbiota could be robust against environmental fluctuations.

An efficient intelligent fault diagnosis model was proposed in this paper to timely and accurately offer a dependable basis for identifying the rolling bearing condition in the actual production application. The model is mainly based on an improved butterfly optimizer algorithm- (BOA-) optimized kernel extreme learning machine (KELM) model. Firstly, the roller bearing’s vibration signals in the four states that contain normal state, outer race failure, inner race failure, and rolling ball failure are decomposed into several intrinsic mode functions (IMFs) using the complete ensemble empirical mode decomposition based on adaptive noise (CEEMDAN). Then, the amplitude energy entropies of IMFs are designated as the features of the rolling bearing. In order to eliminate redundant features, a random forest was used to receive the contributions of features to the accuracy of results, and subsets of features were set up by removing one feature in the descending order, using the classification accuracy of the SBOA-KELM model as the criterion to obtain the optimal feature subset. The salp swarm algorithm (SSA) was introduced to BOA to improve optimization ability, obtain optimal KELM parameters, and avoid the BOA deteriorating into local optimization. Finally, an optimal SBOA-KELM model was constructed for the identification of rolling bearings. In the experiment, SBOA was validated against ten other competitive optimization algorithms on 30 IEEE CEC2017 benchmark functions. The experimental results validated that the SBOA was evident over existing algorithms for most function problems. SBOA-KELM employed for diagnosing the fault diagnosis of rolling bearings obtained improved classification performance and higher stability. Therefore, the proposed SBOA-KELM model can be effectively used to diagnose faults of rolling bearings.

Objective: The present study aimed to explore the function of sirtuin 2 (SIRT2) on cell proliferation, apoptosis, rat sarcoma virus (RAS)/ extracellular signal-regulated kinase (ERK) pathway in endometrial cancer (EC). Methods: SIRT2 expression in human EC cell lines and human endometrial (uterine) epithelial cell (HEEC) line was assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. SIRT2 knock-down and control knock-down plasmids were transfected into HEC1A cells, respectively; SIRT2 overexpression and control overexpression plasmids were transfected into Ishikawa cells, respectively. After transfection, SIRT2, HRas proto-oncogene, GTPase (HRAS) expressions were evaluated by RT-qPCR and western blot. ERK and phosphorylated ERK (pERK) expressions were evaluated by western blot. Meanwhile, cell proliferation and cell apoptosis were measured. Results: Compared to normal HEEC cell line, SIRT2 mRNA and protein expressions were increased in most human EC cell lines (including HEC1A, RL952 and AN3CA), while were similar in Ishikawa cell line. In HEC1A cells, SIRT2 knock-down decreased cell proliferation but increased apoptosis. In Ishikawa cells, SIRT2 overexpression induced cell proliferation but inhibited apoptosis. For RAS/ERK pathway, SIRT2 knock-down reduced HRAS and inactivated pERK in HEC1A cells, whereas SIRT2 overexpression increased HRAS and activated pERK in Ishikawa cells, suggesting that SIRT2 was implicated in the regulation of RAS/ERK pathway in EC cells. Conclusion: SIRT2 contributes to the EC tumorigenesis, which appears as a potential therapeutic target.

Δ6 fatty acyl desaturase (Δ6Fads2) is regarded as the first rate-limiting desaturase that catalyzes the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFA) from 18-carbon fatty acid in vertebrates, but the underlying regulatory mechanism of fads2 has not been comprehensively understood. This study aimed to investigate the regulation role of fads2 subjected to fatty acid in large yellow croaker and rainbow trout. In vivo, large yellow croaker and rainbow trout were fed a fish oil (FO) diet, a soybean oil (SO) diet or a linseed oil (LO) diet for 10 weeks. The results show that LO and SO can significantly increase fads2 expression (p < 0.05). In vitro experiments were conducted in HEK293T cells or primary hepatocytes to determine the transcriptional regulation of fads2. The results show that CCAAT/enhancer-binding protein α (C/EBPα) can up-regulate fads2 expression. GATA binding protein 3 (GATA3) can up-regulate fads2 expression in rainbow trout but showed opposite effect in large yellow croaker. Furthermore, C/EBPα protein levels were significantly increased by LO and SO (p < 0.05), gata3 expression was increased in rainbow trout by LO but decreased in large yellow croaker by LO and SO. In conclusion, we revealed that FO replaced by LO and SO increased fads2 expression through a C/EBPα and GATA3 dependent mechanism in large yellow croaker and rainbow trout. This study might provide critical insights into the regulatory mechanisms of fads2 expression and LC-PUFA biosynthesis.