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Although positive social relationships are assumed to relate to lower levels of chronic systemic inflammation, the empirical evidence on this association is mixed. This study examines whether perceived social support-giving (i.e., the belief that one can be available to give social support to others, henceforward referred to as perceived support-giving) moderates associations between social relationships and inflammation using data from the longitudinal follow-up of the National Survey of Midlife Development in the U.S. (MIDUS II). Middle-aged adults (N = 1054) completed self-report questionnaires on social integration, perceived support-availability from others, positive relations with others, perceived support-giving, socio-demographic information, and health-related information and provided blood samples for measurement of interleukin-6 (IL-6) as a marker of systemic inflammation. The results showed that perceived support-giving moderated the associations between IL-6 and indicators of positive social relationships, including social integration, perceived support-availability, and positive relations with others. Indicators of positive social relationships were associated with lower IL-6 among individuals higher, but not lower, in perceived support-giving. The moderating effects of perceived support-giving held after adjusting for socio-demographic and health-related covariates. Therefore, positive social relationships are associated with lower IL-6 only for individuals who believe they can give more support in those relationships. In addition, preliminary evidence indicated that the moderating effects of perceived support-giving might be further qualified by gender, being significant only in women.

Multiple myeloma, a plasma cell malignancy in the bone marrow, remains largely incurable with currently available therapeutics. In this study, we discovered that the activated leukocyte cell adhesion molecule (ALCAM) interacted with epidermal growth factor receptor (EGFR), and regulated myelomagenesis. ALCAM was a negative regulator of myeloma clonogenicity. ALCAM expression was positively correlated with patients’ survival. ALCAM-knockdown myeloma cells displayed enhanced colony formation in the presence of bone marrow stromal cells (BMSCs). BMSCs supported myeloma colony formation by secreted epidermal growth factor (EGF), which bound with its receptor (EGFR) on myeloma cells and activated Mek/Erk cell signaling, PI3K/Akt cell signaling, and hedgehog pathway. ALCAM could also bind with EGFR, block EGF from binding to EGFR, and abolish EGFR-initiated cell signaling. Hence, our study identifies ALCAM as a novel negative regulator of myeloma pathogenesis.

Objective To explore the main causes of hypertrophied ligamentum flavum (HLF) and the possibility of using bipedal standing mouse model to simulate the pathological changes in human HLF. Methods Thirty‐two 8‐week‐old C57BL/6 male mice were randomly assigned to the experimental group (n = 16) and control group (n = 16). In the experimental group, mice were induced to adopt a bipedal standing posture by their hydrophobia. The experimental mice were maintained bipedal standing for 8 h a day with an interval of 2 h to consume food and water. The control mice were placed in a similar environment without bipedal standing. Eight 18‐month‐old C57BL/6 male mice were compared to evaluate the LF degeneration due to aging factor. Three‐dimensional (3D) reconstruction and finite element models were carried out to analyze the stress and strain distribution of the mouse LF in sprawling and bipedal standing postures. Hematoxylin and Eosin (HE), Verhoeff‐Van Gieson (VVG), and immunohistochemistry (IHC) staining were used to evaluate the LF degeneration of mice and humans. RT‐qPCR and immunofluorescence analysis were used to evaluate the expressions of fibrosis‐related factors and inflammatory cytokines of COL1A1, COL3A1, α‐SMA, MMP2, IL‐1β, and COX‐2. Results The von Mises stress (8.85 × 10−2 MPa) and maximum principal strain (6.64 × 10−1) in LF were increased 4944 and 7703 times, respectively, in bipedal standing mice. HE staining showed that the mouse LF area was greater in the bipedal standing 10‐week‐old group ([10.01 ± 2.93] × 104 μm2) than that in the control group ([3.76 ± 1.87] × 104 μm2) and 18‐month‐old aged group ([6.09 ± 2.70] × 104 μm2). VVG staining showed that the HLF of mice (3.23 ± 0.58) and humans (2.23 ± 0.31) had a similar loss of elastic fibers and an increase in collagen fibers. The cell density was higher during the process of HLF in mice (39.63 ± 4.81) and humans (23.25 ± 2.05). IHC staining showed that the number of α‐SMA positive cells were significantly increased in HLF of mice (1.63 ± 0.74) and humans (3.50 ± 1.85). The expressions of inflammatory cytokines and fibrosis‐related factors of COL1A1, COL3A1, α‐SMA, MMP2, IL‐1β, and COX‐2 were consistently higher in bipedal standing group than the control group. Conclusion Our study suggests that 3D finite element models can help analyze the abnormal stress and strain distributions of LF in modeling mice. Mechanical stress is the main cause of hypertrophied ligamentum flavum compared to aging. The bipedal standing mice model can reflect the pathological characteristics of human HLF. The bipedal standing mice model can provide a standardized condition to elucidate the molecular mechanisms of mechanical stress‐induced HLF in vivo., Mice were induced to adopt a bipedal standing posture by their hydrophobia. Finite element analysis was carried out to analyze the stress and strain distribution of the ligamentum flavum (LF) in different postures. The von Mises stress and Maximum Principal strain in LF were increased 4944 and 7703 times, respectively, in bipedal standing mice. Our study suggests that mechanical stress is the main cause of HLF compared to aging, and that bipedal standing mice can be used to study the mechanism of HLF in vivo.

Background To combat the coronavirus disease 2019 (COVID-19) pandemic, nonpharmaceutical interventions (NPIs) were implemented worldwide, which impacted a broad spectrum of acute respiratory infections (ARIs). Methods Etiologically diagnostic data from 142 559 cases with ARIs, who were tested for 8 viral pathogens (influenza virus [IFV], respiratory syncytial virus [RSV], human parainfluenza virus [HPIV], human adenovirus [HAdV], human metapneumovirus [HMPV], human coronavirus [HCoV], human bocavirus [HBoV], and human rhinovirus [HRV]) between 2012 and 2021, were analyzed to assess the changes in respiratory infections in China during the first COVID-19 pandemic year compared with pre-pandemic years. Results Test-positive rates of all respiratory viruses decreased during 2020, compared to the average levels during 2012–2019, with changes ranging from −17.2% for RSV to −87.6% for IFV. Sharp decreases mostly occurred between February and August when massive NPIs remained active, although HRV rebounded to the historical level during the summer. While IFV and HMPV were consistently suppressed year-round, RSV, HPIV, HCoV, HRV, and HBoV resurged and went beyond historical levels during September 2020–January 2021, after NPIs were largely relaxed and schools reopened. Resurgence was more prominent among children Conclusions Activities of respiratory viral infections were reduced substantially in the early phases of the COVID-19 pandemic, and massive NPIs were likely the main driver. Lifting of NPIs can lead to resurgence of viral infections, particularly in children.

The cortico–basal ganglia–thalamo–cortical loop is one of the fundamental network motifs in the brain. Revealing its structural and functional organization is critical to understanding cognition, sensorimotor behaviour, and the natural history of many neurological and neuropsychiatric disorders. Classically, this network is conceptualized to contain three information channels: motor, limbic and associative1–4. Yet this three-channel view cannot explain the myriad functions of the basal ganglia. We previously subdivided the dorsal striatum into 29 functional domains on the basis of the topography of inputs from the entire cortex5. Here we map the multi-synaptic output pathways of these striatal domains through the globus pallidus external part (GPe), substantia nigra reticular part (SNr), thalamic nuclei and cortex. Accordingly, we identify 14 SNr and 36 GPe domains and a direct cortico-SNr projection. The striatonigral direct pathway displays a greater convergence of striatal inputs than the more parallel striatopallidal indirect pathway, although direct and indirect pathways originating from the same striatal domain ultimately converge onto the same postsynaptic SNr neurons. Following the SNr outputs, we delineate six domains in the parafascicular and ventromedial thalamic nuclei. Subsequently, we identify six parallel cortico–basal ganglia–thalamic subnetworks that sequentially transduce specific subsets of cortical information through every elemental node of the cortico– basal ganglia–thalamic loop. Thalamic domains relay this output back to the originating corticostriatal neurons of each subnetwork in a bona fide closed loop., Mesoscale connectomic mapping of the cortico–basal ganglia–thalamic network reveals key architectural and information processing features.

Tumor microenvironment (TME) is a complex and dynamic evolving environment which facilitates tumor proliferation and progression. We aimed at investigating the characteristics of tumor microenvironment and its prognostic value in gliomas. Transcriptome data of 702 glioma samples from The Cancer Genome Atlas were included as training dataset, while 325 samples from Chinese Glioma Genome Atlas database and 268 samples from GSE16011 database were used to validate. We found that the infiltration of stromal and immune cell varied in gliomas of different grades and pathological types, and was associated with poor prognosis. Based on the gene expression profile, we constructed a TME-related signature (TMERS), which was closely related to clinical features and genomic variation of gliomas. In TMERS-high group, specific gene mutations and increased copy number alternations were observed. Kaplan-Meier survival and Cox regression analysis showed that TMERS was an independent prognostic indicator. Then we developed a nomogram prognostic model to predict 1-year, 3-year and 5-year survival of patients. Functional analysis confirmed that TMERS could reflect the status of glioma microenvironment, and immunological analysis showed that macrophages were significantly enriched in the TMERS-high group. We established a novel TME-related signature for predicting prognosis and provided new insights into immunotherapy.

KIFs have been reported to play a critical role in a variety of tumors, and KIF20B is a protein in KFIs. In this research, KIF20B was highly expressed in the GEO database and our hospital’s data, and high expression of KIF20B suggested poor prognosis. We detect the expression of KIF20B in pancreatic cancer and adjacent normal tissues using immunohistochemistry. Knockdown of KIF20B in pancreatic cancer cell lines, PANC-1 and BxPC-3 cells, inhibited cell proliferation which are detected by colony formation assays, CCK8, and western bolt of Ki-67 and PCNA. Xenograft assay showed a similar result in vivo. KIF20B is a potential therapeutic target in pancreatic cancer.

Introduction Septic cardiomyopathy is a common complication of sepsis with high morbidity and mortality, but lacks specific therapy. This study aimed to reveal the role of circTLK1 and its potential mechanisms in septic cardiomyopathy. Materials and Methods The in vitro and in vivo models of septic cardiomyopathy were established. Cell viability and apoptosis were detected by CCK8, TUNEL and flow cytometry, respectively. LDH, CK, SOD, MDA, ATP, 8‐OHdG, NAD+/NADH ratio, ROS level, mitochondrial membrane potential and cytochrome C distribution were evaluated using commercial kits. qRT‐PCR and western blotting were performed to detect RNA and protein levels. Mitochondrial DNA (mtDNA) copy number and transcription were assessed by quantitative PCR. Dual‐luciferase assay, RNA immunoprecipitation and co‐immunoprecipitation were performed to verify the interaction between circTLK1/PARP1 and miR‐17‐5p. Results CircTLK1, PARP1 and HMGB1 were up‐regulated in the in vitro and in vivo models of septic cardiomyopathy. CircTLK1 inhibition restrained LPS‐induced up‐regulation of PARP1 and HMGB1. Moreover, circTLK1 knockdown repressed sepsis‐induced mtDNA oxidative damage, mitochondrial dysfunction and consequent cardiomyocyte apoptosis by inhibiting PARP1/HMGB1 axis in vitro and in vivo. In addition, circTLK1 enhanced PARP1 expression via sponging miR‐17‐5p. Inhibition of miR‐17‐5p abolished the protective effects of circTLK1 silencing on oxidative mtDNA damage and cardiomyocyte apoptosis. Conclusion CircTLK1 sponged miR‐17‐5p to aggravate mtDNA oxidative damage, mitochondrial dysfunction and cardiomyocyte apoptosis via activating PARP1/HMGB1 axis during sepsis, indicating that circTLK1 may be a putative therapeutic target for septic cardiomyopathy.

The role of bone marrow stem cell (BMSC)-derived exosomal microRNA-1257 (miR-1257) in ovarian cancer (OC) was explored in this research. BMSCs were cultured and the exosomes (exo) were isolated from BMSCs. OC cells were co-cultured with BMSC-exo or BMSC-exo transfected with miR-1257 inhibitor. Cell apoptosis was analyzed by flow cytometry, cell proliferative ability was tested by MTT assay, and apoptotic protein Bax and anti-apoptotic proteins Bcl-2 were assessed by Western blot. MiR-1257 was downregulated in OC cells and tissues, which was closely related to the poor prognosis. The co-culture of BMSC-exo with OC cells upregulated the transcription level of miR-1257, inhibited cell proliferation, and enhanced apoptosis. After silencing of miR-1257, the effects of BMSC-exo on apoptosis and proliferation were eliminated, Bax expression increased, and Bcl-2 level decreased. MiR-1257 from BMSC-exo inhibits the progression of OC.

In order to assess the effect of enhancement release of chum salmon (Oncorhynchus keta), otolith strontium (Sr) marking method was used to tag chum salmon released in Tangwang River in 2016. The homing chum salmon were detected and the samples were collected in Tangwang River, Ussuri River and Suifen River in the autumn of 2018. The samples were analyzed by examining Sr and calcium (Ca) fingerprints in the otolith using electron probe microanalysis. The results suggested that two samples collected in Tangwang River had the marking ring near the core of otolith where the Sr concentration and Sr/Ca ratio were significantly higher than comparative samples. Proving that the two fish belonged to the released population in Tangwang River in 2016. This article indicated the success of the enhancement release of chum salmon from the Tangwang River for the first time and also confirmed the validity of Sr marking in enhancement release of fishes.

BACKGROUND: To investigate the differences in treatment effect sizes between progression-free survival (PFS) and overall survival (OS) in advanced non-small cell lung cancer (NSCLC) treated with programmed cell death 1 (PD-1) and its ligand (PD-L1) blockade-based treatments. METHODS: The differences in treatment effect sizes between PFS and OS were assessed by using a ratio of hazard ratio (rHR): the HR for PFS to that for OS. A random effects meta-analysis across trials was conducted to generate the combined rHR. We also evaluated the feasibility of adopting PFS as the surrogate of OS by using Spearman correlation coefficient (R) between logHR(PFS) and logHR(OS). RESULTS: A total of 27 randomized controlled trials (RCTs) with 15,590 patients were included. Treatment effect sizes were comparable, on average, for OS than for PFS (pooled rHR, 0.98; 95% CI, 0.91 to 1.08). Subgroup analysis revealed that treatment effect sizes were greater for OS than for PFS for trials with immunotherapy as second or above line treatment (rHR, 1.17; 95% CI, 1.06 to 1.29), while the differences were greater for PFS than for OS for trials with immunotherapy as first-line setting (rHR, 0.91; 95% CI, 0.84 to 0.99; P(interaction)

Background Noncoding RNAs such as circular RNAs (circRNAs) are abundant in the human body and influence the occurrence and development of various diseases. However, the biological functions of circRNAs in colorectal cancer (CRC) are largely unknown. Methods RT-qPCR was used to detect the expression of circRNAs and mRNA in CRC cells and tissues. Fluorescence in situ hybridization (FISH) was used to analyze the location of circSPARC. Function-based experiments were performed using circSPARC knockdown and overexpression cell lines in vitro and in vivo, including CCK8, colony formation, transwell and metastasis models. Mechanistically, luciferase reporter assay, western blots, RNA immunoprecipitation (RIP), Chromatin isolation by RNA purification (ChIRP) and immunohistochemical stainings were performed. Results CircSPARC was upregulated in both the tissues and plasma of CRC patients. High expression of circSPARC was associated with advanced TNM stage, lymph node metastases, and poor survival. Silencing circSPARC inhibited CRC cell migration and proliferation in vitro and vivo. Mechanistically, circSPARC sponged miR-485-3p to upregulate JAK2 expression and ultimately contribute to the accumulation of phosphorylated (p)-STAT3. Besides, circSPARC recruited FUS, which facilitated the nuclear translocation of p-STAT3. Conclusions These findings suggest that circSPARC might serve as a potential diagnostic and prognostic biomarker and a therapeutic target for CRC treatment by regulating JAK2/STAT3 pathway.

The STimulator of INterferon Genes (STING) protein is a cornerstone of the human immune response. Its activation by cGAMP upon the presence of cytosolic DNA stimulates the production of type I interferons and inflammatory cytokines which are crucial for protecting cells from infections. STING signaling pathway can also influence both tumor-suppressive and tumor-promoting mechanisms, rendering it an appealing target for drug design. In the human population, several STING variants exist and exhibit dramatic differences in their activity, impacting the efficiency of the host defense against infections. Understanding the differential molecular mechanisms exhibited by these variants is of utmost importance notably towards personalized medicine treatments against diseases such as viral infections (COVID-19, Dengue…), cancers, or auto-inflammatory diseases. Owing to micro-seconds scale molecular modeling simulations and post-processing by contacts analysis and Machine Learning techniques, we reveal the dynamical behavior of four STING variants (wild type, G230A, R293Q, and G230A-R293Q) and we rationalize the variability of efficiency observed experimentally. Our results show that the decrease of STING activity is linked to a stiffening of key-structural features of the binding cavity, together with changes of the interaction patterns within the protein.

Tooth-related diseases and tooth loss are widespread and are a major public health issue. The loss of teeth can affect chewing, speech, appearance and even psychology. Therefore, the science of tooth regeneration has emerged, and attention has focused on tooth regeneration based on the principles of tooth development and stem cells combined with tissue engineering technology. As undifferentiated stem cells in normal tooth tissues, dental mesenchymal stem cells (DMSCs), which are a desirable source of autologous stem cells, play a significant role in tooth regeneration. Researchers hope to reconstruct the complete tooth tissues with normal functions and vascularization by utilizing the odontogenic differentiation potential of DMSCs. Moreover, DMSCs also have the ability to differentiate towards cells of other tissue types due to their multipotency. This review focuses on the multipotential capacity of DMSCs to differentiate into various tissues, such as bone, cartilage, tendon, vessels, neural tissues, muscle-like tissues, hepatic-like tissues, eye tissues and glands and the influence of various regulatory factors, such as non-coding RNAs, signaling pathways, inflammation, aging and exosomes, on the odontogenic/osteogenic differentiation of DMSCs in tooth regeneration. The application of DMSCs in regenerative medicine and tissue engineering will be improved if the differentiation characteristics of DMSCs can be fully utilized, and the factors that regulate their differentiation can be well controlled.

Background Glucocorticoid-induced osteoporosis (GIOP) is the most common secondary osteoporosis. Patients with GIOP are susceptible to fractures and the subsequent delayed bone union or nonunion. Thus, effective drugs and targets need to be explored. In this regard, the present study aims to reveal the possible mechanism of the anti-GIOP effect of all-trans retinoic acid (ATRA). Methods Bone morphogenetic protein 9 (BMP9)-transfected mesenchymal stem cells (MSCs) were used as an in vitro osteogenic model to deduce the relationship between ATRA and dexamethasone (DEX). The osteogenic markers runt-related transcription factor 2 (RUNX2), alkaline phosphatase (ALP), and osteopontin were detected using real-time quantitative polymerase chain reaction, Western blot, and immunofluorescent staining assay. ALP activities and matrix mineralization were evaluated using ALP staining and Alizarin Red S staining assay, respectively. The novel genes associated with ATRA and DEX were detected using RNA sequencing (RNA-seq). The binding of the protein–DNA complex was validated using chromatin immunoprecipitation (ChIP) assay. Rat GIOP models were constructed using intraperitoneal injection of dexamethasone at a dose of 1 mg/kg, while ATRA intragastric administration was applied to prevent and treat GIOP. These effects were evaluated based on the serum detection of the osteogenic markers osteocalcin and tartrate-resistant acid phosphatase 5b, histological staining, and micro-computed tomography analysis. Results ATRA enhanced BMP9-induced ALP, RUNX2 expressions, ALP activities, and matrix mineralization in mouse embryonic fibroblasts as well as C3H10T1/2 and C2C12 cells, while a high concentration of DEX attenuated these markers. When DEX was combined with ATRA, the latter reversed DEX-inhibited ALP activities and osteogenic markers. In vivo analysis showed that ATRA reversed DEX-inhibited bone volume, bone trabecular number, and thickness. During the reversal process of ATRA, the expression of retinoic acid receptor beta (RARβ) was elevated. RARβ inhibitor Le135 partly blocked the reversal effect of ATRA. Meanwhile, RNA-seq demonstrated that serine protease inhibitor, clade A, member 3N (Serpina3n) was remarkably upregulated by DEX but downregulated when combined with ATRA. Overexpression of Serpina3n attenuated ATRA-promoted osteogenic differentiation, whereas knockdown of Serpina3n blocked DEX-inhibited osteogenic differentiation. Furthermore, ChIP assay revealed that RARβ can regulate the expression of Serpina3n. Conclusion ATRA can reverse DEX-inhibited osteogenic differentiation both in vitro and in vivo, which may be closely related to the downregulation of DEX-promoted Serpina3n. Hence, ATRA may be viewed as a novel therapeutic agent, and Serpina3n may act as a new target for GIOP.

Long non-coding RNAs (lncRNAs) play key roles in various human cancers. We aimed to determine the key lncRNAs mediating colorectal cancer (CRC) progression. We identified some lncRNAs aberrantly expressed in CRC tissues by using lncRNA microarrays and demonstrated that SH3PXD2A-AS1 was one of the most highly overexpressed lncRNAs in CRC. We further aimed to explore the roles and possible molecular mechanisms of SH3PXD2A-AS1 in CRC. RNA ISH revealed that SH3PXD2A-AS1 was overexpressed in CRC compared with adjacent normal colon tissues and indicated poor prognosis in CRC. Functional analyses showed that SH3PXD2A-AS1 enhanced cell proliferation, angiogenesis, and metastasis. Mechanistically, SH3PXD2A-AS1 can directly interact with p53 protein and regulate p53-mediated gene transcription in CRC. We provided mechanistic insights into the regulation of SH3PXD2A-AS1 on p53-mediated gene transcription and suggested its potential as a new prognostic biomarker and target for the clinical management of CRC.

N6-methyladeosine (m6A) plays an important role in virus infection and replication. Bombyx mori nuclear polyhedrosis is caused by Bombyx mori nucleopolyhedrovirus (BmNPV) infection. Expression levels of m6A-modification-related genes after the infection of BmNPV were detected at first. Then, expression levels of BmNPV nucleocapsid protein gene VP39 and envelope fusion protein gene GP64 after knockdown of METTL3in vitro were quantified to identify the effect of m6A modification on BmNPV. BmNPV firstly infects the larval midgut in case of oral infection. Subsequently, to clarify the relationship between m6A modification and resistance of the silkworm to BmNPV, we detected the expression levels of m6A-modification-related genes invivo before and after infection of BmNPV. The results indicated that low METTL3 level hindered the proliferation of BmNPV to some extent, and silkworm strain with low METTL3 level showed stronger resistance against BmNPV. This study will accumulate new experimental data for elucidating the resistance mechanism of silkworm against BmNPV.

Intracellular accumulation of tau is a hallmark pathology in Alzheimer disease (AD) and the related tauopathies, thus targeting tau could be promising for drug development. Proteolysis Targeting Chimera (PROTAC) is a novel drug discovery strategy for selective protein degradation from within cells. Methods: A novel small-molecule PROTAC, named as C004019 with a molecular mass of 1,035.29 dalton, was designed to simultaneously recruite tau and E3-ligase (Vhl) and thus to selectively enhance ubiquitination and proteolysis of tau proteins. Western blotting, immunofluoresence and immunohistochemical staining were employed to verify the effects of C004019 in cell models (HEK293 and SH-SY5Y) and mouse models (hTau-transgenic and 3xTg-AD), respectively. The cognitive capacity of the mice was assessed by a suite of behavior experiments. Electrophysiology and Golgi staining were used to evaluate the synaptic plasticity. Results: C004019 induced a robust tau clearance via promoting its ubiquitination-proteasome-dependent proteolysis in HEK293 cells with stable or transient overexpression of human tau (hTau), and in SH-SY5Y that constitutively overexpress hTau. Furthermore, intracerebral ventricular infusion of C004019 induced a robust tau clearance in vivo. Most importantly, both single-dose and multiple-doses (once per 6 days for a total 5 times) subcutaneous administration of C004019 remarkably decreased tau levels in the brains of wild-type, hTau-transgenic and 3xTg-AD mice with improvement of synaptic and cognitive functions. Conclusions: The PROTAC (C004019) created in the current study can selectively and efficiently promote tau clearance both in vitro and in vivo, which provides a promising drug candidate for AD and the related tauopathies.

Activated EGFR signalling drives tumorigenicity in 50% of glioblastoma (GBM). However, EGFR-targeting therapy has proven ineffective in treating patients with GBM, indicating that there is redundant EGFR activation. Circular RNAs are covalently closed RNA transcripts that are involved in various physiological and pathological processes. Herein, we report an additional activation mechanism of EGFR signalling in GBM by an undescribed secretory E-cadherin protein variant (C-E-Cad) encoded by a circular E-cadherin (circ-E-Cad) RNA through multiple-round open reading frame translation. C-E-Cad is overexpressed in GBM and promotes glioma stem cell tumorigenicity. C-E-Cad activates EGFR independent of EGF through association with the EGFR CR2 domain using a unique 14-amino-acid carboxy terminus, thereby maintaining glioma stem cell tumorigenicity. Notably, inhibition of C-E-Cad markedly enhances the antitumour activity of therapeutic anti-EGFR strategies in GBM. Our results uncover a critical role of C-E-Cad in stimulating EGFR signalling and provide a promising approach for treating EGFR-driven GBM.

Otolith chemical signatures are sufficiently stable across time to allow for accurate stock classification. The classification of the southern Yellow Sea population for Larimichthys polyactis (Bleeker, 1877) and its connectivity with others from 1962 is controversial. The study aimed to study the inter-annual variation in otolith strontium:calcium (Sr:Ca) ratios of L. polyactis to determine whether otolith natural tags are representative over long periods and can then be used for population structure classification. Spawning L. polyactis individuals were captured by stow nets in the same site of the southern Yellow Sea coastal waters during April–May in 2003, 2012, and 2013. EPMA (electron probe microanalysis) was used to determine the Sr:Ca ratios of a total of 25 otolith samples. Mann–Whitney U-test was used to test the differences of otolith Sr:Ca ratios from the core to edge for each otolith. One-way ANOVA was performed to compare the mean otolith Sr:Ca values among 2003, 2012, and 2013. Otoliths from 2003, 2012, and 2013 showed similar patterns of Sr:Ca ratios and Sr:Ca ratios could be divided into higher and lower phases in the core and remaining regions, respectively. Inter-annual significant differences for each high or low Sr:Ca phase of otoliths were not observed over short- (between 2012 and 2013) or long-time (between 2003 and 2012, and between 2003 and 2013) scales. Univariate contrasts across the adjacent year and decade classes were statistically similar. The Sr:Ca ratio signatures in the otolith were relatively stable across years and can be used as a reliable natural tag for connectivity assessments and stock identification with little or no genetic differentiation among L. polyactis populations. The short- and long-term temporal stability of otolith Sr:Ca ratios also revealed, the existence of stable L. polyactis stocks in the southern Yellow Sea, consistent with a previous finding of capture survey.

Orthophragminids are a key biostratigraphic proxy for Paleocene–Eocene sequences in western Tethys, but poorly known in eastern Tethys. The orthophragminids were previously misinterpreted as Paleocene's orbitoidiform foraminifera in the Indus Basin, Pakistan. This study focuses on detailed taxonomy and biostratigraphy of orthophragminids. Nine species/subspecies of orthophragminids are identified, including Discocyclina ranikotensis, D. archiaci bakhchisaraiensis, D. a. ex. interc. staroseliensis bakhchisaraiensis, D. dispansa hungarica, D. d. taurica, D. d. broennimanni and Orbitoclypeus schopeni ramaraoi, and two new species Discocyclina pseudoranikotensis n. sp. and Discocyclina debalensis n. sp. are described. The identified orthophragminid taxa represent the orthophragminid zones OZ2-3, corresponding to the shallow benthic zones SBZ5-7 of early Ypresian (early Eocene), which are correlated with those in western Tethys. However, we found that the first appearances of D. d. hungarica and D. d. taurica occur in the OZ3 or SBZ7 in this study instead of the OZ5 or SBZ10 as in western Tethys. The possible paleoecological setting for the occurrences of recognized species is interpreted as inner to middle shelf.

The estuarine tapertail anchovy might comprise a “paired species” of Coilia nasus (which has declined sharply) and Coilia brachygnathus (dominant in some lakes). It has previously been debated whether C. nasus and C. brachygnathus constitute two distinct species or anadromous and freshwater-resident ecotypes. Here, we studied the genetic structure of these species by analyzing the mitochondrial gene cytochrome b (Cyt b) and polymorphic microsatellite loci in 184 anchovies and discriminated their migratory life history using otolith microchemical analysis. Bayesian analysis and a discriminant principal components analysis showed two distinct genetic clusters that corresponded to C. nasus and C. brachygnathus, and we revealed the presence of hybridization between the two closely related sister species. C. nasus has higher genetic diversity within a population and lower genetic divergence between populations than C. brachygnathus. No significant genetic differentiation was detected between the migratory and freshwater-resident C. brachygnathus or between the migratory and freshwater-resident C. nasus. These phenomena suggest that C. brachygnathus and C. nasus are different species, and a strong but permeable reproductive barrier may exist. Both these species have migratory-resident ecological dimorphism, and C. brachygnathus is predominantly a resident species, whereas C. nasus is predominantly an anadromous species.

Cytochrome P450 2A6 (CYP2A6) is an important metabolic enzyme and is involved in the progression of hepatocellular carcinoma (HCC). However, its specific function and the mechanism of modulation remain to be elucidated. In this study, we found that CYP2A6 is dramatically downregulated in HCC. CYP2A6 expression is closely associated with pathological grading, histologic grade, hepatitis, vascular metastasis, liver inflammation, and worse prognosis. Reduced expression of CYP2A6 contributes to alternative activation of macrophage polarization and impairs macrophage maturation and phagocytosis. Mechanistically, CYP2A6 participates in arachidonic acid metabolism, initiates 20‐hydroxyeicosatetraenoic acid (HETE) generation, and inhibits epoxyeicosatrienoic acid (EET) generation. Disruption of the equilibrium between 20‐HETE and EETs can induce macrophage polarization, thereby modulating antitumor immunity., Cytochrome P450 2A6 (CYP2A6) has an antitumor role and is dramatically downregulated in HCC. CYP2A6 participates in arachidonic acid metabolism, initiates 20‐hydroxyeicosatetraenoic acid (HETE) generation, and inhibits epoxyeicosatrienoic acid (EET) generation. Disruption of the equilibrium between 20‐HETE and EETs can induce macrophage polarization, thereby modulating antitumor immunity.

Although several molecular-based studies have demonstrated the involvement of ammonia-oxidizing archaea (AOA) in ammonia oxidation in wastewater treatment plants (WWTPs), factors affecting the persistence and growth of AOA in these engineered systems have not been resolved. Here, we show a seasonal prevalence of AOA in a full-scale WWTP (Shatin, Hong Kong SAR) over a 6-year period of observation, even outnumbering ammonia-oxidizing bacteria in the seasonal peaks in 3 years, which may be due to the high bioavailable copper concentrations. Comparative analysis of three metagenome-assembled genomes of group I.1a AOA obtained from the activated sludge and 16S rRNA gene sequences recovered from marine sediments suggested that the seawater used for toilet flushing was the primary source of the WWTP AOA. A rare AOA population in the estuarine source water became transiently abundant in the WWTP with a metagenome-based relative abundance of up to 1.3% over three seasons of observation. Correlation-based network analysis revealed a robust co-occurrence relationship between these AOA and organisms potentially active in nitrite oxidation. Moreover, a strong correlation between the dominant AOA and an abundant proteobacterial organism suggested that capacity for extracellular polymeric substance production by the proteobacterium could provide a niche for AOA within bioaggregates. Together, the study highlights the importance of long-term observation in identifying biotic and abiotic factors governing population dynamics in open systems such as full-scale WWTPs.

Characterizing the evolutionary trajectory and immune profiling of brain metastasis (BM) may provide insights in the development of novel therapeutic strategies. Here, we performed whole-exome sequencing and multiplex immunofluorescence (MIF) of 40 samples from 12 lung adenocarcinoma (LUAD) patients with BM and compared to their paired primary tumors. We observed significantly higher intertumor heterogeneity between paired primary tumors and BMs, with only a median of 8.3% of genetic mutations identified as shared. Phylogenetic analysis revealed that BM-competent clones genetically diverged from their primary tumors at relatively early stage, suggesting that the parallel progression model is dominant. In cases with synchronous lymph node metastasis (LNM), phylogenetic analysis suggested that BM is a later event than LNM. MIF analysis found that BMs exhibited significantly lower CD8+ T cell infiltration (P = 0.048), and elevated CD4+Foxp3+ T cell infiltration (P = 0.036) and PD-1 expression (P = 0.047) in comparison to the matched primary tumors, indicating an immunosuppressive microenvironment in BMs. The current study revealed the discrepancy of mutational landscape as well as tumor immune microenvironment between BM and its primary tumor – such findings shall help us better understand the unique biological features of BM and develop innovative strategies accordingly for our patients with LUAD.

Gliomas are the most common and malignant intracranial tumors in adults. Recent studies have revealed the significance of functional genomics for glioma pathophysiological studies and treatments. However, access to comprehensive genomic data and analytical platforms is often limited. Here, we developed the Chinese Glioma Genome Atlas (CGGA), a user-friendly data portal for the storage and interactive exploration of cross-omics data, including nearly 2000 primary and recurrent glioma samples from Chinese cohort. Currently, open access is provided to whole-exome sequencing data (286 samples), mRNA sequencing (1018 samples) and microarray data (301 samples), DNA methylation microarray data (159 samples), and microRNA microarray data (198 samples), and to detailed clinical information (age, gender, chemoradiotherapy status, WHO grade, histological type, critical molecular pathological information, and survival data). In addition, we have developed several tools for users to analyze the mutation profiles, mRNA/microRNA expression, and DNA methylation profiles, and to perform survival and gene correlation analyses of specific glioma subtypes. This database removes the barriers for researchers, providing rapid and convenient access to high-quality functional genomic data resources for biological studies and clinical applications. CGGA is available at http://www.cgga.org.cn.

Hepatitis E virus (HEV) is a biological hazard that must be controlled and is a recognized etiological agent in viral hepatitis. This is a zoonotic virus and can be transmitted through the fecal-oral route. The pig is an important reservoir host of HEV, and is a source of contamination for the consumer after the consumption of raw or undercooked pork products. When detected, the most prevalent genotype of HEV in China is genotype 4 (denoted as HEV-4). To ensure the safety of this food of animal origin, we undertook a survey of HEV contamination in pig livers and pork samples available for sale, in retail outlets in selected cities in China. Viral RNA was purified from samples collected by lysing in Trizol followed by purification using trichloromethane and virus RNA extract kit. An additional step was applied to improve the recovery rate by adding RNase OUT when extracting virus RNA from pig livers, and the RNA productions were washed in 75% (v/v) ethanol to remove inhibitors. In total, 158 pig livers and 80 pork samples were procured and analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). After purification of total RNA from all samples taken and analyzed by RT-qPCR, a single pig liver was positive by this method for HEV. The positive rate was calculated as 0.63%. In this study, a single positive sample was detected. Considering the dietary habits of Chinese people, pork is a popular food that on occasion may be contaminated with HEV, thereby posing a threat to consumer health. Ongoing surveillance is required to assess the risk to human health arising from HEV-contaminated pork being offered for sale, at retail outlets, especially in the areas of China where pig production is practiced.

Aims We analyzed the resting state functional magnetic resonance images to investigate the alterations of neural networks in patients with glioma‐related epilepsy (GRE). Methods Fifty‐six patients with right temporal lower‐grade glioma were divided into GRE (n = 28) and non‐GRE groups. Twenty‐eight healthy subjects were recruited after matching age, sex, and education level. Sensorimotor, visual, language, and left executive control networks were applied to generate functional connectivity matrices, and their topological properties were investigated. Results No significant alterations in functional connectivity were found. The least significant discovery test revealed differences only in the language network. The shortest path length, clustering coefficient, local efficiency, and vulnerability were greater in the non‐GRE group than in the other groups. The nodal efficiencies of two nodes (mirror areas to Broca and Wernicke) were weaker in the non‐GRE group than in the other groups. The node of degree centrality (Broca), nodal local efficiency (Wernicke), and nodal clustering coefficient (temporal polar) were greater in the non‐GRE group than in the healthy group. Conclusion Different tumor locations alter different neural networks. Temporal lobe gliomas in the right hemisphere altered the language network. Glioma itself and GRE altered the network in opposing ways in patients with right temporal glioma., Right temporal glioma will make the nodal efficiency of the left part of the language network decline and increased degree centrality, nodal local efficiency, and nodal clustering coefficient of left part of the language network.

Acupuncture can reduce cognitive deficits in Alzheimer's disease. However, whether electroacupuncture can prevent or alleviate the cognitive deficits in animal models of aging remains poorly understood. Studies have shown that disordered epigenetic modifications play a critical role in age-related cognitive decline. Therefore, we hypothesized that preventive electroacupuncture might improve cognitive functions during aging by regulating epigenetic modifications. A rat model of aging was produced by intraperitoneal injection of 120 mg/kg D-galactose for 8 weeks. Baihui and Shenshu acupoints were stimulated by electroacupuncture for 8 weeks from the first day of D-galactose administration. Preventive electroacupuncture alleviated memory impairment, decreased tau hyperphosphorylation, and reduced glycogen synthase kinase-3β protein and mRNA expression levels in the brainstem dorsal raphe nucleus, where intracellular neurofibrillary tangle lesions first occur. In addition, the DNA methylation level in the promoter region of the glycogen synthase kinase-3β gene was increased. The effects of preventive electroacupuncture were stronger than those of preventive acupuncture. Intraperitoneal injection of 0.4 mg/kg 5-aza-2'-deoxycytidine, an inhibitor of DNA methyltransferase that blocks epigenetic modifications, antagonized the effects of preventive electroacupuncture. Our results suggest that preventive electroacupuncture treatment alleviates cognitive impairment in aging rats probably by affecting the epigenetic modification of the glycogen synthase kinase-3β gene in the dorsal raphe nucleus. This study was approved by the Animal Ethics Committee of Hubei University of Chinese Medicine, China (approval No. HUCMS201712001) on November 28, 2017.

Phenylalanine hydroxylase (PAH) deficiency (PAHD) is an autosomal recessive disorder that causes severe injury to the nervous system, the treatment of which mainly depends on dietary therapy. The limited treatment options for PAHD are an incentive to develop new methods to identify more efficient therapeutic drugs, such as agonists which could improve PAH activity. In this study, we aimed to establish a rapid and convenient method for the screening and verification of PAH agonists. We compared fluorospectrophotometry and tandem mass spectrometry for detection of enzymatic formation of tyrosine, finding that the latter was a more sensitive method. We optimized immunoprecipitation purification conditions and measurement conditions of PAH activity. The optimal ratio between PAH protein and magnetic beads was 500 μg protein per 20 μL beads, and the optimized conditions for the detection of PAH enzymatic activity included the presence of 75 μM coenzyme ((6R)-l-erythro-5,6,7,8-tetrahydrobiopterin) and 30 min reaction time. Based on virtual screening, we screened ten candidate agonists from the FDA drug library. Three of these (nefopam, fluocinonide, and risperidone) were found to activate the enzyme in a dose-dependent manner (0.1-10 μM) by the joint method. We tested the efficacy of the three agonists on three PAH mutations (p.I65T, p.H107R, and p.D101N) that influence enzyme activity, and found that risperidone could specifically activate D101N-mutated enzyme. In conclusion, we established a joint method that is highly reliable, cost-effective, labor-saving, and time-saving. And we also found a specific agonist for D101N-mutated PAH by this joint method which may assist the development of clinical treatment for PAHD patients with different enzyme deficiencies.

Japanese Spanish mackerel, Scomberomorus niphonius, is a commercially important, highly migratory species that is widely distributed throughout the northwestern Pacific region. However, its life history and migratory patterns are only partially understood. This study used otolith chemistry to investigate the migratory pattern of S. niphonius in the southern Yellow Sea, an important fishing ground. Transverse sections of otoliths from 15 age-1 spawning or spent individuals, comprising up to one complete migration cycle, were analyzed from the core to the margin by using laser ablation inductively coupled plasma mass spectrometry. The ratios of the element to Ca were integrated with microstructural analysis to produce age-related elemental profiles. Combining multielemental analysis of otolith composition with multivariate analytical models, we quantified structural changes in otolith chemistry profiles. Results revealed there were diverse changing patterns of otolith chemistry profiles for detected elements and the elements of Na, Mg, Sr and Ba were important for the chronological signal. Five clusters were identified through chronological clustering, representing the five life stages from the early stage to the spawning stage. Variation of Ba:Ca ratio was most informative, showing a step-decreasing pattern in the first four stages and a rebound in the spawning stage. These results support the hypothesized migratory pattern of S. niphonius: hatching and spending their early life in the coastal sandy ridges system of the southern Yellow Sea, migrating northeastward and offshore for feeding during juvenile stage, aggregating in early October and migrating outward to the Jeju Island for wintering, and returning to the coastal waters for spawning. This study demonstrated the value of life-history related otolith chemistry profiles combined with multivariate analytical models was a means to verify the migration patterns of S. niphonius at regional scales with potential application in fisheries assessment and management.

Sucrose non-fermenting-1-related protein kinase-1 (SnRK1) regulates carbon and nitrogen metabolism in plants. However, its roles and their underlying mechanisms in tolerance to abiotic stresses are little known. The present study indicated that the IbSnRK1 gene was strongly induced by NaCl, polyethylene glycol (PEG) 6000, hydrogen peroxide (H2O2), cold (4 °C), and abscisic acid (ABA). Its overexpression significantly increased salt, drought, and cold tolerance in transgenic sweet potato plants. ABA, proline, and K+ contents were significantly increased, whereas malondialdehyde (MDA), Na+ and H2O2 contents and O2− production rate were significantly decreased in the transgenic plants under salt, drought, and cold stresses. Overexpression of the gene up-regulated genes involved in ABA biosynthesis, stress response, and stomatal closure; increased enzyme activities in the reactive oxygen species (ROS) scavenging system; and controlled stomatal closure under salt, drought, and cold stresses. These results show that the IbSnRK1 gene confers salt, drought, and cold tolerance in sweet potato by activating the ROS scavenging system and controlling stomatal closure via the ABA signaling pathway.

Activation of Protein Kinase AMP-Activated Catalytic Subunit Alpha (AMPKα) is an important regulatory pathway for osteogenic differentiation. STAT4 acts as a transcriptional activity factor to regulate the transcription of many genes and is potentially a regulatory factor for AMPKα transcription activity. To confirm the regulatory effect of STAT4 on AMPKα and the effect of STAT4 on osteogenic differentiation, the promoter sequence of AMPKα was analyzed via bioinformatics, the STAT4 overexpression vector was constructed and transfected into human osteoblast-like cells MG-63 by cationic liposome, fluorescence quantitative PCR (RT-qPCR) and western blotting technologies were used to detect the effect of STAT4 on the expression of AMPKα. MTT and ALP activity assays were also used to verify the effect of STAT4 on the proliferation and maturation of osteoblasts by regulating AMPKα expression. Our results showed that STAT4 was a co-transcriptional regulator of AMPKα1 and AMPKα2, which combined the enrichment region of CpG on the promoter sequence of AMPKα1/2. Overexpression of STAT4 significantly increased the expression of AMPKα1 and AMPKα2, which promoted the proliferation and maturation of osteoblasts. We concluded that STAT4 was a transcriptional activator of AMPKα and promoting STAT4 expression enhances the proliferation and differentiation activity of AMPKα in osteoblasts.

DNA methylation regulated gene expression is important for osteoblast proliferation and differentiation during bone remodeling and its deregulation leads to the development of osteoporosis. DNA methyltransferase 1 (DNMT1) is an important regulator of DNA methylation. To explore the effect and mechanism of differential expression of DNMT1 in osteoblast precursor cells, DNMT1 siRNAs were designed and synthesized to interfere with DNMT1 expression in the osteoblast precursor cells, MC3T3E1 (Clone 24; MC3T3E1-24). The expression of the target gene, DNMT1, and osteogenic differentiation indicators osteoprotegerin (OPG) and receptor activator of nuclear factor-κB ligand (RANKL) were detected by real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB). MTT assay was used to detect the effect on cell proliferation. Alkaline phosphatase (ALP) activity and alizarin red staining were used to detect the effect of DNMT1 on osteogenic differentiation. Hematoxylin and eosin (H&E) staining was used to detect the morphological changes in MC3T3E1-24 cells. Twenty-four hours following the transfection of MC3T3E1-24 cells with DNMT1 siRNA using cationic liposomes, DNMT1 mRNA and protein levels decreased significantly (P P P P 0.05). The reduced expression of DNMT1 also promoted the proliferation of osteoblast precursor cells. In addition, ALP activity test and alizarin red staining showed that reduced expression of DNMT1 resulted in an increase in OPG/RANKL ratio and promoted the differentiation of the precursor cells. The cultured cells were found to have fibroblast-like appearance, and calcium nodules were observed after 7 days of conventional culture. In addition, to improve the efficiency of RNA extraction and save time, a type of silica nanomagnetic beads was used in the early stage of this study to extract RNA and assist qPCR detection of the target genes. The results showed that the magnetic beads could effectively extract RNA from the cells. In conclusion, low expression of DNMT1 affects proliferation and maturation of osteoblasts by upregulating OPG and OPG/RANKL ratio.

Gliomas grow and invade along white matter fiber tracts. This study assessed the effects of motor cortex gliomas on the cerebral white matter fiber bundle skeleton. The motor cortex glioma group included 21 patients, and the control group comprised 14 healthy volunteers. Both groups underwent magnetic resonance imaging-based 3.0 T diffusion tensor imaging. We used tract-based spatial statistics to analyze the characteristics of white matter fiber bundles. The left and right motor cortex glioma groups were analyzed separately from the control group. Results were statistically corrected by the family-wise error rate. Compared with the controls, patients with left motor cortex gliomas exhibited significantly reduced fractional anisotropy and an increased radial diffusivity in the corpus callosum. The alterations in mean diffusivity (MD) and the axial diffusivity (AD) were widely distributed throughout the brain. Furthermore, atlas-based analysis showed elevated MD and AD in the contralateral superior fronto-occipital fasciculus. Motor cortex gliomas significantly affect white matter fiber microstructure proximal to the tumor. The range of affected white matter fibers may extend beyond the tumor-affected area. These changes are primarily related to early stage tumor invasion.

Ischaemia/reperfusion (I/R)‐induced hepatic injury is regarded as a main reason of hepatic failure after transplantation or lobectomy. The current study aimed to investigate how the opioid analgesic remifentanil treatment affects I/R‐induced hepatic injury and explore the possible mechanisms related to HIF1α. Initially, an I/R‐induced hepatic injury animal model was established in C57BL/6 mice, and an in vitro hypoxia‐reoxygenation model was constructed in NCTC‐1469 cells, followed by remifentanil treatment and HIF1α silencing treatment. The levels of blood glucose, lipids, alanine transaminase (ALT) and aspartate transaminase (AST) in mouse serum were measured using automatic chemistry analyser, while the viability and apoptosis of cells were detected using CCK8 assay and flow cytometry. Our results revealed that mice with I/R‐induced hepatic injury showed higher serum levels of blood glucose, lipids, ALT and AST and leukaemia inhibitory factor (LIF) expression, and lower HIF1α and ZEB1 expression (P

Background The study investigated the resistant pattern and clinical outcomes of epidermal growth factor receptor (EGFR) exon 19 deletion (19del) subtypes to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). Methods Two hundred eight treatment naive NSCLC patients detected as EGFR 19del using amplification-refractory mutation system (ARMS) were included. DNA sequencing was used to detect the subtypes. Clinicopathological features as well as patients' outcomes treated with first-line EGFR-TKIs were analyzed. Results Thirteen EGFR 19del subtypes were confirmed in 181 samples (87.0%). Among these, delE746_A750 was the most frequent subtype (130/181, 71.8%). delE746_A750 and deletions starting from E746 were frequently found in female (P=0.003 and P=0.013, respectively) and never smokers (P=0.002 and P=0.014, respectively) than non-delE746_A750 and deletions starting from L747 patients, respectively. T790M was more frequently occurred in delE746_A750 than non-delE746_A750 (P=0.001) and deletions starting from E746 than L747 patients (P=0.006) after first-line EGFR-TKIs resistance. Patients harboring deletions starting from L747 with insertions had significantly shorter progression-free survival (PFS) than deletions starting from L747 without insertion (8.3 vs. 15.0 m, P=0.017), or all other patients (8.3 vs. 12.6 m, P=0.027). Different 19del subtypes with T790M mutation had similar PFS when treated with osimertinib (P=0.102). Conclusions Patients with EGFR 19del subtypes had different clinicopathological features, and resistant pattern when treated with first-line TKIs. Patients harboring deletions starting from L747 with insertions had inferior outcomes than other subtypes.

Hematopoietic stem and progenitor cells (HSPCs) have the ability to self-renew and differentiate into various blood cells, thus playing an important role in maintenance of lifelong hematopoiesis. Brahma-related gene 1 (BRG1), which acts as the ATP subunit of mammalian SWI-SNF-related chromatin remodeling complexes, is involved in human acute myeloid leukemia and highly expresses in short-term HSPCs. But its role and regulatory mechanism for HSPC development have not yet been well established. Here, we generated a brg1 knockout zebrafish model using TALEN technology. We found that in brg1-/- embryo, the primitive hematopoiesis remained well, while definitive hematopoiesis formation was significantly impaired. The number of hemogenic endothelial cells was decreased, further affecting definitive hematopoiesis with reduced myeloid and lymphoid cells. During embryogenesis, the nitric oxide (NO) microenvironment in brg1-/- embryo was seriously damaged and the reduction of HSPCs could be partially rescued by a NO donor. Chromatin immunoprecipitation (ChIP) assays showed that BRG1 could bind to the promoter of KLF2 and trigger its transcriptional activity of NO synthase. Our findings show that Brg1 promotes klf2a expression in hemogenic endothelium and highlight a novel mechanism for HSPC formation and maintenance.

Long-read sequencing is promising for the comprehensive discovery of structural variations (SVs). However, it is still non-trivial to achieve high yields and performance simultaneously due to the complex SV signatures implied by noisy long reads. We propose cuteSV, a sensitive, fast, and scalable long-read-based SV detection approach. cuteSV uses tailored methods to collect the signatures of various types of SVs and employs a clustering-and-refinement method to implement sensitive SV detection. Benchmarks on simulated and real long-read sequencing datasets demonstrate that cuteSV has higher yields and scaling performance than state-of-the-art tools. cuteSV is available at https://github.com/tjiangHIT/cuteSV.

MicroRNA-34a (miR-34a) has been reported to inhibit TGF-β (transforming growth factor-β)-induced epithelial-mesenchymal transition (EMT) in nasopharyngeal carcinoma (NPC). However, the underlying mechanism remain unclear. Using the bioinformatics, we found that the AXL receptor tyrosine kinase (AXL) is a predicted target of miR-34a. we aimed to reveal the relationship between miR-34a and AXL, and investigate the effect and mechanism of miR-34a in NPC progression. The expression patterns of miR-34a and AXL in 30 paired NPC tissues and the adjacent tissues were examined by quantitative real time PCR (qRT-PCR). The target relationship between miR-34a and AXL was evaluated by the luciferase gene reporter assay. Cell migration and invasion were assessed by wound healing and transwell chamber assays, respectively. miR-34a level was dramatically decreased in the NPC tissues compared to the adjacent tissues, while AXL expression was increased. Overexpression of miR-34a significantly reduced the luciferase activity of the luciferase vector of AXL (pGL3-AXL-WT), whereas this effect was abrogated when binding sites between miR-34a and AXL were mutated. In addition, ectopic expression of miR-34a dramatically inhibited Sune-1 cell migration and invasion abilities, decreased the levels of N-cadherin and Vimentin and increased E-cadherin and γ-catenin expressions, as well as induced significant reductions in the expressions of p-AKT and Snail. However, these effects were attenuated when the cells were treated with recombinant human AXL protein. Our results demonstrate that miR-34a/AXL can inhibit NPC cell migration, invasion and EMT through inhibition of AKT/Snail signaling.

Background The objectives of this study were to reveal the anthocyanin biosynthesis metabolic pathway in white and purple flowers of Salvia miltiorrhiza using metabolomics and transcriptomics, to identify different anthocyanin metabolites, and to analyze the differentially expressed genes involved in anthocyanin biosynthesis. Results We analyzed the metabolomics and transcriptomics data of S. miltiorrhiza flowers. A total of 1994 differentially expressed genes and 84 flavonoid metabolites were identified between the white and purple flowers of S. miltiorrhiza. Integrated analysis of transcriptomics and metabolomics showed that cyanidin 3,5-O-diglucoside, malvidin 3,5-diglucoside, and cyanidin 3-O-galactoside were mainly responsible for the purple flower color of S. miltiorrhiza. A total of 100 unigenes encoding 10 enzymes were identified as candidate genes involved in anthocyanin biosynthesis in S. miltiorrhiza flowers. Low expression of the ANS gene decreased the anthocyanin content but enhanced the accumulation of flavonoids in S. miltiorrhiza flowers. Conclusions Our results provide valuable information on the anthocyanin metabolites and the candidate genes involved in the anthocyanin biosynthesis pathways in S. miltiorrhiza.

International audience; The Upper Cretaceous sedimentary sequence at International Ocean Discovery Program Site U1512 in the Ceduna Sub-basin of the Great Australian Bight represents a continuous, > 690 m thick interval of black silty clay and claystone spanning the lower Turonian through Lower Campanian (~10 million years). Sediments were deposited in an elongate, ~E-W oriented, ~2500 km long rift system that developed between Australia and Antarctica with an open-ocean connection to the west and a continental bridge to the east. Site U1512 cores provide a unique, continuous record of Late Cretaceous deposition in the Ceduna Sub-basin on the hanging wall of the Wallaroo Fault Zone. Study of U1512 samples could provide both an important high-latitude, southern hemisphere perspective on climatic evolution during the peak and demise of the Cretaceous hothouse and an offshore record of the sedimentation history in the basin during the Late Cretaceous portion of the Gondwanan breakup. The Upper Cretaceous sequence at Site U1512 is notable for its lithologic uniformity. Burrow-mottled to massive claystone and silty claystone make up the majority of the almost 700 m section, while rare (n = 28) isolated, 2 to 21 cm thick medium to fine sandstone beds are a minor lithology. Macrofossils present include common inoceramids and rare occurrences of other bivalves and ammonites. Microfossils include common occurrences of calcareous nannofossils, agglutinated and calcareous benthic foraminifera, radiolaria and organic-walled dinoflagellate cysts as well as rare small, surface dwelling planktonic foraminifera. Carbonate (

Selection of rootstock is very important for citrus production. Besides its major role on resistance, the rootstock also can affect fruit production and quality. Currently, the main concerns on selection of rootstock for citrus production are compatibility and resistance, due to less information on the impacts of rootstock to the performance of scion varieties. This study aims to provide information on performances of navel orange varieties on different rootstocks. Three late-ripening navel orange varieties (Citrus sinensis var. Powell, Chislett and Banfield) grafted on seven rootstocks (Swingle citrumelo (C. paradisi×P. trifoliata), Carrizo citrange (C. sinensis×P. trifoliata), X639 (C. reticulata×P. trifoliata), MXT (C. sinensis×P. trifoliata), Hongju (C. reticulata), Ziyang Xiangcheng (C. junos) and trifoliate orange (P. trifoliata)) were used as plant materials for comprehensive comparison of the performances on tree growth, fruit yield and quality in 21 scion–stock combinations. Investigation was carried out in these combinations in field nine years after planting. Vigorous growth of all the three late-ripening navel orange varieties was observed on Carrizo citrange with the largest canopy volume at 33.34 m3 and the highest yield at 29.43 kg per tree, but a low yield efficiency at 2.87 kg m−3. On the contrary, those on trifoliate orange had the smallest canopy volume at 10.79 m3 and the lowest fruit yield at 12.51 kg per tree, but the highest yield efficiency at 3.95 kg m−3. Rootstocks did not show significant effects on fruit size, fruit shape index, peel thickness and the edible rate of the fruits, but fruit quality was significantly affected by the rootstocks. Fruits from the trees grafted on trifoliate orange presented the best quality with significantly higher total soluble solids (TSS) content than those on Ziyang Xiangcheng and Hongju, and also the highest ratio of TSS/titratable acidity (TA). The TA content was observed from the fruits on X639 at 0.59 g 100 mL−1. Vitamin C (Vc) content of fruits on Hongju was the highest at 49.25 mg 100 mL−1. Growth vigor of the trees was positively correlated with fruit yield at an extremely significant level. The canopy volume was negatively correlated with yield efficiency, but positively correlated with compatibility index. Results of this study indicated that the rootstock has great impacts on the growth vigor of the tree, yield efficiency and quality of the fruit. In order to achieve good quality and yield efficiency for navel orange production, less growth vigor rootstock such as trifoliate orange is highly recommended.

Glioma is the most common primary intracranial tumor and is associated with very low survival rates. The development of reliable biomarkers can help to elucidate the molecular mechanisms involved in glioma development. Here the expression of ABCC8 mRNA, clinical characteristics, and survival information based on 1893 glioma samples from four independent databases were analyzed. The expression patterns of ABCC8 mRNA were compared by a Chi square test. The overall survival rate of gliomas was evaluated according to the expression level of ABCC8 mRNA. The prognostic value of this marker in gliomas was tested using Cox single factor and multi factor regression analyses. We found patients with low WHO grade, oligodendrocytoma, low molecular grade, IDH mutation, and 1p19q combined deletion had high ABCC8 mRNA expression. The patients with high expression of ABCC8 mRNA had longer survival. ABCC8 mRNA expression was a new independent prognostic index for glioma. Temozolomide chemotherapy was an independent index to prolong overall survival in high ABCC8 mRNA expression glioma patients, whereas in patients with low expression, there was no significant difference. So ABCC8 mRNA expression could be an independent prognostic indicator for glioma patients and could predict the sensitivity of glioma to temozolomide.

Background: Old age has been demonstrated to be a risk factor for GBM, but the underlying biological mechanism behind this association is still unclear. We designed this study with the goal of determining a mechanistic explanation for the link between age and pathogenesis in GBM. Methods: In total, we enrolled transcriptome data from 616 primary GBM samples and 41 non-tumor brain samples in this study. Transcriptome data and clinical information were obtained from the CGGA, TCGA, and GSE53890 databases. Gene Set Variation Analysis and Gene Ontology analyses were the primary analytical methods used in this study. All statistical analyses were performed using R. Findings: We found that the expression of RPP30, an independent prognostic factor in GBM, was negatively correlated with age in both tumor and non-tumor brain samples. However, the post-transcriptional modifications carried out by RPP30 were different in primary GBM and non-tumor brain samples. RPP30 affected protein expression of cancer pathways by performing RNA modifications. Further, we found that RPP30 was related to drug metabolism pathways important in GBM. Interpretation: The decreased expression of RPP30 in older patients might be a pathogenic factor for GBM. Funding Statement: This work was supported by grants from National Natural Science Foundation of China (No. 81672479, 81802994), National Natural Science Foundation of China (NSFC)/Research Grants Council (RGC) Joint Research Scheme (81761168038), Beijing Municipal Administration of Hospitals’ Mission Plan (SML20180501). Declaration of Interests: No potential conflicts of interest were disclosed. Ethics Approval Statement: This study was approved by Beijing Tiantan Hospital institutional review board (IRB). All patients provided written informed consent for the publication of all associated data in this study.

Three transgenic maize events (IE09S034, Shuangkang 12–5 and C0030.3.5) produced Cry1le, Cry1Ab/Cry2Aj and G10-EPSPS, Cry1Ab and EPSPS, respectively, all of which target the Asian corn borer. The oriental armyworm Mythimna separata (Walker) is the secondary target. In this study, the effects of the three Bt maizes on the development and survival of armyworm were studied. The results showed that IE09S034 had insecticidal activity against 1st instar larvae, and the survival rate of armyworm fed with Bt maize for 10 days was 46.2%, significantly lower than that of the control. The larvae at 3rd–6th instar were more tolerant of the Bt toxin than the early instar larvae. However, Shuangkang 12-5 had good insecticidal activity against 1st–5th instar larvae. The mortality was nearly 100% when the larvae were fed with Shuangkang 12-5 before 3rd instar, and the toxin had quick-acting efficacy. This event significantly inhibited the development of armyworm; that is, the larval duration of the 3rd and 4th instar larvae fed with Shuangkang 12-5 was prolonged by 4.5 and 3.0 days, respectively. The pupal weight and egg number were also significantly lower than those of the control. For C0030.3.5, it could control 1st–5th instar larvae effectively. The mortality rates were all over 50% if 1st–3rd larvae were fed with this event. The pupal weight of 4th–6th instar larvae fed with Bt maize were only 53.9, 56.8 and 54.6%, respectively, compared to that of the control. The number of eggs laid was significantly less than the control. The results indicate that all three transgenic maize events exhibit the potential to provide effective control of early instar larvae of armyworm, which can be commercialized in future to control lepidoptera pests such as Asian corn borer and armyworm.

To advance the scientific understanding of bacteria-driven mercury (Hg) transformation processes in natural environments, thermodynamics and kinetics of divalent mercury Hg(II) chemical speciation need to be understood. Based on Hg LIII-edge extended X-ray absorption fine structure (EXAFS) spectroscopic information, combined with competitive ligand exchange (CLE) experiments, we determined Hg(II) structures and thermodynamic constants for Hg(II) complexes formed with thiol functional groups in bacterial cell membranes of two extensively studied Hg(II) methylating bacteria: Geobacter sulfurreducens PCA and Desulfovibrio desulfuricans ND132. The Hg EXAFS data suggest that 5% of the total number of membranethiol functionalities (Mem-RStot = 380 ± 50 μmol g–1 C) are situated closely enough to be involved in a 2-coordinated Hg(Mem-RS)2 structure in Geobacter. The remaining 95% of Mem-RSH is involved in mixed-ligation Hg(II)-complexes, combining either with low molecular mass (LMM) thiols like Cys, Hg(Cys)(Mem-RS), or with neighboring O/N membrane functionalities, Hg(Mem-RSRO). We report log K values for the formation of the structures Hg(Mem-RS)2, Hg(Cys)(Mem-RS), and Hg(Mem-RSRO) to be 39.1 ± 0.2, 38.1 ± 0.1, and 25.6 ± 0.1, respectively, for Geobacter and 39.2 ± 0.2, 38.2 ± 0.1, and 25.7 ± 0.1, respectively, for ND132. Combined with results obtained from previous studies using the same methodology to determine chemical speciation of Hg(II) in the presence of natural organic matter (NOM; Suwannee River DOM) and 15 LMM thiols, an internally consistent thermodynamic data set is created, which we recommend to be used in studies of Hg transformation processes in bacterium–NOM–LMM thiol systems.

Partial temporal lobe epilepsy (TLE) has an intrauterine developmental origin. This study was aimed at elucidating the heritable effects and programming mechanism of TLE in offspring rats induced by prenatal dexamethasone exposure (PDE). Pregnant Wistar rats were injected subcutaneously with dexamethasone (0.2 mg/kg day) from gestational day 9 to 20. The F1 and F2 generations of male offspring were administered lithium pilocarpine (LiPC) for electroencephalography and video monitoring in epilepsy or behavioral tests. Results showed that the PDE + LiPC group exhibited TLE susceptibility, which continued throughout F2 generation. Expression of hippocampal glucocorticoid receptor (GR), CCAAT enhancer-binding protein α (C/EBPα), intrauterine renin-angiotensin system (RAS) classical pathway related genes, the H3K27ac level in angiotensin-converting enzyme (ACE) promoter, as well as high mobility group box 1 (HMGB1) and toll-like receptor 4 (TLR4) were increased, but glutamate dehydrogenase (GLUD) 1/2 expression were decreased, accompanied by increased glutamate levels in PDE fetal and adult rats, as well as in F1 and F2 offspring of the PDE + LiPC group. These consistent changes were also observed by treating the H19-7 fetal hippocampal cell line with dexamethasone and were reversed by GR inhibitor (RU486) and ACE inhibitor (enalaprilat). Our results confirmed that PDE-induced H3K27ac enrichment in the ACE promoter and enhanced the RAS classic pathway via activating GR-C/EBPα-p300 in utero, which caused changes of the HMGB1 pathway and glutamate excitatory damage. Intrauterine programming mediated by abnormal histone modification of hippocampal ACE could continue to adulthood and even F2 generation, which induced the heritability of TLE in male offspring rats.