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Numerous studies have shown that over-nutritional obesity may lead to pre-diabetes, type 2 diabetes and cognitive decline. As the degree of metabolic disorders increases, the cognitive decline is getting worse. However, the cellular events that cause this cognitive dysfunction is yet to be clarified. We used a high-fat diet (HFD) consumption-induced obesity mouse model to test the effects of metformin on the hippocampal neurogenesis and learning and memory abilities of obese mice. 5-Bromo-2'-deoxyuridine (BrdU) labelling and retrovirus labeling were applied to detect hippocampal newborn neurons. Behavioral experiments were used to detect learning and memory abilities of mice. 16S rRNA gene sequencing was performed to detect the composition of gut microbiota. The positron emission tomography (PET) was conducted to detect the energy metabolism activity of different mouse brain regions. Our results reveal that metformin restores the impairment of neurogenesis in the dentate gyrus and finally prevents the cognitive decline of the obese mice. Moreover, the therapeutic effects of metformin are achieved by regulating the composition of gut microbiota of mice, which may inhibit microglia activation and neuroinflammation in the brain of obese mice. This study suggests that metformin may be taken as a promising candidate for the intervention of cognitive decline related to imbalance of gut microbiota caused by obesity.

Background Pleomorphic liposarcoma is the least common but most aggressive subtype of liposarcoma. Very few studies have presented data on pleomorphic liposarcoma specifically, often including a limited number of cases and short-term follow-up. As a result, the survivorship and prognostic characteristics of this tumor remain incompletely identified. Study design and setting Cross-sectional analysis of the Surveillance Epidemiology and End Results database (1996–2015). Results Overall survival for the entire series was 54% (95% confidence interval [CI], 49–58%) and 40% (95% CI, 35–45%) at 5 and 10 years, respectively. Disease-specific survival for the entire series was 60% (95% CI, 56–65%) and 53% (95% CI, 48–58%) at 5 and 10 years, respectively. Patients who survived 10 years or more were more likely to die of events unrelated to pleomorphic liposarcoma. Univariate and multivariate analysis demonstrated that not receiving cancer-directed surgery was an independent poor prognostic factor. Older age (≥ 65 years old) was associated with worse overall survival but not disease-specific survival. Tumor stage and radiotherapy showed different impact on survival depending on tumor size. In comparison to localized staged tumors, regional stage only predicts poor survival in patients with tumor size less than 5 cm, while distant stage is an independent worse prognosis factor. Radiotherapy only benefits patients with tumor size larger than 10 cm. These results were confirmed in competing risk analysis. Conclusion Survival rates of patients with pleomorphic liposarcoma has not changed over the past 20 years. Patients with distant stage have poor prognosis; regional stage indicates worse survival in patients with tumor size less than 5 cm. Receiving surgery could prolong the survival, while radiotherapy only benefits patients with large tumor size (> 10 cm). Older age is associated with poor overall survival but not disease-specific survival. Routine patient surveillance following initial diagnosis should at least be 10 years for pleomorphic liposarcoma.

This study aimed to perform an updated meta-analysis to explore the clinical, diagnostic, and prognostic values of circRNAs in osteosarcoma.: PubMed, Web of Science, EMBASE, Scopus, and Cochrane Library were systematically searched up to December 15, 2020. Eligible studies regarding the relationship between circRNAs levels and clinicopathological, diagnostic, and prognostic values in osteosarcoma were included for study.31 studies involving 1979 osteosarcoma patients were enrolled, with 22 studies on clinicopathological parameters, eleven on diagnosis, and 23 on prognosis. For clinical parameters, overexpression of oncogenic circRNAs was intimately correlated with larger tumor size, advanced Enneking stage, poor differentiation, and distant metastasis (DM). In contrast, the downregulated circRNAs showed negative correlation with Enneking stage and DM. For the diagnostic values, the summary area under the curve of circRNA for the discriminative efficacy between osteosarcoma patients and non-cancer counterparts was estimated to be 0.87, with a weighted sensitivity of 0.79, specificity of 0.81, respectively. For the prognostic significance, oncogenic circRNAs had poor overall survival (OS) and disease-free survival, while elevated expression of tumor-suppressor circRNAs were closely related to longer OS.This study showed that aberrantly expressed circRNA signatures could serve as potential biomarkers in diagnosis and prognosis in osteosarcoma.

The study was focussed on the inhibitory mechanism associated with the ability of an endophytic bacterium - Bacillus altitudinis Q7, obtained from Ginkgo biloba, to inhibit the growth of Alternaria alternata in vitro. A fungus, identified as Alternaria alternata was isolated from the rotten part of an apple. One of the endophytes was identified as Bacillus altitudinis Q7. Effect of Bacillus altitudinis Q7 on Alternaria alternata was characterized by measuring membrane permeability and lipid peroxidation. Antioxidant enzymes in Alternaria alternata were determined before and after exposure to Bacillus altitudinis Q7. Results indicated that cell membranes in Alternaria alternata were damaged, lipid peroxidation was enhanced, and superoxide dismutase, peroxidase, and polyphenol oxidase were significantly inhibited. Content of lipopeptides produced by Bacillus altitudinis Q7 was higher than other metabolites. The FTIR spectra revealed that the prepared antibacterial lipopeptides is a cyclic lipopeptides. The effect of lipopeptides produced by Bacillus altitudinis Q7 at 2 mg/mL against Alternaria alternata in vitro reached 83.2%. The lipopeptide-treated group showed the same trend as Q7 fermentation broth in inhibition mode of action. Moreover, the utilization of proteins and sugars during culturing of Alternaria alternata decreased when adding lipopeptides to the growth medium. Bacillus altitudinis Q7 from Ginkgo biloba significantly inhibited the growth of Alternaria alternata and is a very promising biocontrol strain against Alternaria alternata. The study of endophytic bacteria and its metabolites is being done to identify biological control alternatives. The results provide a theoretical basis for understanding their antagonistic properties.

Researchers, parents and educators consistently observe a stark mismatch between biologically preferred and socially imposed sleep–wake hours in adolescents, fueling debate about high school start times. We contribute neural evidence to this debate with electroencephalogram data collected from high school students during their regular morning, mid-morning and afternoon classes. Overall, student alpha power was lower when class content was taught via videos than through lectures. Students’ resting state alpha brain activity decreased as the day progressed, consistent with adolescents being least attentive early in the morning. During the lessons, students showed consistently worse performance and higher alpha power for early morning classes than for mid-morning classes, while afternoon quiz scores and alpha levels varied. Together, our findings demonstrate that both class activity and class time are reflected in adolescents’ brain states in a real-world setting, and corroborate educational research suggesting that mid-morning may be the best time to learn.

Vanadium compounds have been reported to mimic the anti-diabetes effects of insulin on rodent models, but their effects on Alzheimer’s disease (AD) have rarely been explored. In this paper, 9-month-old triple transgenic AD model mice (3×Tg-AD) received bis(ethylmaltolato)oxidovanadium(iv) (BEOV) at doses of 0.2 mmol L−1 (68.4 μg mL−1) and 1.0 mmol L−1 (342 μg mL−1) for 3 months. BEOV at both doses was found to improve contextual memory and spatial learning in AD mice. It also improved glucose metabolism and protected neuronal synapses in the AD brain, as evidenced respectively by 18F-labeled fluoro-deoxyglucose positron emission tomography (18F-FDG-PET) scanning and by transmission electron microscopy. Inhibitory effects of BEOV on β-amyloid (Aβ) plaques and neuronal impairment in the cortex and hippocampus of fluorescent AD mice were visualized three-dimensionally by applying optical clearing technology to brain slices before confocal laser scanning microscopy. Western blot analysis semi-quantitatively revealed the altered levels of Aβ42 in the brains of wildtype, AD, and AD treated with 0.2 and 1.0 mmol L−1 BEOV mice (70.3%, 100%, 83.2% and 56.8% in the hippocampus; 82.4%, 100%, 66.9% and 42% in the cortex, respectively). The mechanism study showed that BEOV increased the expression of peroxisome proliferator-activated receptor γ (PPARγ) (140%, 100%, 142% and 160% in the hippocampus; 167%, 100%, 124% and 133% in the cortex) to inactivate the JAK2/STAT3/SOCS-1 pathway and to block the amyloidogenesis cascade, thus attenuating Aβ-induced insulin resistance in AD models. BEOV also reduced protein tyrosine phosphatase 1B (PTP1B) expression (74.8%, 100%, 76.5% and 53.8% in the hippocampus; 71.8%, 100%, 94.2% and 81.8% in cortex) to promote insulin sensitivity and to stimulate the PI3K/Akt/GSK3β pathway, subsequently reducing tau hyperphosphorylation (phosphorylated tau396 levels were 51.1%, 100%, 56.1% and 50.2% in the hippocampus; 22.2%, 100%, 36.1%, and 24% in the cortex). Our results suggested that BEOV reduced the pathological hallmarks of AD by targeting the pathways of PPARγ and PTP1B in 3×Tg AD mice.

On-chip radiometric detection of biological samples using radiotracers has become an emerging research field known as microfluidic radiobioassays. Performing parallel radiobioassays is highly desirable for saving time/effort, reducing experimental variation between assays, and minimizing the cost of the radioisotope. Continuously infused microfluidic radioassay (CIMR) is one of the useful tools for investigating cellular pharmacokinetics and assessing the binding and uptakes of radiopharmaceuticals. However, existing CIMR systems can only measure the dynamics of one sample at a time due to the limited field of view (FOV) of the positron detector. To increase the throughput, we propose a new CIMR system with a custom-built miniaturized panel-based positron-emission tomography (PET) scanner and a parallel infusion setup/method, capable of imaging the cellular pharmacokinetics of three samples in one measurement. With this system, the pharmacokinetics of parallel or comparison samples can be imaged simultaneously. The increased throughput is attributed to two innovations: 1) the large 3D FOV of the mini-panel PET scanner, enabling more samples to be imaged in the microfluidic chip; and 2) a parallel infusion method, in which only one reference chamber is needed for indicating the dynamic input of the infused radiotracer medium, thus saving the total reference chambers needed compared to the current sequential infusion method. Combining the CIMR technique and the mini-panel PET scanner, this study also firstly demonstrated the feasibility of using PET, as an imaging modality, for microfluidic radiobioassays. Besides the increased throughput, the 3D imaging of PET also provides possibilities for further applications such as organoid/3D culturing systems, non-planar microfluidics, and organs-on-chips. The system is more practical for a broader range of applications in nuclear medicine, molecular imaging, and lab-on-a-chip studies.

Background Fibroblast growth factor (FGF) and tumor growth factor-β (TGFβ) have emerged as pivotal regulators during the progression of osteosarcoma (OS). LHX9 is one crucial transcription factor controlled by FGF, however, its function in OS has not been investigated yet. Methods The expression of LHX9, FRS2, BMP4, TGF-beta R1, SMAD2, beta-catenin and metastasis-related proteins was measured by real-time quantitative PCR (RT-qPCR) and Western blot. CCK-8 assay and colony formation assay were employed to determine the proliferation of OS cells, while scratch wound healing assay and transwell assay were used to evaluate their migration and invasion, respectively. In vivo tumor growth and metastasis were determined by subcutaneous or intravenous injection of OS cells into nude mice. Results LHX9 expression was evidently up-regulated in OS tumor tissues and cell lines. Knockdown of LHX9 impaired the proliferation, migration, invasion and metastasis of OS cells. Mechanistically, LHX9 silencing led to the down-regulation of BMP-4, β-catenin and metastasis-related proteins, which was also observed in beta-catenin knockdown OS cells. By contrast, FRS2 knockdown conduced to the up-regulation of LHX9, BMP4, β-catenin and TGF-βR1, while TGF-beta inhibition repressed the expression of LHX9 and metastasis-related proteins. Additionally, let-7c modulates LHX9 and metastasis-related proteins by suppressing TGF-beta R1 expression on transcriptional level. Conclusions This study revealed LHX9 was essential for the proliferation, migration, invasion, and metastasis of OS cells via FGF and TGF-β/β-catenin signaling pathways.

Osteoblastic bone formation and osteoclastic bone resorption dynamically maintain the bone homeostasis; in the present study, we attempt to investigate the mechanism of the excessive activation of osteoclasts inducing the deregulation of bone homeostasis from the perspective of non-coding RNA regulation. Differentially expressed patterns of circRNAs were examined in non-treated and RANKL + CSF1-treated bone marrow monocyte/macrophage (BMM) cells and differentially-expressed miRNAs during osteoclast differentiation were analyzed and identified. We found that circRNA_28313 was significantly induced by RANKL + CSF1 treatment. circRNA_28313 knockdown significantly inhibited RANKL + CSF1-induced differentiation of osteoclasts within BMM cells in vitro, while suppressed ovariectomized (OVX)-induced bone resorption in mice in vivo. Via bioinformatics analyses, it has been demonstrated that miR-195a might bind to circRNA_28313 and CSF1 and together form a circRNA-miRNA-mRNA network. circRNA_28313 relieves miR-195a-mediated suppression on CSF1 via acting as a ceRNA, therefore modulating the osteoclast differentiation in BMM cells. In conclusion, circRNA_28313, miR-195a, and CSF1 form a ceRNA network to function in RANKL + CSF1-induced osteoclast differentiation, thus affecting OVX-induced bone absorption in mice.

The mechanism of exosomes derived from activated hepatic stellate cells (HSCs) involved in liver fibrosis is poorly understood. We previously reported that hypoxia-inducible factor 1 (Hif-1) regulated HSC activation, and, therefore, we investigated in current work whether Hif-1 regulates exosome secretion and the metabolic switch of HSCs, thus affecting the metabolism of liver nonparenchymal cells. In this study, the characteristics of exosomes from HSCs were assessed via electron microscopy, Western blot analysis, and acetylcholinesterase activity. Confocal microscopy was used to measure the uptake of exosomes by quiescent HSCs, Kupffer cells (KCs), and liver sinusoidal endothelial cells (LSECs). Hif-1α was inhibited via 2-ME or specific small interfering RNAs to investigate its role in exosomes derived from HSCs. It was determined that glucose transporter 1 and pyruvate kinase M2 were increasingly expressed in fibrotic liver samples, cell lysates, and exosomes derived from activated HSCs. Exosomes released from HSCs were associated with activation and glucose uptake of HSCs. Delivery of exosomes from activated HSCs induced glycolysis of quiescent HSCs, KCs, and LSECs. Disruption of Hif-1 expression suppressed the glycolysis effect delivered by exosomes. Conclusively, our results demonstrated that exosomes secreted by activated HSCs affect the metabolic switch of liver nonparenchymal cells via delivery of glycolysis-related proteins. These findings represent a novel mechanism that contributes to liver fibrosis and has significant implications for new diagnosis and treatment of liver diseases.-Wan, L., Xia, T., Du, Y., Liu, J., Xie, Y., Zhang, Y., Guan, F., Wu, J., Wang, X., Shi, C. Exosomes from activated hepatic stellate cells contain GLUT1 and PKM2: a role for exosomes in metabolic switch of liver nonparenchymal cells.

Osteosarcoma is a common and highly malignant bone tumor among children, adolescents and young adults. However, the underlying molecular mechanisms remain largely unexplored. LncRNAs are transcripts with no or limited protein-coding capacity in human genomes, and have been demonstrated to play crucial functions in initiation, progression, therapeutic resistance, recurrence and metastasis of tumor. Considerable studies revealed a dysregulated lncRNA expression pattern in osteosarcoma, which may act as oncogenes or suppressors to regulate osteosarcoma progression. Wnt signaling pathway is an important cascade in tumorigenesis by modulation of pleiotropic biological functions including cell proliferation, apoptosis, differentiation, stemness, genetic stability and chemoresistance. Hyperactivation or deficiency of key effectors in Wnt cascade is a common event in many osteosarcoma patients. Recently, increasing evidences have suggested that lncRNAs could interplay with component of Wnt pathway, and thereby contribute to osteosarcoma onset, progression and dissemination. In this review, we briefly summarize Wnt signaling-related lncRNAs in osteosarcoma progression, aiming to gain insights into their underlying crosstalk as well as clinical application in osteosarcoma therapeutic modalities.

Alzheimer&rsquo, s disease (AD) is a neurodegenerative disease characterized by decreased glucose metabolism and increased neuroinflammation. Hexokinase (HK) is the key enzyme of glucose metabolism and is associated with mitochondria to exert its function. Recent studies have demonstrated that the dissociation of HK from mitochondria is enough to activate the NOD-like receptor protein 3 (NLRP3) inflammasome and leads to the release of interleukin-1&beta, (IL-1&beta, ). However, the effect of increased IL-1&beta, on the expression of HK is still unclear in AD. In this paper, we used positron emission tomography (PET), Western blotting and immunofluorescence to study the glucose metabolism, and the expression and distribution of HK in AD. Furthermore, we used lipopolysaccharide (LPS), nigericin (Nig), CY-09 and lonidamine (LND) to treat N2a and N2a-sw cells to investigate the link between IL-1&beta, and HK in AD. The results show decreased expression of HK and the dissociation of HK from mitochondria in AD. Furthermore, a reduction of the expression of IL-1&beta, could increase the expression of HK in AD. These results suggest that inhibiting inflammation may help to restore glucose metabolism in AD.

RNA modifications have emerged as key regulators of transcript expression in diverse physiological and pathological processes. As one of the most prevalent types of RNA modifications, N6-methyladenosine (m6A) has become the highlight in modulation of various diseases through interfering RNA splicing, translation, nuclear export, and decay. In many cases, the detailed functions of m6A in cellular processes and diseases remain unclear. Notably, recent studies have determined the relationship between m6A modification and musculoskeletal disorders containing osteosarcoma, osteoarthritis, rheumatoid arthritis, osteoporosis, etc. Herein, this review comprehensively summarizes the recent advances of m6A modification in pathogenesis and progression of musculoskeletal diseases. Specifically, the underlying molecular mechanisms, detection technologies, regulatory functions, clinical implications, and future perspectives of m6A in musculoskeletal disorders are discussed, with the aim to provide a novel insight into their association.

BACKGROUND Incidence of extraskeletal osteosarcoma (ESOS) is extremely low and the prognosis remains unclear. We conducted this study to explore prognostic factors and the role of chemotherapy in ESOS. MATERIAL AND METHODS We screened data from the Surveillance Epidemiology and End Results (SEER) database (1975-2016). Three hundred ten patients with ESOS were included and 49.4% (107/310) of them underwent chemotherapy. We performed logistic regression analysis to investigate potential factors determining selection of chemotherapy. An inverse probability of treatment weighting (IPTW) and propensity score matching (PSM)-adjusted Kaplan-Meier curve was created and log-rank test and Cox regression analysis were performed to compare overall survival (OS) and cancer-specific survival (CSS) in patients treated with and without chemotherapy. Subgroup analysis also was conducted based on age, tumor site, stage, size, and surgery. RESULTS Chemotherapy in ESOS was not associated with improved OS in the unmatched cohort (HR, 0.764; 95% CI, 0.555-1.051; p=0.098). The insignificant treatment effect of chemotherapy was also noted in IPTW-adjusted (HR, 0.737; 95% CI, 0.533-1.021; p=0.066) and PSM-adjusted (HR, 0.804; 95% CI, 0.552-1.172; p=0.257) Cox regression analysis. The insignificant treatment effect was consistent across all subgroups and there was no significant heterogeneity of chemotherapy effect (all p for interaction >0.05). CONCLUSIONS The study suggested that chemotherapy has no significant benefit on prognosis of patients with ESOS. These findings should be considered when making treatment decisions about patients with ESOS.

Highlights • This is the study with relatively large sample size that mainly focused on the duration of viral shedding and relevant factors in patients with COVID-19 outside of Wuhan, China. • The median duration of viral shedding in patients with COVID-19 outside of Wuhan in the current study was 17 days. • The highest temperature at admission, time from symptoms onset to admission and hospital length of stay were risk factors for prolonged duration of viral shedding., Objectives To investigate factors associated with the duration of viral shedding in patients with COVID-19 outside of Wuhan. Methods In this retrospective cohort study, patients with laboratory-confirmed COVID-19 in Changsha, China were included. Clinical characteristics, laboratory findings, treatment and outcome were retrieved. Univariable and multivariable analysis were performed to explore potential factors. Results Totally 147 patients with COVID-19 were included. The median duration of viral shedding (the number of days from symptoms onset till the successive negative detection of SARS-CoV-2 RNA) was 17 days (interquartile range [IQR], 12 to 21). Multivariable Logistic regression analysis indicated that the highest temperature at admission (odds ratio [OR], 5.200; 95% confidence interval [CI]: 1.190-22.726; p = 0.028) and time from symptom onset to admission (OR, 1.740; 95% CI: 1.296-2.337; p

LncRNAs play a pivotal role in the regulation of epigenetic modification, cell cycle, differentiation, proliferation, migration and other physiological activities. In particular, considerable studies have shown that the aberrant expression and dysregulation of lncRNAs are widely implicated in cancer initiation and progression by acting as tumour promoters or suppressors. Hippo signalling pathway has attracted researchers’ attention as one of the critical cancer‐related pathways in recent years. Increasing evidences have demonstrated that lncRNAs could interact with Hippo cascade and thereby contribute to acquisition of multiple malignant hallmarks, including proliferation, metastasis, relapse and resistance to anti‐cancer treatment. Specifically, Hippo signalling pathway is reported to modulate or be regulated by widespread lncRNAs. Intriguingly, certain lncRNAs could form a reciprocal feedback loop with Hippo signalling. More speculatively, lncRNAs related to Hippo pathway have been poised to become important putative biomarkers and therapeutic targets in human cancers. Herein, this review focuses on the crosstalk between lncRNAs and Hippo pathway in carcinogenesis, summarizes the comprehensive role of Hippo‐related lncRNAs in tumour progression and depicts their clinical diagnostic, prognostic or therapeutic potentials in tumours., Increasing evidences have demonstrated that lncRNAs could interact with Hippo signalling cascade and thereby contribute to acquisition of multiple malignant hallmarks, including proliferation, metastasis, relapse and resistance to anti‐cancer treatment. Specifically, Hippo signalling pathway is reported to modulate or be regulated by widespread lncRNAs. Intriguingly, certain lncRNAs could form a reciprocal feedback loop with Hippo signalling. More speculatively, lncRNAs related to Hippo pathway have been poised to become important putative biomarkers and therapeutic targets in human cancers.

Osteoporosis is a metabolic bone lesion in which the bone mass is reduced per unit volume due to increased bone resorption. Its main characteristics are bone pain and increasing danger of fragility fracture. Excessive osteoclast activation is known to be responsible for extensive bone resorption. Thus, inhibition of osteoclastic bone resorption and regulation of the bone microenvironment are vital treatment strategies for osteoporosis. For the first time, we investigated the effect of proanthocyanidins (PACs) extracted from grape seed, which significantly inhibited osteoclast formation and differentiation from bone marrow macrophages (BMMs) and the RAW264.7 cell line and efficiently attenuated osteoclastic bone resorption without toxicity. These findings were confirmed by changes in the NF-κB and JNK/mitogen-activated protein kinase (MAPK) signaling pathways, which are major and classical signaling pathways involved in RANKL-mediated osteoclastogenesis in vitro. The PACs inhibited osteoclast formation and differentiation by inhibiting the NF-κB and JNK signaling pathways and might be useful for the treatment of osteoporosis.

Here we present a compendium of single-cell transcriptomic data from the model organism Mus musculus that comprises more than 100,000 cells from 20 organs and tissues. These data represent a new resource for cell biology, reveal gene expression in poorly characterized cell populations and enable the direct and controlled comparison of gene expression in cell types that are shared between tissues, such as T lymphocytes and endothelial cells from different anatomical locations. Two distinct technical approaches were used for most organs: one approach, microfluidic droplet-based 3'-end counting, enabled the survey of thousands of cells at relatively low coverage, whereas the other, full-length transcript analysis based on fluorescence-activated cell sorting, enabled the characterization of cell types with high sensitivity and coverage. The cumulative data provide the foundation for an atlas of transcriptomic cell biology.

The human brain has evolved for group living [1]. Yet we know so little about how it supports dynamic group interactions that the study of real-world social exchanges has been dubbed the "dark matter of social neuroscience" [2]. Recently, various studies have begun to approach this question by comparing brain responses of multiple individuals during a variety of (semi-naturalistic) tasks [3-15]. These experiments reveal how stimulus properties [13], individual differences [14], and contextual factors [15] may underpin similarities and differences in neural activity across people. However, most studies to date suffer from various limitations: they often lack direct face-to-face interaction between participants, are typically limited to dyads, do not investigate social dynamics across time, and, crucially, they rarely study social behavior under naturalistic circumstances. Here we extend such experimentation drastically, beyond dyads and beyond laboratory walls, to identify neural markers of group engagement during dynamic real-world group interactions. We used portable electroencephalogram (EEG) to simultaneously record brain activity from a class of 12 high school students over the course of a semester (11 classes) during regular classroom activities (Figures 1A-1C; Supplemental Experimental Procedures, section S1). A novel analysis technique to assess group-based neural coherence demonstrates that the extent to which brain activity is synchronized across students predicts both student class engagement and social dynamics. This suggests that brain-to-brain synchrony is a possible neural marker for dynamic social interactions, likely driven by shared attention mechanisms. This study validates a promising new method to investigate the neuroscience of group interactions in ecologically natural settings.

Scorpion venom could be a useful treatment for a variety of diseases, such as cancer, epilepsy and analgesia. BmKTX is a polypeptide extracts from scorpion venom (PESV), which have attracted much attention from researchers in recent years. mBmKTX is a mutant polypeptide according to the amino acid sequence of BmKTX. We expressed it with the vector pGEX-4T-1 in Escherichia coli, and Caenorhabditis elegans were used as the animal model and fed with the strains. In this study, the expression of pGEX-mBmKTX was analyzed by SDS-PAGE, and GST-mBmKTX purified from pGEX-mBmKTX as a glutathione S-transferase (GST)-tagged fusion protein is approximately 30kDa. The secondary structure prediction shows that mBmKTX is mainly composed of approximately 13% β-sheet and 86% loop. A food clearance assay and brood size assay indicated that the worms fed pGEX-mBmKTX ate more and had greater fecundity than those fed the empty vector. A lifespan analysis demonstrated that mBmKTX could significantly prolong the lifespan of C. elegans, with an increase of 22.5% compared with the control. Behavioral assays confirmed that mBmKTX had no influence on the locomotion of C. elegans. In addition, microarray analysis and quantitative real-time PCR demonstrated that there are 320 differentially expressed genes, 182 of which are related to reproduction, growth and lifespan. In conclusion, the data suggested that mBmKTX has potential utility for increasing fecundity and animal survival.

Bone is a rigid yet dynamic organ, and this dynamism is mediated by the delicate balance between osteoclastic bone resorption and osteoblastic bone formation. However, excessive activation of osteoclasts is responsible for many bone diseases such as osteoporosis, Paget disease, and tumor bone metastasis. Agents that could inhibit osteoclast formation or function are regarded as promising alternatives to treat osteoclast-related diseases. Recently, traditional Chinese medicine has attracted attention because of its multiple activities in bone metabolism. Among them, gastrodin has been reported as an anti-osteoporosis agent that reduces reactive oxygen species. However, the direct action of gastrodin on osteoclast differentiation and bone resorption, and its underlying molecular mechanism, remain unknown. In this study, we investigated the effects of gastrodin on receptor activator NF-κB ligand (RANKL)-activated osteoclasts formation and bone resorption. Our results showed that gastrodin retarded RANKL-induced osteoclast differentiation efficiently by downregulating transcriptional and translational expression of nuclear factor of activated T cells cl (NFATc1), a major factor in RANKL-mediated osteoclastogenesis. Meanwhile, gastrodin prevented osteoclast maturation and migration by inhibiting the gene expression of dendrocyte expressed seven transmembrane protein (DC-STAMP), an osteoclastic-specific gene that controls cells fusion and movement. And gastrodin prevented RANKL-induced osteoclastic bone erosion in vitro. In addition, gastrodin also stimulated bone mesenchymal stem cell (BMSC) spreading and osseointegration in titanium plate. In summary, gastrodin could prevent osteoclasts formation and bone resorption via blockage of NFATc1 activity, and stimulate osseointegration in vitro. Gastrodin could be developed as a potent phytochemical candidate to treat osteolytic diseases.

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disease for which there are limited therapeutic strategies. Protein phosphatase 2A (PP2A) activity is decreased in AD brains, which promotes the hyperphosphorylation of Tau and APP, thus participate in the formation of neurofibrillary tangles (NFTs) and β-amyloid (Aβ) overproduction. In this study, the effect of synthetic tricyclic sulfonamide PP2A activators (aka SMAPs) on reducing AD-like pathogenesis was evaluated in AD cell models and AD-like hyperhomocysteinemia (HHcy) rat models. SMAPs effectively increased PP2A activity, and decreased tau phosphorylation and Aβ(40/42) levels in AD cell models. In HHcy-AD rat models, cognitive impairments induced by HHcy were rescued by SMAP administration. HHcy-induced tau hyperphosphorylation and Aβ overproduction were ameliorated through increasing PP2A activity on compound treatment. Importantly, SMAP therapy also prevented neuronal cell spine loss and neuronal synapse impairment in the hippocampus of HHcy-AD rats. In summary, our data reveal that pharmacological PP2A reactivation may be a novel therapeutic strategy for AD treatment, and that the tricyclic sulfonamides constitute a novel candidate class of AD therapeutic. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-020-00841-6) contains supplementary material, which is available to authorized users.

Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified—such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function1—these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus, and integrated these findings with data from the accompanying Tabula Muris Senis2—or ‘Mouse Ageing Cell Atlas’—which follows on from the original Tabula Muris3. We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions—including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue—including plasma cells that express immunoglobulin J—which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age. Bulk RNA sequencing of organs and plasma proteomics at different ages across the mouse lifespan is integrated with data from the Tabula Muris Senis, a transcriptomic atlas of ageing mouse tissues, to describe organ-specific changes in gene expression during ageing.

BACKGROUND: Regional lymph node involvement is thought to be rare in patients with chondrosarcoma, but its actual prevalence is unclear. Additionally, it is often not considered when prognostic factors are analyzed in patients with chondrosarcoma. However, it has been well established that lymph node involvement is a poor prognostic marker in patients with many types of bone and soft tissue sarcoma, including rhabdomyosarcoma, osteosarcoma, and Ewing’s sarcoma. Although lymph node metastases are rare among all sarcoma types, it is important to consider whether lymph node metastases should be assessed in patients with chondrosarcoma because these metastases may impact survival. QUESTIONS/PURPOSES: (1) What is the reported prevalence of regional lymph node involvement in patients with chondrosarcoma? (2) Do patients who have chondrosarcomas with regional lymph node involvement have different clinicopathologic presentations and survival than patients without regional lymph node involvement? (3) Is regional lymph node involvement independently associated with prognosis in patients with chondrosarcoma? METHODS: The data of patients with chondrosarcoma registered in the Surveillance Epidemiology and End Results database (SEER) (1988-2015) were analyzed for the reported prevalence of regional lymph node involvement and its relationship with clinicopathologic features and the 5-year overall survival rate. From 1988 to 2015, 5528 patients with chondrosarcoma were registered in the SEER database. After screening by the inclusion criterion—chondrosarcoma as the first primary tumor, diagnosis with histology confirmation, patients with active followup and available information about regional node status—3374 patients met the inclusion criteria and were analyzed. Demographics and clinicopathologic data were compared using chi-square or Fisher’s exact tests. Logistic regression analysis was used to assess the adjusted odds ratio. The overall survival rate was estimated with Kaplan-Meier curves and log-rank tests. Univariate and multivariate analyses of overall survival were performed with Cox proportional hazard models. In addition, a series of sensitivity analyses were performed to assess the robustness of the final Cox proportional hazard model. RESULTS: Forty-four patients (1.3%) were recorded in the database as having regional lymph node involvement at the time of the primary diagnosis. Lymph node metastases were more likely to be reported in an extraskeletal primary site (3% [13 of 426] versus 1% [31 of 2948], adjusted odds ratio [OR] = 2.9, 95% CI, 1.5–5.8; p = 0.003) for bone primary sites and tumors with maximum diameter ≥ 8 cm (2% [26 of 1045] versus 1% [10 of 1075], adjusted OR = 2.9, 95% CI, 1.3–6.3; p = 0.008) and poorer differentiation (4% [24 of 608] versus 1% [14 of 2308], adjusted OR = 4.0, 95% CI, 2.0–8.2; p < 0.001), and in those with distant metastases (7% [14 of 203] versus 1% [30 of 3148], adjusted OR = 3.5, 95% CI, 1.7–7.1, p = 0.001). The 5-year overall survival rates of patients with and without regional lymph node involvement were 28% (95% CI, 15–42%) and 77% (95% CI, 75–78%), respectively (p < 0.001). After controlling for age, sex, race, grade, metastatic status, size, and histologic subtype, the presence of regional lymph node involvement was associated with poorer survival (hazard ratio, 2.20; 95% CI, 1.50–3.24; p < 0.001); this finding was confirmed in several sensitivity analyses. CONCLUSION: The prevalence of regional lymph node involvement in patients with chondrosarcoma was 1.3% in the SEER database. Although chondrosarcomas are rare, patients with chondrosarcomas who have regional node metastases have a poorer prognosis than those who have not reported to have them. This may underrepresent the true proportion of patients with lymph node metastases given the inaccuracies of reporting in this database, but we believe these findings indicate that clinicians should examine patients more carefully for chondrosarcoma with lymph node metastases. Future studies are needed to assess potential treatment strategies to improve the prognosis of these patients. LEVEL OF EVIDENCE: Level III, prognostic study.

STUDY QUESTION Do changes in tumor necrosis factor-α-induced protein 8 (TNFAIP8)-like 2 (TIPE2) levels in endometrium of patients with adenomyosis alter the proliferation, migration and invasion ability of endometrial cells? SUMMARY ANSWER TIPE2 expression levels were low in eutopic and ectopic endometrium of adenomyosis patients, and TIPE2 inhibited the migration and invasion of endometrial cells, mainly by targeting β-catenin, to reverse the epithelial-mesenchymal transition (EMT). WHAT IS KNOWN ALREADY Adenomyosis is a benign disease, but it has some pathophysiological characteristics similar to the malignant tumor. TIPE2 is a novel negative immune regulatory molecule, and it also participates in the development of malignant tumors. STUDY DESIGN, SIZE, DURATION Control endometrium (n = 48 women with non-endometrial diseases) and eutopic/ectopic endometrium from patients with adenomyosis (n = 50), human endometrial cancer cell lines, and primary endometrial cells from the eutopic endometrium of adenomyosis patients were used in the study. PARTICIPANTS/MATERIALS, SETTING, METHODS The expression level of TIPE2 mRNA and protein in the eutopic/ectopic endometrial tissues of adenomyosis patients and control endometrium was determined by quantitative RT-PCR (qRT-PCR), western blot and immunohistochemistry. The effects of TIPE2 overexpression and knockdown on the proliferation, migration and invasion of endometrial cell lines and primary adenomyotic endometrial cells were determined using a cell counting kit-8, 5-ethynyl-2′-deoxyuridine assay, colony-forming assay, transwell migration assay and matrigel invasion assay. The expression of EMT-related markers and signal molecules was detected by western blot. The interaction between TIPE2 and β-catenin was detected by co-immunoprecipitation and laser confocal microscopy. MAIN RESULTS AND THE ROLE OF CHANCE The mRNA and protein expression levels of TIPE2 in the eutopic and ectopic endometrial tissues of adenomyosis patients were significantly downregulated compared with the control endometrium (P ˂ 0.01). TIPE2 could bind to β-catenin and inhibit the nuclear translocation of β-catenin, downregulate the expression of stromal cell markers, upregulate the expression of glandular epithelial cell markers, decrease the occurrence of epithelial-mesenchymal transition (EMT) and suppress the migration and invasion of endometrial cells (P ˂ 0.01). LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION In this study, the experiments were performed only in eutopic and ectopic endometrial tissues, endometrial cancer cell lines and primary adenomyotic endometrial cells. A mouse model of adenomyosis will be constructed to detect the effects of TIPE2 in vivo. WIDER IMPLICATIONS OF THE FINDINGS These results suggest that TIPE2 is involved in the development of adenomyosis, which provides a potential new diagnostic and therapeutic strategy for the treatment of adenomyosis. STUDY FUNDINGS/COMPETING INTEREST(S) This present study was supported by grants from the National Natural Science Foundation of China (81471437, 81771554), Natural Science Foundation of Shandong (ZR2018MH013), Science and technology development plan provided by Health and Family Planning Committee in Shandong (2014-25). The authors declare that they have no conflicts of interest.

Nonalcoholic steatohepatitis (NASH) is a progressive disease that is often accompanied by metabolic syndrome and poses a high risk of severe liver damage. However, no effective pharmacological treatment is currently available for NASH. Here we report that CASP8 and FADD-like apoptosis regulator (CFLAR) is a key suppressor of steatohepatitis and its metabolic disorders. We provide mechanistic evidence that CFLAR directly targets the kinase MAP3K5 (also known as ASK1) and interrupts its N-terminus-mediated dimerization, thereby blocking signaling involving ASK1 and the kinase MAPK8 (also known as JNK1). Furthermore, we identified a small peptide segment in CFLAR that effectively attenuates the progression of steatohepatitis and metabolic disorders in both mice and monkeys by disrupting the N-terminus-mediated dimerization of ASK1 when the peptide is expressed from an injected adenovirus-associated virus 8-based vector. Taken together, these findings establish CFLAR as a key suppressor of steatohepatitis and indicate that the development of CFLAR-peptide-mimicking drugs and the screening of small-molecular inhibitors that specifically block ASK1 dimerization are new and feasible approaches for NASH treatment.

It remains unknown whether spinal cord injury (SCI) could indirectly impair or reshape the white matter (WM) of human brain and whether these changes are correlated with injury severity, duration, or clinical performance. We choose tract-based spatial statistics (TBSS) to investigate the possible changes in whole-brain white matter integrity and their associations with clinical variables in fifteen patients with SCI. Compared with the healthy controls, the patients exhibited significant decreases in WM fractional anisotropy (FA) in the left angular gyrus (AG), right cerebellum (CB), left precentral gyrus (PreCG), left lateral occipital region (LOC), left superior longitudinal fasciculus (SLF), left supramarginal gyrus (SMG), and left postcentral gyrus (PostCG) (p<0.01, TFCE corrected). No significant differences were found in all diffusion indices between the complete and incomplete SCI. However, significantly negative correlation was shown between the increased radial diffusivity (RD) of left AG and total motor scores (uncorrectedp<0.05). Our findings provide evidence that SCI can cause not only direct degeneration but also transneuronal degeneration of brain WM, and these changes may be irrespective of the injury severity. The affection of left AG on rehabilitation therapies need to be further researched in the future.

Alpha rhythm (8 to 12 Hz) observed in EEG over human posterior cortex is prominent during eyes-closed (EC) resting and attenuates during eyes-open (EO) resting. Research shows that the degree of EC-to-EO alpha blocking or alpha desynchronization, termed alpha reactivity here, is a neural marker of cognitive health. We tested the role of acetylcholine in EC-to-EO alpha reactivity by applying a multimodal neuroimaging approach to a cohort of young adults and a cohort of older adults. In the young cohort, simultaneous EEG-fMRI was recorded from twenty-one young adults during both EO and EC resting. In the older cohort, functional MRI was recorded from forty older adults during EO and EC resting, along with FLAIR and diffusion MRI. For a subset of twenty older adults, EEG was recorded during EO and EC resting in a separate session. In both young and older adults, functional connectivity between the basal nucleus of Meynert (BNM), the major source of cortical acetylcholine, and the visual cortex increased from EC to EO, and this connectivity increase was positively associated with alpha reactivity; namely, the stronger the BNM-visual cortex functional connectivity increase from EC to EO, the larger the EC-to-EO alpha desynchronization. In older adults, lesions of the fiber tracts linking BNM and visual cortex quantified by leukoaraiosis volume, associated with reduced alpha reactivity. These findings support a role of acetylcholine and particularly cholinergic pathways in mediating EC-to-EO alpha reactivity and suggest that impaired alpha reactivity could serve as a marker of the integrity of the cholinergic system.

Programmed cell death 4 (PDCD4) has been identified as a tumor‑suppressor gene that inhibits neoplastic transformation, tumor progression, and protein translation. It has been reported that multiple factors participate in the regulation of PDCD4 mRNA and protein. The endometrium is regulated by changing concentrations of ovarian hormones, such as estrogen and progesterone, and shows periodical changes. However, whether ovarian hormones regulate PDCD4 expression remains unclear. This study aimed to explore the effect and mechanism of estrogen or progesterone on PDCD4 mRNA and protein expression in human endometrial cancer cells. The expression of PDCD4 mRNA and protein in Ishikawa and HEC‑1‑A cells was detected by quantitative real‑time PCR and western blot analysis. The signaling pathway‑related proteins were detected by western blot analysis. The results showed that PDCD4 mRNA levels exhibited no significant changes after treatment with estrogen or progesterone in both Ishikawa and HEC‑1‑A cell lines. Estrogen also had no obvious effect on PDCD4 protein expression. However, progesterone effectively decreased the expression of PDCD4 protein and the PI3K/AKT pathway may be involved in the downregulation of PDCD4 protein induced by progesterone. These results suggest that the downregulation of PDCD4 induced by progesterone affects the therapeutic efficacy of progesterone in human endometrial cancer or endometriosis, which may have important implications for progesterone treatment in the clinic.

Endometriosis (EM) is a kind of estrogen-dependent disease in reproductive-age women. Ovarian EM is the most common type. Although EM is a benign disease, it shares many similar features with cancers. Programmed cell death 4 (PDCD4), a newly identified tumor suppressor, plays an important role in inhibiting tumorigenesis and tumor progression at the transcriptional and translational levels. To explore the roles of PDCD4 in EM, we detected the expression of PDCD4 in control endometrium and eutopic/ectopic endometrium of ovarian EM patients, and analyzed the effects of PDCD4 on the biological behaviors of endometrial cell lines and primary endometrial cells. The results demonstrated that PDCD4 was downregulated in eutopic and ectopic endometrium of EM patients compared with control endometrium. PDCD4 effectively inhibited the proliferation and colony-forming ability of endometrial cells maybe by inhibiting cell autophagy. In addition, PDCD4 also suppressed the migration and invasion ability of endometrial cells, the mechanism may be related to NF-κB/MMP2/MMP9 signal pathway. Taken together, these results suggest that PDCD4 could be involved in the pathogenesis of EM, and provide a novel approach to target the aberrant PDCD4 expression in EM.

Missed abortion is a special form of spontaneous abortion and its incidence shows a rising trend. Immunological factor is one of the most common reasons. Tumor suppressor gene programmed cell death 4 ( PDCD4) also participates in some immune-mediated inflammation, such as atherosclerosis, and so on, but the role of PDCD4 in missed abortion remains unclear. Here, the expression of PDCD4 was detected in decidual and chorionic tissues, as well as peripheral blood mononuclear cells from patients with missed abortion and healthy controls using quantitative real-time polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemistry. The expression of cytokines was also detected in decidual tissues using qRT-PCR. The levels of serum estradiol and progesterone were measured by radioimmunoassay. In addition, the correlations of PDCD4 expression with cytokines and hormones were analyzed. The results demonstrated that PDCD4 expression was reduced in decidual tissues from the missed abortion group compared with the control group. The levels of tumor necrosis factor α were significantly higher in decidual tissues of missed abortion patients than those in normal controls. We also found serum estradiol and progesterone levels were significantly lower in the missed abortion group than those in the control group, and serum progesterone level was inversely related to PDCD4 messenger RNA level. The data suggested that reduced PDCD4 expression may be involved in the occurrence of missed abortion. This may facilitate the potential development of novel diagnostic and therapeutic strategies for the treatment of missed abortion.

Liver fibrosis is characterized by deposition of excessive extracellular matrix (ECM). The major source of ECM is activated hepatic stellate cells (HSCs). Previously, we reported that hypoxia-inducible factor-1 (Hif-1) regulates activation of HSCs through autophagy. In current work, human HSC cell line LX-2 was used as cell model. It was determined that trimethylation of H3 histone on lysine 4 (H3K4me3) occurred in the Hif-1 transcriptional complex. Inhibition of modifications of histone methylation suppressed Hif-1 nuclear transport, autophagosome formation, and activation of LX-2 cells. These data suggest that histone methylation modification plays an important role in the Hif-1 signaling cascade regulating HSC activation.

The aim of this study was to explore possible changes in whole brain gray matter volume (GMV) after spinal cord injury (SCI) using voxel-based morphometry (VBM), and to study their associations with the injury duration, severity, and clinical variables. In total, 21 patients with SCI (10 with complete and 11 with incomplete SCI) and 21 age- and sex-matched healthy controls (HCs) were recruited. The 3D high-resolution T1-weighted structural images of all subjects were obtained using a 3.0 Tesla MRI system. Disease duration and American Spinal Injury Association (ASIA) Scale scores were also obtained from each patient. Voxel-based morphometry analysis was carried out to investigate the differences in GMV between patients with SCI and HCs, and between the SCI sub-groups. Associations between GMV and clinical variables were also analyzed. Compared with HCs, patients with SCI showed significant GMV decrease in the dorsal anterior cingulate cortex, bilateral anterior insular cortex, bilateral orbital frontal cortex (OFC), and right superior temporal gyrus. No significant difference in GMV in these areas was found either between the complete and incomplete SCI sub-groups, or between the sub-acute (duration 1 year) sub-groups. Finally, the GMV of the right OFC was correlated with the clinical motor scores of left extremities in not only all SCI patients, but especially the CSCI subgroup. In the sub-acute subgroup, we found a significant positive correlation between the dACC GMV and the total clinical motor scores, and a significant negative correlation between right OFC GMV and the injury duration. These findings indicate that SCI can cause remote atrophy of brain gray matter, especially in the salient network. In general, the duration and severity of SCI may be not associated with the degree of brain atrophy in total SCI patients, but there may be associations between them in subgroups.

Background Missed abortion is a common occurrence for otherwise healthy women. Immunological factor is one of the most important reasons. Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) is a novel negative immune regulator related to several human diseases. However, the expression level and clinical significance of TIPE2 in missed abortion remain unclear. Methods The expression of TIPE2 mRNA and protein in decidua and chorion from 36 missed abortion patients and 36 healthy controls was detected using quantitative real-time PCR, western blot and immunohistochemistry. In addition, serum TNF-ɑ and IL-10 levels were measured using flow cytometry. Serum estradiol and progesterone levels were measured by radioimmunoassay test. The correlations of TIPE2 protein levels with TNF-ɑ, IL-10, estradiol and progesterone were further analyzed. Results TIPE2 protein levels were significantly lower in decidual tissues of missed abortion patients than those in healthy controls. The patients with missed abortion had significantly higher levels of serum TNF-ɑ, and lower levels of serum IL-10, estradiol and progesterone compared with healthy controls. The TIPE2 protein levels were positively related to serum IL-10 levels. Conclusion Our data indicate TIPE2 could play important roles in maintaining the maternal-fetal tolerance and decreased TIPE2 expression in the decidua may be related to the development of missed abortion.

This study aimed to determine the association between different lymphocyte subsets and cytomegalovirus (CMV) infection status in patients with systemic lupus erythematosus (SLE). We performed a retrospective study among SLE patients with CMV infection and collected patient socio-demographic and clinical characteristics, as well as their recorded circulating lymphocyte subsets. Univariate and multivariable logistic regression analyses examined the relationship between CMV infection status and lymphocyte subset counts. We included 125 hospitalized patients with SLE, consisting of 88 with documented CMV infection and 37 without any evidence of CMV or other infections. Among the 88 CMV-infected patients, 65 (73.8%) patients developed CMV disease and 23 (26.2%) presented as CMV viremia. Compared to uninfected patients (1520 ± 101 cells/μL), lymphocytes remained stable among those with CMV viremia (1305 ± 272 cells/μL, P = .995). However, compared to their uninfected counterparts, there was a marked decrease in lymphocytes among patients with CMV disease (680 ± 513 cells/μL, P

Chun-Xiao Zhang,* Shu-Yi Wang,* Shuang-Qian Chen, Shuai-Long Yang, Lu Wan, Bin Xiong Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study Center, Wuhan, Hubei, People’s Republic of China *These authors contributed equally tothis work Background: Glasgow prognostic score (GPS) is widely known as a systemic inflammatory-based marker. The relationship between pretreatment GPS and gastric cancer (GC) survival and clinicopathological features remains controversial. The aim of the study was to conduct a meta-analysis of published studies to evaluate the association between pretreatment GPS and survival and clinicopathological features in GC patients. Methods: We searched PubMed, Embase, MEDLINE, and BioMed databases for relevant studies. Combined analyses were used to assess the association between pretreatment GPS and overall survival, disease-free survival, and clinicopathological parameters by Stata Version 12.0. Results: A total of 14 studies were included in this meta-analysis, including 5,579 GC patients. The results indicated that pretreatment high GPS (HGPS) predicted poor overall survival (hazard ratio =1.51, 95% CI: 1.37–1.66, P

Ovarian cancer is the leading cause of death among gynecological malignancies, and high grade serous ovarian carcinoma is the most common and most aggressive subtype. Recently, it was demonstrated that cAMP mediates protein kinase A-independent effects through Epac (exchange protein directly activated by cAMP) proteins. Epac proteins, including Epac1 and Epac2, are implicated in several diverse cellular responses, such as insulin secretion, exocytosis, cellular calcium handling and formation of cell-cell junctions. Several reports document that Epac1 could play vital roles in promoting proliferation, invasion and migration of some cancer cells. However, the expression levels and roles of Epac1 in ovarian cancer have not been investigated. In the present study, we detected the expression levels of Epac1 mRNA and protein in three kinds of ovarian cancer cells SKOV3, OVCAR3 and CAOV3. Furthermore, the effect of Epac1 knockdown on the proliferation and apoptosis of SKOV3 and OVCAR3 cells was evaluated in vitro and in vivo. The results showed that there was higher expression of Epac1 mRNA and protein in SKOV3 and OVCAR3 cells. Epac1 knockdown inhibited the proliferation of SKOV3 and OVCAR3 cells in vitro and in vivo. Decreased proliferation may be due to downregulation of Epac1-induced G1 phase arrest by inactivating the AKT/Cyclin D1/CDK4 pathway, but not to alterations in the MAPK pathway or to apoptosis. Taken together, our data provide new insight into the essential role of Epac1 in regulating growth of ovarian cancer cells and suggest that Epac1 might represent an attractive therapeutic target for treatment of ovarian cancer.

Nat. Med. 23, 439–449 (2017); published online 20 February 2017; corrected after print 26 July 2017 In the version of this article initially published, the authors inadvertently left out information in the Online Methods section regarding a second injection of AAV8-CFLAR(S1) 7 weeks after the first injection in the monkey experiments to ensure stable expression of CFLAR(S1) in the livers of the monkeys that received the injections.

The scorpion has been extensively used in various pharmacological profiles or as food supplies. The exploration of scorpion venom has been reported due to the presence of recombinant peptides. rBmαTX14 is an α-neurotoxin extracted from the venom gland of the East Asian scorpion Buthus martensii Karsch and can affect ion channel conductance. Here, we investigated the functions of rBmαTX14 using the Caenorhabditis elegans model. Using western blot analysis, rBmαTX14 was shown to be expressed both in the cytoplasm and inclusion bodies in the E.coli Rosetta (DE3) strain. Circular dichroism spectroscopy analysis demonstrated that purified rBmαTX14 retained its biological structures. Next, feeding nematodes with E.coli Rosetta (DE3) expressing rBmαTX14 caused extension of the life span and promoted the locomotion of the nematodes. In addition, we identified several genes that play various roles in the life span and locomotion of C. elegans through microarray analysis and quantitative real-time PCR. Furthermore, if the amino acid site H15 of rBmαTX14 was mutated, rBmαTX14 no longer promoted the C. elegans life span. In conclusion, the results not only demonstrated the functions and mechanism of rBmαTX14 in C. elegans, but also provided the new sight in the utility of recombinant peptides from scorpion venom.