Although long non-coding RNAs (lncRNAs) predominately reside in the nucleus and exert their functions in many biological processes, their potential involvement in cytoplasmic signal transduction remains unexplored. Here, we identify a cytoplasmic lncRNA, LINK-A (long intergenic non-coding RNA for kinase activation), which mediates HB-EGF-triggered, EGFR:GPNMB heterodimer-dependent HIF1α phosphorylation at Tyr 565 and Ser 797 by BRK and LRRK2, respectively. These events cause HIF1α stabilization, HIF1α-p300 interaction, and activation of HIF1α transcriptional programs under normoxic conditions. Mechanistically, LINK-A facilitates the recruitment of BRK to the EGFR:GPNMB complex and BRK kinase activation. The BRK-dependent HIF1α Tyr 565 phosphorylation interferes with Pro 564 hydroxylation, leading to normoxic HIF1α stabilization. Both LINK-A expression and LINK-A-dependent signalling pathway activation correlate with triple-negative breast cancer (TNBC), promoting breast cancer glycolysis reprogramming and tumorigenesis. Our findings illustrate the magnitude and diversity of cytoplasmic lncRNAs in signal transduction and highlight the important roles of lncRNAs in cancer.

Many patients with irritable bowel syndrome IBS not only have abdominal pain but also may suffer from visceral hypersensitivity and heighted visceral nociception. Moreover, IBS has few effective therapeutic agents and mechanisms of disease are unclear. Our goals were to (i) identify microRNA (miRNA) expression, signalling and targets in human colon (controls; patients with IBS); (ii) verify in vitro, IBS-associated changes in miRNAs, especially miR-199, which is complementary to the transient receptor potential vanilloid type 1 (TRPV1) gene; and (iii) determine whether modulating the expression of miRNAs in vivo, especially miR-199, reverses associated changes and pathological hallmarks of visceral hypersensitivity via TRPV1 signalling.

The nuclear p68 RNA helicase (referred to as p68) is a prototypical member of the DEAD box family of RNA helicases. The protein plays a very important role in early organ development. In the present study, we characterized the tyrosine phosphorylation of p68 under platelet-derived growth factor (PDGF) stimulation. We demonstrated that tyrosine phosphorylation of p68 at Y593 mediated PDGF-stimulated epithelial-mesenchymal transition (EMT). We showed that PDGF treatment led to phosphorylation of p68 at Y593 in the cell nucleus. The Y593-phosphorylated p68 (referred to as phosphor-p68) promotes beta-catenin nuclear translocation via a Wnt-independent pathway. The phosphor-p68 facilitates beta-catenin nuclear translocation by blocking phosphorylation of beta-catenin by GSK-3beta and displacing Axin from beta-catenin. The beta-catenin nuclear translocation and subsequent interaction with the LEF/TCF was required for the EMT process. These data demonstrated a novel mechanism of phosphor-p68 in mediating the growth factor-induced EMT and uncovered a new pathway to promote beta-catenin nuclear translocation.

Schizophrenia is a disorder characterized by functional dysconnectivity among distributed brain regions. However, it is unclear how causal influences among large-scale brain networks are disrupted in schizophrenia. In this study, we used dynamic causal modeling (DCM) to assess the hypothesis that there is aberrant directed (effective) connectivity within and between three key large-scale brain networks (the dorsal attention network, the salience network and the default mode network) in schizophrenia during a working memory task. Functional MRI data during an n-back task from 40 patients with schizophrenia and 62 healthy controls were analyzed. Using hierarchical modeling of between-subject effects in DCM with Parametric Empirical Bayes, we found that intrinsic (within-region) and extrinsic (between-region) effective connectivity involving prefrontal regions were abnormal in schizophrenia. Specifically, in patients (i) inhibitory self-connections in prefrontal regions of the dorsal attention network were decreased across task conditions; (ii) extrinsic connectivity between regions of the default mode network was increased; specifically, from posterior cingulate cortex to the medial prefrontal cortex; (iii) between-network extrinsic connections involving the prefrontal cortex were altered; (iv) connections within networks and between networks were correlated with the severity of clinical symptoms and impaired cognition beyond working memory. In short, this study revealed the predominance of reduced synaptic efficacy of prefrontal efferents and afferents in the pathophysiology of schizophrenia.

Arc is a synaptic protein essential for memory consolidation. Recent studies indicate that Arc originates in evolution from a Ty3-Gypsy retrotransposon GAG domain. The N-lobe of Arc GAG domain acquired a hydrophobic binding pocket in higher vertebrates that is essential for Arc's canonical function to weaken excitatory synapses. Here, we report that Arc GAG also acquired phosphorylation sites that can acutely regulate its synaptic function. CaMKII phosphorylates the N-lobe of the Arc GAG domain and disrupts an interaction surface essential for high-order oligomerization. In Purkinje neurons, CaMKII phosphorylation acutely reverses Arc's synaptic action. Mutant Arc that cannot be phosphorylated by CaMKII enhances metabotropic receptor-dependent depression in the hippocampus but does not alter baseline synaptic transmission or long-term potentiation. Behavioral studies indicate that hippocampus- and amygdala-dependent learning requires Arc GAG domain phosphorylation. These studies provide an atomic model for dynamic and local control of Arc function underlying synaptic plasticity and memory.

In spring 2013, a novel avian-origin influenza A (H7N9) virus emerged in mainland China. The burden of H7N9 infection was estimated based on systematic review and meta-analysis. The systematic search for available literature was conducted using Chinese and English databases. We calculated the pooled seroprevalence of H7N9 infection and its 95% confidence interval by using Freeman-Tukey double arcsine transformation. Out of 16 890 records found using Chinese and English databases, 54 articles were included in the meta-analysis. These included studies of a total of 64 107 individuals. The pooled seroprevalence of H7N9 infection among humans was 0.122% (95% CI: 0.023, 0.275). In high-risk populations, the highest pooled seroprevalence was observed among close contacts (1.075%, 95% CI: 0.000, 4.357). The seroprevalence among general population was (0.077%, 95% CI: 0.011, 0.180). Our study discovered that asymptomatic infection of H7N9 virus did occur, even if the seroprevalence among humans was low.

Sliding window analysis has been extensively applied in evolutionary biology. With the development of the high-throughput DNA sequencing of organisms at the population level, an application that is dedicated to visualizing population genetic test statistics at the genomic level is needed. We have developed the sliding window analysis viewer (SWAV), which is a web-based program that can be used to integrate, view and browse test statistics and perform genome annotation. In addition to browsing, SAV can mark, generate and customize statistical images and search by sequence alignment, position or gene name. These features facilitate the effectiveness of sliding window analysis. As an example application, yeast and silkworm resequencing data are analyzed with SWAV. The SWAV package, user manual and usage demo are available at http://swav.popgenetics.net.

PVT1 has emerged as an oncogene in many tumor types. However, its role in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) is unknown. The aim of this study was to assess the role of PVT1 in BE/EAC progression and uncover its therapeutic value against EAC.

Norovirus (NoV) is a major cause of sporadic cases and outbreaks of acute gastroenteritis (AGE), thereby imposing threat to health globally. It is unclear how quantitation of wastewater NoV reflects the incidence of human AGE infections; therefore, we conducted this systematic review and meta-analysis of published NoV wastewater surveillance studies. A literature search was performed, and all studies on NoV wastewater surveillance were identified. Quantitative results were evaluated. The results showed that the overall detection rate of NoV in wastewater was 82.10% (95% confidence interval [CI]: 74.22-89.92%); NoV concentration was statistically significant in terms of season (P < 0.001), with higher concentration in spring and winter. There were positive correlations between NoV GII concentration in wastewater and GII AGE cases (rs = 0.51, 95% CI: 0.18-0.74, I2 = 0%), total AGE cases (rs = 0.40, 95% CI: 0.15-0.61, I2 = 23%) and NoV outbreaks (rs = 0.47, 95% CI: 0.30-0.62, I2 = 0%). Results of cross-correlation analysis of partial data indicated that variations in GII concentration were consistent with or ahead of those in the number of AGE cases. The diversity of NoV genotypes in wastewater was elucidated, and the dominant strains in wastewater showed a consistent temporal distribution with those responsible for human AGE. Our study demonstrated the potential association of NoV detected in wastewater with AGE infections, and further studies are needed to confirm this conclusion.

Radix Puerariae (RP), a dry root of Pueraria lobata (Willd.) Ohwi, is used to treat a variety of diseases, including cancer. Several in vitro and in vivo studies have demonstrated the efficacy of RP in the treatment of colon cancer (CC). However, the biological mechanism of RP in the treatment of colon cancer remains unclear. In this study, the active component of RP and its potential molecular mechanism against CC were studied by network pharmacology and enrichment analysis. The methods adopted included screening active ingredients of Chinese medicine, predicting target genes of Chinese medicine and disease, constructing of a protein interaction network, and conducting GO and KEGG enrichment analysis. Finally, the results of network pharmacology were further validated by molecular docking experiments and cell experiments. Eight active constituents and 14 potential protein targets were screened from RP, including EGFR, JAK2 and SRC. The biological mechanism of RP against CC was analysed by studying the relationship between active components, targets, and enrichment pathways. These findings provide a basis for understanding the clinical application of RP in CC.

Gastric cancer is one of the most common malignancies harmful to human health. The search for effective drugs or gene therapy has aroused the attention of scientists. So far, microRNAs, as small non-coding RNAs, have the potential to be therapeutic targets for cancer. Herein, we found a highly expressed miR-25 in gastric cancer cell. However, the function of miR-25 for gastric cancer cell growth and apoptosis was unknown. Functionally, we used RT-qPCR, western blot, CCK-8, and flow cytometry to detect gastric cancer cell growth and apoptosis. The results indicated that miR-25 promoted gastric cancer cell growth and inhibited their apoptosis. Mechanistically, we found that a gene EGR2 was a potential target gene of miR-25. Further dual-luciferase results supported this prediction. Moreover, knockdown of EGR2 promoted gastric cancer cell growth and inhibited their apoptosis by flow cytometry detection. Altogether, these findings revealed miR-25 as a regulator of gastric cancer cell growth and apoptosis through targeting EGR2.

One of the major obstacles to treating pancreatic ductal adenocarcinoma (PDAC) is its immunoresistant microenvironment. The functional importance and molecular mechanisms of Schwann cells in PDAC remains largely elusive. We characterized the gene signature of tumor-associated nonmyelinating Schwann cells (TASc) in PDAC and indicated that the abundance of TASc was correlated with immune suppressive tumor microenvironment and the unfavorable outcome of patients with PDAC. Depletion of pancreatic-specific TASc promoted the tumorigenesis of PDAC tumors. TASc-expressed long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was triggered by the tumor cell-produced interleukin-6. Mechanistically, PVT1 modulated RAF proto-oncogene serine/threonine protein kinase-mediated phosphorylation of tryptophan 2,3-dioxygenase in TASc, facilitating its enzymatic activities in catalysis of tryptophan to kynurenine. Depletion of TASc-expressed PVT1 suppressed PDAC tumor growth. Furthermore, depletion of TASc using a small-molecule inhibitor effectively sensitized PDAC to immunotherapy, signifying the important roles of TASc in PDAC immune resistance.

The importance of ambient particulate matter (PM2.5) in lung cancer progression is well established; however, the precise mechanisms by which PM2.5 modulates lung cancer development have not yet been determined. The present study demonstrated increased mRNA and protein expression levels of vascular endothelial growth factor in PM2.5-induced macrophages. However, no significant changes to the expression levels of angiogenic cytokines (vascular endothelial growth factor A, matric metallopeptidase 9, basic fibroblast growth factor and platelet-derived growth factor) were observed in the Lewis lung carcinoma (LLC) cell line in response to acute PM2.5 exposure. PM2.5-induced activated macrophages were revealed to upregulate angiogenic cytokine expression following the acute exposure of LLC cells to PM2.5-induced macrophage supernatant. In vivo, the pro-angiogenic and macrophage accumulation functions of PM2.5 were supported by the establishment of a polyvinyl alcohol sponge implantation mouse model. Furthermore, PM2.5 was demonstrated to increase angiogenesis and macrophage recruitment in mice that were subcutaneously injected with LLCs. These results indicated that PM2.5 increases angiogenesis, and macrophages are crucial mediators of PM2.5-induced angiogenesis in lung cancer. These findings may provide novel insights for the development of lung cancer treatment strategies.

Sertoli cells (SCs) are important testicular somatic cells that carry out various functions in spermatogenesis. Understanding the biological mechanisms underlying SC development may facilitate the understanding of animal reproduction. Anti-Mullerian hormone (AMH) is a dimeric glycoprotein produced by SCs and plays essential roles in spermatogenesis. In this study, we cloned the coding sequence of the yak AMH, predicated the structure of AMH protein, analyzed AMH expression in the testis at different stages, and studied the functions of AMH in yak SCs. The open reading frame (ORF) of the yak AMH contained 1728 bp and encoded 575 amino acids. Structural analysis revealed that the yak AMH protein had a highly conserved transforming growth factor-β (TGF-β) domain. The mRNA expression level for the AMH gene in yak testis increased significantly from the fetal stage to calf stage, then decreased with the increase of age. The highest expression was found in calf stage. Cell proliferation was depressed in AMH-deficient SCs. Expression of several genes involved in SC proliferation and development, including PCNA, BCL-2, BAX, CASP3, AR and AMHR2 were altered after knockdown of AMH. Also, three SC-secreted factors essential for spermatogenesis, SCF, GDNF and ABP, were repressed at the transcription level after AMH knockdown in yak SCs. Moreover, supplementation with exogenous AMH protein partially rescued SC proliferation, and the expression of PCNA, BCL-2, AR and AMHR2 after AMH gene interference. This research provided theoretical basis for understanding the mechanism by which AMH regulates yak spermatogenesis and might give new insights in improving yak reproductive performance in the future.

Carbon quantum dots (CQDs) were manufactured from citric acid and urea in a gram-scale synthesis with a controlled size range between 1. 5 and 23.8 nm. The size control was realized by varying volume of the precursor solution in a hydrothermal synthesis method. The prepared CQDs were investigated using electrochemiluminescence (ECL) spectroscopy at interfaces of their electrode films and electrolyte solution containing coreactants rather than conventional optoelectronic tests, providing an in-depth analysis of light-emission mechanisms of the so-called half-cells. ECL from the CQD films with TPrA and K2S2O8 as coreactants provided information on the stability of the CQD radicals in the films. It was discovered that CQD•- has a powerful electron donating nature to sulfate radical to generate ECL at a relative efficiency of 96% to the Ru(bpy)3Cl2/K2S2O8 coreactant system, indicating a strong performance in light emitting applications. The smaller the CQD particle sizes, the higher the ECL efficiency of the film interface, most likely due to the increased presence of surface states per mass of CQDs. Spooling ECL spectroscopy of the system revealed a potential-dependent light emission starting from a deep red color to blue-shifted intensity maximum, cool bright white emission with a correlated color temperature of 3,200 K. This color temperature is appropriate for most indoor lighting applications. The above ECL results provide information on the performance of CQD light emitters in films, permitting preliminary screening for light emitting candidates in optoelectronic applications. This screening has revealed CQD films as a powerful and cost-effective light emitting layer toward lighting devices for indoor applications.

Intrauterine adhesion seriously affects reproductive health in women. Hysteroscopic adhesiolysis using cold scissors or electrosurgery is the main treatment, although there is no consensus on the preferable method. This review aimed to compare the efficacy and safety of these methods for treating moderate to severe intrauterine adhesion.

Obesity, in which the functional importance of small nucleolar RNAs (snoRNAs) remains elusive, correlates with risk for many cancer types. Here, we identify that the serum copies of adipocyte-expressed SNORD46 correlate with body mass index (BMI), and serum SNORD46 antagonizes interleukin-15 (IL-15) signaling. Mechanically, SNORD46 binds IL-15 via G11, and G11A (a mutation that significantly enhances binding affinity) knockin drives obesity in mice. Functionally, SNORD46 blocks IL-15-induced, FER kinase-dependent phosphorylation of platelet glycoprotein 4 (CD36) and monoglyceride lipase (MGLL) in adipocytes, leading to inhibited lipolysis and browning. In natural killer (NK) cells, SNORD46 suppresses the IL-15-dependent autophagy, leading to reduced viability of obese NK. SNORD46 power inhibitors exhibit anti-obesity effects, concurring with improved viability of obese NK and anti-tumor immunity of CAR-NK cell therapy. Hence, our findings demonstrate the functional importance of snoRNAs in obesity and the utility of snoRNA power inhibitors for antagonizing obesity-associated immune resistance.

Effective pain control of herpes zoster ophthalmicus (HZO) is not only essential to attenuate the clinical symptoms but to reduce the risk of postherpetic neuralgia development. Recently, neuromodulation therapy has been one promising option for neuropathic pain and increasingly applied in management of zoster-related pain. One key factor of neuromodulation treatment is the therapeutic site for the impaired nerves. In this study we aim to investigate one novel dual-neuromodulation strategy, targeting the level of the peripheral branch and trigeminal ganglion, in the pain management of HZO.

Accurate identification and localization of multiple abnormalities are crucial steps in the interpretation of chest X-rays (CXRs); however, the lack of a large CXR dataset with bounding boxes severely constrains accurate localization research based on deep learning. We created a large CXR dataset named CXR-AL14, containing 165,988 CXRs and 253,844 bounding boxes. On the basis of this dataset, a deep-learning-based framework was developed to identify and localize 14 common abnormalities and calculate the cardiothoracic ratio (CTR) simultaneously. The mean average precision values obtained by the model for 14 abnormalities reached 0.572-0.631 with an intersection-over-union threshold of 0.5, and the intraclass correlation coefficient of the CTR algorithm exceeded 0.95 on the held-out, multicentre and prospective test datasets. This framework shows an excellent performance, good generalization ability and strong clinical applicability, which is superior to senior radiologists and suitable for routine clinical settings.

Although recent studies have indicated roles of long non-coding RNAs (lncRNAs) in physiological aspects of cell-type determination and tissue homeostasis, their potential involvement in regulated gene transcription programs remains rather poorly understood. The androgen receptor regulates a large repertoire of genes central to the identity and behaviour of prostate cancer cells, and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy. Here we report that two lncRNAs highly overexpressed in aggressive prostate cancer, PRNCR1 (also known as PCAT8) and PCGEM1, bind successively to the androgen receptor and strongly enhance both ligand-dependent and ligand-independent androgen-receptor-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the carboxy-terminally acetylated androgen receptor on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the androgen receptor amino terminus that is methylated by DOT1L. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited pygopus 2 PHD domain enhances selective looping of androgen-receptor-bound enhancers to target gene promoters in these cells. In 'resistant' prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full-length androgen receptor, causing ligand-independent activation of the androgen receptor transcriptional program and cell proliferation. Conditionally expressed short hairpin RNA targeting these lncRNAs in castration-resistant prostate cancer cell lines strongly suppressed tumour xenograft growth in vivo. Together, these results indicate that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumours.