Search

Our objective was to examine the impact of elective neck dissection (END) on the prognosis of patients with cT2N0 maxillary sinus squamous cell carcinoma (MS-SCC) and to determine factors that predict the occurrence of occult metastasis in this patient population. A retrospective analysis was conducted using data from the SEER database. Patients with cT2N0 MS-SCC were included in the study and divided into two groups: those who received END and those who did not. The impact of END on disease-specific survival (DSS) and overall survival (OS) was assessed using propensity score matching. Multivariate logistic regression analysis was performed to determine predictors for occult metastasis. A total of 180 patients were included in the study, with 40 cases receiving END. Following propensity score matching, patients treated with END and those without showed similar DSS and OS rates. Occult metastasis was observed in 9 patients, corresponding to a rate of 22.5%. High-grade tumors were independently associated with a higher risk of occult metastasis compared to low-grade tumors (hazard ratio 1.52, 95% confidence interval 1.17-2.00). cT2 MS-SCC carries an occult metastasis rate of 22.5%, with histologic grade being the primary determinant of occult metastasis. END does not confer a significant survival benefit in this patient population., (© 2024. The Author(s).)

Despite extensive research on the relationship between choline and cardiovascular disease (CVD), conflicting findings have been reported. We aim to investigate the relationship between choline and CVD. Our analysis screened a retrospective cohort study of 14,663 participants from the National Health and Nutrition Examination Survey conducted between 2013 and 2018. Propensity score matching and restricted cubic splines was used to access the association between choline intake and the risk of CVD. A two-sample Mendelian randomization (MR) analysis was conducted to examine the potential causality. Additionally, sets of single cell RNA-sequencing data were extracted and analyzed, in order to explore the role of choline metabolism pathway in the progression and severity of the CVD and the underlying potential mechanisms involved. The adjusted odds ratios and 95% confidence intervals for stroke were 0.72 (0.53-0.98; p = 0.035) for quartile 3 and 0.54 (0.39-0.75; p < 0.001) for quartile 4. A stratified analysis revealed that the relationship between choline intake and stroke varied among different body mass index and waist circumference groups. The results of MR analysis showed that choline and phosphatidylcholine had a predominantly negative causal effect on fat percentage, fat mass, and fat-free mass, while glycine had opposite effects. Results from bioinformatics analysis revealed that alterations in the choline metabolism pathway following stroke may be associated with the prognosis. Our study indicated that the consumption of an appropriate quantity of choline in the diet may help to protect against CVD and the effect may be choline-mediated, resulting in a healthier body composition. Furthermore, the regulation of the choline metabolism pathway following stroke may be a promising therapeutic target., (© 2024. The Author(s).)

Microglia are natural immune cells in the central nervous system, and the activation of microglia is accompanied by a reprogramming of glucose metabolism. In our study, we investigated the role of long non-coding RNA taurine-upregulated gene 1 (TUG1) in regulating microglial glucose metabolism reprogramming and activation. BV2 cells were treated with Lipopolysaccharides (LPS)/Interferon-γ (IFN-γ) to establish a microglial activation model. The glycolysis inhibitor 2-Deoxy-D-glucose (2-DG) was used as a control. The expression levels of TUG1 mRNA and proinflammatory cytokines such as Interleukin-1β (IL-1β), Interleukin -6, and Tumor Necrosis Factor-α mRNA and anti-inflammatory cytokines such as IL-4, Arginase 1(Arg1), CD206, and Ym1 were detected by RT-qPCR. TUG1 was silenced using TUG1 siRNA and knocked out using CRISPR/Cas9. The mRNA and protein expression levels of key enzymes involved in glucose metabolism, such as Hexokinase2, Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Lactate dehydrogenase, Glucose 6 phosphate dehydrogenase, and Pyruvate dehydrogenase (PDH), were determined by RT-qPCR and Western blotting. The glycolytic rate of microglial cells was measured using Seahorse. Differential metabolites were determined by metabolomics, and pathway enrichment was performed using these differential metabolites. Our findings revealed that the expression of TUG1 was elevated in proinflammatory-activated microglia and positively correlated with the levels of inflammatory factors. The expression of anti-inflammatory cytokines such as IL-4, Arg1, CD206, and Ym1 were decreased when induced with LPS/IFN-γ. However, this decrease was reversed by the treatment with 2-DG. Silencing of GAPDH led to an increase in the expression of TUG1 and inflammatory factors. TUG1 knockout (TUG1KO) inhibited the expression of glycolytic key enzymes and promoted the expression of oxidative phosphorylation key enzymes, shifting the metabolic profile of activated microglia from glycolysis to oxidative phosphorylation. Additionally, TUG1KO reduced the accumulation of metabolites, facilitating the restoration of the tricarboxylic acid cycle and enhancing oxidative phosphorylation in microglia. Furthermore, the downregulation of TUG1 was found to reduce the expression of both proinflammatory and anti-inflammatory cytokines under normal conditions. Interestingly, when induced with LPS/IFN-γ, TUG1 downregulation showed a potentially beneficial effect on microglia in terms of inflammation. Downregulation of TUG1 expression inhibits glycolysis and facilitates the shift of microglial glucose metabolism from glycolysis to oxidative phosphorylation, promoting their transformation towards an anti-inflammatory phenotype and exerting anti-inflammatory effects in BV2., (© 2024. The Author(s).)

Childhood trauma is strongly linked to emotional distress. However, few studies have explored the impact of sense of coherence (SOC) on the relationship between childhood trauma and emotional distress in college students. This study aimed to explore its impact on the relationship between childhood trauma and emotional distress. Analyzing data from 2307 Chinese college students, we found that SOC moderated the association between childhood trauma and anxiety/depression levels. Females showed higher SOC and lower anxiety/depression despite experiencing more childhood trauma. Multiple linear regression revealed that anxiety was negatively associated with SOC(P < 0.001) and grade(P = 0.027), and positively with childhood trauma(P < 0.001) and male gender(P = 0.004). Similarly, the depression exhibited similar associations. SOC moderated negatively the relationship between CTQ and anxiety, as well as between CTQ and depression. Childhood trauma is associated with increased emotional distress risk among college students, but a strong SOC can reduce this risk., (© 2024. The Author(s).)

Simple dynamic modeling tools can help generate real-time short-term forecasts with quantified uncertainty of the trajectory of diverse growth processes unfolding in nature and society, including disease outbreaks. An easy-to-use and flexible toolbox for this purpose is lacking. This tutorial-based primer introduces and illustrates GrowthPredict, a user-friendly MATLAB toolbox for fitting and forecasting time-series trajectories using phenomenological dynamic growth models based on ordinary differential equations. This toolbox is accessible to a broad audience, including students training in mathematical biology, applied statistics, and infectious disease modeling, as well as researchers and policymakers who need to conduct short-term forecasts in real-time. The models included in the toolbox capture exponential and sub-exponential growth patterns that typically follow a rising pattern followed by a decline phase, a common feature of contagion processes. Models include the 1-parameter exponential growth model and the 2-parameter generalized-growth model, which have proven useful in characterizing and forecasting the ascending phase of epidemic outbreaks. It also includes the 2-parameter Gompertz model, the 3-parameter generalized logistic-growth model, and the 3-parameter Richards model, which have demonstrated competitive performance in forecasting single peak outbreaks. We provide detailed guidance on forecasting time-series trajectories and available software ( https://github.com/gchowell/forecasting&#95;growthmodels ), including the full uncertainty distribution derived through parametric bootstrapping, which is needed to construct prediction intervals and evaluate their accuracy. Functions are available to assess forecasting performance across different models, estimation methods, error structures in the data, and forecasting horizons. The toolbox also includes functions to quantify forecasting performance using metrics that evaluate point and distributional forecasts, including the weighted interval score. This tutorial and toolbox can be broadly applied to characterizing and forecasting time-series data using simple phenomenological growth models. As a contagion process takes off, the tools presented in this tutorial can help create forecasts to guide policy regarding implementing control strategies and assess the impact of interventions. The toolbox functionality is demonstrated through various examples, including a tutorial video, and the examples use publicly available data on the monkeypox (mpox) epidemic in the USA., (© 2024. The Author(s).)

The patterns of communication among different chondrocyte subtypes in human cartilage degeneration and regeneration help us understand the microenvironment of osteoarthritis and optimize cell-targeted therapies. Here, a single-cell transcriptome dataset of chondrocytes is used to explore the synergistic and communicative patterns of different chondrocyte subtypes. We collected 1600 chondrocytes from 10 patients with osteoarthritis and analyzed the active communication patterns for the first time based on network analysis and pattern recognition at the single-cell level. Manifold learning and quantitative contrasts were performed to analyze conserved and specific communication pathways. We found that ProCs (Proliferative chondrocytes), ECs (Effector chondrocytes), preHTCs (Prehypertrophic chondrocytes), HTCs (Hypertrophic chondrocytes), and FCs (Fibrocartilage chondrocytes) are more active in incoming and outgoing signaling patterns, which is consistent with studies on their close functional cooperation. Among them, preHTCs play multiple roles in chondrocyte communication, and ProCs and preHTCs have many overlapping pathways. These two subtypes are the most active among all chondrocyte subtypes. Interestingly, ECs and FCs are a pair of "mutually exclusive" subtypes, of which ECs are predominant in incoming patterns and FCs in outgoing patterns. The active signaling pathways of ECs and FCs largely do not overlap. COLLAGEN and LAMININ are the main pivotal pathways, which means they are very important in the repair and expansion of joint homeostasis. Notably, only preHTCs assume multiple roles (including sender, receiver, mediator, and influencer) and are involved in multiple communication pathways. We have examined their communication patterns from the perspective of cellular interactions, revealed the relationships among different chondrocyte subtypes, and, in particular, identified a number of active subtypes and pathways that are important for targeted therapy in the osteoarthritic microenvironment. Our findings provide a new research paradigm and new insights into understanding chondrocyte activity patterns in the osteoarthritic microenvironment., (© 2023. Springer Nature Limited.)

Sensitive detection of Mycobacterium tuberculosis (TB) in small percentages in metagenomic samples is essential for microbial classification and drug resistance prediction. However, traditional methods, such as bacterial culture and microscopy, are time-consuming and sometimes have limited TB detection sensitivity. Oxford nanopore technologies (ONT) MinION sequencing allows rapid and simple sample preparation for sequencing. Its recently developed adaptive sequencing selects reads from targets while allowing real-time base-calling to achieve sequence enrichment or depletion during sequencing. Another common enrichment method is PCR amplification of the target TB genes. In this study, we compared both methods using ONT MinION sequencing for TB detection and variant calling in metagenomic samples using both simulation runs and those with synthetic and patient samples. We found that both methods effectively enrich TB reads from a high percentage of human (95%) and other microbial DNA. Adaptive sequencing with readfish and UNCALLDE achieved a 3.9-fold and 2.2-fold enrichment compared to the control run. We provide a simple automatic analysis framework to support the detection of TB for clinical use, openly available at https://github.com/HKU-BAL/ONT-TB-NF . Depending on the patient's medical condition and sample type, we recommend users evaluate and optimize their workflow for different clinical specimens to improve the detection limit., (© 2023. The Author(s).)

Structural variation (SV) is a major cause of genetic disorders. In this paper, we show that low-depth (specifically, 4×) whole-genome sequencing using a single Oxford Nanopore MinION flow cell suffices to support sensitive detection of SV, particularly pathogenic SV for supporting clinical diagnosis. When using 4× ONT WGS data, existing SV calling software often fails to detect pathogenic SV, especially in the form of long deletion, terminal deletion, duplication, and unbalanced translocation. Our new SV calling software SENSV can achieve high sensitivity for all types of SV and a breakpoint precision typically ± 100 bp; both features are important for clinical concerns. The improvement achieved by SENSV stems from several new algorithms. We evaluated SENSV and other software using both real and simulated data. The former was based on 24 patient samples, each diagnosed with a genetic disorder. SENSV found the pathogenic SV in 22 out of 24 cases (all heterozygous, size from hundreds of kbp to a few Mbp), reporting breakpoints within 100 bp of the true answers. On the other hand, no existing software can detect the pathogenic SV in more than 10 out of 24 cases, even when the breakpoint requirement is relaxed to ± 2000 bp., (© 2022. The Author(s).)

The variant virulent porcine epidemic diarrhea virus (PEDV) strain (YN15) can cause severe porcine epidemic diarrhea (PED); however, the attenuated vaccine-like PEDV strain (YN144) can induce immunity in piglets. To investigate the differences in pathogenesis and epigenetic mechanisms between the two strains, differential expression and correlation analyses of the microRNA (miRNA) and mRNA in swine testicular (ST) cells infected with YN15, YN144, and mock were performed on three comparison groups (YN15 vs Control, YN144 vs Control, and YN15 vs YN144). The mRNA and miRNA expression profiles were obtained using next-generation sequencing (NGS), and the differentially expressed (DE) (p-value < 0.05) mRNA and miRNA were obtained using DESeq R package. mRNAs targeted by DE miRNAs were predicted using the miRanda algortithm. 8039, 8631 and 3310 DE mRNAs, and 36, 36, and 22 DE miRNAs were identified in the three comparison groups, respectively. 14,140, 15,367 and 3771 DE miRNA-mRNA (targeted by DE miRNAs) interaction pairs with negatively correlated expression patterns were identified, and interaction networks were constructed using Cytoscape. Six DE miRNAs and six DE mRNAs were randomly selected to verify the sequencing data by real-time relative quantitative reverse transcription polymerase chain reaction (qRT-PCR). Based on bioinformatics analysis, we discovered the differences were mostly involved in host immune responses and viral pathogenicity, including NF-κB signaling pathway and bacterial invasion of epithelial cells, etc. This is the first comprehensive comparison of DE miRNA-mRNA pairs in YN15 and YN144 infection in vitro, which could provide novel strategies for the prevention and control of PED.

Most speech separation studies in monaural channel use only a single type of network, and the separation effect is typically not satisfactory, posing difficulties for high quality speech separation. In this study, we propose a convolutional recurrent neural network with an attention (CRNN-A) framework for speech separation, fusing advantages of two networks together. The proposed separation framework uses a convolutional neural network (CNN) as the front-end of a recurrent neural network (RNN), alleviating the problem that a sole RNN cannot effectively learn the necessary features. This framework makes use of the translation invariance provided by CNN to extract information without modifying the original signals. Within the supplemented CNN, two different convolution kernels are designed to capture information in both the time and frequency domains of the input spectrogram. After concatenating the time-domain and the frequency-domain feature maps, the feature information of speech is exploited through consecutive convolutional layers. Finally, the feature map learned from the front-end CNN is combined with the original spectrogram and is sent to the back-end RNN. Further, the attention mechanism is further incorporated, focusing on the relationship among different feature maps. The effectiveness of the proposed method is evaluated on the standard dataset MIR-1K and the results prove that the proposed method outperforms the baseline RNN and other popular speech separation methods, in terms of GNSDR (gloabl normalised source-to-distortion ratio), GSIR (global source-to-interferences ratio), and GSAR (gloabl source-to-artifacts ratio). In summary, the proposed CRNN-A framework can effectively combine the advantages of CNN and RNN, and further optimise the separation performance via the attention mechanism. The proposed framework can shed a new light on speech separation, speech enhancement, and other related fields.

Robotic rectal cancer resection with natural orifice extraction is a recently developed minimally invasive surgery used in the treatment of patients with rectal cancer. However, its safety and feasibility remain undiscussed and controversial. This study reported the clinical outcomes and prognostic factors pertaining to traditional robotic assisted rectal cancer resection alone against that of robotic rectal cancer resection with natural orifice extraction to provide a discussion on this issue. 49 patients who underwent robotic rectal cancer resection with natural orifice extraction and 49 matched patients who underwent conventional robotic assisted rectal cancer resection were systematically analyzed in this study. Regarding the baseline characteristics, after matching, no significant differences were observed between the natural orifice specimen extraction (NOSE) group and the robotic assisted rectal cancer resection (RARC) group. Patients in the NOSE group had a reduced visual analog scale (p < 0.001), passed flatus more quickly (p = 0.002) and suffered less surgical stress than those in the RARC group. Moreover, 4 complications were observed in the NOSE group and 7 complications in the RARC group with no significant difference (p = 0.337) in terms of complications. The two groups had a similar survival outcomes, where the 3-year overall survival (p = 0.738) and 3-year progression-free survival (p = 0.986) were all comparable between the two groups. Histological differentiation and T stage could be regarded as independent prognostic factors for 3-year overall survival and 3-year progression-free survival. Robotic rectal cancer resection with natural orifice extraction is a safe and feasible minimally invasive surgery for patients suffering from rectal cancer as it encompasses considerable several advantages. Histological differentiation and T stage may serve as independent prognostic factors for 3-year overall survival and 3-year progression-free survival.

Forestland soils play vital role in regulating global soil greenhouse gas (GHG) budgets, but the interactive effect of the litter layer management and simulated nitrogen (N) deposition on these GHG flux has not been elucidated clearly in subtropical forestland. A field trial was conducted to study these effects by using litter removal method under 0 and 40 kg N ha -1 yr -1 addition in a subtropical forestland in Yingtan, Jiangxi Province, China. Soil CO 2 emission was increased by N addition (18-24%) but decreased by litter removal (24-32%). Litter removal significantly (P < 0.05) decreased cumulative N 2 O emission by 21% in treatments without N addition but only by 10% in treatments with 40 kg N ha -1 yr -1 addition. Moreover, litter-induced N 2 O emission under elevated N deposition (0.094 kg N 2 O-N ha -1 ) was almost the same as without N addition (0.088 kg N 2 O-N ha -1 ). Diffusion of atmospheric CH 4 into soil was facilitated by litter removal, which increased CH 4 uptake by 55%. Given that the increasing trend of atmospheric N deposition in future, which would reduce litterfall in subtropical N-rich forest, the effect of surface litter layer change on soil GHG emissions should be considered in assessing forest GHG budgets and future climate scenario modeling.

Previously, we developed a CHO cell display-based antibody maturation procedure in which an antibody (or other protein) gene of interest was induced to mutate by activation-induced cytidine deaminase (AID) and then form a library by simply proliferating the CHO cells in culture. In this study, we further improved the efficiency of this maturation system by reengineering AID, and optimizing the nucleic acid sequence of the target antibody gene and AID gene as well as the protocol for AID gene transfection. These changes have increased both the mutation rate and the number of mutation type of antibody genes by more than 10 fold, and greatly improved the maturation efficiency of antibody/other proteins.

Cryptosporidium spp. and Enterocytozoon bieneusi are two well-known protist pathogens which can result in diarrhea in humans and animals. To examine the occurrence and genetic characteristics of Cryptosporidium spp. and E. bieneusi in pet red squirrels (Sciurus vulgaris), 314 fecal specimens were collected from red squirrels from four pet shops and owners in Sichuan province, China. Cryptosporidium spp. and E. bieneusi were examined by nested PCR targeting the partial small subunit rRNA (SSU rRNA) gene and the ribosomal internal transcribed spacer (ITS) gene respectively. The infection rates were 8.6% (27/314) for Cryptosporidium spp. and 19.4% (61/314) for E. bieneusi. Five Cryptosporidium species/genotypes were identified by DNA sequence analysis: Cryptosporidium rat genotype II (n = 8), Cryptosporidium ferret genotype (n = 8), Cryptosporidium chipmunk genotype III (n = 5), Cryptosporidium rat genotype I (n = 4), and Cryptosporidium parvum (n = 2). Additionally, a total of five E. bieneusi genotypes were revealed, including three known genotypes (D, SCC-2, and SCC-3) and two novel genotypes (RS01 and RS02). Phylogenetic analysis revealed that genotype D fell into group 1, whereas the remaining genotypes clustered into group 10. To our knowledge, this is the first study to report Cryptosporidium spp. and E. bieneusi in pet red squirrels in China. Moreover, C. parvum and genotype D of E. bieneusi, previously identified in humans, were also found in red squirrels, suggesting that red squirrels may give rise to cryptosporidiosis and microsporidiosis in humans through zoonotic transmissions. These results provide preliminary reference data for monitoring Cryptosporidium spp. and E. bieneusi infections in pet red squirrels and humans.

This retrospective study was to investigate whether radiomics feature come from radiotherapy treatment planning CT can predict prognosis in locally advanced rectal cancer patients treated with neoadjuvant chemoradiation followed by surgery. Four-hundred-eleven locally advanced rectal cancer patients which were treated with neoadjuvant chemoradiation enrolled in this study. All patients' radiotherapy treatment planning CTs were collected. Tumor was delineated on these CTs by physicians. An in-house radiomics software was used to calculate 271 radiomics features. The results of test-retest and contour-recontour studies were used to filter stable radiomics (Spearman correlation coefficient > 0.7). Twenty-one radiomics features were final enrolled. The performance of prediction model with the radiomics or clinical features were calculated. The clinical outcomes include local control, distant control, disease-free survival (DFS) and overall survival (OS). Model performance C-index was evaluated by C-index. Patients are divided into two groups by cluster results. The results of chi-square test revealed that the radiomics feature cluster is independent of clinical features. Patients have significant differences in OS (p = 0.032, log rank test) for these two groups. By supervised modeling, radiomics features can improve the prediction power of OS from 0.672 [0.617 0.728] with clinical features only to 0.730 [0.658 0.801]. In conclusion, the radiomics features from radiotherapy CT can potentially predict OS for locally advanced rectal cancer patients with neoadjuvant chemoradiation treatment.

Status epilepticus (SE) can cause brain damage and lead to neural dysfunction. Developing novel targets for SE therapy and diagnosis is important and necessary. Previously, we found several differentially expressed microRNAs (miRNAs) in the developing hippocampus following SE, including the autophagy-related miR-96. In the present study, we employed immunofluorescence staining and Western blot analysis to assess the expression of autophagy-related 7 (Atg7) and Atg16L1 and the status of autophagosome formation in the hippocampus of immature rats with SE. Additional in vivo intervention was also performed to investigate the potential therapeutic function of miR-96 in developing rats with SE. We found that Atg7 and Atg16L1 were up-regulated in the neurons after SE, together with an increase in autophagosome formation. Meanwhile, overexpression of miR-96 significantly prevented brain damage in SE rats by inhibiting Atg7 and Atg16L1 expression and autophagosome formation in the hippocampus. Furthermore, Rapamycin negated miR-96 mediated brain injury attenuation through inducing autophagosome formation. Our study indicates that miR-96 might be a potential target for therapy of pediatric SE.

Protein kinase B (PknB) is one of the Mycobacterium tuberculosis serine/threonine protein kinases and has an essential role in sustaining mycobacterial growth. Here, we identified and characterized a novel small molecule compound named IMB-YH-8 that inhibited PknB and served as anti-mycobacteria lead compound. IMB-YH-8 inhibited PknB auto-phosphorylation and the phosphorylation of GarA by PknB in a dose-dependent manner. The compound did not inhibit human Akt1 or other serine/threonine kinases in M. tuberculosis except for the highly homologous PknA. IMB-YH-8 bound to PknB with a moderate affinity. Molecular docking revealed that IMB-YH-8 interacts with the catalytic domain of PknB. Observations of electron microscopy showed that IMB-YH-8 changed the morphology of H37Rv and disrupted the cell wall. The differential transcriptional response of M. tuberculosis to IMB-YH-8 revealed changes in SigH regulatory pathways modulated by PknB. Notably IMB-YH-8 not only potently inhibited drug-sensitive and multidrug-resistant clinical isolates but also exhibited a dose dependent inhibition of intracellular M. tuberculosis. Taken together, these in vitro data demonstrate that IMB-YH-8 is a novel inhibitor of PknB, which potently prevents growth of M. tuberculosis. It is as yet unclear whether inhibition of PknA contributes to the anti-tubercular action of IMB-YH-8.

The purpose of this study was to develop matrix-matched hair standards and a LA-ICP-MS technique for determination of the As and Pb in a single human hair using single spot scan mode. These results could subsequently be used to infer when the element entered the body. This study was conducted in two parts. First, a method was developed and validated for the elemental analysis of hair by LA-ICP-MS. A calibration strategy in LA-ICP-MS was developed using prepared matrix-matched laboratory hair standards doped with analytes of interest at a defined concentration. The use of hair strand standards enables calibration curves to be obtained by plotting the analyte ion (M + ) intensity normalized to 34 S + (the ratio M + / 34 S + ) as a function of the concentration determined by ICP-MS of the acidic digests. The linear correlation coefficients (R 2 ) of the calibration curves for the analytes As and Pb were typically between 0.9970 and 0.9998, respectively. Second, an actual hair was measured using the developed method. The spatial distribution of As along the hair was observed in a hair sample from a leukaemia patient treated with arsenic trioxide (As 2 O 3 ). The actual and estimated times over which the drug entered the body were compared and discussed.

In the clinic, approximately 30% of children with adenoid hypertrophy (AH) concomitant with allergic rhinitis (AR) report poor responses to intranasal steroids. To determine whether the combination of mometasone furoate (MF) and oxymetazoline (OXY) is more effective than either agent alone, we performed a two-stage, parallel, randomized, double-blind, double-dummy, clinical trial with 240 AH children with concomitant perennial AR. During the first stage, all children were randomly assigned to the MF or control group for six weeks of treatment. During the second stage, the non-responders from stage one were randomly assigned to 4 groups for 8 weeks of treatment that involved receiving the following treatments: MF/OXY, MF/placebo, placebo/OXY, or placebo/placebo. During the first stage of treatment, 39% of the responders treated with MF achieved greater reductions in total and individual symptom scores than did those on placebo. During the second stage of treatment, the nasal congestion scores of the MF/OXY group significantly decreased. The adenoid/choana ratio of the MF/OXY-treated group decreased and the nasal volume increased significantly. Our results suggest that the combination of OXY and MF is effective and safe for the treatment of AH children with concomitant AR and has a rapid onset of action.

We normally react to individuals who exclude us socially by either avoiding them or increasing our attempts to interact with them. The neuropeptide oxytocin can promote social bonds and reduce social conflict and we therefore investigated whether it facilitates more positive social responses towards individuals who exclude or include us. In a double-blind, placebo-controlled, between-subject design 77 healthy Chinese male and female participants received intranasal oxytocin (40 IU) or placebo before playing a modified virtual ball-tossing game with three fictitious partners who either showed exclusion, inclusion or neutral behavioral interactions with them. Results showed that both male and female subjects threw the ball more often to individuals who excluded rather than included them, although oxytocin did not alter this or awareness/feelings of exclusion or inclusion. However, when subjects returned a week later males, but not females, in the oxytocin group exhibited an increased liking for, and preference for playing again with, players who had previously excluded them. This oxytocin effect was positively associated with independent traits. Our findings suggest that in a collectivist culture oxytocin may promote the desire of males, but not females, with a stronger independent orientation to rebuild social connections with individuals who have previously excluded them.

Streptonigrin methylesterase A (StnA) is one of the tailoring enzymes that modify the aminoquinone skeleton in the biosynthesis pathway of Streptomyces species. Although StnA has no significant sequence homology with the reported α/β-fold hydrolases, it shows typical hydrolytic activity in vivo and in vitro. In order to reveal its functional characteristics, the crystal structures of the selenomethionine substituted StnA (SeMet-StnA) and the complex (S185A mutant) with its substrate were resolved to the resolution of 2.71 Å and 2.90 Å, respectively. The overall structure of StnA can be described as an α-helix cap domain on top of a common α/β hydrolase domain. The substrate methyl ester of 10'-demethoxystreptonigrin binds in a hydrophobic pocket that mainly consists of cap domain residues and is close to the catalytic triad Ser185-His349-Asp308. The transition state is stabilized by an oxyanion hole formed by the backbone amides of Ala102 and Leu186. The substrate binding appears to be dominated by interactions with several specific hydrophobic contacts and hydrogen bonds in the cap domain. The molecular dynamics simulation and site-directed mutagenesis confirmed the important roles of the key interacting residues in the cap domain. Structural alignment and phylogenetic tree analysis indicate that StnA represents a new subfamily of lipolytic enzymes with the specific binding pocket located at the cap domain instead of the interface between the two domains.

It has been well characterized that the neonatal Fc receptor (FcRn) transports maternal IgG to a fetus or newborn and protects IgG from degradation. We previously reported that FcRn is expressed in a model of normal porcine intestinal epithelial cells (IPEC-J2). Transmissible gastroenteritis is an acute enteric disease of swine that is caused by transmissible gastroenteritis virus (TGEV). How porcine FcRn (pFcRn) expression is regulated by pathogenic infection remains unknown. Our research shows that IPEC-J2 cells infected with TGEV had up-regulated pFcRn expression. In addition, the NF-κB signaling pathway was activated in IPEC-J2 cells by TGEV infection. Furthermore, treatment of TGEV-infected IPEC-J2 cells with the NF-κB-specific inhibitor BAY 11-7082 resulted in down-regulation of pFcRn expression. Transient transfection of pFcRn promoter luciferase report plasmids with overexpression of NF-κB p65 transcription factor enhanced the activation of the luciferase report plasmids. We identified four NF-κB transcription factor binding sites in the promoter region of this gene using luciferase reporter system, chromatin immunoprecipitation, electromobility shift assay, and supershift analysis. Together, the data provide the first evidence that TGEV infection up-regulates pFcRn expression via activation of NF-κB signaling.

Riboswitches are a class of metabolism control elements mostly found in bacteria. Due to their fundamental importance in bacteria gene regulation, riboswitches have been proposed as antibacterial drug targets. Prequeuosine (preQ1) is the last free precursor in the biosynthetic pathway of queuosine that is crucial for translation efficiency and fidelity. However, the regulation mechanism for the preQ1 riboswitch remains unclear. Here we constructed fluctuation correlation network based on all-atom molecular dynamics simulations to reveal the regulation mechanism. The results suggest that the correlation network in the bound riboswitch is distinctly different from that in the apo riboswitch. The community network indicates that the information freely transfers from the binding site of preQ1 to the expression platform of the P3 helix in the bound riboswitch and the P3 helix is a bottleneck in the apo riboswitch. Thus, a hypothesis of "preQ1-binding induced allosteric switching" is proposed to link riboswitch and translation regulation. The community networks of mutants support this hypothesis. Finally, a possible allosteric pathway of A50-A51-A52-U10-A11-G12-G56 was also identified based on the shortest path algorithm and confirmed by mutations and network perturbation. The novel fluctuation network analysis method can be used as a general strategy in studies of riboswitch structure-function relationship.

Although Lands' cycle was discovered in 1958, its function and cellular regulation in membrane homeostasis under physiological and pathological conditions remain largely unknown. Nonbiased high throughput metabolomic profiling revealed that Lands' cycle was impaired leading to significantly elevated erythrocyte membrane lysophosphatidylcholine (LysoPC) content and circulating and erythrocyte arachidonic acid (AA) in mice with sickle cell disease (SCD), a prevalent hemolytic genetic disorder. Correcting imbalanced Lands' cycle by knockdown of phospholipase 2 (cPLA2) or overexpression of lysophosphatidycholine acyltransferase 1 (LPCAT1), two key enzymes of Lands' cycle in hematopoietic stem cells, reduced elevated erythrocyte membrane LysoPC content and circulating AA levels and attenuated sickling, inflammation and tissue damage in SCD chimeras. Human translational studies validated SCD mouse findings and further demonstrated that imbalanced Lands' cycle induced LysoPC production directly promotes sickling in cultured mouse and human SCD erythrocytes. Mechanistically, we revealed that hypoxia-mediated ERK activation underlies imbalanced Lands' cycle by preferentially inducing the activity of PLA2 but not LPCAT in human and mouse SCD erythrocytes. Overall, our studies have identified a pathological role of imbalanced Lands' cycle in SCD erythrocytes, novel molecular basis regulating Lands' cycle and therapeutic opportunities for the disease.

Histone modification plays a key role in gene regulation and gene expression. TRIM24 as a histone reader can recognize histone modification. However the specific recognition mechanism between TRIM24 and histone modification is unsolved. Here, systems biology method of dynamics correlation network based on molecular dynamics simulation was used to answer the question. Our network analysis shows that the dynamics correlation network of H3K23ac is distinctly different from that of wild type and other modifications. A hypothesis of "synergistic modification induced recognition" is then proposed to link histone modification and TRIM24 binding. These observations were further confirmed from community analysis of networks with mutation and network perturbation. Finally, a possible recognition pathway is also identified based on the shortest path search for H3K23ac. Significant difference of recognition pathway was found among different systems due to methylation and acetylation modifications. The analysis presented here and other studies show that the dynamic network-based analysis might be a useful general strategy to study the biology of protein post-translational modification and associated recognition.

From 2010 to 2012, large outbreaks of EV-A71-related- hand foot and mouth disease (HFMD) occurred annually in China. Some cases had neurological complications and were closely associated with fatal cardiopulmonary collapse, but not all children with central nervous system (CNS) involvement demonstrated a poor prognosis. To identify which patients and which neurological complications are more likely to progress to cardiopulmonary failure, we retrospectively studied 1,125 paediatric inpatients diagnosed with EV-A71-related HFMD in Hunan province, including 1,017 cases with CNS involvement. These patients were divided into cardiopulmonary failure (976 people) group and group without cardiopulmonary failure (149 people). A logistic regression analysis was used to compare the clinical symptoms, laboratory test results, and neurological complications between these two groups. The most significant risk factors included young age, fever duration ≥3 days, coma, limb weakness, drowsiness and ANS involvement. Patients with brainstem encephalitis and more CNS-involved regions were more likely to progress to cardiopulmonary failure. These findings can help front-line clinicians rapidly and accurately determine patient prognosis, thus rationally distributing the limited medical resources and implementing interventions as early as possible.

Cut slopes are frequently generated by construction work in hilly areas, and artificial soil is often sprayed onto them to promote ecological rehabilitation. The artificial soil properties are very important for effective management of the slopes. This paper uses fractal and moment methods to characterize soil particle size distribution (PSD) and aggregates composition. The fractal dimension (D) showed linear relationships between clay, silt, and sand contents, with coefficients of determination from 0.843 to 0.875, suggesting that using of D to evaluate the PSD of artificial soils is reasonable. The bias (CS) and peak convex (CE) coefficients showed significant correlations with structure failure rate, moisture content, and total porosity, which validated the moment method to quantitatively describe soil structure. Railway slope (RS) soil has lower organic carbon and soil moisture, and higher pH than natural slope soil. Overall, RS exhibited poor soil structure and physicochemical properties, increasing the risk of soil erosion. Hence, more effective management measures should be adopted to promote the restoration of cut slopes.

Preeclampsia, a relatively common pregnancy disorder, is a major contributor to maternal mortality and morbidity worldwide. An elevation in microRNA-210 (miR-210) expression in the placenta has been reported to be associated with preeclampsia. Our bioinformatic analysis showed that thrombospondin type I domain containing 7A (THSD7A) is a predicted target for miR-210. The aim of this study was to determine whether miR-210 is involved in preeclampsia through its targeting of THSD7A in human placental trophoblasts. In preeclamptic placental tissues, THSD7A levels were significantly downregulated, and were inversely correlated with the levels of miR-210. THSD7A was validated as a direct target of miR-210 using quantitative real time PCR (qRT-PCR), Western blotting, and dual luciferase assays in HTR8/SVneo cells. Transwell insert invasion assays showed that THSD7A mediated the invasion-inhibitory effect of miR-210 in HTR8/SVneo cells. Interestingly, hypoxia markedly increased miR-210 expression while suppressing THSD7A expression in a time-dependent manner in HTR8/SVneo cells. This study provides novel data on the function of THSD7A in human placental cells, and extends our knowledge of how miR-210 is involved in the development of the preeclampsia.

Blood inside mammals is a forbidden area for the majority of prokaryotic microbes; however, red blood cells tropism microbes, like "vampire pathogens" (VP), succeed in matching scarce nutrients and surviving strong immunity reactions. Here, we found VP of Mycoplasma, Rhizobiales, and Rickettsiales showed significantly higher counts of (AG)n dimeric simple sequence repeats (Di-SSRs) in the genomes, coding and non-coding regions than non Vampire Pathogens (N&#95;VP). Regression analysis indicated a significant correlation between GC content and the span of (AG)n-Di-SSR variation. Gene Ontology (GO) terms with abundance of (AG)3-Di-SSRs shared by the VP strains were associated with purine nucleotide metabolism (FDR < 0.01), indicating an adaptation to the limited availability of purine and nucleotide precursors in blood. Di-amino acids coded by (AG)n-Di-SSRs included all three six-fold code amino acids (Arg, Leu and Ser) and significantly higher counts of Di-amino acids coded by (AG)3, (GA)3, and (TC)3 in VP than N&#95;VP. Furthermore, significant differences (P < 0.001) on the numbers of triplexes formed from (AG)n-Di-SSRs between VP and N&#95;VP in Mycoplasma suggested the potential role of (AG)n-Di-SSRs in gene regulation.

Viral infection triggers a series of signaling cascades, which converge to activate the transcription factors nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3), thereby inducing the transcription of type I interferons (IFNs). Although not fully characterized, these innate antiviral responses are fine-tuned by dynamic ubiquitination and deubiquitination processes. In this study, we report ubiquitin-specific protease (USP) 15 is involved in regulation of the retinoic acid-inducible gene I (RIG-I)-dependent type I IFN induction pathway. Knockdown of endogenous USP15 augmented cellular antiviral responses. Overexpression of USP15 inhibited the transcription of IFN-β. Further analyses identified histidine 862 as a critical residue for USP15's catalytic activity. Interestingly, USP15 specifically removed lysine 63-linked polyubiquitin chains from RIG-I among the essential components in RIG-I-like receptor-dependent pathway. In addition, we demonstrated that in contrast to USP15 de-ubiquitinating (DUB) activity, USP15-mediated inhibition of IFN signaling was not abolished by mutations eliminating the catalytic activity, indicating that a fraction of USP15-mediated IFN antagonism was independent of the DUB activity. Catalytically inactive USP15 mutants, as did the wild-type protein, disrupted virus-induced interaction of RIG-I and IFN-β promoter stimulator 1. Taken together, our data demonstrate that USP15 acts as a negative regulator of RIG-I signaling via DUB-dependent and independent mechanisms.

Recreation of neural network in vitro with designed topology is a valuable tool to decipher how neurons behave when interacting in hierarchical networks. In this study, we developed a simple and effective platform to pattern primary neurons in array formats for interrogation of neural circuitry with single cell resolution. Unlike many surface-chemistry-based patterning methods, our NeuroArray technique is specially designed to accommodate neuron's polarized morphologies to make regular arrays of cells without restricting their neurite outgrowth, and thus allows formation of freely designed, well-connected, and spontaneously active neural network. The NeuroArray device was based on a stencil design fabricated using a novel sacrificial-layer-protected PDMS molding method that enables production of through-structures in a thin layer of PDMS with feature sizes as small as 3 µm. Using the NeuroArray along with calcium imaging, we have successfully demonstrated large-scale tracking and recording of neuronal activities, and used such data to characterize the spiking dynamics and transmission within a diode-like neural network. Essentially, the NeuroArray is a universal patterning platform designed for, but not limited to neuron cells. With little adaption, it can be readily interfaced with other interrogation modalities for high-throughput drug testing, and for building neuron culture based live computational devices.

We previously demonstrated that CBF activity is needed for cell proliferation and early embryonic development. To examine the in vivo function of CBF in differentiated hepatocytes, we conditionally deleted CBF-B in hepatocytes after birth. Deletion of CBF-B resulted in progressive liver injury and severe hepatocellular degeneration 4 weeks after birth. Electron microscopic examination demonstrated pleiotropic changes of hepatocytes including enlarged cell and nuclear size, intracellular lipid deposition, disorganized endoplasmic reticulum, and mitochondrial abnormalities. Gene expression analyses showed that deletion of CBF-B activated expression of specific endoplasmic reticulum (ER) stress-regulated genes. Inactivation of CBF-B also inhibited expression of C/EBP alpha, an important transcription factor controlling various metabolic processes in adult hepatocytes. Altogether, our study reveals for the first time that CBF is a key transcription factor controlling ER function and metabolic processes in mature hepatocytes.