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Background: Tumor necrosis factor-α (TNF-α) is an important mediator of the immune response. At present, the improvement of TNF-α after continuous positive airway pressure (CPAP) treatment of obstructive sleep apnea-hypopnea syndrome (OSAHS) is still controversial. Methods: We conducted a systematic review of the present evidence based on a meta-analysis to elucidate the effects of TNF-α on OSAHS after CPAP treatment. Results: To measure TNF-α, ten studies used enzyme-linked immunosorbent assay (ELISA), and one used radioimmunoassay. The forest plot outcome indicated that CPAP therapy would lower the TNF-α levels in OSAHS patients, with a weighted mean difference (WMD) of 1.08 (95% CI: 0.62–1.55; P < 0.001) based on the REM since there is highly significant heterogeneity (I2 = 90%) among the studies. Therefore, we used the subgroup and sensitivity analyses to investigate the source of heterogeneity. The findings of the sensitivity analysis revealed that the pooled WMD ranged from 0.91 (95% CI: 0.52–1.31; P < 0.001) to 1.18 (95% CI: 0.74–1.63; P < 0.001). The findings were not influenced by any single study. Notably, there was homogeneity in the Asia subgroup and publication year: 2019, implying that these subgroups could be the source of heterogeneity. Conclusion: Our meta-analysis recommends that CPAP therapy will decrease the TNF-α level in OSAHS patients, but more related research should be conducted. [ABSTRACT FROM AUTHOR]

Background: Hypertrophic cardiomyopathy (HCM) is a grave hazard to human health. Circular RNA (circRNAs) and micro RNA (miRNAs), which are competitive endogenous RNA, have been shown to play a critical role inHCM pathogenicity. However, to a great extent, the biological activities of ceRNA in HCM pathophysiology and prognosis remain to be investigated. Materials and methods: By analyzing the expression files in the Gene Expression Comprehensive (GEO) database, differentially expressed (DE) circRNAs, miRNAs, and mRNAs in HCM were identified, and the target molecules of circRNAs and miRNAs were predicted. The intersection of the differentially expressed RNA molecules and the expected target was then calculated, and a ceRNA network was subsequently constructed using RNA molecules. Using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, the potential etiology was elucidated. qPCR was used to validate a portion of the hub gene using Angiotensin II to generate a cell hypertrophy model. Results: Three large-scale HCM sample datasets were extracted from the GEO database. After crossing these molecules with their expected targets, the circRNA-miRNA-mRNA network had two DEcircRNAs, two DEmiRNAs, and thirty DEmRNAs, compared to normal tissues. Functional enrichment analysis of GO and KEGG demonstrated that many of the HCM pathways and mechanisms were associated with calcium channel release, which is also the primary focus of future research. The qPCR results revealed that circRNA, miRNA, and mRNA expression levels were different. They may include novel noninvasive indicators for the early screening and prognostic prediction of HCM. Conclusion: In this study, we hypothesized a circRNA-miRNA-mRNA regulation network that is closely related to the progression and clinical outcomes of HCM and may contain promising biomarkers and treatment targets for HCM. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the influence of road factors on the safety speed threshold of a lorry turning right around a corner at a the bottom of a long downhill T-junction. Trucksim simulation software was chosen to construct a model for investigating the turning instability mechanism. A three-axle truck was chosen as the simulation vehicle and road adhesion coefficients of 0.2–0.75, road super-elevations of -2–8%, turning radii of 20–100 m, and vehicle overcharge of 0–100% selected for tuning. Simulation experiments were carried out for different bending conditions, investigating the effects of each influencing factor on the destabilization speed threshold using the control variable method. The vehicle's lateral load transfer rate and lateral acceleration were indicators for determining whether a truck was unstable. The results showed that: a) the turning radius had the most significant influence on the speed threshold for cornering instability; b) the road surface adhesion coefficient and vehicle overweight had secondary effects; and c) the road height had a general influence. [ABSTRACT FROM AUTHOR]

Introduction: Kidney renal clear cell carcinoma (KIRC) has a high incidence globally, and its pathogenesis remains unclear. Long non-coding RNA (lncRNA), as a molecular sponge, participates in the regulation of competitive endogenous RNA (ceRNA). We aimed to construct a ceRNA network and screened out possible lncRNAs to predict KIRC prognosis. Material and methods: All KIRC data were downloaded from the TCGA database and screened to find the possible target lncRNA; a ceRNA network was designed. Next, GO functional enrichment and KEGG pathway of differentially expressed mRNA related to lncRNA were performed. We used Kaplan-Meier curve analysis to predict the survival of these RNAs. We used Cox regression analysis to construct a model to predict KIRC prognosis. Results: In the KIRC datasets, 1457 lncRNA, 54 miRNA and 2307 mRNA were screened out. The constructed ceRNA network contained 81 lncRNAs, nine miRNAs, and 17 mRNAs differentially expressed in KIRC. Survival analysis of all differentially expressed RNAs showed that 21 lncRNAs, four miRNAs, and two mRNAs were related to the overall survival rate. Cox regression analysis was performed again, and we found that eight lncRNAs were related to prognosis and used to construct predictive models. Three lnRNAs from independent samples were meaningful. Conclusion: The construction of ceRNA network was involved in the process and transfer of KIRC, and three lncRNAs may be potential targets for predicting KIRC prognosis. [ABSTRACT FROM AUTHOR]

The lipopolysaccharide O-antigen structure expressed by the European Helicobacter pylori model strain G27 encompasses a trisaccharide, an intervening glucan-heptan and distal Lewis antigens that promote immune escape. However, several gaps still remain in the corresponding biosynthetic pathway. Here, systematic mutagenesis of glycosyltransferase genes in G27 combined with lipopolysaccharide structural analysis, uncovered HP0102 as the trisaccharide fucosyltransferase, HP1283 as the heptan transferase, and HP1578 as the GlcNAc transferase that initiates the synthesis of Lewis antigens onto the heptan motif. Comparative genomic analysis of G27 lipopolysaccharide biosynthetic genes in strains of different ethnic origin revealed that East-Asian strains lack the HP1283/HP1578 genes but contain an additional copy of HP1105 and JHP0562. Further correlation of different lipopolysaccharide structures with corresponding gene contents led us to propose that the second copy of HP1105 and the JHP0562 may function as the GlcNAc and Gal transferase, respectively, to initiate synthesis of the Lewis antigen onto the Glc-Trio-Core in East-Asian strains lacking the HP1283/HP1578 genes. In view of the high gastric cancer rate in East Asia, the absence of the HP1283/HP1578 genes in East-Asian H. pylori strains warrants future studies addressing the role of the lipopolysaccharide heptan in pathogenesis. Author summary: The human gastric pathogen Helicobacter pylori is the most important aetiological factor for gastric cancer. H. pylori lipopolysaccharide, a major bacterial surface molecule, plays essential roles in host-pathogen interactions. Due to the scattered organisation of the lipopolysaccharide genes in its genome, several key enzymes involved in H. pylori lipopolysaccharide biosynthesis remain to be identified. Here, through systematic mutagenesis of glycosyltransferase genes in the model strain G27 combined with lipopolysaccharide structural analysis, we identified novel glycosyltransferases and established the first complete lipopolysaccharide biosynthetic pathway in G27. Furthermore, we analysed the conservation of the lipopolysaccharide genes across a large panel of H. pylori strains and demonstrated that many of the lipopolysaccharide genes are highly conserved, whereas the genes involved in lipopolysaccharide heptan incorporation are lacking in East-Asian strains. Finally, based on the correlation of lipopolysaccharide structure and gene contents in specific strains, we proposed a lipopolysaccharide biosynthetic model of how East-Asian strains, missing the heptan moiety, attach Lewis antigens onto the conserved Glc-Trio-Core. Future studies are needed to address whether the lack of heptan in lipopolysaccharide of East-Asian H. pylori strains is related to the high gastric cancer rate in East Asia, accounting for almost half of the worldwide gastric cancer cases. [ABSTRACT FROM AUTHOR]

Rapid horizontal directional well drilling in hard or fractured formations requires efficient drilling technology. The penetration rate of conventional hard rock drilling technology in horizontal directional well excavations is relatively low, resulting in multiple overgrinding of drill cuttings in bottom boreholes. Conventional drilling techniques with reamer or diamond drill bit face difficulties due to the long construction periods, low penetration rates, and high engineering costs in the directional well drilling of hard rock. To improve the impact energy and penetration rate of directional well drilling in hard formations, a new drilling system with a percussive and rotary drilling technology has been proposed, and a hydro-hammer with a jet actuator has also been theoretically designed on the basis of the impulse hydro-turbine pressure model. In addition, the performance parameters of the hydro-hammer with a jet actuator have been numerically and experimentally analyzed, and the influence of impact stroke and pumped flow rate on the motion velocity and impact energy of the hydro-hammer has been obtained. Moreover, the designed hydro-hammer with a jet actuator has been applied to hard rock drilling in a trenchless drilling program. The motion velocity of the hydro-hammer ranges from 1.2 m/s to 3.19 m/s with diverse flow rates and impact strokes, and the motion frequency ranges from 10 Hz to 22 Hz. Moreover, the maximum impact energy of the hydro-hammer is 407 J, and the pumped flow rate is 2.3 m3/min. Thus, the average penetration rate of the optimized hydro-hammer improves by over 30% compared to conventional directional drilling in hard rock formations. [ABSTRACT FROM AUTHOR]

Increasing attention has been attracted by exosomes in blood-based diagnosis because cancer cells release more exosomes in serum than normal cells and these exosomes overexpress a certain number of cancer-related biomarkers. However, capture and biomarker analysis of exosomes for clinical application are technically challenging. In this study, we developed a microfluidic chip for immunocapture and quantification of circulating exosomes from small sample volume and applied this device in clinical study. Circulating EpCAM-positive exosomes were measured in 6 cases breast cancer patients and 3 healthy controls to assist diagnosis. A significant increase in the EpCAM-positive exosome level in these patients was detected, compared to healthy controls. Furthermore, we quantified circulating HER2-positive exosomes in 19 cases of breast cancer patients for molecular classification. We demonstrated that the exosomal HER2 expression levels were almost consistent with that in tumor tissues assessed by immunohistochemical staining. The microfluidic chip might provide a new platform to assist breast cancer diagnosis and molecular classification. [ABSTRACT FROM AUTHOR]

Carcinoma-associated fibroblasts (CAFs) are critical in determining tumor invasion and metastasis. However the role of CAFs in the invasion of salivary gland adenoid cystic carcinoma (ACC) is poorly understood. In this study, we isolated primary CAFs from two ACC patients. ACC-derived CAFs expressed typical CAF biomarkers and showed increased migration and invasion activity. Conditioned medium collected from CAFs significantly promoted ACC cell migration and invasion. Co-culture of CAFs with ACC cells in a microfluidic device further revealed that CAFs localized at the invasion front and ACC cells followed the track behind the CAFs. Interfering of both matrix metalloproteinase and CXCL12/CXCR4 pathway inhibited ACC invasion promoted by CAFs. Overall, our study demonstrates that ACC-derived CAFs exhibit the most important defining feature of CAFs by promoting cancer invasion. In addition to secretion of soluble factors, CAFs also lead ACC invasion by creating an invasive track in the ECM. [ABSTRACT FROM AUTHOR]

Large-scale climate history of the past millennium reconstructed solely from tree-ring data is prone to underestimate the amplitude of low-frequency variability. In this paper, we aimed at solving this problem by utilizing a novel method termed “MDVM”, which was a combination of the ensemble empirical mode decomposition (EEMD) and variance matching techniques. We compiled a set of 211 tree-ring records from the extratropical Northern Hemisphere (30–90°N) in an effort to develop a new reconstruction of the annual mean temperature by the MDVM method. Among these dataset, a number of 126 records were screened out to reconstruct temperature variability longer than decadal scale for the period 850–2000 AD. The MDVM reconstruction depicted significant low-frequency variability in the past millennium with evident Medieval Warm Period (MWP) over the interval 950–1150 AD and pronounced Little Ice Age (LIA) cumulating in 1450–1850 AD. In the context of 1150-year reconstruction, the accelerating warming in 20th century was likely unprecedented, and the coldest decades appeared in the 1640s, 1600s and 1580s, whereas the warmest decades occurred in the 1990s, 1940s and 1930s. Additionally, the MDVM reconstruction covaried broadly with changes in natural radiative forcing, and especially showed distinct footprints of multiple volcanic eruptions in the last millennium. Comparisons of our results with previous reconstructions and model simulations showed the efficiency of the MDVM method on capturing low-frequency variability, particularly much colder signals of the LIA relative to the reference period. Our results demonstrated that the MDVM method has advantages in studying large-scale and low-frequency climate signals using pure tree-ring data. [ABSTRACT FROM AUTHOR]

Summer temperature extremes over the global land area were investigated by comparing 26 models of the fifth phase of the Coupled Model Intercomparison Project (CMIP5) with observations from the Goddard Institute for Space Studies (GISS) and the Climate Research Unit (CRU). Monthly data of the observations and models were averaged for each season, and statistics were calculated for individual models before averaging them to obtain ensemble means. The summers with temperature anomalies (relative to 1951–1980) exceeding 3σ (σ is based on the local internal variability) are defined as “extremely hot”. The models well reproduced the statistical characteristics evolution, and partly captured the spatial distributions of historical summer temperature extremes. If the global mean temperature increases 2°C relative to the pre-industrial level, “extremely hot” summers are projected to occur over nearly 40% of the land area (multi-model ensemble mean projection). Summers that exceed 5σ warming are projected to occur over approximately 10% of the global land area, which were rarely observed during the reference period. Scenarios reaching warming levels of 3°C to 5°C were also analyzed. After exceeding the 5°C warming target, “extremely hot” summers are projected to occur throughout the entire global land area, and summers that exceed 5σ warming would become common over 70% of the land area. In addition, the areas affected by “extremely hot” summers are expected to rapidly expand by more than 25%/°C as the global mean temperature increases by up to 3°C before slowing to less than 16%/°C as the temperature continues to increase by more than 3°C. The area that experiences summers with warming of 5σ or more above the warming target of 2°C is likely to maintain rapid expansion of greater than 17%/°C. To reduce the impacts and damage from severely hot summers, the global mean temperature increase should remain low. [ABSTRACT FROM AUTHOR]

To determine the influence of plant density and powdery mildew infection of winter wheat and to predict grain yield, hyperspectral canopy reflectance of winter wheat was measured for two plant densities at Feekes growth stage (GS) 10.5.3, 10.5.4, and 11.1 in the 2009–2010 and 2010–2011 seasons. Reflectance in near infrared (NIR) regions was significantly correlated with disease index at GS 10.5.3, 10.5.4, and 11.1 at two plant densities in both seasons. For the two plant densities, the area of the red edge peak (Σdr680–760 nm), difference vegetation index (DVI), and triangular vegetation index (TVI) were significantly correlated negatively with disease index at three GSs in two seasons. Compared with other parameters Σdr680–760 nm was the most sensitive parameter for detecting powdery mildew. Linear regression models relating mildew severity to Σdr680–760 nm were constructed at three GSs in two seasons for the two plant densities, demonstrating no significant difference in the slope estimates between the two plant densities at three GSs. Σdr680–760 nm was correlated with grain yield at three GSs in two seasons. The accuracies of partial least square regression (PLSR) models were consistently higher than those of models based on Σdr680760 nm for disease index and grain yield. PLSR can, therefore, provide more accurate estimation of disease index of wheat powdery mildew and grain yield using canopy reflectance. [ABSTRACT FROM AUTHOR]

Background: One of the crucial steps toward understanding the biological functions of a cellular system is to investigate protein–protein interaction (PPI) networks. As an increasing number of reliable PPIs become available, there is a growing need for discovering PPIs to reconstruct PPI networks of interesting organisms. Some interolog-based methods and homologous PPI families have been proposed for predicting PPIs from the known PPIs of source organisms. Results: Here, we propose a multiple-strategy scoring method to identify reliable PPIs for reconstructing the mouse PPI network from two well-known organisms: human and fly. We firstly identified the PPI candidates of target organisms based on homologous PPIs, sharing significant sequence similarities (joint E-value ≤ 1 × 10−40), from source organisms using generalized interolog mapping. These PPI candidates were evaluated by our multiple-strategy scoring method, combining sequence similarities, normalized ranks, and conservation scores across multiple organisms. According to 106,825 PPI candidates in yeast derived from human and fly, our scoring method can achieve high prediction accuracy and outperform generalized interolog mapping. Experiment results show that our multiple-strategy score can avoid the influence of the protein family size and length to significantly improve PPI prediction accuracy and reflect the biological functions. In addition, the top-ranked and conserved PPIs are often orthologous/essential interactions and share the functional similarity. Based on these reliable predicted PPIs, we reconstructed a comprehensive mouse PPI network, which is a scale-free network and can reflect the biological functions and high connectivity of 292 KEGG modules, including 216 pathways and 76 structural complexes. Conclusions: Experimental results show that our scoring method can improve the predicting accuracy based on the normalized rank and evolutionary conservation from multiple organisms. Our predicted PPIs share similar biological processes and cellular components, and the reconstructed genome-wide PPI network can reflect network topology and modularity. We believe that our method is useful for inferring reliable PPIs and reconstructing a comprehensive PPI network of an interesting organism. [ABSTRACT FROM AUTHOR]

Purpose: Transdifferentiation of human Tenon fibroblasts to myofibroblasts and subsequent deposition of extracellular matrix is a key step in the scarring after glaucoma filtration surgery. The p38 signaling pathway plays an important role in cell proliferation and differentiation, and its upstream regulators and downstream molecules are widely distributed in the eye. We aimed to investigate the role of p38 in the activation of Tenon fibroblasts and that of the anti-fibrotic mechanism of rosiglitazone in the modulation of the p38 signaling pathway. Methods: Cultured Tenon fibroblasts were stimulated with transforming growth factor (TGF)-β1. Activation of p38 was examined by western blot analysis. Rosiglitazone and blocking of the p38 signaling pathway by SB203580 were used to antagonize stimulation by TGF-β1. Fibroblast motility was examined by wound closure assay; alpha-smooth muscle actin, connective tissue growth factor, and collagen type I were determined by qPCR and western blot. Expression and localization of alpha-smooth muscle actin were determined by immunofluorescence staining. Results: Phosphorylated p38 was upregulated in fibroblasts stimulated with TGF-β1, and this effect was substantially inhibited by rosiglitazone. Proliferation and migration of fibroblasts were suppressed by rosiglitazone and SB203580. Expression of alpha-smooth muscle actin, connective tissue growth factor, and collagen type I were decreased at the mRNA and protein levels by rosiglitazone and SB203580. However, the inhibitory effect of SB203580 on transcription and protein expression was weaker than that of rosiglitazone. Similar phenomena were found on immunofluorescence microscopy of alpha-smooth muscle actin. Conclusions: The p38 signaling pathway mediates the TGF-β1-induced transdifferentiation of human Tenon fibroblasts to myofibroblasts. Rosiglitazone can exert anti-fibrotic activity by interfering with the TGF-β/p38 signaling pathway and might be useful for modulating scar formation after glaucoma filtration surgery. [ABSTRACT FROM AUTHOR]

Background: MiRNA primarily acts to repress gene expression at the post-transcriptional level through imperfect complementarity of its 5′ region to the “seed site” in the 3′ untranslated region of target mRNAs, with its “3′–supplementary site” and “center site” also playing important roles under certain circumstances. The aim of this study was to test if artificial miRNA mimics (miR-Mimics) that are designed to target the “centered sites” without “seed sites” complementarity are able to repress gene expression as natural miRNAs. Methods: We designed miR-Mimics carrying centered-site matches (CS–miR-Mimics) or seed-site matches (SS–miR-Mimics) and siRNA to two antiapoptotic genes BCL2 and AKT1. We tested the gene targeting of these constructs using real-time RT-PCR and Western blot to quantify mRNA and protein levels of BCL2 and AKT1, respectively, luciferase reporter gene assay to investigate the interaction between miR-Mimics and their target sites, and cell survival assay to study the functional outcomes of the miR-Mimics. Results: We found that CS-miR-Mimic, SS-miR-Mimic and siRNA, all down regulated the mRNA and protein levels of their cognate target BCL2 or AKT1 in a concentration-dependent manner. Luciferase reporter gene assay further confirmed the functional interactions of CS–miR-Mimic, SS-miR-Mimic and siRNA with their target sites. We then observed that the miR-Mimics and siRNAs were all able to induce cell death, as indicated by the reduced survival rate of cells. Conclusions: We have provided evidence for the feasibility of CS–miR-Mimics for post-transcriptional repression of genes, which can be designed to have reduced numbers of seed type off-target sites compared to the number of target sites from an average endogenous seed–site miRNA. CS–miR-Mimics may be a novel approach for miRNA research requiring miRNA gain-of-function. [ABSTRACT FROM AUTHOR]

Human bocavirus 1 (HBoV1) has been identified as one of the etiological agents of wheezing in young children with acute respiratory-tract infections. In this study, we have obtained the sequence of a full-length HBoV1 genome (including both termini) using viral DNA extracted from a nasopharyngeal aspirate of an infected patient, cloned the full-length HBoV1 genome, and demonstrated DNA replication, encapsidation of the ssDNA genome, and release of the HBoV1 virions from human embryonic kidney 293 cells. The HBoV1 virions generated from this cell line-based production system exhibits a typical icosahedral structure of approximately 26 nm in diameter, and is capable of productively infecting polarized primary human airway epithelia (HAE) from the apical surface. Infected HAE showed hallmarks of lung airway-tract injury, including disruption of the tight junction barrier, loss of cilia and epithelial cell hypertrophy. Notably, polarized HAE cultured from an immortalized airway epithelial cell line, CuFi-8 (originally derived from a cystic fibrosis patient), also supported productive infection of HBoV1. Thus, we have established a reverse genetics system and generated the first cell line-based culture system for the study of HBoV1 infection, which will significantly advance the study of HBoV1 replication and pathogenesis.

Given that macrophages can proliferate and that certain microbes survive inside phagocytic cells, the question arises as to the post-mitotic distribution of microbial cargo. Using macrophage-like cells we evaluated the post-mitotic distribution of intracellular Cryptococcus yeasts and polystyrene beads by comparing experimental data to a stochastic model. For beads, the post-mitotic distribution was that expected from chance alone. However, for yeast cells the post-mitotic distribution was unequal, implying preferential sorting to one daughter cell. This mechanism for unequal distribution was phagosomal fusion, which effectively reduced the intracellular particle number. Hence, post-mitotic intracellular particle distribution is stochastic, unless microbial and/or host factors promote unequal distribution into daughter cells. In our system unequal cargo distribution appeared to benefit the microbe by promoting host cell exocytosis. Post-mitotic infectious cargo distribution is a new parameter to consider in the study of intracellular pathogens since it could potentially define the outcome of phagocytic-microbial interactions.