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Accurate calculation of lateral displacements and internal forces of retaining structures and analysis of stability against sliding has great significance. This paper presents an analytic method to calculate displacements of anchored retaining piles and analyzes excavation stability with the modified mechanical model specified in the Chinese code of excavation. This research work is financially supported by the National Natural Science Foundation of China with Grant No. 51379122.

Heterogeneity in the development and progression of cigarette smoke-induced lung diseases strongly argues for a need to improve the clinical and phenotypic characterization of patients with chronic obstructive lung disease and emphysema. Smokers with emphysema are at a much higher risk for accelerated loss of lung function, increased cardiovascular morbidity, and development of lung cancer. Recent evidence in human translational studies and animal models suggests that emphysema is associated with activation of specialized antigen-presenting cells and that cigarette smoke can disrupt the induction of immune tolerance in the lungs. Quantitative assessment of cytokines expressed by autoreactive T lymphocytes in response to human lung elastin fragments has shown a strong positive correlation between T helper Type 1 (Th1) and Th17 cells' immune responses and emphysema. In search of factors that could reduce the threshold for induction of autoimmune inflammation, we have discovered that cleavage of complement protein 3 (C3) generates bioactive molecules (e.g., C3a) and activates lung antigen-presenting cells. The autocrine and paracrine function of C3a and its receptor are required in T cell-mediated inflammatory responses to cigarette smoke in both human and preclinical models of emphysema. Targeting upstream molecules that reduce the potential for generation of autoreactive T cells could lead to the development of novel therapeutics to prevent progression of emphysema in smokers.

Smoking-related emphysema is a chronic inflammatory disease driven by the T(H)17 subset of helper T cells through molecular mechanisms that remain obscure. Here we explored the role of the microRNA miR-22 in emphysema. We found that miR-22 was upregulated in lung myeloid dendritic cells (mDCs) of smokers with emphysema and antigen-presenting cells (APCs) of mice exposed to smoke or nanoparticulate carbon black (nCB) through a mechanism that involved the transcription factor NF-κB. Mice deficient in miR-22, but not wild-type mice, showed attenuated T(H)17 responses and failed to develop emphysema after exposure to smoke or nCB. We further found that miR-22 controlled the activation of APCs and T(H)17 responses through the activation of AP-1 transcription factor complexes and the histone deacetylase HDAC4. Thus, miR-22 is a critical regulator of both emphysema and T(H)17 responses.

The past 15 years of allergic disease research have produced extraordinary improvements in our understanding of the pathogenesis of airway allergic diseases such as asthma. Whereas it was previously viewed as largely an immunoglobulin E-mediated process, the gradual recognition that T cells, especially Type 2 T helper (Th2) cells and Th17 cells, play a major role in asthma and related afflictions has inspired clinical trials targeting cytokine-based inflammatory pathways that show great promise. What has yet to be clarified about the pathogenesis of allergic inflammatory disorders, however, are the fundamental initiating factors, both exogenous and endogenous, that drive and sustain B- and T-cell responses that underlie the expression of chronic disease. Here we review how proteinases derived from diverse sources drive allergic responses. A central discovery supporting the proteinase hypothesis of allergic disease pathophysiology is the role played by airway fibrinogen, which in part appears to serve as a sensor of unregulated proteinase activity and which, when cleaved, both participates in a novel allergic signaling pathway through Toll-like receptor 4 and forms fibrin clots that contribute to airway obstruction. Unresolved at present is the ultimate source of airway allergenic proteinases. From among many potential candidates, perhaps the most intriguing is the possibility such enzymes derive from airway fungi. Together, these new findings expand both our knowledge of allergic disease pathophysiology and options for therapeutic intervention.

Perioperative organ injury has a significant impact on surgical outcomes and presents a leading cause of death in the United States. Recent research has pointed out an important role of hypoxia signaling in the protection from organ injury, including for example myocardial infarction, acute respiratory distress syndrome, acute kidney, or gut injury. Hypoxia induces the stabilization of hypoxia-inducible factors (HIFs), thereby leading to the induction of HIF target genes, which facilitates adaptive responses to low oxygen. In this review, we focus on current therapeutic strategies targeting hypoxia signaling in various organ injury models and emphasize potential clinical approaches to integrate these findings into the care of surgical patients. Conceptually, there are 2 options to target the HIF pathway for organ protection. First, drugs became recently available that promote the stabilization of HIFs, most prominently via inhibition of prolyl hydroxylase. These compounds are currently trialed in patients, for example, for anemia treatment or prevention of ischemia and reperfusion injury. Second, HIF target genes (such as adenosine receptors) could be activated directly. We hope that some of these approaches may lead to novel pharmacologic strategies to prevent or treat organ injury in surgical patients.

Of the total human body’s surface, the majority is internal surface, belonging to the lungs (100 m2) and intestinal tract (400 m2). In comparison, the external surface area, belonging to the skin, comprises less than 1% (2 m2). Continuous exposure of the mucosal surface to external factors (e.g., pathogens, food particles) requires tight regulation to maintain homeostasis. MicroRNAs (miRNAs) have gained noticeable attention as playing important roles in maintaining the steady-state of tissues by modulating immune functions and inflammatory responses. Accordingly, associations have been found between miRNA expression levels and human health conditions and diseases. These findings have important implications in inflammatory diseases involving pulmonary and intestinal mucosa, such as acute lung injury or inflammatory bowel disease. In this review, we highlight the known biology of miRNAs and discuss the role of miRNAs in modulating mucosal defense and homeostasis. Additionally, we discuss miRNAs serving as potential therapeutic targets to treat immunological conditions, particularly mucosal inflammation.

Measles is one of the leading causes of death among young children. In many developed countries with high measles, mumps, and rubella (MMR) vaccine coverage, measles outbreaks still happen each year. Previous research has demonstrated that what underlies the paradox of high vaccination coverage and measles outbreaks is the ineffectiveness of “herd immunity”, which has the false assumption that people are mixing randomly and there’s equal distribution of vaccinated population. In reality, the unvaccinated population is often clustered instead of not equally distributed. Meanwhile, the Internet has been one of the dominant information sources to gain vaccination knowledge and thus has also been the locus of the “anti-vaccine movement”. In this paper, we propose an agent-based model that explores sentiment diffusion and how this process creates anti-vaccination opinion clusters that leads to larger scale disease outbreaks. The model separates cyber space (where information diffuses) and physical space (where both information diffuses and diseases transmit). The results show that cyber space anti-vaccine opinion leaders have such an influence on anti-vaccine sentiments diffusion in the information network that even if the model starts with the majority of the population being pro-vaccine, the degree of disease outbreaks increases significantly.

The development of emphysema in humans and mice exposed to cigarette smoke is promoted by activation of an adaptive immune response. Lung myeloid dendritic cells (mDCs) derived from cigarette smokers activate autoreactive Th1 and Th17 cells. mDC-dependent activation of T cell subsets requires expression of the SPP1 gene, which encodes osteopontin (OPN), a pleiotropic cytokine implicated in autoimmune responses. The upstream molecular events that promote SPP1 expression and activate mDCs in response to smoke remain unknown. Here, we show that peroxisome proliferator–activated receptor γ (PPARG/Pparg) expression was downregulated in mDCs of smokers with emphysema and mice exposed to chronic smoke. Conditional knockout of PPARγ in APCs using Cd11c-Cre Ppargflox/flox mice led to spontaneous lung inflammation and emphysema that resembled the phenotype of smoke-exposed mice. The inflammatory phenotype of Cd11c-Cre Ppargflox/flox mice required OPN, suggesting an antiinflammatory mechanism in which PPARγ negatively regulates Spp1 expression in the lung. A 2-month treatment with a PPARγ agonist reversed emphysema in WT mice despite continual smoke exposure. Furthermore, endogenous PPARγ agonists were reduced in the plasma of smokers with emphysema. These findings reveal a proinflammatory pathway, in which reduced PPARγ activity promotes emphysema, and suggest that targeting this pathway in smokers could prevent and reverse emphysema.

Allergy Induction Proteinases found in fungi and other allergens elicit allergic inflammation, but how they do so is far from clear. It is also unclear how pattern recognition receptors, which detect invading microbes, drive allergic inflammation. Millien et al. (p. 792 ) shed light on this puzzle by showing that, in mice, induction of allergic inflammation requires proteinase-dependent cleavage of the clotting factor fibrinogen, leading to generation of a ligand that activates the pattern-recognition receptor, Toll-like receptor 4 (TLR4). Cleaved fibrinogen signals through TLR4 to activate the innate immune system and recruit cells to the airway, which drives both allergic responses and antifungal immunity.

AIMS To explore the value of perineal ultrasound and urodynamic study in the clinical diagnosis with the morphological and functional changes and evaluation of clinical type in female patients with stress urinary incontinence (SUI). Methods The records of 64 female patients with SUI were reviewed. Fifty females with urinary frequency but with no SUI symptoms served as controls. All of them underwent ultrasound and urodynamic measurement. PResults The maximum flow rate (Q max) was significantly higher in the patients than in the control group, but the maximal urethral pressure (MUP), maximal urethral closing pressure (MUCP) and functional urethral length (FUL) were significantly lower than in the control group. Ultrasound measurements showed that the rotation angle and movement of urethrovesical junction, funneling of bladder neck and posterior urethrovesical angle (PUVA) at rest and during straining were greater in patients than in the control group. Patients with higher abdominal leak point pressure (ALPP) had higher maximal urethral closing pressure (MUCP), greater rotation angle and movement of urethrovesical junction. Patients with higher MUCP had higher ALPP, greater rotation angle and movement of urethrovesical junction. Conclusions The urodynamic study and perineal ultrasound have a great significance in the diagnosis and typing of SUI.

The correlation between the anatomic site of spinal cord injury and real-time conditions of bladder and urethral function was assessed in order to provide a reasonable basis for the clinical treatment of neurogenic bladder. A total of 134 patients with spinal cord injuries (105 males, 29 females; averaged 34.1 years old) were involved in this retrospective analysis, including urodynamic evaluation, clinical examination and imaging for anatomical position, and Bors-Comarr classification. The associations between the levels of injury and urodynamic findings were analyzed. The results showed that mean follow-up duration was 16.7 months (range 8-27 months). Complete spinal cord injuries occurred in 21 cases, and incomplete spinal cord injuries in 113 cases. Of the 43 patients with upper motor neuron (UMN) injuries, hyperreflexia and (or) detrusor sphincter dyssynergia were demonstrated in 30 (69.8%), 31 (72.1%) suffered low bladder compliance (less than 12.5 mL/cmH(2)O), 28 (65.1%) had high detrusor leak point pressures (greater than 40 cmH(2)O), and 34 (79.1%) had residual urine. Of the 91 patients with lower motor neuron (LMN) injuries, areflexia occurred in 78 (85.7%), high compliance in 75 (82.4%), low leak point pressures in 80 (87.9%), and residual urine in 87 (95.6%), respectively. The associations between the anatomical site of spinal cord injury and urodynamic findings were ill defined. In patients with spinal cord injury, this study revealed a significant association between the level of injury and the type of voiding dysfunction. The anatomical site of spinal cord injury can not be predicted in real-time condition of bladder and urethral function. Management of neurogenic bladder in patients with spinal cord injury must be based on urodynamic findings rather than inferences from the neurologic evaluation.

In this report, we investigated the adjuvant effect of CpG-ODN on the immunogenicity and protective efficacy of influenza M2e peptide vaccine. We found that the addition of CpG-ODN 1826 into aluminum-adjuvant M2e peptide vaccine increased M2e-specific Th1 immune response, indicated by higher titers of M2e-specific IgG2a and more IFN-gamma-secreting lymphocytes. However, according to the result from virus challenge, enhancement of M2e-specific Th1 immune response failed to increase the protection against influenza virus. Moreover, when challenged with high dose of influenza virus, the addition of CpG-ODN even weakened the protective activity. These results suggested that the intensity of immune responses was not simply correlated with protective activity of influenza M2e vaccine and more comprehensive criterion should be built up for the evaluation of M2e-based vaccine.

The extracellular-domain of influenza Matrix 2 protein (M2e) is considered as a putative target for designing universal influenza vaccines. However, the mechanism by which M2-based vaccine induces protection has not been clear. In this study, we analyzed the immunity induced by free synthetic M2e peptide and found the peptide was highly immunogenic. Without carrier proteins, the synthetic M2e peptide could induce M2e-specific IgG antibodies in both incomplete Freund's and aluminum adjuvant. The peptide could also provoke M2e-specific T cell response, which could not be mounted by influenza virus. Moreover, immunization with M2e peptide could protect mice from a lethal challenge with influenza virus. These results provide useful information for the development of M2e-based influenza vaccine.

Chronic inhalation of cigarette smoke is the major cause of sterile inflammation and pulmonary emphysema. The effect of carbon black (CB), a universal constituent of smoke derived from the incomplete combustion of organic material, in smokers and non-smokers is less known. In this study, we show that insoluble nanoparticulate carbon black (nCB) accumulates in human myeloid dendritic cells (mDCs) from emphysematous lung and in CD11c+ lung antigen presenting cells (APC) of mice exposed to smoke. Likewise, nCB intranasal administration induced emphysema in mouse lungs. Delivered by smoking or intranasally, nCB persisted indefinitely in mouse lung, activated lung APCs, and promoted T helper 17 cell differentiation through double-stranded DNA break (DSB) and ASC-mediated inflammasome assembly in phagocytes. Increasing the polarity or size of CB mitigated many adverse effects. Thus, nCB causes sterile inflammation, DSB, and emphysema and explains adverse health outcomes seen in smokers while implicating the dangers of nCB exposure in non-smokers. DOI: http://dx.doi.org/10.7554/eLife.09623.001, eLife digest Smoking for many years damages the lungs and leads to a disease called emphysema that makes it difficult to breathe and is often deadly. There are thousands of chemicals in cigarette smoke and many of them have been linked to the development of lung cancer, although it has been difficult to pinpoint those that are responsible for smoking-related emphysema. Moreover, cigarette smoke also contains large numbers of small particles and relatively little is known about the role played by these particles in smoking-related disease. One of the hallmarks of long-term smoking is a blackening of the lung tissue that persists even if someone stops smoking. Previously, little was known about the composition of the substance that causes this blackening, or its significance in the development of emphysema. Now, by studying lung tissue taken from smokers with emphysema, You et al. have shown that this black substance is made of nano-sized particles of a material called carbon black (which is also known as elemental carbon). These nanoparticles are produced by the incomplete combustion of the cigarettes. You et al. also confirmed that nanoparticles of carbon black can cause emphysema in mice. Closer examination of the lung damage caused by the nanoparticles revealed that they trigger breakages in DNA, which leads to inflammation of the lung. And because the nanoparticles cannot be cleared, they are released into the lung when cells die, which perpetuates lung inflammation and damage. You et al. then went on to show that nanoparticles of carbon black can be modified in a way that allows them to be cleared from the lungs. Such modifications could potentially protect people who are exposed to carbon black nanoparticles in the environment or in workplaces where carbon black is used, such as factories that produce automobile tires and other rubber products. DOI: http://dx.doi.org/10.7554/eLife.09623.002

Asthma is one of the most common of medical illnesses and is treated in part by drugs that activate the beta-2-adrenoceptor (β2-AR) to dilate obstructed airways. Such drugs include long acting beta agonists (LABAs) that are paradoxically linked to excess asthma-related mortality. Here we show that LABAs such as salmeterol and structurally related β2-AR drugs such as formoterol and carvedilol, but not short-acting agonists (SABAs) such as albuterol, promote exaggerated asthma-like allergic airway disease and enhanced airway constriction in mice. We demonstrate that salmeterol aberrantly promotes activation of the allergic disease-related transcription factor signal transducer and activator of transcription 6 (STAT6) in multiple mouse and human cells. A novel inhibitor of STAT6, PM-242H, inhibited initiation of allergic disease induced by airway fungal challenge, reversed established allergic airway disease in mice, and blocked salmeterol-dependent enhanced allergic airway disease. Thus, structurally related β2-AR ligands aberrantly activate STAT6 and promote allergic airway disease. This untoward pharmacological property likely explains adverse outcomes observed with LABAs, which may be overcome by agents that antagonize STAT6.

Smoking-related lung diseases are among the leading causes of death worldwide, underscoring the need to understand their pathogenesis and develop new effective therapies. We have shown that CD1a+ antigen-presenting cells (APCs) from lungs of patients with emphysema can induce autoreactive T helper 1 (T(H)1) and T(H)17 cells. Similarly, the canonical cytokines interferon-γ (IFN-γ) and interleukin-17A (IL-17A) are specifically linked to lung destruction in smokers, but how smoke activates APCs to mediate emphysema remains unknown. Here, we show that, in addition to increasing IFN-γ expression, cigarette smoke increased the expression of IL-17A in both CD4+ and γδ T cells from mouse lung. IL-17A deficiency resulted in attenuation of, whereas lack of γδ T cells exacerbated, smoke-induced emphysema in mice. Adoptive transfer of lung APCs isolated from mice with emphysema revealed that this cell population was capable of transferring disease even in the absence of active smoke exposure, a process that was dependent on IL-17A expression. Spp1 (the gene for osteopontin) was highly expressed in the pathogenic lung APCs of smoke-exposed mice and was required for the T(H)17 responses and emphysema in vivo, in part through its inhibition of the expression of the transcription factor Irf7. Thus, the Spp1-Irf7 axis is critical for induction of pathological T(H)17 responses, revealing a major mechanism by which smoke activates lung APCs to induce emphysema and identifying a pathway that could be targeted for therapeutic purposes.

This study examined the effect of silencing LRIG3 expression on the proliferation and apoptosis of bladder cancer T24 cells and explored the role of LRIG3 in the tumorigenesis of bladder cancer. Bladder cancer T24 cells were routinely cultured and pSilencer plasmids were employed to construct LRIG3 eukaryotic expression vector of LRIG3-siRNA, i.e., pSilencer-LRIG3-siRNA. After confirmation, the vector was transfected into HEK293 cells to make a replication-deficient adenovirus, pAd-LRIG3-siRNA, which was then introduced into bladder cancer T24 cells. RT-PCR, Western-blotting were performed to detect the levels of LRIG3 mRNA and proteins. Cells number was determined by using MTT test. Hoechst33258 staining, transmission microscopy, flow cytometery were conducted to examine the cell apoptosis. Three groups included a blank control group, a negative control group (containing non-interfering plasmids) and a pAd-LRIG3-siRNA group. Our results showed that the recombinant pAd-LRIG3-siRNA was successfully transfected into the bladder cancer T24 cells. The siRNA formed by the transcription of the recombinant plasmids resulted in significantly reduced expressions of LRIG3 gene and protein and significantly decreased cell proliferation and growth in the pAd-LRIG3-siRNA group as compared with the control group (P