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The stability of the landfill is an environmental issue. The collapse of the landfill causes environmental pollution and influences human life. In the present study, the crack on the cover of the landfill was simulated. Rankine’s theory and the Phantom Node Method were used for the simulation length of the crack and the mechanism of the crack propagation in the nonlinear extended finite element method (NXFEM). Artificial Neural Networks (ANNs) based on Levenberg-Marquardt Algorithm and Abalone Rings Data Set mode were used to predict displacement in critical points of the model. The vibration mechanism of the landfill was changed in each model. During applying seismic load on the model, the optimized thickness of the clay cover on the landfill was discussed. The thickness of the landfill cover controls the seismic response of the landfill. The numerical simulation shows differential displacement of the landfill impacts on the crack propagation and the need for the appropriate design of the cover thickness of the landfill.

Background: Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy. Pathogenic germline variation in genes encoding the sarcomere is the predominant cause of disease. However diagnostic features, including unexplained left ventricular hypertrophy, typically do not develop until late adolescence or after. The early stages of disease pathogenesis and the mechanisms underlying the transition to a clinically overt phenotype are not well understood. In this study, we investigated if circulating microRNAs (miRNAs) could stratify disease stage in sarcomeric HCM. Methods: We performed arrays for 381 miRNAs using serum from HCM sarcomere variant carriers with and without a diagnosis of HCM and healthy controls. To identify differentially expressed circulating miRNAs between groups, multiple approaches were used including random forest, Wilcoxon rank sum test, and logistic regression. The abundance of all miRNAs was normalized to miRNA-320. Results: Of 57 sarcomere variant carriers, 25 had clinical HCM and 32 had subclinical HCM with normal left ventricular wall thickness (21 with early phenotypic manifestations and 11 with no discernible phenotypic manifestations). Circulating miRNA profile differentiated healthy controls from sarcomere variant carriers with subclinical and clinical disease. Additionally, circulating miRNAs differentiated clinical HCM from subclinical HCM without early phenotypic changes; and subclinical HCM with and without early phenotypic changes. Circulating miRNA profiles did not differentiate clinical HCM from subclinical HCM with early phenotypic changes, suggesting biologic similarity between these groups. Conclusions: Circulating miRNAs may augment the clinical stratification of HCM and improve understanding of the transition from health to disease in sarcomere gene variant carriers.

The mechanisms responsible for heart failure in single-ventricle congenital heart disease are unknown. Using explanted heart tissue, we showed that failing single-ventricle hearts have dysregulated metabolic pathways, impaired mitochondrial function, decreased activity of carnitine palmitoyltransferase activity, and altered functioning of the tricarboxylic acid cycle. Interestingly, nonfailing single-ventricle hearts demonstrated an intermediate metabolic phenotype suggesting that they are vulnerable to development of heart failure in the future. Mitochondrial targeted therapies and treatments aimed at normalizing energy generation could represent a novel approach to the treatment or prevention of heart failure in this vulnerable group of patients.

Aims Pediatric dilated cardiomyopathy (pDCM) is characterized by unique age-dependent molecular mechanisms that include myocellular responses to therapy. We previously showed that pDCM, but not adult DCM patients respond to phosphodiesterase 3 inhibitors (PDE3i) by increasing levels of the second messenger cAMP and consequent phosphorylation of phospholamban (PLN). However, the molecular mechanisms involved in the differential pediatric and adult response to PDE3i are not clear. Methods and results Quantification of serum response factor (SRF) isoforms from the left ventricle of explanted hearts showed that PDE3i treatment affects expression of SRF isoforms in pDCM hearts. An SRF isoform lacking exon 5 (SRFdel5) was highly expressed in the hearts of pediatric, but not adult DCM patients treated with PDE3i. To determine the functional consequence of expression of SRFdel5, we overexpressed full length SRF or SRFdel5 in cultured cardiomyocytes with and without adrenergic stimulation. Compared to a control adenovirus, expression of SRFdel5 increased phosphorylation of PLN, negatively affected expression of the phosphatase that promotes dephosphorylation of PLN (PP2Ce), and promoted faster calcium reuptake, whereas expression of full length SRF attenuated calcium reuptake through blunted phosphorylation of PLN. Conclusions Taken together, these data indicate that expression of SRFdel5 in pDCM hearts in response to PDE3i contributes to improved function through regulating PLN phosphorylation and thereby calcium reuptake.

Mixture of sand-expanded polystyrene (EPS) beads is one of the new geo-materials with high compressibility that can be used as a seismic buffer and base isolation due to its great capability for energy dissipation. In this study, a series of 1-g shaking table tests is conducted to assess the dynamic properties of the sand-EPS beads mixtures with a particular focus on the stress-strain response and the variation of shear modulus and damping ratio at the range of medium to large levels of strain. The influence of various parameters, including the amplitude of input base acceleration and EPS content, on the response of sand-EPS beads mixtures is examined. The physical model of sand-EPS bead mixtures showed a lower induced peak acceleration compared to the clean sand model. Moreover, the addition of EPS beads to sand reduced the deformations caused by dynamic loading. The results also revealed that the damping ratio and shear modulus of the samples depend on the EPS bead content, such that its increase results in the damping ratio increasing to 100% or more. On the contrary, the shear modulus of all sand-EPS bead mixtures undergoes a significant reduction with the increase in EPS bead content.

MicroRNAs (miRNAs) are short single-stranded nucleotides that can regulate gene expression. Although we previously evaluated the expression of miRNAs in pediatric dilated cardiomyopathy (DCM) by miRNA array, pathway prediction based on changes in mRNA expression has not been previously analyzed in this population. The current study aimed to determine the regulation of miRNA expression by miRNA-sequencing (miRNA-seq) and, through miRNA-sequencing (mRNA-seq), analyze their putative target genes and altered pathways in pediatric DCM hearts.miRNA expression was determined by miRNA-seq [n = 10 non-failing (NF), n = 20 DCM]. Expression of a subset of miRNAs was evaluated in adult DCM patients (n = 11 NF, n = 13 DCM). miRNA-mRNA prediction analysis was performed using mRNA-seq data (n = 7 NF, n = 7 DCM) from matched samples.Expression of 393 miRNAs was significantly different (p 0.05) in pediatric DCM patients compared to NF controls. TargetScan-based miRNA-mRNA analysis revealed 808 significantly inversely expressed genes. Functional analysis suggests upregulated pathways related to the regulation of stem cell differentiation and cardiac muscle contraction, and downregulated pathways related to the regulation of protein phosphorylation, signal transduction, and cell communication.Our results demonstrated a unique age-dependent regulation of miRNAs and their putative target genes, which may contribute to distinctive phenotypic characteristics of DCM in children.This is the first study to compare miRNA expression in the heart of pediatric DCM patients to age-matched healthy controls by RNA sequencing. Expression of a subset of miRNAs is uniquely dysregulated in children. Using mRNA-seq and miRNA-seq from matched samples, target prediction was performed. This study underscores the importance of pediatric-focused studies.

Background:Milrinone is a phosphodiesterase type 3 inhibitor that results in a positive inotropic effect in the heart through an increase in cyclic adenosine monophosphate. The purpose of this study was to evaluate circulating cyclic adenosine monophosphate and milrinone concentrations in milrinone treated paediatric patients undergoing congenital heart surgery.Methods:Single-centre prospective observational pilot study from January 2015 to December 2017 including children aged birth to 18 years. Milrinone and circulating cyclic adenosine monophosphate concentrations were measured at four time points through the first post-operative day and compared between patients with and without low cardiac output syndrome, defined using clinical and laboratory criteria.Results:Fifty patients were included. Nine (18%) developed low cardiac output syndrome. For all patients, 22% had single ventricle heart disease. The density and distribution of cyclic adenosine monophosphate concentrations varied between those with and without low cardiac output syndrome but were not significantly different. Milrinone concentrations increased in all patients. Paired t-tests demonstrated an increase in circulating cyclic adenosine monophosphate concentrations during the post-operative period among patients without low cardiac output syndrome.Conclusions:In this prospective observational study, circulating cyclic adenosine monophosphate concentrations increased in those without low cardiac output syndrome during the first 24 post-operative hours and milrinone concentrations increased in all patients. Further study of the utility of cyclic adenosine monophosphate concentrations in milrinone treated patients is necessary.

The reuse of scrap and by-product materials in civil engineering applications has increased in recent years due to environmental considerations. Soil-tire mixtures can be used in land reclamation i...

The geotechnical properties of municipal solid waste (MSW) in landfills vary considerably depending on the composition, time, and the rate of waste density. This variability in geotechnical properties leads to many uncertainties in the analysis of landfill slope stability. This study, using probabilistic methods investigates the slope stability and the probability of failure of a Kahrizak landfill under the conditions of spatial variability of physical and geotechnical properties of MSW. To achieve this goal, the random field theory has been used with a finite difference numerical method in the framework of the Monte Carlo simulation. MSW’s shear strength parameters such as cohesion and friction angle as well as the unit weight of layers are considered as random variables. An extensive literature review was conducted to address the probable variation of above-mentioned parameters in Kahrizak landfill. The results of several different laboratory researches on MSW samples collected from Kahrizak landfill were also employed in the modelings. Output results are presented in the form of probability distributions of the factor of safety as well as the probability of failure corresponding to these distributions. Moreover, the effect of various parameters such as coefficient of variation and correlation distance of input parameters on these output results has been investigated. The results show that considering the spatial variability in probabilistic methods would help to determine the various mechanisms affecting the performance and the probability of failure of the landfill slope. In addition, the output of such probabilistic analyses can be used as guidance for engineers to design safe and reliable landfill.

Early-stage leukemia identification is crucial for effective disease management and leads to an improvement in the survival of leukemia patients. Approaches based on cutting-edge biomarkers with excellent accuracy in body liquids provide patients with the possibility of early diagnosis with high sensitivity and specificity. Non-coding RNAs have recently received a great deal of interest as possible biomarkers in leukemia due to their participation in crucial oncogenic processes such as proliferation, differentiation, invasion, apoptosis, and their availability in body fluids. Recent studies have revealed a strong correlation between leukemia and the deregulated non-coding RNAs. On this basis, these RNAs are also great therapeutic targets. Based on these advantages, we tried to review the role of non-coding RNAs in leukemia. Here, the significance of several non-coding RNA types in leukemia is highlighted, and their potential roles as diagnostic, prognostic, and therapeutic targets are covered.

Twin-twin transfusion syndrome (TTTS) is a rare but serious cause of fetal cardiomyopathy with poorly understood pathophysiology and challenging prognostication. This study sought a nonbiased, comprehensive assessment of amniotic fluid (AF) microRNAs from TTTS pregnancies and associations of these miRNAs with clinical characteristics. For the discovery cohort, AF from ten fetuses with severe TTTS cardiomyopathy were selected and compared to ten normal singleton AF. Array panels assessing 384 microRNAs were performed on the discovery cohort and controls. Using a stringent q < 0.0025, arrays identified 32 miRNAs with differential expression. Top three microRNAs were miR-99b, miR-370 and miR-375. Forty distinct TTTS subjects were selected for a validation cohort. RT-PCR targeted six differentially-expressed microRNAs in the discovery and validation cohorts. Expression differences by array were confirmed by RT-PCR with high fidelity. The ability of these miRNAs to predict clinical differences, such as cardiac findings and later demise, was evaluated on TTTS subjects. Down-regulation of miRNA-127-3p, miRNA-375-3p and miRNA-886 were associated with demise. Our results indicate AF microRNAs have potential as a diagnostic and prognostic biomarker in TTTS. The top microRNAs have previously demonstrated roles in angiogenesis, cardiomyocyte stress response and hypertrophy. Further studies of the mechanism of actions and potential targets is warranted.

Acute respiratory distress syndrome is a heterogeneous pathophysiological process responsible for significant morbidity and mortality in pediatric intensive care patients. Diagnosis is defined by clinical characteristics that identify the syndrome after development. Subphenotyping patients at risk of progression to ARDS could provide the opportunity for therapeutic intervention. microRNAs, non-coding RNAs stable in circulation, are a promising biomarker candidate. We conducted a single-center prospective cohort study to evaluate random forest classification of microarray-quantified circulating microRNAs in critically ill pediatric patients. We additionally selected a sub-cohort for parallel metabolomics profiling as a pilot study for concurrent use of miRNAs and metabolites as circulating biomarkers. In 35 patients (n = 21 acute respiratory distress, n = 14 control) 15 microRNAs were differentially expressed. Unsupervised random forest classification accurately grouped ARDS and control patients with an area under the curve of 0.762, which was improved to 0.839 when subset to only patients with bacterial infection. Nine metabolites were differentially abundant between acute respiratory distress and control patients (n = 4, both groups) and abundance was highly correlated with miRNA expression. Random forest classification of microRNAs differentiated critically ill pediatric patients who developed acute respiratory distress relative to those who do not. The differential expression of microRNAs and metabolites provides a strong foundation for further work to validate their use as a prognostic biomarker.

Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy and main indication for heart transplantation in children. Therapies specific to pediatric DCM remains limited due to lack of a disease model. Our previous study showed that treatment of neonatal rat ventricular myocytes (NRVMs) with non-failing or DCM pediatric patient serum activates the fetal gene program (FGP). Here we show that serum treatment with Proteinase K prevents activation of the FGP, whereas RNase treatment exacerbates it, suggesting that circulating proteins, but not circulating microRNAs, promote these pathological changes. Evaluation of the protein secretome showed that midkine (MDK) is up-regulated in DCM serum, and NRVM treatment with MDK activates the FGP. Changes in gene expression in serum-treated NRVMs, evaluated by next-generation RNA sequencing (RNA-Seq), indicates extracellular matrix remodeling and focal adhesion pathways are upregulated in pediatric DCM serum and serum-treated NRVMs, suggesting alterations in cellular stiffness. Cellular stiffness was evaluated by Atomic Force Microscopy, which showed an increase in stiffness in DCM serum-treated NRVMs. Of the proteins increased in DCM sera, secreted frizzled related protein 1 (sFRP1) was a potential candidate for the increase in cellular stiffness, and sFRP1 treatment of NRVMs recapitulated the increase in cellular stiffness observed in response to DCM-serum treatment. Our results show that serum circulating proteins promote pathological changes in gene expression and cellular stiffness, and circulating miRNAs are protective against pathological changes.

Carbonate sediments are originated from the skeletal remains of marine organisms, which are abundantly situated at the tropical and petrochemical reservoir in Australia, India, the North Sea coasts, and the Persian Gulf. The different behavior of carbonate remains in comparison to siliceous soils has attracted attention among researchers. Crushability is a significant feature of carbonate sands which leads to changes in particle size distribution at high pressures and causes enormous damage to structures. This study aims to evaluate the compressibility of Hormuz Island carbonate sand and compare it to the Chamkhaleh Beach siliceous sand through one-dimensional compression tests in a pneumatic oedometer apparatus. Experiments were subjected to overburden pressures up to 2 MPa, and grain crushing was measured after each experiment. Results illustrated that particle crushing in the Hormuz Island sand impacted its compressibility and led to an abrupt increase in strain and settlement.

Dopamine has a favorable therapeutic profile but has not been widely used to treat hypotension during microvascular breast reconstruction. The purpose of this study was to evaluate outcomes in patients who received dopamine during breast reconstruction using deep inferior epigastric perforator (DIEP) free flaps and compare them with patients who did not receive dopamine.A single-center retrospective review was performed for patients who underwent breast reconstruction with DIEP free flaps between October 2018 and March 2020. Patient demographics, comorbidities, fluid balance, hospital stay, and adverse outcomes were compared between patients who received at least 1 h of dopamine (DA) and patients who did not receive dopamine (ND). Subgroup analyses were performed for bilateral procedures and patients who received dopamine.Twenty-five patients in the DA group and 43 patients in the ND group met the inclusion criteria. There were no flap-related complications. Patients who had dopamine initiated to maintain blood pressures had a higher total volume of intravenous fluid (ND:3.81L vs. DA:5.04L, p = 0.005). However, DA patients exhibited decreased fluid requirements (ND:839 mL/h vs. DA:479 mL/h, p = 0.004) and increased urine output (ND:98.0 mL/h vs. DA:340 mL/h, p = 0.001) once dopamine was initiated. Intraoperative urine output (ND:1.37 L vs. DA:3.48 L, p 0.001) and rate (ND:1.9 ml/kg/h vs. DA:3.7 ml/kg/h, p 0.001) were increased in the DA group. The fluid balance of patients undergoing bilateral procedures was closer to neutral for patients who received dopamine (ND:+3.43 L vs. DA:+2.26 L, p = 0.03).Dopamine is safe to use in microvascular breast reconstruction. It may be beneficial for hemodynamically labile patients by stabilizing blood pressure and facilitating a neutral fluid balance.

In this paper, the deformation properties of sand, reinforced with carpet waste, are investigated by carrying out a set of large-scale oedometer tests under different overburden pressures. The oedometer apparatus employed in this study has been equipped with vertical and lateral pressure cells, which allow the value of the soil’s coefficient of lateral pressure at rest, to be determined as well as its compressibility. Carpet waste was added to sand at weight percentages of 0, 5, 10 and 15%. Results were indicative of a reduction in the coefficient of lateral pressure at rest, K0 with the increase in carpet content of the mixtures. The reduction in the value of K0 amounted to 10% at a carpet content of 15%. The compressibility properties of the mixtures were evaluated as well, by recording one-dimensional displacement in the samples. Results demonstrated an increase in the coefficient of volume change with the increase in carpet content, particularly for lower levels of overburden pressure. Predictive models were developed based on the multi-linear regression (MLR) procedure to predict the coefficient of lateral pressure at rest and coefficient of volume change for the sand–carpet mixtures normalized to the values of sand.

Keloids are benign fibroproliferative skin tumors that can cause disfigurement and disability. Although they frequently recur after excision or medical management and can affect 6 to 16 percent of African Americans, there is no gold standard therapy. Keloids are challenging to study because there are no animal or in vitro models of this disorder. This makes it very difficult to validate data from treated tissue samples or cells and develop targeted therapies for this disease. In this study, the authors demonstrate that intralesional 5-fluorouracil injection after keloid excision prevents recurrence for 2 years, with no reported adverse events. The authors analyze the expression of treated and untreated biopsy specimens of the same keloids in their native context to capture insights that may be missed by in vitro cell culture models and correct for intrakeloid variability. Random forest analysis of the microarray data dramatically increased the statistical power of the authors' results, permitting hypothesis-free creation of a gene expression profile of 5-fluorouracil-treated keloids. Through this analysis, the authors found a set of genes, including YAP1 and CCL-2, whose expression changes predict 5-fluorouracil therapy status and include genes that have not previously been associated with keloid biology and are of unknown function. The authors further describe keloid heterogeneity for the first time using multidimensional analysis of their microarray results. The methods and tools the authors developed in this research may overcome some of the challenges in studying keloids and developing effective treatments for this disease. CLINICAL QUESTION/LEVEL OF EVIDENCE:: Therapeutic, V.

Probabilistic methods in geotechnical engineering have received a lot of attention during the last decade and different methodologies are used to capture the inherent variability of soil in...

Prostate cancer genomic subtypes that stratify aggressive disease and inform treatment decisions at the primary stage are currently limited. Previously, we functionally validated an aggressive subtype present in 15% of prostate cancer characterized by dual deletion of MAP3K7 and CHD1. Recent studies in the field have focused on deletion of CHD1 and its role in androgen receptor (AR) chromatin distribution and resistance to AR-targeted therapy; however, CHD1 is rarely lost without codeletion of MAP3K7. Here, we show that in the clinically relevant context of co-loss of MAP3K7 and CHD1 there are significant, collective changes to aspects of AR signaling. Although CHD1 loss mainly impacts the expansion of the AR cistrome, loss of MAP3K7 drives increased AR target gene expression. Prostate cancer cell line models engineered to cosuppress MAP3K7 and CHD1 also demonstrated increased AR-v7 expression and resistance to the AR-targeting drug enzalutamide. Furthermore, we determined that low protein expression of both genes is significantly associated with biochemical recurrence (BCR) in a clinical cohort of radical prostatectomy specimens. Low MAP3K7 expression, however, was the strongest independent predictor for risk of BCR over all other tested clinicopathologic factors including CHD1 expression. Collectively, these findings illustrate the importance of MAP3K7 loss in a molecular subtype of prostate cancer that poses challenges to conventional therapeutic approaches. Implications: These findings strongly implicate MAP3K7 loss as a biomarker for aggressive prostate cancer with significant risk for recurrence that poses challenges for conventional androgen receptor–targeted therapies.

Although the problems associated with the repeatability of the standard penetration test (SPT) measurements have long been recognized, SPT results are the basis of many direct methods to estimate the axial capacity of driven piles. In this paper, a new approach is proposed to estimate the bearing capacity of driven piles in various soils, based on soil SPT values estimated from cone penetration test (CPT) data and soil behavior index, Ic. A databank consisted of results of 63 full-scale pile load tests has been compiled. Thirty-eight cases have been employed for calibration and 25 for validation. CPT records were converted to N60 values using a popular equation. Calibration was conducted using multilinear regression and pile bearing capacity was correlated with the estimated SPT values. Depending on the soil type, different pile bearing capacity coefficients are suggested for unit base and shaft resistance. The current method was compared with other methods using the log normal distribution, which showed that the current method exhibits the least average error. The average error of the current method was found to be −2% and the probability of accurate prediction with a ±10% error was found to be equal to 45%. Applying the new method to the 25 verification cases showed an error of 3% with a probability of 34.1% in prediction with error of ±10% showing that this approach could be successfully employed to estimate the bearing capacity of piles in different soil types.

Objective: Rheumatoid arthritis is a chronic disease with various clinical characteristics. The introduction of biological drugs has enhanced the efficacy and increased diversity of treatment options. Considering the patients’ preferences in decision-making about treatment can improve their adherence. A discrete choice experiment is a type of conjoint method that can elicit preferences in more realistic scenarios. This article reviewed discrete choice experiment (DCE) studies to extract which attributes and levels were included in surveys. In addition, we focused on the process of designing surveys and the method that they used. Method: PubMed, EMBASE, Web of Science, Scopus, Ovid (Medline) and ProQuest were systematically searched in order to find studies that evaluated rheumatoid arthritis patients’ preferences about biological medicines. Studies published in peer-reviewed journals between 1/1/1990 and 12/31/2019 were included. The included studies were analyzed using a narrative synthesis method and descriptive statistics. Results: A total of 7124 studies were initially found. After deleting irrelevant and duplicate studies, 15 studies were included. The most common attributes that were used in surveys were efficacy, adverse effect, route of administration, frequency of administration, and cost. Most studies used a literature review for developing attributes and levels. The median number of included attributes and levels were seven and three, respectively. Eight studies explained their experimental design while seven studies did not. Conditional logit and mixed logit were the most common methods for modeling reciprocally. Conclusion: Several aspects of DCE studies investigating biological drugs in RA were assessed. Explaining the sample size, experimental design, and qualitative work for developing attributes can improve this type of study.

In this study, a reliability-based analysis of slope stability in a landfill considering the spatial variability of shear strength (c and φ) and unit weight ( γ) of municipal solid waste was performed using the random finite difference method. The effect of the anisotropic correlation (AC) structure of random variables including c, φ, and γ on mean and coefficient of variation (CoV) of safety factor values was investigated using Monte Carlo simulation. Also, probability of failure was determined through probability distribution fitting to a series of safety factor data. The results showed that the AC of the random variables has a significant effect on the stochastic safety factor of landfill slope. In general, the mean of the stochastic safety factor decreases with increasing horizontal and vertical correlation lengths (CLs). Also, the CoV of the safety factor increased with increase in horizontal or vertical CLs or both. Moreover, it was found that failure probability increases with an increase in the horizontal and vertical CLs and assuming isotropic structure for the correlation of random variables leads to the underestimation of failure probability. Overall, the results indicate that assuming an AC structure results in different failure mechanisms in the landfill slope, which are different from the deterministic cases.

Background: Pediatric dilated cardiomyopathy (DCM) is a disease with a poor prognosis that affects 1 in 100,000 children. Girls with DCM have worse outcomes than boys, and the mechanisms that lead to these differences are not clear. We have identified a cytokine, midkine (MDK) that is significantly upregulated in the serum from pediatric DCM patients. Circulating MDK is significantly higher in girls with DCM requiring heart transplantation compared to girls with DCM who are stable. Objective: The objective of this study is to determine if MDK impacts cardiomyocyte function in a sex-specific manner in juvenile male and female cells. Methods: Cardiomyocytes isolated from 3 week old juvenile male and female rats (JRVMs) were treated with 1μg MDK for 48 hours. Cardiomyocyte function and calcium dynamics were assessed using an IonOptix system. Myofibril mechanics and calcium sensitivity were measured. In addition, RNA sequencing was completed to identify differentially regulated pathways in juvenile male and female cardiomyocytes in response to MDK. Results: Female JRVMs treated with MDK had higher peak calcium and slower calcium reuptake compared to vehicle-treated female JRVMs. In contrast, male JRVMs treated with MDK did not demonstrate a change in peak calcium and had faster calcium reuptake compared to vehicle-treated male JRVMs. Myofibril calcium sensitivity was decreased in female JRVMs in response to MDK whereas calcium sensitivity was unchanged in male MDK-treated JRVMs. Analysis of the genes that were differentially expressed in cardiomyocytes in response to MDK demonstrated a sex-dependent regulation. Specifically, pathways which regulate calcium handling were only altered in female JRVMs treated with MDK but not in MDK-treated male JRVMs. Conclusions: This study demonstrates sex-specific differences in cardiomyocyte function in response to MDK. Particularly, female cardiomyocytes respond to MDK by regulating genes involved in calcium handling pathways. This suggests that elevated circulating MDK in pediatric DCM patients may lead to different cardiac responses in male and female patients. Therefore, elucidating these sex-specific disease mechanisms is critical to define therapies focused on male and female pediatric DCM patients.

Oxidative stress is a key contributor to the development of dysregulated inflammation in acute lung injury (ALI). A naturally occurring single nucleotide polymorphism in the key extracellular antioxidant enzyme, extracellular superoxide dismutase (EC-SOD), results in an arginine to glycine substitution (R213G) that promotes resolution of inflammation and protection against bleomycin-induced ALI. Previously we found that mice harboring the R213G mutation in EC-SOD exhibit a transcriptomic profile consistent with a striking suppression of inflammatory and immune pathways 7 days postbleomycin. However, the alterations in noncoding regulatory RNAs in wild-type (WT) and R213G EC-SOD lungs have not been examined. Therefore, we used next-generation microRNA (miR) Sequencing of lung tissue to identify dysregulated miRs 7 days after bleomycin in WT and R213G mice. Differential expression analysis identified 92 WT and 235 R213G miRs uniquely dysregulated in their respective genotypes. Subsequent pathway analysis identified that these miRs were predicted to regulate approximately half of the differentially expressed genes previously identified. The gene targets of these altered miRs indicate suppression of immune and inflammatory pathways in the R213G mice versus activation of these pathways in WT mice. Triggering receptor expressed on myeloid cells 1 (TREM1) signaling was identified as the inflammatory pathway with the most striking difference between WT and R213G lungs. miR-486b-3p was identified as the most dysregulated miR predicted to regulate the TREM1 pathway. We validated the increase in TREM1 signaling using miR-486b-3p antagomir transfection. These findings indicate that differential miR regulation is predicted to regulate the inflammatory gene profile, contributing to the protection against ALI in R213G mice.

Kawasaki Disease (KD) is an acute vasculitis of unknown etiology in children that can lead to coronary artery lesions (CAL) in 25% of untreated patients. There is currently no diagnostic test for KD, and the clinical presentation is often difficult to differentiate from other febrile childhood illnesses. Circulating microRNAs (miRNAs) are small noncoding RNA molecules that control gene expression by inducing transcript degradation or by blocking translation. We hypothesize that the expression of circulating miRNAs will differentiate KD from non-KD febrile illnesses in children.Circulating miRNA profiles from 84 KD patients and 29 non-KD febrile controls (7 viral and 22 bacterial infections) were evaluated. 3 ul of serum from each subject was submitted to 3 freeze/heat cycles to ensure miRNA release from microvesicles or interaction with serum proteins. miRNAs were reverse transcribed using a pool of primers specific for each miRNA. Real-time PCR reactions were performed in a 384 well plate containing sequence-specific primers and TaqMan probes in the ABI7900. '.KD patients (3.6 ± 2.2 yrs., 58% male) were found to have a unique circulating miRNA profile, including upregulation of miRNA-210-3p, -184, and -19a-3p (p .0001), compared to non-KD febrile controls (8.5 ± 6.1 yrs., 72% male).Circulating miRNAs can differentiate KD from infectious febrile childhood diseases, supporting their potential as a diagnostic biomarker for KD.

Supplemental material, Supplementary for Effects of anisotropy in correlation structure on reliability-based slope stability analysis of a landfill by Mohammad Javad Mehdizadeh, Nader Shariatmadari and Mehran Karimpour-Fard in Waste Management & Research

Background: Intraindividual copy number variation (CNV) origin is largely unknown. They might be due to aging and/or common genome instability at the preimplantation stage while contribution of preimplantation in human intraindividual CNVs occurrence is unknown. To address this question, we investigated mosaicism and its origin in the fetuses of natural conception. Methods: We studied normal fetuses following therapeutic abortion due to maternal indications. We analyzed the genome of 22 tissues of each fetus by array comparative genomic hybridization for intraindividual CNVs. Each tissue was studied in 2 microarray experiments; the reciprocal aberrations larger than 40 Kb, identified by comparing tissues of each fetus, were subsequently validated using quantitative polymerase chain reaction. Results: Through intraindividual comparison, frequency of reciprocal events varied from 2 to 9. According to the distribution pattern of the frequent CNV in derivatives of different germ layers, we found that its origin is early development including preimplantation, whereas CNVs with low frequency have occurred in later stages. Shared CNVs in both fetuses were belonged to thymus and related to the functional role of genes located in these CNVs. Conclusions: The origin of some of fetal CNVs is preimplantation stage. Each organ might inherit CNVs with an unpredictable pattern due to the extensive cell mixing/migration in embryonic development.

A series of laboratory large-scale model tests were conducted on piled raft founded on sand with different compaction levels. The numbers of piles are 1, 4, 5 and 9. All the piles are 40 cm in length and the slenderness ratio is 20. In these tests, the variation of load improvement ratio (LIR), load-sharing ratio (αp) and settlement ratio (SR) are reported for different relative densities and number of piles. Moreover, the variation of ultimate bearing capacity of piled raft system was investigated for different conditions. Results showed that LIR ratio will be more noticeable in loose state in comparison to dense sand, and also increasing the number of settlement reducing piles proved to decrease the SR values or increasing the SIF values in other words. In the end, a sensitivity analysis was performed to investigate the influence of each parameter in affecting the performance of the piled raft system. Based on the sensitivity analyses, relative density of soil was proven to be the most effective parameter in comparison to the number of piles. Finite element analyses have also been performed using the ABAQUS software. The numerical results from the FEM were first validated with the experimental results and then parametric study was carried out to investigate the effect of load eccentricities. It was shown that the ultimate bearing capacity of the piled raft foundation decreases significantly with an increase in the load eccentricity.

This paper presents some attempts at prediction of compaction characteristics of soils using the results of the index tests. A data bank, including 728 compaction tests, was compiled. Each case includes the results of soil type, grain size distribution, Atterberg limits (WL and WP) and specific gravity of soil particles, as well as the compaction characteristics, maximum dry density and optimum moisture content were calculated under different levels of compaction energy. Using artificial neural networks (ANNs) and multi-linear regression (MLR), the applicability of basic information about soils to estimate the compaction characteristics was evaluated. A sensitivity analysis accomplished on the results of ANN method, demonstrated that fine content has the most pronounced effect on the accuracy of compaction characteristics prediction. Using a trial and error approach and combining the different individual variables, the efficiency of multi-linear regression models were improved. However, the comparisons showed that ANN models are more effective in capturing the correlation among compaction characteristics of soils and their index properties, while the ANN shortcomings, due to their black box nature, make MLR models more useful in prompt estimations.

In this study the stress–strain characteristics of sand-ground rubber mixtures are investigated in the sandlike zone, at different confining pressures, using hollow cylinder specimens subjected to torsional monotonic and cyclic loading. Under monotonic loading a mixture of sand-ground rubber with 10% and 25% rubber content show more contraction behaviour than that observed in a pure sand specimen. Phase transformation point in these mixtures are located on a larger shear strain. As expected, the shear strength of specimens decreases with increase of ground rubber content. However, with increasing of effective confining pressure, the loss in shear strength of the mixture is decreased. In addition, a mixture with 25% ground rubber shows a smaller loss in shear strength compared to a mixture with 10% ground rubber mixture. Under cyclic loading mixtures with 10% and 25% ground rubber have similar liquefaction resistance, especially at confining pressures of 110 kPa and 260 kPa. Therefore, by using of the mixture with 25% ground rubber, a larger volume of scrap tires could be recycled. The addition of ground rubber to sand would affect the shear strain variation and excess pore water pressure trends, and this effect was further intensified with increasing ground rubber percentage.

Accepting and landfilling municipal solid waste, MSW, in non-engineered conditions since 1984, has made the Saravan dumpsite as one of the biggest environmental concerns in northern Iran. Due to a lack of any type of coverage, precipitation is infiltrated into the waste piles, increasing the amount of leachate production. The average annual discharge rate of leachate is estimated to be 7 L per second, which all are discharged to the downstream rivers and creeks. To reduce the produced leachate, the construction of soil cover, leachate drainage system, gas collection systems and other requirements were planned. To construct the soil cover, stability analyses to reach a safe side slope were necessary; therefore, geotechnical evaluation of MSW was vital. MSW samples with different age and conditions were collected, and geotechnical tests such as moisture and organic content, composition, grain size distribution and direct shear tests were performed. Back-calculation analyses performed on unstable slopes at the site resulted in situ shear strength of MSW, comparable with those achieved in laboratory tests. Results showed that the soil-like fraction, moisture and organic content decrease with depth and age, leading to an increase in foil-like contents and reduction in shear strength of MSW. Direct shear tests with different shearing rates showed that the MSW in Saravan dumpsite exhibits higher strength at higher rates of shearing which means a higher safety factor for slopes during seismic condition could be expected.

In the present study, a series of stress-controlled undrained cyclic torsional tests were performed to study the liquefaction resistance and equivalent shear modulus of sand–ground rubber mixture. By considering the mixture in which compressibility may be tolerable for geotechnical design (sand-like behaviour), four percentages of ground rubber (0, 5, 10, and 25%, by volume) were selected in the research. The tests were performed under three different confining pressures, at a constant relative density, and the effects of various parameters such as rubber fraction, and confining pressure were investigated. From the test results it is seen that the shear stiffness of sand decreases drastically, even when it is mixed with low percentages of the ground rubber. The liquefaction resistance of sand decreases by adding the ground rubber (up to 25% by volume) to it. The maximum and minimum decrease in the cyclic resistance ratio, caused by increasing the rubber fractions, occurred for corresponding confining pressures of 110 and 400 kPa, respectively. However, despite the large differences in the fraction of ground rubber in the soil, the liquefaction resistance of mixtures with 10 and 25% ground rubber is almost the same.

In this study, the critical depth of un-braced open cuts is investigated using physical and numerical modeling carried out by the centrifuge machine at the Iran University of Science and Technology and a FISH code developed in the finite difference software, FLAC, respectively. The undrained shear strength of the soil was measured using Unconfined Compression Test (UCT), Miniature Vane Shear Test (MVST), and Pocket Penetrometer Test (PPT) and the results were used to develop a statistical correlation between the soil water content and its strength. In addition, upper and lower bound limit analysis solutions were used as benchmarks to verify the results. Finally, the values of critical excavation depth obtained through numerical analysis and centrifuge modeling in this study were compared with those estimated by the limit analysis and limit equilibrium methods.

This paper presents Artificial Neural Network (ANN) prediction models that relate the safety factors of a quay wall against sliding, overturning and bearing capacity failure to the soil geotechnical properties, the geometry of the gravity hunched back quay walls and the loading conditions. In this study, a database of around 80000 hypothetical data sets was created using a conceptual model of a gravity hunched back quay wall with different geometries, loading conditions and geotechnical properties of the soil backfill and the wall foundation. To create this database a MATLAB aided program was written based on one of the most common manuals, OCDI (2002). Comparison between the results of the developed models and cases in the data bank indicates that the predictions are within a confidence interval of 95%. To evaluate the effect of each factor on these values of factor of safety, sensitivity analysis were performed and discussed. According to the performed sensitivity analysis, shear strength parameters of the soil behind and beneath the walls are the most important variables in predicting the safety factors.

This research explores performance of the energy approach for evaluating the liquefaction potential of sand–tire crumb mixtures. Thirty-six stress-controlled undrained cyclic torsional tests were performed under three different confining pressures on samples with different rubber contents. The effect of such parameters as the rubber content and confining pressure on liquefaction behavior of sand–rubber mixtures was studied using the energy approach. Test results indicated that, unlike the observations made on the pure sand sample, in the case of sand–rubber mixture with 25% rubber content, when the initial liquefaction is triggered, the dissipated shear energy increases with continued cyclic loading. The increasing trend is stopped when the pore water pressure reached the initial consolidation stress (Ru = 1). This observation indicates that for the case of sand–tire crumb mixture, the dissipated energy per volume is associated only with the progression of pore water pressure. Moreover, the results show that the required energy for liquefaction occurrence decreases with the increase in the rubber content. The minimum amount of required energy is determined for mixtures with 10% rubber content. As the result, the inclusion of crumb rubber decreases the liquefaction resistance of sand. However, when the rubber content increases from 10 to 25%, the resistance to liquefaction improves. The generation rate for mixture with 25% rubber content is somewhat faster than that of the clean sand and the mixture with 10% tire crumbs, as it is expected.

Stone column technique has been successfully applied for the foundation improvement. A rigid box with dimensions of 1.5 × 1.5 × 1.2 m equipped with a jacking-pump system was used to loading the stone column reinforced bed. Laboratory tests are carried out on stone columns with 6.3 cm diameter and different patterns surrounded by loose sand. The parameters varied in this experimental and numerical investigation are length, diameter and number of stone columns. The number of stone columns in these tests are 4, 5 and 9 and lengths of stone columns are 30, 40 and 50. A 40 × 40 × 2 cm steel plate is used as the model foundation. In these tests, the variation of bearing capacity ratio (BCR) and settlement reduction factor (SRF) are reported for different length and number of stone columns. The results show that by increasing the number and length of stone columns, BCR value will increase and SRF value will decrease. Finite-element analyses have also been performed using the ABAQUS software. The numerical results from the FEM were first validated with the experimental results and then some parametric analyses were conducted to investigate the effect of stone column diameter.

This paper proposes a model to represent the MSW undrained mechanical behavior, which is an extension of the previous models developed by the authors. A more comprehensive formulation for effective stress is adopted taking into account the compressibility of waste particles and the concepts embraced in the Skempton’s equation for effective stress. The model reproduces the main MSW features such as high pore water pressure generation, concave upward curves and high shear strength values, even for u = σ 3 (zero net confining stress). Model predictions showed good adherence to experimental results. MSW samples of different sources were used in the simulations.

The increasing demand of engineering landfills requires that designers propose a framework for landfill design, construction, repair and maintenance. As municipal solid waste (MSW) is a major part of a landfill, the analysis should consider MSW mechanical behavior using a constitutive model. To investigate this, 18 direct shear (DS) and triaxial (TX) tests were conducted on MSW samples with different fiber contents. Different shearing mechanisms lead to understand effects of fibers on stress–strain response. Based on obtained results the hyperbolic model Duncan and Chang (J Soil Mech Found Div 96(5):1629–1653, 1970) has been employed to simulate the TX results indicating the ability of the model to predict stress–strain behavior of MSW. This model could also be employed to the DS test results with some assumptions. The model can capture DS stress–strain response well whereas for TX tests the predictions were just enough. The experimental results and two sets of proposed MSW parameters of hyperbolic model have been compared and discussed.

Protective T cell memory is an acquired trait that is contingent upon the preservation of its constituents and therefore vulnerable to the potentially deleterious effects of organismal aging. Here, however, we have found that long-term T cell memory in a natural murine host-pathogen system can substantially improve over time. Comprehensive molecular, phenotypic, and functional profiling of aging antiviral CD8+ memory T cells (CD8+ TM) revealed a pervasive remodeling process that promotes the gradual acquisition of distinct molecular signatures, of increasingly homogeneous phenotypes, and of diversified functionalities that combine to confer a CD8+ TM–autonomous capacity for enhanced recall responses and immune protection. Notably, the process of CD8+ TM aging is characterized by a progressive harmonization of memory and naive T cell traits, is broadly amenable to experimental acceleration or retardation, and serves as a constitutional component for the “rebound model” of memory T cell maturation. By casting CD8+ TM populations within the temporal framework of their slowly evolving properties, this model establishes a simple ontogenetic perspective on the principal organization of CD8+ T cell memory that may directly inform the development of improved diagnostic, prophylactic, and therapeutic modalities.

The applicability of Expanded PolyStyrene (EPS) beads mixed with sand in five different contents was investigated for use in geotechnical engineering applications utilizing a newly designed and fabricated large scale oedometer apparatus. Permeability, coefficient of earth pressure “at rest” and the volume compressibility coefficient were measured and calculated for different EPS beads contents. Consolidation and permeability tests were conducted under different overburden pressures. The main findings of major recent studies were compared with current study and verification of new results was undertaken. Permeability, coefficient of earth pressure “at rest” and the volume compression coefficient along with some important deformation and strength characteristics parameters namely, the internal friction angle, constraint modulus and the drained 3-D elasticity modulus were investigated. The Results revealed that permeability, internal friction angle, constraint modulus and 3-D Young modulus decreases with inclusion content. However, the volume compressibility coefficient and the K0 coefficient showed opposite trends. Predictive models were submitted in forms of Multi Linear Regression, MLR simulations and their performances were evaluated.

Kahrizak landfill could be called the largest dumpsite not only in the Tehran province but also in the country. In some parts of this dumpsite, there are piles of municipal solid waste (MSW), with considerable height and very steep slopes, the stability of which is a constant matter of concern not only in static loading condition but also under dynamic loading. As this region is subjected to a high seismic activity, the dynamic properties of the dumped MSW would be necessary to perform stress–strain analysis and estimate the deformation in the body of a landfill cell. The estimation of deformations in a cell mainly at the crown of landfills is vital, as different types of facilities like gas drainage and leachate re-circulation systems are installed in landfills. This paper presents the results of some strain-controlled cyclic triaxial test on fresh MSW materials with a diameter of 100 mm to estimate the shear stiffness and damping of these materials. To normalize the estimated shear stiffness from laboratory tests, the measured G max from field continuous surface wave system was employed. The results showed that the damping ratio for MSW materials is considerably higher when soils. The results of this study showed that in the range of applied shear strains, G-reduction curve has a good agreement with the graph proposed in the literature; however, variation of damping ratio by shear strain seems to be lower than values proposed by these researchers.