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A metabolomics-based approach to address the molecular mechanism of childhood asthma with immunoglobulin E (IgE) or allergen sensitization related to microbiome in the airways remains lacking. Fifty-three children with lowly sensitized non-atopic asthma (n = 15), highly sensitized atopic asthma (n = 13), and healthy controls (n = 25) were enrolled. Blood metabolomic analysis with 1H-nuclear magnetic resonance (NMR) spectroscopy and airway microbiome composition analysis by bacterial 16S rRNA sequencing were performed. An integrative analysis of their associations with allergen-specific IgE levels for lowly and highly sensitized asthma was also assessed. Four metabolites including tyrosine, isovalerate, glycine, and histidine were uniquely associated with lowly sensitized asthma, whereas one metabolite, acetic acid, was strongly associated with highly sensitized asthma. Metabolites associated with highly sensitized asthma (valine, isobutyric acid, and acetic acid) and lowly sensitized asthma (isovalerate, tyrosine, and histidine) were strongly correlated each other (P Atopobium (P Fusobacterium (P

The Epstein–Barr virus (EBV) transforms resting B cells and is involved in the development of B cell lymphomas. We report here that the viral noncoding RNA EBER2 accelerates B cell growth by potentiating expression of the UCHL1 deubiquitinase that itself increased expression of the Aurora kinases and of cyclin B1. Importantly, this effect was also visible in Burkitt’s lymphoma cells that express none of the virus’s known oncogenes. Mechanistically, EBER2 bound the UCHL1 messenger RNA (mRNA), thereby bringing a protein complex that includes PU.1, a UCHL1 transactivator, to the vicinity of its promoter. Although the EBV oncogene LMP1 has been suggested to induce UCHL1, we show here that EBER2 plays a much more important role to reach significant levels of the deubiquitinase in infected cells. However, some viruses that carried a polymorphic LMP1 had an increased ability to achieve full UCHL1 expression. This work identifies a direct cellular target of a viral noncoding RNA that is likely to be central to EBV’s oncogenic properties.

Intelligent fault diagnosis (IFD) plays an important role to increase the safety and reliability of rotating machinery. In recent years, there is a large number of deep-learning-based algorithms applied to IFD. Many studies have shown that the one-dimension convolutional neural network (1D-CNN) performs well in fault diagnosis on original vibration signals. However, the original vibration signals are very complicated and difficult to analyze directly. Some critical information is often hidden in different frequency subbands, such as some fault state is only related to specific subbands. In order to enhance the learning progression well organized for the 1D-CNN model, the proposed approach is based on wavelet packet decomposition (WPD) and 1D-CNN. First, decompose the original vibration signal into different frequency subbands with WPD to make the signals more concise. Next, to be compatible with the 1D-CNN model, we proposed a novel 1D-CNN with multi-resolution (CNN-MR) and the experiment result according to Case Western Reserve University (CWRU) Bearing Data Center. Through CNN-MR, it achieves high accuracy for fault diagnosis.

Airway microbiota may play an important role in regulating the immune response related to allergic respiratory diseases. A molecular-based approach was used to analyze the association between nasopharyngeal microbiota, serum immunoglobin (Ig)E levels, and childhood respiratory allergies.Nasopharyngeal swabs were collected from children aged 36 months with three phenotypes, including allergic respiratory diseases plus atopy, atopy alone, and healthy controls for microbiome analysis using Illumina-based 16S rRNA gene sequencing.In total, 87 children were enrolled, including 36 with allergic respiratory diseases plus atopy, 21 with atopy alone, and 30 healthy controls. Proteobacteria (45.7%), Firmicutes (29.3%), and Actinobacteria (15.3%) were the most prevalent phyla in the study population. Compared with healthy controls, a lower Chao1 index was found in children with allergies (P 0.035), indicating that bacterial richness was inversely associated with airway allergies. Additionally, in comparison with healthy controls, the genera Acinetobacter, Moraxella, Asaia, and Rhodococcus were more abundant and positively correlated with total serum IgE levels in children with allergies (P 0.01), whereas the genera Enterococcus and Rickettsia were inversely correlated with total IgE levels, and also appeared to be negatively associated with airway allergies (P 0.01).The composition of the nasopharyngeal microbiota alteration may have an influence on childhood respiratory allergies. The inverse association between bacterial richness and allergies postulated that children living in a microbially hygienic environment may increase their risk of developing respiratory allergies.

The Epstein–Barr virus M81 strain, isolated from a nasopharyngeal carcinoma, induces potent spontaneous virus production in infected B cells. We found that the M81 non-coding Epstein–Barr-encoded RNA EBER2, which carries polymorphisms that are mainly restricted to viruses found in endemic nasopharyngeal carcinomas, markedly stimulated this process. M81 EBER2 increased CXCL8 expression, and this chemokine enhanced spontaneous lytic replication levels in M81-infected B cells. Both events resulted from the endocytosis of extracellular vesicles containing EBER2 that were generated by neighbouring M81-infected B cells, thereby generating a paracrine loop. These effects were strictly dependent on a functional Toll-like receptor 7 (TLR7), a sensor of single-stranded RNA located in the endosome of these cells. These unique properties of M81 EBER2 could be ascribed to its unusually high expression level and to the ability of its single-stranded region to activate TLR7; both of these properties were dependent on M81-specific polymorphisms. Thus, M81 induced chronic inflammation in its target cells and this resulted in increased virus production. These observations provide a mechanistic molecular link between M81 virus replication—a central viral function and a cancer risk factor—and the production of a chemokine involved in inflammation and carcinogenesis. The non-coding RNA EBER2 of the Epstein–Barr virus M81 strain potentiates virus lytic replication in B cells by generating a paracrine loop whereby the chemokine CXCL8 is released from infected cells via extracellular vesicles—which are taken up by neighbouring cells—thereby enhancing its own expression.

Exchange bias, a shift in the hysteresis loop of a ferromagnet arising from interfacial exchange coupling between adjacent ferromagnetic and antiferromagnetic layers, is an integral part of spintronic devices. Here, we show that spin–orbit torque generated from spin current, a promising approach to switch the ferromagnetic magnetization of next-generation magnetic random access memory, can also be used to manipulate the exchange bias. Applying current pulses to a Pt/Co/IrMn trilayer causes concurrent switching of ferromagnetic magnetization and exchange bias, but with different underlying mechanisms. This implies that the ferromagnetic magnetization and exchange bias can be manipulated independently. Our work demonstrates that spin–orbit torque in ferromagnet/antiferromagnet heterostructures facilitates independent manipulations of distinct magnetic properties, motivating innovative designs for future spintronics devices. Spin–orbit torque is used to control the magnetic exchange bias in a Pt/Co/IrMn trilayer.

Dysregulation of eicosanoids is associated with asthma and a composite of oxylipins, including exhaled leukotriene BLevels of 6 exhaled eicosanoid species in asthmatic children and healthy subjects were evaluated using ELISA.In addition to those previously reported, including LTBThe exhaled 15-HETE was found to discriminate childhood asthma while decreased levels of exhaled TXB

This study aimed to investigate whether fecal human beta-defensins (HBD)-2 and eosinophil cationic protein (ECP) expression in preterm infants are associated with allergic disease development by age 2 years.Preterm infants' stool samples were collected at the age of 6 and 12 months postnatally. Information regarding medication exposure histories (antibiotics, antipyretics, probiotics) and physician-diagnosed allergic diseases was obtained using age-specific questionnaires and medical records. We compared the 6-month and 12-month fecal HBD-2 and ECP concentrations between the medication exposure and non-exposure group, respectively, and between children who developed allergic diseases and those who did not by 2 years of age. Univariate and multivariable logistic regression analyses were performed to investigate independent variables related to physician-diagnosed allergic diseases by 2 years of age.Seventy-four preterm infants (gestational age, 31-36 weeks) were included. Fecal HBD-2 levels were significantly increased at 12 months of age among children who developed allergic diseases compared to those who did not (37.18 ± 11.80 ng/gWe found that preterm infants who expressed high fecal HBD-2 at 12 months of age were associated with physician-diagnosed allergic diseases by the age of 2 years. Further studies are needed to determine the role of fecal HBD-2 in the development of allergic diseases.

As part of ongoing efforts to effectively remove ammonia from industrial wastewater, electrochemical oxidation has become an alternative to conventional biological treatment due to its easier operation and better tolerance of toxic pollutants. This study aims to prepare CuCo/nickel foam (CuCo/NF) electrodes by depositing different ratios of Cu and Co as catalysts and investigate their performance for ammonia electrooxidation (EO). Under optimum conditions (pH 11 and applied voltage of 1.1 V vs Ag/AgCl), excellent ammonia removal was obtained using the Cu0.5Co0.5/NF electrode system, with 93% removal after 5 h for a low level of ammonia loading (50 mg-N/L), which was superior to the performance of the bare NF electrode (only 54%). The Cu0.5Co0.5/NF electrode also had a higher current efficiency of 34% and lower energy consumption of 0.11 kWh g−1 compared to the bare NF and single metal Cu (Cu1Co0/NF) or Co (Cu0Co1/NF) electrodes. The high catalytic performance of the Cu0.5Co0.5/NF electrode towards ammonia indicates that a CuCo bimetallic catalyst on a NF substrate is a promising solution for effective removal of ammonia from industrial wastewater.

Background Few studies address the dynamic changes of body mass index (BMI) Z-scores during infancy with breastfeeding and their impact on childhood atopic diseases. Methods A total of 183 children from a birth cohort regularly followed-up for 4 years were enrolled in this study. Time series data of BMI Z-scores from 1 month to 2 years of age was clustered using K-means method in R software. Breastfeeding status during the first 6 months of life was recorded and classified. The total serum and specific immunoglobulin E (IgE) levels to food and inhalant allergens were measured at age 0.5, 1, 1.5, and 2 years. Results Using K-means clustering, the dynamic changes in BMI Z-scores were classified into three clusters (cluster A, increasing, n = 62; cluster B; decreasing, n = 62; cluster C, constant low, n = 59). Despite having no statistical association with atopic diseases, a decreasing trend in infantile BMI Z-scores was significantly associated with a higher prevalence of IgE sensitization at age 1 which increased the risk of rhinitis development at age 4 (P = 0.007). No difference in BMI Z-scores was determined between different breastfeeding patterns. However, exclusive formula feeding ≥6 months was found to be significantly associated with mite sensitization at age 1.5 years which risks asthma development at age 4 (P = 0.001). Conclusions A decreasing trend of BMI Z-scores during infancy is determined to be inversely associated with IgE and allergen sensitization, which may potentially increase the risk of allergies in early childhood.

Background: The impact of abdominal obesity (AO) on plasma fatty acid changes and cardiometabolic risk in children who are obese and overweight has rarely been investigated. This study determined whether plasma fatty acid composition differed between children with AO and those without AO and its relationship with metabolic risk, particularly in the obese and overweight groups.Methods: A total of 181 schoolchildren (aged 7–18 years) were included. Anthropometric and biochemical data and plasma fatty acid profiles were analyzed, and the indices of desaturase activity were estimated. Children were categorized based on their body weight and AO status. A continuous metabolic risk score was calculated using the sum of the z-scores of metabolic variables. A one-way analysis of variance test was used to compare the composition ratio of fatty acids between children with and without AO in the obese and overweight groups and normal-weight controls. Pearson analysis was also used to explore significant fatty acid and desaturase indicators associated with metabolic abnormalities.Results: Children who were obese and overweight (N = 126) displayed higher dihomo-γ-linolenic acid (20:3n-6) and γ-linolenic acid (18:3n-6) proportions than normal-weight controls (N = 55), but lower heptadecanoic acid (17:0) proportion, regardless of the AO status of each individual. Obese and overweight children with AO (N = 89), but not their non-AO counterparts (N = 37), exhibited a significantly higher proportion of palmitoleic acid (16:1n-7) than the remaining study groups. Pearson analysis showed that high proportions of palmitoleic acid and dihomo-γ-linolenic acid, as well as increased stearoyl-coenzyme A desaturase-1(16) and delta-6 desaturase and decreased delta-5 desaturase activities, are strongly correlated with weight-height ratio, homeostasis model of assessment values for insulin resistance, hypertriglyceridemia, and continuous metabolic risk scores.Conclusion: Higher palmitoleic acid and dihomo-γ-linolenic acid proportions, as well as increased stearoyl-coenzyme A desaturase-1(16) and delta-6 desaturase and decreased delta-5 desaturase activities are associated with AO and increased metabolic risk in children who are obese and overweight.

A connection between airway and gut microbiota related to allergen exposure in childhood allergies was not well addressed. We aimed to identify the microbiota alterations in the airway and gut related to mite-specific IgE responses in young children with airway allergies. This study enrolled 60 children, including 38 mite-sensitized children (20 rhinitis and 18 asthma), and 22 non-mite-sensitized healthy controls. Microbiome composition analysis of the throat swab and stool samples was performed using bacterial 16S rRNA sequencing. An integrative analysis of the airway and stool microbial profiling associated with IgE reactions in childhood allergic rhinitis and asthma was examined. The Chao1 and Shannon indices in the airway were significantly lower than those in the stool. Additionally, an inverse association of the airway microbial diversity with house dust mite (HDM) sensitization and allergic airway diseases was noted. Fecal IgE levels were positively correlated with the serum Dermatophagoides pteronyssinus- and Dermatophagoides farinae-specific IgE levels. Airway Leptotrichia spp. related to asthma were strongly correlated with fecal Dorea and Ruminococcus spp., which were inversely associated with fecal IgE levels and risk of allergic rhinitis. Moreover, four airway genera, Campylobacter, Selenomonas, Tannerella, and Atopobium, were negatively correlated with both serum mite-specific and fecal IgE levels. Among them, the airway Selenomonas and Atopobium spp. were positively correlated with stool Blautia and Dorea spp. related to asthma and allergic rhinitis, respectively. In conclusion, airway microbial dysbiosis in response to HDM and its cross-talk with the gut microbial community is related to allergic airway diseases in early childhood.

Reports on the relationship between prenatal exposure to bisphenol-A (BPA) and the development of childhood allergy have been conflicting. This study aimed to investigate the impact of prenatal BPA exposure on several objective outcomes such as cytokine profile, atopic sensitization, and infant lung function (ILF) tests in addition to clinical allergic symptoms.A subset of 274 children from the PATCH cohort study with available cord BPA data were followed until 3 years of age. Total and specific IgE level and Toll-like receptor (TLR) stimulated cytokine production were assessed yearly since birth. ILF such as tidal volume, VmaxThere was significant association between BPA concentration and IgE level in the cord blood (p 0.01), but the correlation was no longer significant at ages 1 through 3 years. In addition, cord BPA concentration was associated with dysregulated TLR stimulated TNF-α and IL-6 production, but the correlation was significant only at birth. No relationship was found between cord BPA concentration and ILF measurements or allergic symptoms (wheezing, rhino-conjunctivitis, or eczema) throughout early childhood.Results showed that prenatal exposure to BPA was not associated with increased risk of childhood allergy or impaired ILF. However, with its impact on biomarkers for allergy such as alterations in perinatal cytokine profile and elevated cord IgE level, the potential role of prenatal BPA exposure on the development of allergy cannot be disregarded.

There are few studies addressing the longitudinal analysis of serum IgE levels and its impact to the development of atopic diseases in early childhood. We investigated 170 children who regularly followed up at our clinic for 4 years in a birth cohort study with at least 3 time-points of serum samples. The pattern of total serum IgE levels from 6 months to 4 years of age was clustered using K-means method in R software. Specific immunoglobulin E antibodies against food (egg white and milk) and inhalant allergens (D. pteronyssinus and D. farinae) were measured at 0.5, 1, 1.5, 2, 3 and 4 years of age. By using K-means clustering, the dynamic changes in serum IgE levels was significantly stratified into 3 clusters (cluster A

Background Serum or cord blood soluble Fas ligand (FasL) has been related to asthma, allergic rhinitis, and atopic dermatitis in cross-sectional and short-term follow-up studies. However, the association of cord blood soluble FasL with long-term allergic outcomes has seldom been investigated. Thus, this study investigated the relationship between cord blood soluble FasL and long-term allergic outcomes in a follow-up birth cohort. Methods The Prediction of Allergies in Taiwanese Children birth cohort study recruited healthy newborns upon delivery. At birth, blood was collected from the umbilical cords of these children, and the cord blood soluble Fas ligand levels were measured. At the age of seven years, the allergic outcome of each child was diagnosed by pediatric allergists and pulmonologists. Tests were conducted to measure the specific immunoglobulin E, fractional exhaled nitric oxide (FeNO), and pulmonary function levels of each child. Results Cord blood soluble FasL levels were higher in 7-year-old children with allergic rhinitis (Odds ratio [OR] = 2.41, p = .012) and expiratory airway obstruction (the highest forced expiratory volume in 1 second/ forced vital capacity p = .022). The FeNO and Dermatophagoides pteronyssinus-specific immunoglobulin E levels of 7-year-old children were positively correlated with cord blood soluble FasL levels (p = .006 and .02, respectively). Conclusions In this birth cohort, the cord blood soluble FasL levels were associated with allergic rhinitis, obstructive-type lung function, FeNO, and house dust mite sensitization in 7-year-old children. The cord blood soluble FasL level might be used as a predictor for allergic diseases in children who are 7 years old.

The Epstein-Barr virus (EBV) causes human cancers, and epidemiological studies have shown that lytic replication is a risk factor for some of these tumors. This fits with the observation that EBV M81, which was isolated from a Chinese patient with nasopharyngeal carcinoma, induces potent virus production and increases the risk of genetic instability in infected B cells. To find out whether this property extends to viruses found in other parts of the world, we investigated 22 viruses isolated from Western patients. While one-third of the viruses hardly replicated, the remaining viruses showed variable levels of replication, with three isolates replicating at levels close to that of M81 in B cells. We cloned one strongly replicating virus into a bacterial artificial chromosome (BAC); the resulting recombinant virus (MSHJ) retained the properties of its nonrecombinant counterpart and showed similarities to M81, undergoing lytic replication in vitro and in vivo after 3 weeks of latency. In contrast, B cells infected with the nonreplicating Western B95-8 virus showed early but abortive replication accompanied by cytoplasmic BZLF1 expression. Sequencing confirmed that rMSHJ is a Western virus, being genetically much closer to B95-8 than to M81. Spontaneous replication in rM81- and rMSHJ-infected B cells was dependent on phosphorylated Btk and was inhibited by exposure to ibrutinib, opening the way to clinical intervention in patients with abnormal EBV replication. As rMSHJ contains the complete EBV genome and induces lytic replication in infected B cells, it is ideal to perform genetic analyses of all viral functions in Western strains and their associated diseases. IMPORTANCE The Epstein-Barr virus (EBV) infects the majority of the world population but causes different diseases in different countries. Evidence that lytic replication, the process that leads to new virus progeny, is linked to cancer development is accumulating. Indeed, viruses such as M81 that were isolated from Far Eastern nasopharyngeal carcinomas replicate strongly in B cells. We show here that some viruses isolated from Western patients, including the MSHJ strain, share this property. Moreover, replication of both M81 and of MSHJ was sensitive to ibrutinib, a commonly used drug, thereby opening an opportunity for therapeutic intervention. Sequencing of MSHJ showed that this virus is quite distant from M81 and is much closer to nonreplicating Western viruses. We conclude that Western EBV strains are heterogeneous, with some viruses being able to replicate more strongly and therefore being potentially more pathogenic than others, and that the virus sequence information alone cannot predict this property.

Design discussion is a very important course in architecture education. In this paper, we developed a VR based architecture design discussion system that allows members to visualize and discuss the architectural models and to modify the models during discussion. Since the system is designed to work on top of Rhinoceros and Grasshopper, the object database is updated right after the object modification. Members communicate via voice, object manipulations, and mid-air sketching as well as on-surface sketching in the virtual environment. Several tools have been designed to enhance the sense of presence and to make the discussion more effective. We also developed a rollback mechanism to help users intuitively and quickly revert to a previous state of discussion to make some changes or to start a new direction of discussion. To evaluate the system, we conducted an initial user study with 14 participants to assess the user experience, user impression and effectiveness of the system. The feedback from participants were positive and suggested that the system could be effective and useful for supporting architecture design discussion.

To investigate the evolution of lung function in preterm infants with and without bronchopulmonary dysplasia (BPD) and to determine the perinatal characteristics associated with indexes of lung function in later infancy. Longitudinal lung function assessments were performed at approximately 6, 12, 18, and 24 months of corrected age in preterm infants. Perinatal characteristics were further analyzed to ascertain the determinants of lung function indexes. Although all preterm infants (n = 121; 61 without BPD and 60 with BPD) exhibited decreased lung function in early infancy (6 months of age), after body length was adjusted for, only infants with BPD exhibited poor performance. Furthermore, the lung function of infants with mild to moderate BPD caught up gradually, but the generally poor lung function performance of infants with severe BPD, especially in forced expiratory flow, persisted until later age (24 months). Regarding perinatal characteristics, the z-score of body length at the time of examination and total number of days on positive-pressure ventilation are the major determinants of lung function in later infancy.

Streptococcus pneumoniae is a common cause of infectious diseases such as pneumonia and sepsis. Its colonization is thought to be the first step in the development of invasive pneumococcal diseases. This study aimed to investigate pneumococcal colonization patterns in early childhood. A longitudinal birth cohort study was conducted for investigating nasopharyngeal colonized pneumococci at 1, 6, 12, 18, 24, and 36 months of age, particularly focusing on the serotype distribution and antimicrobial susceptibilities. Pneumococcal conjugate vaccine (PCV) effect on nasopharyngeal colonization was also assessed. During 2013-2017, 855 infants were enrolled and a total of 107 isolates were recovered from 95 infants during the first three years of life. In this period, the prevalence of pneumococcal colonization increased, with values ranging from 0.2% (2/834) at 1 month of age to 5.9% (19/323) at 36 months of age. The investigation of serotype revealed that 81.1% (73/90) belonged to the non-PCV13 serotypes-23A, 15A, 15C, and 15B. Moreover, PCV13 serotypes significantly decreased during 2014-2015, when routine PCV13 vaccination was initiated in Taiwan. PCV13 introduction may lead to the reduction in the rates of pneumococcal isolates resistant (R) to penicillin. Under conditional PCV13 vaccination, pneumococcal isolates primarily belonged to non-PCV13 serotypes. This non-PCV13 serotype replacement exhibited lower rates of penicillin R isolates, suggesting that PCV13 administration may reduce the antibiotic-nonsusceptible pneumococcal disease burden and antibiotic use.

Background Several metabolites and altered metabolic pathways have been reported to be associated with asthma. However, longitudinal analysis of the dynamics of metabolites contributing to the development of asthma has not yet been fully clarified. Methods We sought to identify the metabolic mechanisms underlying asthma development in early childhood. Thirty children with asthma and paired healthy controls from a prospective birth cohort were enrolled. Time series analysis of urinary metabolites collected at ages 1, 2, 3, and 4 years was assessed using 1 H nuclear magnetic resonance (NMR) spectroscopy coupled with partial least squares discriminant analysis (PLS-DA). Metabolites identified were studied in relation to changes over time in a linear mixed model for repeated measures. Results A total of 172 urine samples collected from the enrolled children were analyzed. Urinary metabolomics identified four metabolites significantly associated with childhood asthma development, with longitudinal analysis. Among them, dimethylamine, a metabolite produced by intestinal bacteria, appeared to shift from higher to lower level during asthma development. A persistent lower level of 1-methylnicotinamide and allantoin was found in children with asthma, with a peak difference at age 3 years (P = .032 and P = .021, respectively). Furthermore, a significant inverse correlation was found between allantoin and house dust mite sensitization (Spearman's r = -.297 P = .035). Conclusions Longitudinal urinary metabolomic profiling provides a link of microbe-environment interactions in the development of childhood asthma. 1-Methylnicotinamide and allantoin may participate in allergic reactions in response to allergen exposure, potentially serving as specific biomarkers for asthma.

Anemia is a major public health problem in young children. Reports on the role of anemia on infectious diseases remained controversial. We aim to investigate the effect of anemia on innate immunity, nasopharyngeal bacterial colonization, and subsequent infectious outcome. Blood tests were examined at the age of 12 months. TLR-induced cytokine production was assessed by ELISA. Bacteria from nasopharyngeal specimens were identified with traditional culture. Clinical infectious diseases were followed yearly until 3 years of age. Result showed that of the 423 infants, 72 had hemoglobin level ≤ 11 g/dL, among which 55% had normal iron level. There was significant association between hemoglobin level and TLR1–2, and 4 induced IL-6 (p = 0.04, 0.02) and that of TLR4 stimulated TNF-α response (p = 0.04). Children with anemia had higher nasopharyngeal colonization with Moxarella catarrhalis. Clinical analysis did not show anemia to be associated with infectious morbidity. However, children who developed LRTIs had mean lower ferritin levels. We speculated that iron might be the key factor related to infectious morbidity. Thus, to investigate the role of anemia in infectious diseases, it is important to first consider the prevalence of iron deficit, since the incidence of iron deficiency-induced anemia may vary among different regions.

The Epstein-Barr virus (EBV) genome encodes several hundred transcripts. We have used ribosome profiling to characterize viral translation in infected cells and map new translation initiation sites. We show here that EBV transcripts are translated with highly variable efficiency, owing to variable transcription and translation rates, variable ribosome recruitment to the leader region and coverage by monosomes versus polysomes. Some transcripts were hardly translated, others mainly carried monosomes, showed ribosome accumulation in leader regions and most likely represent non-coding RNAs. A similar process was visible for a subset of lytic genes including the key transactivators BZLF1 and BRLF1 in cells infected with weakly replicating EBV strains. This suggests that ribosome trapping, particularly in the leader region, represents a new checkpoint for the repression of lytic replication. We could identify 25 upstream open reading frames (uORFs) located upstream of coding transcripts that displayed 5′ leader ribosome trapping, six of which were located in the leader region shared by many latent transcripts. These uORFs repressed viral translation and are likely to play an important role in the regulation of EBV translation.

With the advancement of industrial intelligence, defect recognition has become an indispensable part of facilitating surface quality in the steel manufacturing process. To assure product quality, most previous studies were typically trained with many defect samples. Nonetheless, a large quantity of defect samples is difficult to obtain, owing to the rare occurrence of defects. In general, deep learning-based methods underperformed as they have inherent limitations due to inadequate information, thereby restraining the application of models. In this study, a two-level Gaussian pyramid is applied to decompose raw data into different resolution levels simultaneously filtering the noises to acquire compact and representative features. Subsequently, a multi-receptive field fusion-based network (MRFFN) is developed to learn the hierarchical features and synthesize the respective prediction scores to form the final recognition result. As a result, the proposed method is capable of exhibiting an outstanding performance of 99.75% when trained using a lightweight dataset. In addition, the experiments conducted using the disturbance defect dataset showed the robustness of the proposed MRFFN against common noises and motion blur.

Background Aberrant generation of eicosanoids is associated with asthma, but the evidence remains incomplete and its potential utility as biomarkers is unclear. Major eicosanoids in exhaled breath condensates (EBCs) were assessed as candidate markers for childhood asthma. Methods Ten exhaled eicosanoid species was evaluated using ELISA in the discovery phase, followed by prediction model-building and validation phases. Results Exhaled LTB4 , LTE4 , PGE2, and LXA4 showed significant difference between asthmatics (N = 60) and controls (N = 20). For validation, an expanded study population consisting of 626 subjects with asthma and 161 healthy controls was partitioned into a training subset to establish a prediction model and a test sample subset for validation. Receiver operating characteristic (ROC) analyses of the training subset revealed the level of exhaled LTB4 to be the most discriminative among all parameters, including FeNO, and a composite of exhaled LTB4 , LXA4 , together with FeNO and FEV1 , distinguishing asthma with high sensitivity and specificity. Further, the Youden index (J) indicated the cut point value of 0.598 for this composite of markers as having the strongest discriminatory ability (sensitivity = 85.2% and specificity = 83.6%). The predictive algorithm as "asthma classification ratio" was further validated in an independent test sample with sensitivity and specificity being 84.4% and 84.8%, respectively. Conclusions In a pediatric study population in Taiwan, the levels of exhaled LTB4 , LTE4 , LXA4, and PGE2 in asthmatic children were significantly different from those of healthy controls, and the combination of exhaled LTB4 and LXA4 , together with FeNO and FEV1 , best characterized childhood asthma.

Background Diagnosing intestinal strangulation as a complication of small bowel obstruction (SBO) remains a considerable challenge in children. We evaluated the clinicoradiological parameters for predicting the presence of a strangulated intestine. Methods We reviewed the medical records of 69 pediatric patients who underwent operation for acute SBO. Regression analysis was used to identify the parameters for predicting strangulated SBO. Results Of the 69 patients with SBO, 27 patients had intestinal strangulation and were awarded one point each towards the overall clinical score: intractable continuous abdominal pain, tachycardia, white blood cell count >13,600/mm 3 , and abdominal distention. Patients with a clinical score ≥2 combined with the presence of ascites in ultrasound (US) results or with wall thickness and reduced wall contrast enhancement in abdominal computed tomography (CT) scans showed strong evidence for intestinal strangulation. Conclusion The combination of two or more clinical parameters, including intractable continuous abdominal pain, tachycardia, leukocytosis, and abdominal distention with the presence of ascites in US or wall thickness and reduced wall contrast enhancement in, is useful for the identification of strangulated SBO. The type of study and level of evidence Prognosis study; Level III.

// Andrea Bilger 1 , Julie Plowshay 2, 6 , Shidong Ma 1, 5 , Dhananjay Nawandar 3, 7 , Elizabeth A. Barlow 1 , James C. Romero-Masters 4 , Jillian A. Bristol 1 , Zhe Li 8 , Ming-Han Tsai 8 , Henri-Jacques Delecluse 8 and Shannon C. Kenney 1, 2 1 Department of Oncology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA 2 Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA 3 Department Cellular and Molecular Biology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, USA 4 Department of Cellular and Molecular Pathology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA 5 Sanofi Pharmaceuticals, Cambridge, Massachusetts, USA 6 Rocky Mountain Infectious Disease Specialists, Aurora, Colorado, USA 7 Department of Cancer Biology and Immunology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, Cambridge, Massachusetts, USA 8 Joint DKFZ Inserm Unit U1074, German Cancer Center (DKFZ), Heidelberg, Germany Correspondence to: Shannon C. Kenney, email: skenney@wisc.edu Keywords: therapy, lymphoma, lymphoproliferative disease, humanized mouse model, FDA-approved Received: March 17, 2017 Accepted: April 27, 2017 Published: May 15, 2017 ABSTRACT EBV infection causes mononucleosis and is associated with specific subsets of B cell lymphomas. Immunosuppressed patients such as organ transplant recipients are particularly susceptible to EBV-induced lymphoproliferative disease (LPD), which can be fatal. Leflunomide (a drug used to treat rheumatoid arthritis) and its active metabolite teriflunomide (used to treat multiple sclerosis) inhibit de novo pyrimidine synthesis by targeting the cellular dihydroorotate dehydrogenase, thereby decreasing T cell proliferation. Leflunomide also inhibits the replication of cytomegalovirus and BK virus via both “on target” and “off target” mechanisms and is increasingly used to treat these viruses in organ transplant recipients. However, whether leflunomide/teriflunomide block EBV replication or inhibit EBV-mediated B cell transformation is currently unknown. We show that teriflunomide inhibits cellular proliferation, and promotes apoptosis, in EBV-transformed B cells in vitro at a clinically relevant dose. In addition, teriflunomide prevents the development of EBV-induced lymphomas in both a humanized mouse model and a xenograft model. Furthermore, teriflunomide inhibits lytic EBV infection in vitro both by preventing the initial steps of lytic viral reactivation, and by blocking lytic viral DNA replication. Leflunomide/teriflunomide might therefore be clinically useful for preventing EBV-induced LPD in patients who have high EBV loads yet require continued immunosuppression.

Infections with Epstein–Barr virus (EBV) are associated with cancer development, and EBV lytic replication (the process that generates virus progeny) is a strong risk factor for some cancer types. Here we report that EBV infection of B-lymphocytes (in vitro and in a mouse model) leads to an increased rate of centrosome amplification, associated with chromosomal instability. This effect can be reproduced with virus-like particles devoid of EBV DNA, but not with defective virus-like particles that cannot infect host cells. Viral protein BNRF1 induces centrosome amplification, and BNRF1-deficient viruses largely lose this property. These findings identify a new mechanism by which EBV particles can induce chromosomal instability without establishing a chronic infection, thereby conferring a risk for development of tumours that do not necessarily carry the viral genome., Infection with Epstein–Barr virus (EBV) is associated with increased risk of cancer development. Here the authors show that EBV particles, and more specifically the viral protein BNRF1, induce centrosome amplification and chromosomal instability in host cells in the absence of chronic infection.

Background A regional antibiotic susceptibility data of common pathogens is crucial to first-line physician for clinical judgment and appropriate selection of antimicrobial agents. The aim of this study is to update the epidemiology data of drug resistance of pneumococcus causing invasive pneumococcal disease (IPD) in adults. Methods From the logbooks of microbiology laboratories, we retrospectively retrieved Streptococcus pneumoniae isolates, collected from normally sterile sites in adult patients in three hospitals in Taiwan from July 2011 to June 2015. Antibiotic resistance and serotypes of the isolates and clinical manifestations were further analyzed. Results A total of 150 non-duplicated isolates were collected. According to CLSI meningitis breakpoint, the proportion of ceftriaxone non-susceptible pneumococcus (CNSP) showed an increasing trend from 4.5% in 2011 to > 40% in 2013–2015 (p = 0.007). Serotypes 19A and 23F were significantly associated with CNSP. Imipenem and meropenem had a relative low susceptible rate of 36.7% and 50.7%, respectively. Serotypes 6A, 14, 19A and 19F were significantly associated with the non-susceptibility to these carbepanems. Conclusion The increase in the prevalence of CNSP using meningitis breakpoint was observed. For treating pneumococcal meningitis, empirical monotherapy with ceftriaxone might not be adequate. Imipenem and meropenem might not be a good choice for empirical treatment of adult IPDs. Antibiotic resistance of pneumococcus to ceftriaxone, cefepime, imipenem and meropenem were associated with 13-velent pneumococcal conjugate vaccine serotypes.

This study aimed to compare the trajectory of serum 25(OH)D, micronutrient levels, and anthropometric measurements between exclusively breastfed and mixed-fed children. This is a prospective cohort study. Anthropometric measurements of the children were obtained during scheduled clinical visits. Tests for 25(OHD), ferritin, zinc and complete blood count were performed yearly until 3 years of age. Clinical records and questionnaires on dietary habits were obtained. The results showed that despite official recommendations on vitamin D/iron supplements for breastfed children, less than 10% of our exclusively breastfed children received regular supplements. Thus, after 1 year, the odds for having iron deficiency anemia and vitamin D insufficiency were 9 [95% CI, 4–19] and 6 [95% CI, 2–16], respectively. Longitudinal follow-up showed the prevalence of iron deficiency to decrease from 34% at 1 year to 2% at age 3 years. However, the prevalence of vitamin D insufficiency remained persistently high throughout the first three years of life (60% at 1 to 44% at 3 years). Very few children had zinc deficiency. Anthropometric measurements showed exclusively breastfed children to have lower mean z-scores for body weight and height when compared to mixed-fed children after 12 months. In conclusion, children who were exclusively breastfed for longer than 4 months without proper supplement were more likely to have transient iron deficiency anemia and persistent vitamin D insufficiency. Their growth became relatively slower after infancy. Whether this was associated with underlying inadequate serum vitamin D and iron level remains an important issue to be explored.

Background and objective: This study aimed to establish reference equations for spirometry in healthy Taiwanese children and assess the applicability of the Global Lung Function Initiative (GLI)-2012 equations to Taiwanese children. Methods: Spirometric data collected from 757 healthy Taiwanese children aged 5 to 18 years in a population-based cohort study. Prediction equations derived using linear regression and the generalized additive models for location, scale and shape (GAMLSS) method, respectively. Results: The GLI-2012 South East Asian equations did not provide a close fit with mean ± standard error z-scores of −0.679 ± 0.030 (FVC), −0.186 ± 0.044 (FEV1), −0.875 ± 0.049 (FEV1/FVC ratio) and −2.189 ± 0.063 (FEF25-75) for girls; and 0.238 ± 0.059, −0.061 ± 0.053, −0.513 ± 0.059 and −1.896 ± 0.077 for boys. The proposed GAMLSS models took age, height, and weight into account. GAMLSS models for boys and girls captured the characteristics of spirometric data in the study population closely in contrast to the linear regression models and the GLI-2012 equations. Conclusion: This study provides up-to-date reference values for spirometry using GAMLSS modeling in healthy Taiwanese children aged 5 to 18 years. Our study provides evidence that the GLI-2012 reference equations are not properly matched to spirometric data in a contemporary Taiwanese child population, indicating the urgent need for an update of GLI reference values by inclusion of more data of non-Caucasian decent. Keywords: Asian, Children, Prediction equations, Pulmonary function, Reference values, Spirometry

The Epstein-Barr virus (EBV) induces B-cell proliferation with high efficiency through expression of latent proteins and microRNAs. This process takes place in vivo soon after infection, presumably to expand the virus reservoir, but can also induce pathologies, e.g. an infectious mononucleosis (IM) syndrome after primary infection or a B-cell lymphoproliferation in immunosuppressed individuals. In this paper, we investigated the growth characteristics of EBV-infected B-cells isolated from transplant recipients or patients with IM. We found that these cells grew and withstood apoptosis at highly variable rates, suggesting that the expansion rate of the infected B-cells widely varies between individuals, thereby influencing the size of the B-cell reservoir and the ability to form tumors in infected individuals. All viruses investigated were type 1 and genetically close to western strains. EBV-infected B-cells expressed the transforming EBV latent genes and microRNAs (miRNAs) at variable levels. We found that the B-cell growth rates positively correlated with the BHRF1 miRNA levels. Comparative studies showed that infected B-cells derived from transplant recipients with iEBVL on average expressed higher levels of EBV miR-BHRF1 miRNAs and grew more rapidly than B-cells from IM patients, suggesting infection by more transforming viruses. Altogether, these findings suggest that EBV infection has a highly variable impact on the B-cell compartment that probably reflects the genetic diversity of both the virus and the host. It also demonstrates the unexpected finding that B-cells from different individuals can grow at different speed under the influence of the same virus infection.

BACKGROUND A comprehensive metabolomics-based approach to address the impact of specific gut microbiota on allergen sensitization for childhood rhinitis and asthma is still lacking. METHODS Eighty-five children with rhinitis (n = 27) and with asthma (n = 34) and healthy controls (n = 24) were enrolled. Fecal metabolomic analysis with 1 H-nuclear magnetic resonance (NMR) spectroscopy and microbiome composition analysis by bacterial 16S rRNA sequencing were performed. An integrative analysis of their associations with allergen-specific IgE levels for allergic rhinitis and asthma was also assessed. RESULTS Amino acid, β-alanine, and butanoate were the predominant metabolic pathways in the gut. Among them, amino acid metabolism was negatively correlated with the phylum Firmicutes, which was significantly reduced in children with rhinitis and asthma. Levels of histidine and butyrate metabolites were significantly reduced in children with rhinitis (P = 0.029) and asthma (P = 0.009), respectively. In children with asthma, a reduction in butyrate-producing bacteria, including Faecalibacterium and Roseburia spp., and an increase in Clostridium spp. were negatively correlated with fecal amino acids and butyrate, respectively (P

Pediatric myocarditis symptoms can be mild or as extreme as sudden cardiac arrest. Early identification of the severity of illness and timely provision of critical care is helpful; however, the risk factors associated with mortality remain unclear and controversial. We undertook a retrospective review of the medical records of pediatric patients with myocarditis in a tertiary care referral hospital for over 12 years to identify the predictive factors of mortality. Demographics, presentation, laboratory test results, echocardiography findings, and treatment outcomes were obtained. Regression analyses revealed the clinical parameters for predicting mortality. During the 12-year period, 94 patients with myocarditis were included. Of these, 16 (17%) patients died, with 12 succumbing in the first 72 hours after admission. Fatal cases more commonly presented with arrhythmia, hypotension, acidosis, gastrointestinal symptoms, decreased left ventricular ejection fraction, and elevated isoenzyme of creatine kinase and troponin I levels than nonfatal cases. In multivariate analysis, troponin I > 45 ng/mL and left ventricular ejection fraction < 42% were significantly associated with mortality. Pediatric myocarditis had a high mortality rate, much of which was concentrated in the first 72 hours after hospitalization. Children with very high troponin levels or reduced ejection fraction in the first 24 hours were at higher risk of mortality, and targeting these individuals for more intensive therapies may be warranted.

BACKGROUND: Lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare variant of intrahepatic cholangiocarcinoma, which is highly associated with Epstein-Barr virus (EBV) infection and abundant lymphoplasmacytic cells infiltration. However, the genetic background of LELCC and the immune profiling of their microenvironment remain largely un-elucidated. METHODS: Retrospectively collected formalin-fixed, paraffin-embedded (FFPE) tissue of 5 EBER-positive LELCCs and 7 non-LELCCs were included. PDL1 expression was examined by anti-PD-L1 immunohistochemical (IHC) 22C3 PharmDx (Agilent Technologies, Santa Clara, CA, USA). Peripheral blood mononuclear cells (PBMCs) from two LELCC patients were served as background of germline mutations. Gene expression profiling was determined by next generation sequencing (ACTOnco(®)+ Comprehensive Cancer Panel, ACT Genomics Co., LTD) on DNA samples. The nCounter(®) PanCancer Immune Profiling Panel (NanoString Technologies, Inc., Seattle, WA, USA) was used for Immune profiling on RNA samples. RESULTS: All EBV-related LELCCs were positive for PD-L1 staining, with combined positive score of 25 to 80, mainly in peritumoral immune cells. After adjusting for frequency of germline mutation from PBMC, only mutations with allele frequency less than or around 10% were considered as somatic mutations. Overall, LELCCs with 10 nonsynonymous somatic mutations were detected in 4 LELCCs with 0 to 5 mutations per sample. Identified mutations included BARD1 (allele frequency: 8.1%), EPHA5 (5.8%), MUC16 (7.6%), TNFAIP3 (5.8%), CD19 (5.6%), PTEN (8.8%), TET1 (7.2%), RECQL4 (6.4%), CD79B (10.1%), and KDM5A (10.2%), with all 20% of incidence. Each mutation is independent between four cases. Of the immune profiling, EBV-related LELCCs display significantly higher signature of cytotoxic cells, CD45 cells, T cells, Th1 cells, CD8 T cells, NK cells, and B cells than those of non-LELCC. Of the one LELCC patient who had anti-PD-1 treatment after gemcitabine/cisplatin therapy failure got a durable partial response to the anti-PD-1 immunotherapy. CONCLUSIONS: LELCC is highly correlated with PDL1 expression in tumor and immune cells. Based on results of NanoString immune panel, EBV-related LELCC is characterized by a T cell-inflamed tumor microenvironment.

Fibrin formation in infectious parapneumonic effusion (IPE) characterizes complicated parapneumonic effusion and is important for providing guidelines for the management of IPEs that require aggressive interventions. We aim to identify metabolic mechanisms associated with bacterial invasion, inflammatory cytokines, and biochemical markers in cases of fibrinous infectious pleural effusions in children with pneumonia. Pleural fluid metabolites were determined by 1H nuclear magnetic resonance spectroscopy. Metabolites that contributed to the separation between fibrinous and nonfibrinous IPEs were identified using supervised partial least squares discriminant analysis ( Q2/ R2 = 0.84; Ppermutation < 0.01). IL-1β in the inflammatory cytokines and glucose in the biochemical markers were significantly correlated with 11 and 9 pleural fluid metabolites, respectively, and exhibited significant overlaps. Four metabolites, including glucose, lactic acid, 3-hydroxybutyric acid, and hypoxanthine, were significantly correlated with plasminogen activator inhibitor type 1 in the fibrinolytic system enzymes. Metabolic pathway analysis revealed that anaerobic bacterial fermentation with increased lactic acid and butyric acid via glucose consumption and adenosine triphosphate hydrolysis with increased hypoxanthine appeared to be associated with fibrinous IPE. Our results demonstrate that an increase in lactic acid anaerobic fermentation and hypoxanthine accumulation under hypoxic conditions are associated with fibrin formation in IPE, representing advanced pleural inflammatory progress in children with pneumonia.

This paper presents a system that can efficiently detect objects and estimate their 6D postures with RGB-D and motion sensor data on a mobile device. We apply a template-based method to detect the pose of an object, in which the matching process is accelerated through dimension reduction of the vectorized template matrix. After getting the initial pose, the proposed system then tracks the detected objects by a modified bidirectional iterative closest point algorithm. Furthermore, our system checks information from the inertial measurement unit on a mobile device to alleviate intensive computation for ease of interactive applications.