Search

Background: Genomic prediction describes the use of SNP genotypes to predict complex traits and has been widely applied in humans and agricultural species. Genotyping-by-sequencing, a method which uses low-coverage sequence data paired with genotype imputation, is becoming an increasingly popular SNP genotyping method for genomic prediction. The development of Oxford Nanopore Technologies' (ONT) MinION sequencer has now made genotyping-by-sequencing portable and rapid. Here we evaluate the speed and accuracy of genomic predictions using low-coverage ONT sequence data in a population of cattle using four imputation approaches. We also investigate the effect of SNP reference panel size on imputation performance. Results: SNP array genotypes and ONT sequence data for 62 beef heifers were used to calculate genomic estimated breeding values (GEBVs) from 641 k SNP for four traits. GEBV accuracy was much higher when genome-wide flanking SNP from sequence data were used to help impute the 641 k panel used for genomic predictions. Using the imputation package QUILT, correlations between ONT and low-density SNP array genomic breeding values were greater than 0.91 and up to 0.97 for sequencing coverages as low as 0.1 × using a reference panel of 48 million SNP. Imputation time was significantly reduced by decreasing the number of flanking sequence SNP used in imputation for all methods. When compared to high-density SNP arrays, genotyping accuracy and genomic breeding value correlations at 0.5 × coverage were also found to be higher than those imputed from low-density arrays. Conclusions: Here we demonstrated accurate genomic prediction is possible with ONT sequence data from sequencing coverages as low as 0.1 × , and imputation time can be as short as 10 min per sample. We also demonstrate that in this population, genotyping-by-sequencing at 0.1 × coverage can be more accurate than imputation from low-density SNP arrays. [ABSTRACT FROM AUTHOR]

Predicting the structural condition of sewer pipes plays a vital role in the predictive maintenance of sewer pipes and renewal plans of many water utilities. This study explores the simultaneous utilization of physical and environmental features of sewer pipes in sewer structural condition prediction. Three (3) hybrid machine learning models which are the combination of Bagging (BG), Dagging (DG), and Rotation Forest (RotF) ensembles with a J48 Decision Tree (J48DT) based classifier were used to predict sewer pipe conditions in Ålesund city, Norway. The classification performance of the machine learning models was evaluated using the area under the receiver operating characteristic (AUC-ROC) and the area under the precision-recall (AUC-PRC) curves. The RotF-J48DT model had the highest (AUC-ROC = 0.857, AUC-PRC = 0.918) values, followed by the BG-J48DT, and the base classifier J48DT. The RotF-J48DT hybrid model should be considered when predicting the condition of sewer pipes in the study area. [ABSTRACT FROM AUTHOR]

Context: Genotyping-by-sequencing, the use of sequence reads to genotype single-nucleotide polymorphisms (SNPs), has seen an increase in popularity as a tool for genomic prediction. Oxford Nanopore Technologies (Nanopore) sequencing is an emerging technology that produces long sequence reads in real-time. Recent studies have established the ability for low-coverage Nanopore sequence data to be used for genomic prediction. However, the value proposition of Nanopore sequencing for individuals could be improved if both genotyping and disease diagnosis are achieved from a single sample. Aims: This study aimed to demonstrate that Nanopore sequencing can be used for both rapid genotyping and as a disease diagnostic tool using the same sample in livestock. Methods: Total DNA extracts from nasal swabs collected from 48 feedlot cattle presenting with clinical signs of bovine respiratory disease (BRD) were sequenced using the Nanopore PromethION sequencer. After 24 h of sequencing, genotypes were imputed and genomic estimated breeding values (GEBVs) for four traits were derived using 641 163 SNPs and corresponding SNP effects. These GEBVs were compared with GEBVs derived from SNP array genotypes and calculated using the same SNP effects. Unmapped sequence reads were classified into taxa using Kraken2 and compared with quantitative real-time polymerase chain reaction (qPCR) results for five BRD-associated pathogens of interest. Key results: Sequence-derived genotypes for 46 of the 48 animals were produced in 24 h and GEBV correlations ranged between 0.92 and 0.94 for the four traits. Eleven different BRD-associated pathogens (two viruses and nine bacterial species) were detected in the samples using Nanopore sequence data. A significant (P < 0.001) relationship between Nanopore and qPCR results was observed for five overlapping species when a maximum threshold cycle was used. Conclusions: The results of this study indicated that 46 cattle genomes can be multiplexed and accurately genotyped for downstream genomic prediction by using a single PromethION flow cell (ver. R9.4) in 24 h. This equates to a cost of AUD35.82 per sample for consumables. The concordance between qPCR results and pathogen proportion estimates also indicated that some pathogenic species, in particular bacterial species, can be accurately identified from the same test. Implications: Using Nanopore sequencing, routine genotyping and disease detection in livestock could be combined into one cost-competitive test with a rapid turnaround time. Genotyping, to test an animal or herd genetic merit, has become a routine part of most livestock production systems. New genotyping methods offer the potential to significantly decrease the turnaround time of genotyping and also incorporate new genetic information into the analysis. In this study, we have demonstrated that one such genotyping method can be used to genotype cattle and detect bacterial bovine respiratory pathogens in 24 h at a cost similar to that of existing methods. [ABSTRACT FROM AUTHOR]

Neurogenic orthostatic hypotension (nOH) secondary to amyloidosis is a rare condition associated with significant blood pressure (BP) drops and problematic symptoms for patients. There is limited literature on the management of nOH secondary to amyloidosis. In this report, we describe a case on a 60-year-old female with an extensive past medical history, including amyloidosis, pulmonary hypertension, heart failure with preserved ejection fraction, and episodic hypotension, who presents to the hospital with dizziness and home systolic BP readings in the 80s. Due to hypoperfusion, she eventually developed acute kidney failure and was transferred to the intensive care unit (ICU) for intermittent continuous renal replacement therapy with pressor support using norepinephrine. She had difficulty maintaining adequate BPs while on midodrine, so fludrocortisone, followed by pseudoephedrine, were added to improve her pressures. She was subsequently transferred out of the ICU, but her BPs still remained low, and she was not able to sit up without getting dizzy. Droxidopa was eventually added on to help treat her refractory nOH. After droxidopa initiation, her BPs improved and she was able to sit up without dizziness and was finally discharged home. This case report demonstrates the therapeutic usefulness of droxidopa in improving both BPs and symptoms in refractory nOH secondary to amyloidosis. [ABSTRACT FROM AUTHOR]

We first provide new sufficient conditions for the existence of minima of functions defined on 0-complete partial metric spaces. We then apply the obtained results to derive some fixed point results for single-valued and set-valued mappings that improve and generalize several well-known results in the literature. Examples are given to illustrate our findings. [ABSTRACT FROM AUTHOR]

Surface patterning of inorganic nanoparticles through site-selective functionalization with mixed-ligand shells or additional inorganic material is an intriguing approach to developing tailored nanomaterials with potentially novel and/or multifunctional properties. The unique physicochemical properties of such nanoparticles are likely to impact their behavior and functionality in biological environments, catalytic systems, and electronics applications, making it vital to understand how we can achieve and characterize such regioselective surface functionalization. This Feature Article will review methods by which chemists have selectively modified the surface of colloidal nanoparticles to obtain both two-sided Janus particles and nanoparticles with patchy or stripey mixed-ligand shells, as well as to achieve directed growth of mesoporous oxide materials and metals onto existing nanoparticle templates in a spatially and compositionally controlled manner. The advantages and drawbacks of various techniques used to characterize the regiospecificity of anisotropic surface coatings are discussed, as well as areas for improvement, and future directions for this field. [ABSTRACT FROM AUTHOR]

Objective: To compare the cost-effectiveness of cervical pessary vs vaginal progesterone to prevent preterm birth and neonatal morbidity in women with twin pregnancy and a short cervix.Methods: Between 4 March 2016 and 3 June 2017, we performed this economic analysis following a randomized controlled trial (RCT), performed at My Duc Hospital, Ho Chi Minh City, Vietnam, that compared cervical pessary to vaginal progesterone in women with twin pregnancy and cervical length < 38 mm between 16 and 22 weeks of gestation. We used morbidity-free neonatal survival as a measure of effectiveness. Data on pregnancy outcome, maternal morbidity and neonatal complications were collected prospectively from medical files; additional information was obtained via telephone interviews with the patients. The incremental cost-effectiveness ratio was calculated as the incremental cost required to achieve one extra surviving morbidity-free neonate in the pessary group compared with in the progesterone group. Probabilistic and one-way sensitivity analyses were also performed.Results: During the study period, we screened 1113 women with twin pregnancy, of whom 300 fulfilled the inclusion criteria of the RCT and gave informed consent to participate. These women were assigned randomly to receive cervical pessary (n = 150) or vaginal progesterone (n = 150), with two women and one woman, respectively, being lost to follow-up. The rate of morbidity-free neonatal survival was significantly higher in the pessary group compared with the progesterone group (n = 241/296 (81.4%) vs 219/298 (73.5%); relative risk, 1.11 (95% CI, 1.02-1.21), P = 0.02). The mean total cost per woman was 3146 € in the pessary group vs 3570 € in the progesterone group (absolute difference, -424 € (95% CI, -842 to -3 €), P = 0.048). The cost per morbidity-free neonate was significantly lower in the pessary group compared with that in the progesterone group (2492 vs 2639 €; absolute difference, -147 € (95% CI, -284 to 10 €), P = 0.035).Conclusion: In women with twin pregnancy and a short cervix, cervical pessary improves significantly the rate of morbidity-free neonatal survival while reducing costs, as compared with vaginal progesterone. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd. [ABSTRACT FROM AUTHOR]

This study reports on the as-cast microstructures of AlCrFeMnV, AlCrFeTiV, and AlCrMnTiV equimolar multi-principal element alloys. Thermodynamic modeling predicts that these alloys solidify as BCC solid solutions, with additional phases forming at lower temperatures. We present the measured densities, the elastic modulus values measured by nanoindentation, and the Vickers microhardness of the alloys. These properties are correlated to the underlying microstructures, as measured by x-ray diffraction, scanning electron microscopy, and atom-probe tomography. The densities of the alloys range from 5.53 to 6.42 × 10 3 kg m − 3 . The elastic modulus of AlCrFeMnV, AlCrFeTiV, and AlCrMnTiV are 211, 194, and 175 GPa, respectively, and their Vickers microhardness values are 3.9, 6.1, and 5.7 GPa, respectively. After arc-melting, AlCrFeMnV and AlCrFeTiV are BCC solid solutions while AlCrMnTiV has two phases: a BCC phase and a minor hexagonal C14 Laves phase that is enriched in V and Cr. [ABSTRACT FROM AUTHOR]

In this article, a wideband linearization technique for distributed amplifiers (DAs) is presented. In particular, an auxiliary transistor is employed to create additional intermodulation distortion components that will be feed-forwarded to the output of each gain unit cell to significantly suppress the third-order intermodulation (IM3) distortion. To verify the concept, two DAs are fabricated in an indium phosphide (InP) process. One amplifier employs a conventional stacked-heterojunction bipolar transistor (HBT) gain unit cell, and the other linearized amplifier utilizes the proposed technique. The linearized DA exhibits a measured gain of 10.5 dB with a 3-dB gain bandwidth from dc to 90 GHz. The maximum 1-dB gain compression output power ($P_{\text {1 dB}}$) is 20.5 dBm, and the third-order intercept point (OIP3) is 33 dBm. Compared to the conventional amplifier, the two values are improved by 3.5 and 4.5 dB on average, respectively. Moreover, the linearization technique only increases very little dc power consumption at high power and has the same chip size as compared to the conventional design. To the best of the authors’ knowledge, compared to published state-of-the-art DAs, the proposed DA achieves among the highest OIP3 over a wide bandwidth. [ABSTRACT FROM AUTHOR]

Phyllosticta cavendishii has been recorded in the Northern Territory (NT) of Australia occurring on non‐Cavendish bananas since 1991. The race of P. cavendishii that infects Cavendish bananas is considered exotic to Australia and classified as an emergency plant pest. In July 2013, P. cavendishii was detected on Cavendish bananas near Darwin, NT. Here, the diagnoses and field observations carried out during the Incident Definition Phase of the national biosecurity response, from July 2013 to October 2014, are reported. Of 1395 banana samples collected from 676 properties, 480 were positive for freckle disease, including 463 samples with P. cavendishii and 17 samples with P. maculata. Phyllosticta cavendishii was detected in 256 properties, including 62 properties where it was detected on Cavendish banana plants, within six distinct geographical zones across the NT. Phyllosticta cavendishii was detected on two cultivars within the Cavendish subgroup and six non‐Cavendish cultivars. Multigene characterization of Phyllosticta cultures showed that P. cavendishii was isolated from both Cavendish and non‐Cavendish cultivars. Multilocus phylogeny analyses also revealed that the P. cavendishii strain in the outbreak had identical sequence similarity to the holotype (CBS H‐20918) clade 2 P. cavendishii isolates that infect both Cavendish and non‐Cavendish cultivars in Southeast Asia and Oceania. The genetic data in this study showed that there was one P. cavendishii strain infecting both Cavendish and non‐Cavendish cultivars in the outbreak. However, historical data and field observations provided anecdotal evidence for the existence of two races of P. cavendishii, including one that does not infect Cavendish bananas. [ABSTRACT FROM AUTHOR]

Ill this paper, we provide theoretical justification for the application of higher degree fuzzy transform in time series analysis. Under the assumption that a time series can be additively decomposed into a trendcycle, a seasonal component and a random noise, we demonstrate that the higher degree fuzzy transform technique can be used for the estimation of the trend-cycle, which is one of the basic tasks in time series analysis. We prove that high frequencies appearing in the seasonal component can be arbitrarily suppressed and that random noise, as a stationary process, can be successfully decreased using the fuzzy transform of higher degree with a reasonable adjustment of parameters of a generalized uniform fuzzy partition. [ABSTRACT FROM AUTHOR]

In this paper, we provide theoretical justification for the appli- cation of higher degree fuzzy transform in time series analysis. Under the assumption that a time series can be additively decomposed into a trend- cycle, a seasonal component and a random noise, we demonstrate that the higher degree fuzzy transform technique can be used for the estimation of the trend-cycle, which is one of the basic tasks in time series analysis. We prove that high frequencies appearing in the seasonal component can be arbitrarily suppressed and that random noise, as a stationary process, can be success- fully decreased using the fuzzy transform of higher degree with a reasonable adjustment of parameters of a generalized uniform fuzzy partition. [ABSTRACT FROM AUTHOR]

The pressure-driven phase transformation in polycrystalline BaTi 1 − x FexO3 (x = 1 %), synthesized by a solid-state reaction method, was investigated using synchrotron X-ray diffraction and Raman spectroscopy. All measurements were performed at room temperature within a large pressure range up to 36.5 GPa. The results clearly demonstrate a phase transformation from the ferroelectric tetragonal structure of P4mm symmetry to the paraelectric cubic structure of Pm-3m symmetry in the studied sample at the pressure of about 18 GPa. This phase transformation pressure is much higher than those previously reported for BaTiO3-based systems, indicating the stabilization of the ferroelectric phase by doping 1% Fe into BaTiO3. Feature modes of the tetragonal phase still persist while some new modes appear in the Raman spectra at pressures above 18 GPa. This is probably due to accumulated stress and/or local microscopic disorders in the sample, which are associated with the displacement of the Ti atoms along unit-cell diagonals. [ABSTRACT FROM AUTHOR]

Modelling phenomena with interval differential equations (IDEs) is an effective way to consider the uncertainties that are unavoidable when collecting data. Similarly to the theory of ordinary differential equations, IDEs have been parallelly investigated with the interval difference equations from the beginning. These two branches can be regarded as one when unifying continuous and discrete solution domains. A conspicuous advantage when merging these areas is that the proof of several analogous properties in both theories need not be repeated. The paper provides a common and efficient tool for studying IDEs not only with continuous or discrete solution domains but also with more general ones. We propose the diamond-α derivative for interval-valued functions (IVFs) on time scales with respect to the generalized Hukuhara difference. Differently from most of the studies on the derivatives of functions on time scales, using the language of epsilon-delta, the novel concept is naturally studied according to the limit of IVFs on time scales as in classical mathematics. A particular class of IDEs on time scales is then considered with respect to the diamond-α derivative. Numerical problems are elaborated to illustrate the necessity and efficiency of the latter. [ABSTRACT FROM AUTHOR]

The adipose tissue has been recognized as an active endocrine organ which can modulate numerous physiological processes such as metabolism, appetite, immunity, and reproduction. The aim of this study was to look for differentially abundant proteins and their biological functions in the abdominal adipose tissue between pre- and postpubertal Brahman heifers. Twelve Brahman heifers were divided into 2 groups and paired on slaughter day. Prepubertal heifers had never ovulated and postpubertal heifers were slaughtered on the luteal phase of their second estrous cycle. After ensuring the occurrence of puberty in postpubertal heifers, abdominal adipose tissue samples were collected. Mass spectrometry proteomic analysis identified 646 proteins and revealed that 171 proteins showed differential abundance in adipose tissue between the pre- and postpuberty groups (adjusted P-value < 0.05). Data are available via ProteomeXchange with identifier PXD009452. Using a list of 51 highly differentially abundant proteins as the target (adjusted P-value < 10−5), we found 14 enriched pathways. The results indicated that gluconeogenesis was enhanced when puberty approached. The metabolism of glucose, lipids, and AA in the adipose tissue mainly participated in oxidation and energy supply for heifers when puberty occurred. Our study also revealed the differentially abundant proteins were enriched for estrogen signaling and PI3K-Akt signaling pathways, which are known integrators of metabolism and reproduction. These results suggest new candidate proteins that may contribute to a better understanding of the signaling mechanisms that relate adipose tissue function to puberty. Protein–protein interaction network analysis identified 4 hub proteins that had the highest degrees of connection: PGK1, ALDH5A1, EEF2, and LDHB. Highly connected proteins are likely to influence the functions of all differentially abundant proteins identified, directly or indirectly. [ABSTRACT FROM AUTHOR]

Abstract: A digestibility trial was conducted to determine apparent digestibility coefficients of dry matter, protein, energy and amino acids of animal, plant and microbial ingredients for Pacific white shrimp, Litopenaeus vannamei. The tested ingredients included traditional soybean meal (TSBM), PepsoyGen soybean meal (PSBM), NutriVance soybean meal (NSBM), fish meal (FM), poultry meal (PM), squid hydrolysis (SQH), scallop hydrolysis (SCH), flash dried yeast (FDY), two batches of Ulva meal (UMF and UMS) and bacteria biomass (BB). A basal diet was formulated and produced along with the experimental diets which included 300 g/kg of each ingredient and 700 g/kg of the basal diet. Juvenile shrimp (initial mean weight: 12 g, six shrimp/tank, n = 3) were stocked in a recirculation system. Apparent dry matter, protein and energy digestibility coefficients ranged from −40.11% to 78.51%, 15.17% to 97.03% and 13.33% to 82.56% among different protein sources, respectively. In general, protein and energy digestibilities in soy sources (77.6% to 97.03% and 62.77% to 82.56%, respectively) are higher than the tested animal protein (51.39% to 71.41% and 45.29% to 69.77%, respectively) and single‐cell protein sources (15.17% to 53.47% and 13.33% to 40.39%, respectively). Among the three soybean sources, TSBM showed highest protein and energy digestibility. Apparent individual amino acid digestibility coefficients were also variable among different types of ingredients, and there was a reasonable correspondence to protein digestibility. The most digestible feed ingredients for Pacific white shrimp in this study were conventional soybean meal (SBM) and NutriVance soybean meal (NSBM), which indicated that these ingredients are good protein and amino acid sources for Pacific white shrimp. Resultant digestibility data may provide useful information to commercial shrimp feed industry. [ABSTRACT FROM AUTHOR]

FePt thin films (70 nm thick) have been prepared by dc sputtering under a variable Ar pressure (4×10-3–4×10-2 mb) and have been annealed at temperatures ranging from 300 to 400 °C. With increasing Ar pressure, the ordering process requires a lower annealing temperature. However, further increase of Ar pressure deteriorates the crystallinity of the film which hinders the transformation from fcc to fct structure. The structural analyses show a strong correlation between the ordering process and the microstructure. © 2004 American Institute of Physics. [ABSTRACT FROM AUTHOR]

We report the growth and properties of a thin film tape, which can be equivalently recorded in both directions. The experimental tape consists of a 20 nm thick Co layer grown on top of a Cr underlayer (120 nm). The two layers were consecutively sputtered at incident angle of 70° at room temperature onto a rotating drum covered with a polymer substrate. In such growth geometry the running direction of drum is perpendicular to the incidence plane of arriving atoms. As a result of this configuration, a medium with a good orientation of the easy axis along the recording direction as well as a high coercivity of 180 kA/m has been prepared. Recording measurements have been carried out and illustrate the bidirectional recording behavior of this experimental tape, which seems to be very promising for high-density tape recording. [ABSTRACT FROM AUTHOR]

To understand genes, pathways, and networks related to puberty, we characterized the transcriptome of two tissues: the pituitary gland and ovaries. Samples were harvested from pre- and postpubertal Brahman heifers (same age group). Brahman heifers (Bos indicus) are older at puberty compared with Bos taurus, a productivity issue. With RNA sequencing, we identified differentially expressed (DEx) genes and important transcription factors (TF) and predicted coexpression networks. The number of DEx genes detected in the pituitary gland was 284 (P < 0.05), and VWC2L was the most DEx gene (fold change = 4.12, P = 0.01). The gene VWC2L promotes bone mineralization through transforming growth factor-β (TGFβ) signaling. Further studies of the link between bone mineralization and puberty could target VWC2L. In ovaries, 3,871 genes were DEx (P < 0.05). Four highly DEx genes were noteworthy for their function: SLC6A13 (a γ-aminobutyric acid [GABA] transporter), OXT (oxytocin), and NPY (neuropeptide Y) and its receptor NPY2R. These genes had higher ovarian expression in postpubertal heifers. The GABA and its receptors and transporters were expressed in the ovaries of many mammals, suggesting a role for this pathway beyond the brain. The OXT pathway has been known to influence the timing of puberty in rats, via modulation of GnRH. The effects of NPY at the hypothalamus, pituitary gland, and ovaries have been documented. Neuropeptide Y and its receptors are known factors in the release of GnRH, similar to OXT and GABA, although their roles in ovarian tissue are less clear. Pathways previously related to puberty such as TGFβ signaling (P = 6.71 × 10-5), Wnt signaling (P = 4.1 × 10-2), and peroxisome proliferator-activated receptor (PPAR) signaling (P = 4.84 × 10-2) were enriched in our data set. Seven genes were identified as key TF in both tissues: HIC2, ZIC4, ZNF219, ZSCAN26, LHX1, OLIG1, and a novel gene. An ovarian subnetwork created with TF and significant ovarian DEx genes revealed five zinc fingers as regulators: ZNF507, ZNF12, ZNF512, ZNF184, and ZNF432. Recent work of hypothalamic gene expression also pointed to zinc fingers as TF for bovine puberty. Although some zinc fingers may be ubiquitously expressed, the identification of DEx genes in common across tissues points to key regulators of puberty. The hypothalamus and pituitary gland had eight DEx genes in common. The hypothalamus and ovaries had 89 DEx genes in common. The pituitary gland and ovaries had 48 DEx genes in common. Our study confirmed the complexity of puberty and suggested further investigation on genes that code zinc fingers. [ABSTRACT FROM AUTHOR]

Puberty onset is a developmental process influenced by genetic determinants, environment, and nutrition. Mutations and regulatory gene networks constitute the molecular basis for the genetic determinants of puberty onset. The emerging knowledge of these genetic determinants presents opportunities for innovation in the breeding of early pubertal cattle. This paper presents new data on hypothalamic gene expression related to puberty in Bos indicus (Brahman) in age- and weight-matched heifers. Six postpubertal heifers were compared with 6 prepubertal heifers using whole-genome RNA sequencing methodology for quantification of global gene expression in the hypothalamus. Five transcription factors (TF) with potential regulatory roles in the hypothalamus were identified in this experiment: E2F8, NFAT5, SIX5, ZBTB38, and ZNF605. These TF genes were significantly differentially expressed in the hypothalamus of postpubertal versus prepubertal heifers and were also identified as significant according to the applied regulatory impact factor metric (P < 0.05). Two of these 5 TF, ZBTB38 and ZNF605, were zinc fingers, belonging to a gene family previously reported to have a central regulatory role in mammalian puberty. The SIX5 gene belongs to the family of homologues of Drosophila sine oculis (SIX) genes implicated in transcriptional regulation of gonadotrope gene expression. Tumor-related genes such as E2F8 and NFAT5 are known to affect basic cellular processes that are relevant in both cancer and developmental processes. Mutations in NFAT5 were associated with puberty in humans. Mutations in these TF, together with other genetic determinants previously discovered, could be used in genomic selection to predict the genetic merit of cattle (i.e., the likelihood of the offspring presenting earlier than average puberty for Brahman). Knowledge of key mutations involved in genetic traits is an advantage for genomic prediction because it can increase its accuracy. [ABSTRACT FROM AUTHOR]

Background Hepatitis B surface antigen ( HBsAg) positivity is associated with increased risk for cirrhosis and hepatocellular carcinoma ( HCC). HBsAg seroclearance is thought to be rare in general, but cohort data from US patients are limited. Aim To determine the incidence of HBsAg seroclearance in a real-life US cohort. Methods In total, 4737 patients with chronic hepatitis B from five primary care, gastroenterology and multispecialty centres, and a university medical centre were retrospectively enrolled between 2001 and 2014 with data obtained by manual review of individual patient medical records. Seroclearance was determined by loss of HBsAg seropositivity. Persistent HBsAg was confirmed by direct serology or by proxy with positive hepatitis B e-antigen ( HBeAg) or HBV DNA levels. Results HBsAg seroclearance occurred in 52 patients over 16 844 person-years (0.31% annually, 1.2% overall). Median follow-up was 32 months, and mean age 45 ± 14 years. Incidence of HBsAg seroclearance was higher in non-Asians, age >45, males, and those with baseline HBV DNA ≤10 000 IU/mL. On multivariate Cox proportional modelling, non-Asian ethnicity ( HR 2.8), male sex ( HR 2.1), baseline HBVDNA ≤10 000 ( HR 2.0) and age >45 ( HR 1.8) were significant independent predictors of seroclearance. Conclusion HBsAg seroclearance rates were lower than previously described in this real-life cohort of patients with chronic hepatitis B, especially among Asian, female and younger patients. [ABSTRACT FROM AUTHOR]

Camellia is a large genus in the tea family of Theaceae. In this genus, several species serve different purposes, such as, medicinal and ornamental plants and beverage production. Thus, country-wide cultivation of various species of Camellia genus sought to alleviate poverty and promote economic development in many regions. However, studies on evaluating its genetic resources as a foundation for the conservation and development of this plant are yet to start. Currently, using DNA barcoding often serves as a highly reliable approach to identifying and characterizing numerous plants. In the presented study, a total of 10 Camellia accessions collected from Dong Bua village, Tam Quan commune, District Tam Dao, and Vinh Phuc province, Vietnam, underwent study during 2020-2022 at Ho Chi Minh City University of Food Industry, Vietnam. Evaluation of two DNA barcoding regions, namely, rbcL and trnH-psbA, transpired for their ability to distinguish the Camellia accessions belonging to different species in Vietnam. The results revealed a significant difference in the DNA sequences of the rbcL and trnH-psbA regions among the Camellia species. In addition, the trnH-psbA barcode region also showed higher effectiveness versus the rbcL region in recognizing various species of Camellia. The results authenticated the potential of DNA barcoding in the management, conservation, and development of the genetic resources of Camellia in Vietnam. [ABSTRACT FROM AUTHOR]

This paper presents an experimental investigation into the ballistic resistance of ultra-high molecular weight polyethylene (UHMW-PE) composite, and compares its performance against a range of common metallic and composite armour materials. An extensive experimental program was conducted to determine the ballistic limit velocity (V) of UHMW-PE composite against 12.7 and 20 mm fragment simulating projectiles (FSPs) for a wide range of thicknesses. For protection against these projectiles, UHMW-PE composite was found to be consistently more mass efficient than rolled homogeneous armour steel (RHA), high hardness armour steel (HHA), aluminium alloy 5059-H131, and polymer composites reinforced with aramid, glass or carbon fibres. In terms of armour space claim, UHMW-PE composite was found to be less efficient than both steel types and glass fibre-reinforced plastic, though it was comparable to aramid fibre-reinforced plastic, and was more efficient than aluminium 5059-H131 and carbon fibre-reinforced plastic. Scaling effects were observed that showed metals were more effective against smaller projectiles in terms of armour mass required to stop a given projectile kinetic energy. These effects were not observed to the same extent for UHMW-PE composite, giving rise to a higher UHMW-PE mass efficiency against larger projectiles. [ABSTRACT FROM AUTHOR]

A Correction to this paper has been published: https://doi.org/10.1007/s11051-021-05178-5 [ABSTRACT FROM AUTHOR]

Optical 64‐QAM transmitter using QPSK modulators in tandem driven by binary electrical signals is proposed. The proposed transmitter eliminates the need for complex electronics required for the generation of multiple‐level signals and provides a Gray‐coded constellation with high quality eye diagrams. The design could be scaled to higher‐order QAM based on the user needs. [ABSTRACT FROM AUTHOR]

Absolute added correlative coding with eight levels has been proposed and demonstrated numerically at bit rates of 30 and 60 Gbps back‐to‐back, and up to 75 Gbps over 2000 and 3000 m standard single‐mode fibre using a single‐drive multiple quantum‐well Mach–Zehnder modulator. The transmission performance is compared with the conventional eight‐level pulse amplitude modulation. [ABSTRACT FROM AUTHOR]

Background: High seroprevalence of parvovirus B19 (B19V) coinfection with Plasmodium falciparum has been previously reported. However, the impact of B19V-infection on the clinical course of malaria is still elusive. In this study, we investigated the prevalence and clinical significance of B19V co-infection in Gabonese children with malaria.Methods: B19V prevalence was analyzed in serum samples of 197 Gabonese children with P. falciparum malaria and 85 healthy controls using polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and direct DNA-sequencing.Results: B19V was detected in 29/282 (10.28%) of Gabonese children. B19V was observed more frequently in P. falciparum malaria patients (14.21%) in comparison to healthy individuals (1.17%) (P<0.001). Notably, the mild-malaria group revealed significantly lower hematocrit levels in B19V/P. falciparum co-infection than in P. falciparum mono-infection (P<0.05). Genetic analysis revealed a predominance of B19V genotype-1 (71.43%) in the studied population. However, B19V-genotype 2 was observed significantly more often in children with severe-malaria than in mild-malaria (P=0.04).Conclusion: Our findings reveal that B19V-infection is frequent in Gabonese children with P. falciparum malaria and signifies a possible contribution of B19V on the clinical course of malaria in a genotype-dependent manner. B19V co-infection should be considered as a additional diagnostic measure in malaria patients with life threatening anemia. [ABSTRACT FROM AUTHOR]

Background Chronic hepatitis C ( CHC) infection is a risk factor for both the development of end-stage liver disease and hepatocellular carcinoma ( HCC). Globally, approximately 170 million people are chronically infected with the hepatitis C virus ( HCV), and the majority of these individuals come from the western Pacific and Southeast Asia regions (94.6 million persons combined). CHC is an understudied and underappreciated health problem in many Asian countries and in the US, where Asians represent one of the fastest growing groups of new Americans. Aim To perform a systematic review of the current literature on the epidemiology, diagnosis and screening, clinical characteristics and response to anti-viral therapy of Asians with CHC. Methods Using a PubMed search of 'hepatitis C' and 'Asia,' 341 original manuscripts published in peer-reviewed journals were identified, and 99 were selected based on their relevance. Results Many Asian CHC patients do not have easily identifiable risk factors and may be underdiagnosed. Rates of HCV infection in Asians on community screening in the US are unexpectedly high, and there is a high prevalence of HCV genotype 6 in Southeast Asia and Southern China. HCV-infected Asians tend to present at older age and may have higher risk of HCC; however, they respond better to anti-viral therapy than non-Asians across all HCV genotypes. Conclusions Given the high HCV endemicity in Asia, lack of identifiable risk factors and favourable treatment response rates in Asians, we advocate the screening for HCV infection of all Asians who come from areas where HCV prevalence is ≥2%. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Busulfan is widely used in a neuroblastoma setting, with several studies reporting marked inter-patient variability in busulfan pharmacokinetics and pharmacodynamics. The current study reports on the pharmacokinetics of oral versus intravenous (IV) busulfan in high-risk neuroblastoma patients treated on the European HR-NBL-1/SIOPEN study. Methods: Busulfan was administered four times daily for 4days to children aged 0.7–13.1years, either orally (1.45–1.55mg/kg) or by the IV route (0.8–1.2mg/kg according to body weight strata). Blood samples were obtained prior to administration, 2, 4, and 6h after the start of administration on dose 1. Busulfan analysis was carried out by gas chromatography–mass spectrometry and data analysed using a NONMEM population pharmacokinetic approach. Results: Busulfan plasma concentrations obtained from 38 patients receiving IV busulfan and 25 patients receiving oral busulfan, were fitted simultaneously using a one-compartment pharmacokinetic model. Lower variability in drug exposure was observed following IV administration, with a mean busulfan area under the plasma concentration versus time curve (AUC) of 1146±187μM.min (range 838–1622), as compared to 953±290μM.min (range 434–1427) following oral busulfan. A total of 87% of children treated with IV busulfan achieved AUC values within the target of 900–1500μM.min versus 56% of patients following oral busulfan. Busulfan AUC values were significantly higher in HR-NBL-1/SIOPEN trial patients who experienced hepatic toxicity or veno-occlusive disease (VOD) (1177±189μM.min versus 913±256μM.min; p =0.0086). Further stratification based on route of administration suggested that the incidence of hepatic toxicity was related to both high busulfan AUC and oral drug administration. Conclusion: The reduced pharmacokinetic variability and improved control of busulfan AUC observed following IV administration support its utility within the ongoing HR-NBL-1/SIOPEN trial. [Copyright &y& Elsevier]

The nonsense-mediated mRNA decay (NMD) pathway was originally discovered by virtue of its ability to rapidly degrade aberrant mRNAs with premature termination codons. More recently, it was shown that NMD also directly regulates subsets of normal transcripts, suggesting that NMD has roles in normal biological processes. Indeed, several NMD factors have been shown to regulate neurological events (for example, neurogenesis and synaptic plasticity) in numerous vertebrate species. In man, mutations in the NMD factor gene UPF3B, which disrupts a branch of the NMD pathway, cause various forms of intellectual disability (ID). Using Epstein Barr virus-immortalized B cells, also known as lymphoblastoid cell lines (LCLs), from ID patients that have loss-of-function mutations in UPF3B, we investigated the genome-wide consequences of compromised NMD and the role of NMD in neuronal development and function. We found that ∼5% of the human transcriptome is impacted in UPF3B patients. The UPF3B paralog, UPF3A, is stabilized in all UPF3B patients, and partially compensates for the loss of UPF3B function. Interestingly, UPF3A protein, but not mRNA, was stabilised in a quantitative manner that inversely correlated with the severity of patients' phenotype. This suggested that the ability to stabilize the UPF3A protein is a crucial modifier of the neurological symptoms due to loss of UPF3B. We also identified ARHGAP24, which encodes a GTPase-activating protein, as a canonical target of NMD, and we provide evidence that deregulation of this gene inhibits axon and dendrite outgrowth and branching. Our results demonstrate that the UPF3B-dependent NMD pathway is a major regulator of the transcriptome and that its targets have important roles in neuronal cells. [ABSTRACT FROM AUTHOR]

We consider riggings of G-translators on manifolds with multidimensional singularities. We derive a condition for the ellipticity of G-riggings, prove the finiteness theorem, and analyze the relationship between the notions of G-ellipticity and ordinary ellipticity of the riggings. The interest in this class of operators arises in connection with the study of nonlocal pseudodifferential operators. [ABSTRACT FROM AUTHOR]

The article examines the role of thermal activation in the plausibility of dislocation nucleation from voids under laboratory conditions. An atomistic simulation technique that allows the accurate calculation of finite temperature nucleation rates at time scales beyond those accessible to standard molecular dynamics (MD) simulations was utilized. The authors conclude that nucleation is unlikely to occur under ordinary laboratory conditions.

Human Ficolin-2 (L-ficolins) encoded by FCN2 gene is a soluble serum protein that plays an important role in innate immunity and is mainly expressed in the liver. Ficolin-2 serum levels and FCN2 single nucleotide polymorphisms were associated to several infectious diseases. We initially screened the complete FCN2 gene in 48 healthy individuals of Vietnamese ethnicity. We genotyped a Vietnamese cohort comprising of 423 clinically classified hepatitis B virus patients and 303 controls for functional single nucleotide polymorphisms in the promoter region (-986G>A, -602G>A, -4A>G) and in exon 8 (+6424G>T) by real-time PCR and investigated the contribution of FCN2 genotypes and haplotypes to serum Ficolin-2 levels, viral load and liver enzyme levels. Haplotypes differed significantly between patients and controls (P = 0.002) and the haplotype AGGG was found frequently in controls in comparison to patients with hepatitis B virus and hepatocellular carcinoma (P = 0.0002 and P<0.0001) conferring a protective effect. Ficolin-2 levels differed significantly between patients and controls (p<0.0001). Patients with acute hepatitis B had higher serum Ficolin-2 levels compared to other patient groups and controls.The viral load was observed to be significantly distributed among the haplotypes (P = 0.04) and the AAAG haplotype contributed to higher Ficolin-2 levels and to viral load. Four novel single nucleotide polymorphisms in introns (-941G>T, -310G>A, +2363G>A, +4882G>A) and one synonymous mutation in exon 8 (+6485G>T) was observed. Strong linkage was found between the variant -986G>A and -4A>G. The very first study on Vietnamese cohort associates both Ficolin-2 serum levels and FCN2 haplotypes to hepatitis B virus infection and subsequent disease progression. [ABSTRACT FROM AUTHOR]

The combined use of atomistic simulations and transition state theory (TST) has enabled significant improvements in the prediction of thermally activated processes in a wide range of applications, e.g., conformation changes in molecules, chemical reactions, kinetic phase transitions, and solid-state diffusion. However, such an approach is still in its infancy with regard to mechanics of materials applications. Focusing here on dislocation nucleation in Al, we examine the utility of five TST-based approaches. Using the finite-temperature string method, we interpret the success and failure of each approach in terms of a full energetic analysis of the nucleation processes. After showing that advanced TST approaches such as variational TST can accurately predict nucleation rates, we employ variational TST to study dislocation nucleation from a free surface under ordinary laboratory conditions. The predictions (1) demonstrate that nucleation will only occur under very high stresses at room temperature, (2) provide an upper bound on the shear strength of Al in dislocation starved contexts, and (3) provide a rate sensitivity signature of the nucleation process. [ABSTRACT FROM AUTHOR]

The effects of split injection, oxygen enriched air, and heavy exhaust gas recirculation (EGR) on soot emissions in a direct injection diesel engine were studied using the KIVA-3V code. When split injection is applied, the second injection of fuel into a cylinder results in two separate stoichiometric zones, which helps soot oxidation. As a result, soot emissions are decreased. When oxygen enriched air is applied together with split injection, a higher concentration of oxygen causes higher temperatures in the cylinder. The increase in temperature promotes the growth reaction of acetylene with soot. However, it does not improve acetylene formation during the second injection of fuel. As more acetylene is consumed in the growth reaction with soot, the concentration of acetylene in the cylinder is decreased, which leads to a decrease in soot formation and thus soot emissions. A combination of split injection, a high concentration of oxygen, and a high EGR ratio shows the best results in terms of diesel emissions. In this paper, the split injection scheme of 75.8.25, in which 75% of total fuel is injected in the first pulse, followed by 8°CA of dwell time, and 25% of fuel is injected in the second pulse, with an oxygen concentration of 23% in volume and an EGR ratio of 30% shows a 45% reduction in soot emissions, with the same NOx emissions as in single injection. [ABSTRACT FROM AUTHOR]

SOI technology offers ample room for scaling, performance improvement, and innovations. The current status is reviewed by focusing on several technological options for boosting the transport properties in SOI MOSFETs. The impact of series resistance, high-K dielectrics, and metal gate in advanced transistors is discussed. Carrier mobility measurements as a function of channel length and temperature reveal the beneficial effect of strain, mitigated however by various types of defects. The experimental data is exclusively collected from state-of-the-art, ultrathin body, fully depleted MOSFETs. Simple models are presented to clarify the mobility behavior. [ABSTRACT FROM AUTHOR]

One of the main challenges in pervasive computing is how we can establish secure communication over an untrusted high-bandwidth network without any initial knowledge or a Public Key Infrastructure. An approach studied by a number of researchers is building security though human work creating a low-bandwidth empirical (or authentication) channel where the transmitted information is authentic and cannot be faked or modified. In this paper, we give an analytical survey of authentication protocols of this type. We start with non-interactive authentication schemes, and then move on to analyse a number of strategies used to build interactive pair-wise and group protocols that minimise the human work relative to the amount of security obtained as well as optimising the computation processing. In studying these protocols, we will discover that their security is underlined by the idea of commitment before knowledge, which is refined by two protocol design principles introduced in this survey. [ABSTRACT FROM AUTHOR]

Clin Microbiol Infect 2010; 16: 1264–1269 The dupA gene of Helicobacter pylori was suggested to be a risk factor for duodenal ulcer but protective against gastric cancer. The present study aimed to re-examine the role of dupA in H. pylori-infected Japanese patients. We found that dupA status was not associated with any gastroduodenal disease, histological score of chronic gastritis or with the extent of interleukin-8 production from gastric cell lines. These results indicate that dupA is unlikely to be a virulence factor of H. pylori in the Japanese population. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to investigate the relationship between clinical outcome and the intactness of cagPAI in Helicobacter pylori strains from Vietnam. The presence or absence of 30 cagPAI genes was investigated by polymerase chain reaction (PCR) and dot-blotting. H. pylori-induced interleukin-8 secretion and hummingbird phenotype, and H. pylori adhesion to gastric epithelial cells were examined. The serum concentration of pepsinogen 1, pepsinogen 2, and gastrin was also measured in all patients. cagPAI was present in all 103 Vietnamese H. pylori isolates, of which 91 had intact cagPAI and 12 contained only a part of cagPAI. Infection with the partial cagPAI strains was less likely to be associated with peptic ulcer and chronic gastric mucosal inflammation than infection with strains possessing intact cagPAI. The partial cagPAI strains lacked almost all ability to induce interleukin-8 secretion and the hummingbird phenotype in gastric cells. Their adhesion to epithelial cells was significantly decreased in comparison with intact cagPAI strains. Moreover, for the first time, we found an association between cagPAI status and the serum concentration of pepsinogens 1 and 2 in infected patients. H. pylori strains with internal deletion within cagPAI are less virulent and, thus, less likely to be associated with severe clinical outcomes. [ABSTRACT FROM AUTHOR]

Background Atypical genital naevi (AGN) are naevi of special sites with atypical histological features that overlap with those of malignant melanoma. Activating BRAF mutations, identified in the majority of banal melanocytic naevi and cutaneous melanomas, are reportedly uncommon in naevomelanocytic proliferations in nonsun-exposed sites. We have recently shown that constitutive activation of the BRAF-MEK-ERK signalling pathway in oncogenic BRAF-positive naevi increases expression and secretion of IGFBP7, which induces senescence and apoptosis. Objectives To ascertain the frequency of BRAF V600E mutations in AGN compared with banal naevi without atypia. An additional aim was to assess the expression of IGFBP7 in oncogenic BRAF-positive AGN. Methods Genomic DNA was isolated per protocol from seven genital naevi without atypia and 13 AGN for BRAF genotyping. Immunohistochemical staining for IGFBP7 was performed on all cases. Results The BRAF V600E mutation was identified in 43% of genital naevi without atypia and 23% of AGN ( P = 0·61). In both groups, IGFBP7 expression was maintained in 67% of BRAF V600E-positive cases. Conclusions The prevalence of BRAF V600E in AGN suggests that ultraviolet exposure is not essential for generating the mutation. The BRAF V600E mutational status appears to be of limited diagnostic utility in distinguishing genital naevi that exhibit atypia from those that do not. Similar to oncogenic BRAF-positive common naevi without atypia, enhanced expression of the tumour suppressor IGFBP7 in oncogenic BRAF-positive AGN supports that they are biologically inert. [ABSTRACT FROM AUTHOR]

Abstract: The electrical properties of front and back channels in advanced SOI MOSFETs (ultrathin film, short length, metal-gate/high-K stack, thin BOX) are used to reveal the impact of tensile and compressive CESL strain. The benefit of compressive strain is maximized in 100nm long MOSFETs, where the hole mobility can be increased by a factor of two. In shorter devices, the mobility gain fades away due to neutral defects and remote Coulomb scattering. The short-channel scattering and strain mechanisms are identified by low temperature measurements and explained by an original physics-based model. [Copyright &y& Elsevier]

Single crystals of the type-I clathrate Ba8Ni3.5Ge42.10.4(space group Pm3n, no. 223, a= 10.798(2) Å, l= 30 mm, ∅ = 8 mm) were grown from the melt using the Bridgman technique. Their composition, determined by microprobe analysis, reveals a distinctly lower Ni content than previously reported for the lower limit (x= 5.4) of the homogeneity range of the clathrate-I phase Ba8NixGe46−x. From single crystal X-ray diffraction data we introduce a crystal structure model that takes point defects (vacancies) in the Ge network into account. It reveals that both Ni and accumulate at a single site (6c) and that, as a consequence, the Ge network distorts considerably. Ba8Ni3.5Ge42.10.4shows metal-like behaviour (dρ/dT> 0) albeit with high resistivity at room temperature (ρ(300 K) 1 mΩ cm). Together with the low charge carrier concentration of 2.3 e−/unit cell at 300 K this is typical of a degenerate semiconductor. The lattice thermal conductivity is distinctly smaller than that of Ba8Ge433, where the vacancies partially order, and smaller than those of Ba–Ni–Ge type-I clathrates without vacancies, suggesting that disordered vacancies efficiently scatter heat-transporting phonons. We provide evidence that the maximum value of the thermoelectric figure of merit reached in Ba8Ni3.5Ge42.10.4, ZT(680 K) ≅ 0.21, can be further improved by adjusting the charge carrier concentration. [ABSTRACT FROM AUTHOR]

Combined sewer overflows and stormwater discharges represent an important source of contamination to the environment. However, the harsh environment inside sewers and particular hydraulic conditions during rain events reduce the reliability of traditional flow measurement probes. In the following, we present and evaluate an in situ system for the monitoring of water flow in sewers based on video images. This paper focuses on the measurement of the water level based on image-processing techniques. The developed image-based water level algorithms identify the wall/water interface from sewer images and measure its position with respect to real world coordinates. A web-based user interface and a 3-tier system architecture enable the remote configuration of the cameras and the image-processing algorithms. Images acquired and processed by our system were found to reliably measure water levels and thereby to provide crucial information leading to better understand particular hydraulic behaviors. In terms of robustness and accuracy, the water level algorithm provided equal or better results compared to traditional water level probes in three different in situ configurations. [ABSTRACT FROM AUTHOR]

This study was conducted to retrospectively compare the area under the curve (AUC) and the total clearance of busulfan (Bu) following oral and intravenous (IV) administrations and to determine which intravenous dose generated equivalent exposure to that of the oral form that has been marketed for decades. Patient pharmacokinetics were assessed at dose 9 during a conditioning regimen for stem-cell transplantation and included data from 277 patients for oral Bu (71 from fixed-dose studies and 206 from studies with dose adjustment allowed) and 120 patients for IV Bu (fixed dose). AUCs were compared between patients with fixed dose of oral Bu ( n = 71, 1 mg/kg) and those of IV Bu ( n = 120, 0.8 mg/kg). Total clearances were calculated for all 277 patients with oral Bu and compared to those with IV Bu, with the ratio of IV-to-oral clearance representing the absolute bioavailability of the oral form. Oral and IV populations differed on disease-type distribution but presented comparable demography parameters. IV Bu dosing was mostly based on the ideal body weight index while actual body weight or adjusted ideal body weight indexes were mostly used for oral. When normalised to comparable indexes, bioequivalent AUCs were achieved between oral and IV populations. Oral Bu bioavailability was about 80% when calculated from the ratio of IV-to-oral total clearances. This retrospective study carried out on a large set of data showed that similar plasma exposures were achieved with 1.0 mg/kg oral Bu or 0.8 mg/kg IV Bu. [ABSTRACT FROM AUTHOR]

Busulfan (Bu) is commonly used in preparative conditioning regimen prior to bone marrow transplantation in infants (< 1 year old), children and adolescents (up to 17 years old). The clinical development of an intravenous form of busulfan (Busilvex®) was based on pharmacokinetic (PK) modeling and simulation techniques. A retrospective population PK analysis was initially performed from a first study in 24 pediatric patients (0.45–16.7 years old) and a log-linear relationship between body weight and Busilvex® clearance was demonstrated with no age-dependency. For an optimal area under the curve (AUC) targeting, a new Bu dosing regimen [i.e. 5 dose levels (0.80 to 1.20 mg/kg) adjusted to 5 discrete weight categories] was developed and assessed through population PK-based simulations. The benefit from this new dosing strategy was validated in a second trial including 55 children (0.30–17.2 years old). This prospective trial confirmed the previous simulations: an efficient therapeutic targeting whatever the patient's age or body weight. Over 80% of the children were within the desired plasma exposure window, and the initial PK model was validated on the confirmatory dataset. [ABSTRACT FROM AUTHOR]

Objective: The hepatitis B virus X (HBx) protein plays an important role in the pathogenesis of hepatocellular carcinoma (HCC). One potential mechanism by which HBx can cause liver cancer may involve intracellular distribution and consecutively modulation of the proliferative important STAT/SOCS signaling with upregulation of STAT3. Methods: 153 Vietnamese HBV-infected patients, including 48 patients with HCC, were analyzed. HBx sequences were determined by sequencing and subcloned for functional experiments. Intracellular localization of HBx mutants was determined by immunofluorescence assays. The impact of HBx mutants on JAK/STAT/SOCS signaling was investigated using Western blot and PCR analyses. Results: In 4/48 HCC patients, truncated HBx together with full-length mutated HBx proteins were observed. Expression of HBx mutant proteins demonstrated an atypical nuclear and perinuclear localization. Functional experiments to determine the effect of HBx mutants on STAT/SOCS signaling demonstrated a significantly increased upregulation of STAT3 activation (p > 0.001) in comparison to wild-type (wt)-HBx. STAT1 was not activated either by wt-HBx or HBx mutants. Interestingly, SOCS1 and SOCS3 expression was not activated by wt-HBx and HBx mutants. Conclusions: Our results suggest that atypical nuclear/perinuclear localization of HBx mutants might be responsible for an enhanced activation of STAT3, inhibition of STAT1 and silencing of SOCS1/SOCS3 expression. This observation points to an active role of HBx mutants in hepatocarcinogenesis that involves dysregulation of STAT/SOCS signaling. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]