Miracle-dz/UniFAR-FTUs huggingface dataset:
An experimental study of the pathogenicity of a duck hepatitis A virus genotype C isolate in specific pathogen free ducklings

Duck hepatitis A virus genotype C (DHAV-C), recognized recently, is one of the pathogens causing fatal duck viral hepatitis in ducklings, especially in Asia. To demonstrate the pathogenesis of the DHAV-C isolate, 3-day-old specific pathogen free ducklings were inoculated subcutaneously with a DHAV-C isolate and the clinical signs were observed. Virus distribution, histological and apoptotic morphological changes of various tissues were examined at different times post inoculation. The serial, characteristic changes included haemorrhage and swelling of the liver. Apoptotic cells and virus antigen staining were found in all of the tissues examined. Where more virus antigen staining was detected, there were more severe histopathological and apoptotic changes. The amount of virus antigen and the histological and apoptotic morphological changes agreed with each other and became increasingly severe with length of time after infection. Apoptotic cells were ubiquitously distributed, especially among lymphocytes, macrophages and monocytes in immune organs such as the bursa of Fabricius, thymus and spleen, and in liver, kidney and cerebral cells. Necrosis was also observed within 72 h post inoculation in all organs examined, except the cerebrum, and was characterized by cell swelling and collapsed plasma membrane. These results suggest that the recent outbreak of disease caused by DHAV-C virus is pantropic, causing apoptosis and necrosis of different organs. The apoptosis and necrosis caused by the DHAV-C field strain in this study is associated with pathogenesis and DHAV-C-induced lesions.
The expression of E‐cadherin and catenins in colorectal tumours from familial adenomatous polyposis patients

Familial adenomatous polyposis patients (FAP) harbour a germline mutation of the adenomatous polyposis coli gene (APC), and APC mutations are early events in the development of sporadic colorectal neoplasms. The APC protein interacts with β‐catenin and γ‐catenin and APC mutations are believed to play a role in the altered levels of β‐catenin in colorectal tumours. Immunohistochemical studies have shown changes in the expression and distribution of E‐cadherin and catenins in sporadic colorectal neoplasms. This study assessed the expression and distribution of E‐cadherin and catenins in colorectal neoplasms and non‐neoplastic mucosa from FAP patients. The expression and cellular distribution of E‐cadherin and catenins were studied by immunohistochemistry in 61 adenomas, five carcinomas, and non‐neoplastic mucosa from 18 FAP patients. mRNA levels in the carcinomas were studied by in situ hybridization. The expression of E‐cadherin and catenins was increased in over 80% of the adenomas, with evident cytoplasmic immunoreactivity. There was increased expression of E‐cadherin and catenin in the carcinomas, with a notable increase in the levels of mRNA, in comparison with the non‐neoplastic mucosa. Copyright © 2002 John Wiley & Sons, Ltd.
Sex differences in outcomes of very low birthweight infants: the newborn male disadvantage

OBJECTIVE To determine the differences in short term outcome of very low birthweight infants attributable to sex. METHODS Boys and girls weighing 501–1500 g admitted to the 12 centres of the National Institute of Child Health and Human Development Neonatal Research Network were compared. Maternal information and perinatal data were collected from hospital records. Infant outcome was recorded at discharge, at 120 days of age if the infant was still in hospital, or at death. Best obstetric estimate based on the last menstrual period, standard obstetric factors, and ultrasound were used to assign gestational age in completed weeks. Data were collected on a cohort that included 3356 boys and 3382 girls, representing all inborn births from 1 May 1991 to 31 December 1993. RESULTS Mortality for boys was 22% and that for girls 15%. The prenatal and perinatal data indicate few differences between the sex groups, except that boys were less likely to have been exposed to antenatal steroids (odds ratio (OR) = 0.80) and were less stable after birth, as reflected in a higher percentage with lower Apgar scores at one and five minutes and the need for physical and pharmacological assistance. In particular, boys were more likely to have been intubated (OR = 1.16) and to have received resuscitation medication (OR = 1.40). Boys had a higher risk (OR > 1.00) for most adverse neonatal outcomes. Although pulmonary morbidity predominated, intracranial haemorrhage and urinary tract infection were also more common. CONCLUSIONS Relative differences in short term morbidity and mortality persist between the sexes.
Biofabricated Nanoparticle Coating for Liver‐Cell Targeting

Biology routinely uses noncovalent interactions to perform complex functions that range from the molecular recognition of ligand–receptor binding to the reversible self‐assembly/disassembly of hierarchical nanostructures (e.g., virus particles). Potentially, biological materials that offer such recognition and reversible self‐assembly functionality can be applied to nanomedicine. Here, polysaccharides with the multifunctional polysaccharide‐binding protein Concanavalin A (Con A) are coupled to create a functional nanoparticle coating. This coating is self‐assembled in a layer‐by‐layer format by sequentially contacting a nanoparticle with Con A and the polysaccharide glycogen. In the final assembly step, a galactomannan targeting ligand is self‐assembled into the coating. Evidence indicates that the mannose residues of the galactomannan backbone are responsible for assembly into the coating by Con A binding, while the galactose side chain residues are responsible for targeting to the liver‐specific asialoglycoprotein receptor (ASGP‐R). Binding to ASGP‐R induces endocytic uptake, while the low endosomal pH triggers disassembly of the coating and release of the nanoparticle‐entrapped drug. In vitro cell studies indicate that the coating confers liver‐cell‐specific function for both nanoparticle uptake and drug delivery. These studies extend the use of Con A to sugar‐mediated and organ‐specific targeting, and further illustrate the potential of biologically based fabrication for generating functional materials.
Backbone dynamics of chymotrypsin inhibitor 2: effect of breaking the active site bond and its implications for the mechanism of inhibition of serine proteases.

The backbone dynamics of uniformly 15N-labeled chymotrypsin inhibitor 2 (CI2) and of the complex formed by the association of two fragments consisting of residues 20-59 and 60-83 have been studied. A data set consisting of 15N longitudinal (T1) and transverse (T1 rho) relaxation times and (1H)-15N NOE enhancements has been measured for all backbone NH groups in both proteins. Information on internal motions has been extracted from these data using the model-free approach to determine order parameters (S2) and effective internal correlation times (tau e). The data indicate that most of the backbone of CI2 is highly constrained (S2 approximately 0.9) with the exception of residues in the binding loop (residues 54-64), which have slightly lower order parameters. Most of the residues in the CI2(20-59). (60-83) complex are also highly constrained (S2 approximately 0.9). However, the loss of the covalent bond between Met59 and Glu60 leads to a large increase in the mobility of residues in the loop region. The residues in the first half of the loop region have significantly lower order parameters than those in the second half of the loop. This observation suggests that the NH2 group that is released on cleavage of the scissile bond remains anchored in its original position, inhibiting the attack of water on the acyl-enzyme that is formed between the protease and the cleaved inhibitor. More importantly, the NH2 group is optimally placed for reversing the formation of the acyl-enzyme so that the equilibrium between the cleaved and uncleaved inhibitor, bound to the protease, greatly favors the uncleaved complex.
A Novel Mutation in the Mitochondrial 16S rRNA Gene in a Patient with MELAS Syndrome, Diabetes Mellitus, Hyperthyroidism and Cardiomyopathy

Using RNase protection analysis, we found a novel C to G mutation at nucleotide position 3093 of mitochondrial DNA (mtDNA) in a previously reported 35-year-old woman exhibiting clinical features of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome together with diabetes mellitus, hyperthyroidism and cardiomyopathy. The patient also had an A3243G mutation in the tRNALeu(UUR) gene and a 260-base pair duplication in the D-loop of mtDNA. The fibroblasts of the patient were cultured and used for the construction of cybrids using cytoplasmic transfer of the patient’s mtDNA to the mtDNA-less ρ⁰ cells. RNA isolated from the cybrids was subjected to RNase protection analysis, and a C3093G transversion at the 16S rRNA gene and a MELAS-associated A3243G mutation of mtDNA were detected. The novel C3093G mutation together with the A3243G transition were found in muscle biopsies, hair follicles and blood cells of this patient and also in her skin fibroblasts and cybrids. The proportion of the C3093G mutant mtDNA in muscle biopsies of the patient was 51%. In contrast, the mutation was not detected in three sons of the proband. To characterize the impact of the mtDNA mutation-associated defects on mitochondrial function, we determined the respiratory enzyme activities of the primary culture of fibroblasts established from the proband, her mother and her three sons. The proportions of mtDNA with the C3093G transversion and the A3243G transition in the fibroblasts of the proband were 45 and 58%, respectively. However, the fibroblasts of the proband’s mother and children harbored lower levels of mtDNA with the A3243G mutation but did not contain the C3093G mutation. The complex I activity in the proband’s fibroblasts was decreased to 47% of the control but those of the fibroblasts of the mother and three sons of the proband were not significantly changed. These findings suggest that the C3093G transversion together with the A3243G transition of mtDNA impaired the respiratory function of mitochondria and caused the atypical MELAS syndrome associated with diabetes mellitus, hyperthyroidism and cardiomyopathy in this patient.
p62 is Negatively Implicated in the TRAF6-BECN1 Signaling Axis for Autophagy Activation and Cancer Progression by Toll-Like Receptor 4 (TLR4)

Toll-like receptors (TLRs) induce the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and autophagy through the TNF (Tumor necrosis factor) receptor-associated factor 6 (TRAF6)-evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) and TRAF6-BECN1 signaling axes, respectively. Having shown that p62 negatively regulates Toll-like receptor 4 (TLR4)-mediated signaling via TRAF6-ECSIT signaling axis, we herein investigated whether p62 is functionally implicated in the TRAF6-BECN1 signaling axis, thereby regulating cancer cell migration and invasion. p62 interacted with TRAF6 and BECN1, to interrupt the functional associations required for TRAF6-BECN1 complex formation, leading to inhibitions of BECN1 ubiquitination and autophagy activation. Importantly, p62-deficient cancer cells, such as p62-knockdown (p62KD) SK-HEP-1, p62KD MDA-MB-231, and p62-knockout (p62KO) A549 cells, showed increased activation of autophagy induced by TLR4 stimulation, suggesting that p62 negatively regulates autophagy activation. Moreover, these p62-deficient cancer cells exhibited marked increases in cell migration and invasion in response to TLR4 stimulation. Collectively, these results suggest that p62 is negatively implicated in the TRAF6-BECN1 signaling axis, thereby inhibiting cancer cell migration and invasion regulated by autophagy activation in response to TLR4 stimulation.
Production of metallothionein and heat-shock proteins in response to metals.

Acute stress, such as heat, and some metals, such as arsenite, will induce a specific group of stress proteins referred to as heat-shock proteins. The heat-shock proteins contribute to the survival of cells following a variety of stresses. Similarly, metals such as cadmium and zinc, will increase the levels of metallothionein (MT). The metal-binding protein, MT, has also been found to have a protective role in the cellular response to acute stresses like heavy metals. The purpose of the present study was to examine the production of these proteins in response to metals. Rat hepatocytes were maintained in monolayer culture for 22 hr, and subsequently treated with various concentrations of metals for 4 hr, or incubated at 43.5 degrees C for 15-60 min. Following two washes with fresh media, the cells were labeled with [35S]-methionine (25 microCi/ml) in methionine-free media for 4 hr for determination of heat-shock protein production, or reincubated in fresh media for 20 hr for MT determination. Heat-shock protein production was determined by SDS-polyacrylamide gel electrophoresis followed by autoradiography. The autoradiograms were quantified by densitometric scanning. MT was determined by the Cd/hemoglobin affinity assay. Three metals (arsenite, cadmium, and zinc) strongly increased the heat-shock proteins. Whereas arsenite was a much less effective inducer of MT than was cadmium or zinc, arsenite was as effective as the other metals in inducing heat-shock proteins. Nickel was a good inducer of MT; however, it resulted in only a slight increase in the levels of heat-shock proteins. (ABSTRACT TRUNCATED AT 250 WORDS)
Neurogenesis and glial proliferation are stimulated following diffuse traumatic brain injury in adult rats

Although increased neurogenesis has been described in rodent models of focal traumatic brain injury (TBI), the neurogenic response occurring after diffuse TBI uncomplicated by focal injury has not been examined to date, despite the pervasiveness of this distinct type of brain injury in the TBI patient population. Here we characterize multiple stages of neurogenesis following a traumatic axonal injury (TAI) model of diffuse TBI as well as the proliferative response of glial cells. TAI was induced in adult rats using an impact‐acceleration model, and 5‐bromo‐2′‐deoxyuridine (BrdU) was administered on days 1–4 posttrauma or sham operation to label mitotic cells. Using immunohistochemistry for BrdU combined with phenotype‐specific markers, we found that proliferation was increased following TAI in the subventricular zone of the lateral ventricles and in the hippocampal subgranular zone, although the ultimate production of new dentate granule neurons at 8 weeks was not significantly enhanced. Also, abundant proliferating and reactive astrocytes, microglia, and polydendrocytes were detected throughout the brain following TAI, indicating that a robust glial response occurs in this model, although very few new cells in the nonneurogenic brain regions became mature neurons. We conclude that diffuse brain injury stimulates early stages of a neurogenic response similar to that described for models of focal TBI. © 2011 Wiley‐Liss, Inc.
miRNA regulation in the context of functional protein networks: principles and applications

MicroRNAs (miRNAs) are small non‐coding endogenous regulatory RNAs that fine‐tune gene expression in a wide range of biological processes and diseases. miRNAs exert their function by targeting mRNAs to trigger their degradation or inhibit protein translation. The proteins encoded by the genes targeted by miRNAs may act as key components of cellular networks, thus the use of biological molecular network information for the purposes of elucidating the role of miRNAs in molecular disease mechanism is a key objective in systems biomedicine. The crosstalk layer between miRNA–target networks and functional protein is rich sources of information to explore the function of miRNAs at the system level. Characterizing the influence of miRNAs in the context of the target (protein interactors of the target) is in the early stages with potential to help better understand how miRNAs function within the cellular networks. In this article, the latest research on the cross‐talk between miRNAs and protein networks, particularly physical protein interactions and gene regulatory networks is summarized. This article also covers recent research on understanding the biology of miRNAs at the system level and defines principles of miRNA regulation of protein and gene regulatory networks. The second part of the article highlights the promise of considering the protein context of the miRNA target when searching for functional miRNA–target interactions. Some of the applications of integrating protein networks with miRNA–targets that have clinical and functional utility are described. WIREs Syst Biol Med 2014, 6:189–199. doi: 10.1002/wsbm.1251
Diurnal variation in serum levels of cartilage oligomeric matrix protein in patients with knee osteoarthritis or rheumatoid arthritis

Objective: To monitor changes in serum concentrations of cartilage oligomeric matrix protein (COMP) during a 24-h period to determine any diurnal variation, and to estimate the half life of COMP in the circulation in patients with symptomatic knee osteoarthritis and in those with rheumatoid arthritis. Methods: Serum samples were drawn every 4 h (7 samples/patient over 24 h) in 10 patients with knee osteoarthritis and 14 patients with rheumatoid arthritis. Osteoarthritis was defined radiographically and clinically (American College of Rheumatology (ACR) criteria) and rheumatoid arthritis according to the 1987 ACR criteria. Serum COMP was measured by sandwich ELISA. A statistical model for the diurnal variation in the COMP levels was developed using the computer program NONMEM. Results: No considerable changes in COMP levels were observed during the day between 08:00 and 21:00 in either group. A significant decrease in serum COMP was apparent during bed rest at night, reaching the lowest levels between 04:00 and 05:00 (p<0.03 or better v all other time points) in patients with osteoarthritis and in those with rheumatoid arthritis. From the rate of decreasing serum COMP levels, a putative half life of COMP in the circulation was estimated to be 7.4 h. Conclusion: During normal daytime activities, serum COMP levels are constant. The decrease during the night indicates a rapid elimination of COMP once it has reached the circulation. The stable COMP levels during the day suggest that it is not necessary to further standardise the time of serum sampling in clinical practice.
A CASE STUDY OF DNAPL REMEDIATION IN NORTHEASTERN BRAZIL

Aquifer restoration in the United States is recognized as a technically challenging objective when dense non-aqueous phase liquids (DNAPLs) are present [1]. In fact, only a few aquifers impacted by DNAPLs have been restored. Factors that have typically contributed to the lack of successful aquifer restoration include the chemical properties of the DNAPL, the physical properties of the aquifer, the absence of cost-effective technologies, and an incomplete or inaccurate development of a conceptual hydrogeological model for the site. In Latin America, environmental studies historically have been related to biological quality of surface water and groundwater. Recently, the U.S. and Canada have experienced an increased influx of foreign students and professionals interested in studying specialized courses in environmental engineering, or participating in conferences. This exposure to current topics has strengthened the awareness of these professionals regarding groundwater contamination from gasoline-derived compounds and chlorinated solvents. As a result of this increased awareness, Latin American hydrogeologists and environmental regulators have been able to recognize the potential problems that could result from DNAPL spills that may impact groundwater and have learned to approach them using locally available technology and resources. A case study of such an example is presented below.
The Role of Business Intelligence in Business Performance Management

Business performance management (BPM) is a key business initiative that enables companies to align strategic and operational objectives with business activities in order to fully manage performance through better informed decision making and action. Effective business performance requires an organization to model and monitor not only its tactics but also its strategies and the assumption on which these strategies are built. The aim of this paper is to examine the processes, methodologies and technologies underlying BPM, the relation between BPM and business intelligence, and to propose a framework for integrating corporate performance management and business intelligence in a holistic approach of managing business performance. Finally we come to the conclusion: Managing and optimizing business performance is a critical requirement not only for maximizing business profitability but even for remaining in viable in today’s fast moving and competitive business environment.
Nonspecific yet decisive: Ubiquitination can affect the native‐state dynamics of the modified protein

Ubiquitination is one of the most common post‐translational modifications of proteins, and mediates regulated protein degradation among other cellular processes. A fundamental question regarding the mechanism of protein ubiquitination is whether and how ubiquitin affects the biophysical nature of the modified protein. For some systems, it was shown that the position of ubiquitin within the attachment site is quite flexible and ubiquitin does not specifically interact with its substrate. Nevertheless, it was revealed that polyubiquitination can decrease the thermal stability of the modified protein in a site‐specific manner because of alterations of the thermodynamic properties of the folded and unfolded states. In this study, we used detailed atomistic simulations to focus on the molecular effects of ubiquitination on the native structure of the modified protein. As a model, we used Ubc7, which is an E2 enzyme whose in vivo ubiquitination process is well characterized and known to lead to degradation. We found that, despite the lack of specific direct interactions between the ubiquitin moiety and Ubc7, ubiquitination decreases the conformational flexibility of certain regions of the substrate Ubc7 protein, which reduces its entropy and thus destabilizes it. The strongest destabilizing effect was observed for systems in which Lys48‐linked tetra‐ubiquitin was attached to sites used for in vivo degradation. These results reveal how changes in the configurational entropy of the folded state may modulate the stability of the protein's native state. Overall, our results imply that ubiquitination can modify the biophysical properties of the attached protein in the folded state and that, in some proteins, different ubiquitination sites will lead to different biophysical outcomes. We propose that this destabilizing effect of polyubiquitin on the substrate is linked to the functions carried out by the modification, and in particular, regulatory control of protein half‐life through proteasomal degradation.
Randomized comparison of photodynamic therapy with topical 5‐fluorouracil in Bowen's disease

Summary Background Bowen's disease (BD; intraepithelial squamous cell carcinoma) is therapeutically challenging because lesions, which may be multiple, are frequently located at sites that heal poorly. There is a small risk of progression to invasive carcinoma. Photodynamic therapy (PDT) is an effective treatment for certain non melanoma skin cancers, but comparison studies with other, better‐established therapies are limited.