Lipopolysaccharide inhibits transforming growth factor-beta1-stimulated Smad6 expression by inducing phosphorylation of the linker region of Smad3 through a TLR4–IRAK1–ERK1/2 pathway

AbstractSmad6, one of the inhibitory Smads, plays an important role in transforming growth factor-beta1 (TGF-β1)-mediated negative regulation of pro-inflammatory signaling. In this study, we found that bacterial endotoxin lipopolysaccharide (LPS) inhibits TGF-β1-induced expression of Smad6 in RAW264.7 cells. This repression was accompanied by increased Smad3 linker phosphorylation at Thr-179 and Ser-208 and was dependent on ERK1/2 activity via the TLR4–IRAK1-linked signaling cascade. The expression of a mutant Smad3, that lacks the phosphorylation sites in the linker regions, significantly reversed the inhibitory effect of LPS on TGF-β1-induced Smad6 expression and its anti-inflammatory capacity. Collectively, our findings show how LPS pro-inflammatory signal antagonizes the anti-inflammatory activity of TGF-β1

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Department of Chemical EngineeringThe glycolytic pathway has a central role in metabolism by supplying precursor, energy and redox molecules for supporting well being of microorganism at natural habitat. Advent of synthetic biology, however, facilitates proliferation of microorganisms beyo nd their original niche. The native glycolytic pathway often contains thermodynamic bottleneck and stoichiometry limiting their wide range application. Adopting alternative glycolytic structure bypassing such metabolic hurdles enables to expand and diversi fy traits of a microbial strain. Here, we completely inactivate the Embden-Meyerhof-Parnas (EMP) pathway in Escherichia coli which functions as major glycolytic route. In order to surpass sub optimality of latent alternative glycolytic routes in glucose ca tabolism, E . coli strain without the functional EMP pathway was subjected to adaptive evolution with glucose as sole carbon source. The evolved mutant exhibiting 6.6 fold higher growth rate was isolated. Based on whole genome sequencing data, key genotype changes were identified from genotype phenotype relationship. Disabilities of glucose uptake and glucose catabolism sole via the Pentose phosphate (PP) pathway were identified as primary metabolic bottlenecks upon complete loss of the upper EMP pathway. Th ese can be resolved by simultaneous enabling of glucose uptake and activating latent the Entner Doudoroff (ED) pathway for glucose catabolism. By rebalancing two alternative glycolytic pathways, the ED and PP pathway, tuning profile of carbon, energy and r edox equivalents yield from glucose was demonstrated. Combining the rebalancing strategy to adaptive evolution, 3-hydroxypropionic acid (3-HP) production titer was increased up to 3.2 fold compared to the unevolved strainclos

Effects of Rhythmic Auditory Stimulation During Hemiplegic Arm Reaching in Individuals with Stroke: An Exploratory Study

SummaryObjective/BackgroundThis study investigated the effects of rhythmic auditory stimulation (RAS) on muscle activity and elbow motion during arm reaching with hemiplegic arm in participants with stroke.MethodsSixteen adults with stroke who resided in a community were recruited in this study. The RAS consisted of sound emitted from a digital metronome. While sitting upright in a chair, participants reached their arms towards a target (a switch on a table) both with and without RAS. The three-dimensional motion analysis system and surface electromyography system were used for measurements during the reaching tasks.ResultsWe found that RAS elicited better performance in reaching movements than those movements performed without RAS. RAS shortened the movement time (p = .002), reduced the change in acceleration (p = .001), increased the elbow extension range of motion (p = .001), increased muscle activation of the triceps brachii (p = .024), and reduced the co-contraction ratio (p = .015) of the affected arm.ConclusionRAS might be a useful technique to facilitate improvements in motor function of the affected arm in patients with stroke

Immunoglobulin G Subclass Deficiency is the Major Phenotype of Primary Immunodeficiency in a Korean Adult Cohort

Primary immunodeficiency disease (PID) is a rare disorder in adults. Most often, serious forms are detected during infancy or childhood. However, mild forms of PID may not be diagnosed until later in life, and some types of humoral immunodeficiency may occur in adulthood. The purpose of this study was to identify clinical features of PID in Korean adults. A retrospective study was performed on 55 adult patients who were diagnosed as PID between January 1998 and January 2009 at a single tertiary medical center in Korea. IgG subclass deficiency was the most common phenotype (67%, 37/55), followed by total IgG deficiency (20%, 11/55), IgM deficiency (7%, 4/55), common variable immunodeficiency (2%, 1/55), and X-linked agammaglobulinemia (2%, 1/55). IgG3 and IgG4 were the most affected subclasses. Upper and lower respiratory tract infections (76%) were the most frequently observed symptoms, followed by multiple site infection (11%), urinary tract infection, and colitis. Bronchial asthma, rhinitis, and several autoimmune diseases were common associated diseases. IgG and IgG subclass deficiency should be considered in adult patients presenting with recurrent upper and lower respiratory infections, particularly in those with respiratory allergies or autoimmune diseases

Antigen-binding Characteristics of Circulating IgG Autoantibodies to Cytokeratin 18 Protein in Patients with Nonallergic Asthma

Cytokeratin 18 (CK18) protein was identified as an airway epithelial cell autoantigen associated with nonallergic asthma. Cleavage of CK18 protein by caspase-3 is a marker of early apoptosis in epithelial cells. It has been shown that the expression of active caspase-3 was increased in bronchial epithelial cells of asthmatic patients, when compared with healthy controls. To investigate the antigen-binding characteristics of IgG autoantibodies to CK18 protein in nonallergic asthma, the bindings of IgG autoantibodies to the fragments of CK18 protein cleaved by caspase-3 were analyzed by Western blot using serum samples from three patients with nonallergic asthma. Recombinant human CK18 protein was treated by caspase-3 and cleaved into N-terminal fragment (1-397 amino acids) and C-terminal fragment (398-430 amino acids). The binding capacity of IgG autoantibodies to N-terminal fragment of CK18 was maintained in one patient and reduced in other two patients. IgG autoantibodies from all three patients did not bind to C-terminal fragment of CK18. In conclusion, IgG autoantibodies to CK18 protein from patients with nonallergic asthma seems to preferentially bind to the whole molecule of CK18 protein and their antigen-binding characteristics were heterogeneous among the patients with nonallergic asthma

Assessment of Bone Quality using Finite Element Analysis Based upon Micro-CT Images

BACKGROUND: To evaluate the feasibility of a micro-image based finite element model to determine the efficacy of sequential treatments on the bone quality in a rat osteoporosis model. METHODS: Rat osteoporosis and treated osteoporosis models were established with the bone loss, restore and maintain concept. Thirty Sprague-Dawley rats were used in this study. A sham operation or ovariectomy was performed at 20 weeks after birth, which was followed by the respective sequential trials as follows: (1) sham-operation only, (2) ovariectomy only, (3) ovariectomized rats with parathyroid hormone maintenance, (4) ovariectomized rats treated with PTH for 5 weeks and then withdrawal, (5) ovariectomized rats treated with PTH for 5 weeks and then with 17 beta-estradiol, and (6) ovariectomized rats treated with parathyroid hormone for 5 weeks and then treated with zoledronate. The histomorphometry indices were determined using the micro-images from a micro-computed tomogram. Finite element analysis was carried out to determine the mechanical properties (Stiffness and Young's modulus) of the vertebra bodies. The differences in properties between the groups were compared using ANOVA and a Bonferroni's multiple group comparison procedure. RESULTS: The histomorphometry and mechanical properties were significantly better in groups (3) and (6) than in the groups (1) and (2) (p < 0.05). The stiffness (sigma(s)) and Young's modulus (E) was highest in group (3) following by group (6). CONCLUSIONS: Finite element analysis based on micro-images provides a useful tool that reflects the changes in micro-structural and mechanical properties of a rat vertebral body with the bone loss, restore and maintain concept.ope

New Sensitization to House Dust Mites in Cefteram-Induced Occupational Asthma: A Case Report

Occupational asthma (OA) can improve after cessation of exposure; however, some patients suffer from persistence or aggravation of their asthmatic symptoms. Here we report a case of a new sensitization to house dust mites during the follow-up period in a 37-year-old female patient with OA induced by cefteram pivoxil powder (cefteram powder). She was previously diagnosed with OA caused by inhalation of cefteram powder. Consequently, she left her job and had been well for 9 subsequent years. She began to experience aggravation of her rhinitis and asthmatic symptoms again several months prior to presentation. Her skin-prick test results had converted to strongly positive responses to two types of house dust mites. The serum levels of eosinophil cationic protein (ECP) and the total and specific immunoglobulin (Ig)E levels against the two types of house dust mites were elevated. An inhalation challenge test with Dermatophagoides farinae was performed, and significant bronchoconstriction (21.1% reduction in the forced expiratory volume in the first second) with asthma symptoms was observed at 10 minutes. To our knowledge, this is the first case demonstrating a new sensitization to house dust mites in a patient with OA caused by cefteram powder. Regular monitoring, including skin-prick tests and measurement of specific serum IgE/ECP levels, may help to screen potential cases

Performance of the tuberculin skin test and interferon-γ release assay for detection of tuberculosis infection in immunocompromised patients in a BCG-vaccinated population

<p>Abstract</p> <p>Background</p> <p>Interferon-γ release assay (IGRA) may improve diagnostic accuracy for latent tuberculosis infection (LTBI). This study compared the performance of the tuberculin skin test (TST) with that of IGRA for the diagnosis of LTBI in immunocompromised patients in an intermediate TB burden country where BCG vaccination is mandatory.</p> <p>Methods</p> <p>We conducted a retrospective observational study of patients given the TST and an IGRA, the QuantiFERON-TB Gold In-Tube (QFT-IT), at Severance Hospital, a tertiary hospital in South Korea, from December 2006 to May 2009.</p> <p>Results</p> <p>Of 211 patients who underwent TST and QFT-IT testing, 117 (55%) were classified as immunocompromised. Significantly fewer immunocompromised than immunocompetent patients had positive TST results (10.3% vs. 27.7%, p 0.001), whereas the percentage of positive QFT-IT results was comparable for both groups (21.4% vs. 25.5%). However, indeterminate QFT-IT results were more frequent in immunocompromised than immunocompetent patients (21.4% vs. 9.6%, p 0.021). Agreement between the TST and QFT-IT was fair for the immunocompromised group (κ = 0.38), but moderate agreement was observed for the immunocompetent group (κ = 0.57). Indeterminate QFT-IT results were associated with anaemia, lymphocytopenia, hypoproteinemia, and hypoalbuminemia.</p> <p>Conclusion</p> <p>In immunocompromised patients, the QFT-IT may be more sensitive than the TST for detection of LTBI, but it resulted in a considerable proportion of indeterminate results. Therefore, both tests may maximise the efficacy of screening for LTBI in immunocompromised patients.</p