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Showing 100 Latest Publications
TitleDate Created
Decoding transcriptional enhancers: Evolving from annotation to functional interpretation.Wednesday, May 25, 2016
Engel KL, Mackiewicz M, Hardigan AA, Myers RM, Savic D,
Seminars in cell & developmental biology. 22-May-2016
Deciphering the intricate molecular processes that orchestrate the spatial and temporal regulation of genes has become an increasingly major focus of biological research. The differential expression of genes by diverse cell types with a common genome is a hallmark of complex cellular functions, as well as the basis for multicellular life. Importantly, a more coherent understanding of gene regulation is critical for defining developmental processes, evolutionary principles and disease etiologies. Here we present our current understanding of gene regulation by focusing on the role of enhancer elements in these complex processes. Although functional genomic methods have provided considerable advances to our understanding of gene regulation, these assays, which are usually performed on a genome-wide scale, typically provide correlative observations that lack functional interpretation. Recent innovations in genome editing technologies have placed gene regulatory studies at an exciting crossroads, as systematic, functional evaluation of enhancers and other transcriptional regulatory elements can now be performed in a coordinated, high-throughput manner across the entire genome. This review provides insights on transcriptional enhancer function, their role in development and disease, and catalogues experimental tools commonly used to study these elements. Additionally, we discuss the crucial role of novel techniques in deciphering the complex gene regulatory landscape and how these studies will shape future research.
Innovations in interventional pain management of chronic spinal pain.Wednesday, May 25, 2016
Manchikanti L, Boswell MV, Hirsch JA,
Expert review of neurotherapeutics. 25-May-2016
Interventional pain management and interventional techniques include neural blockade, neural ablative procedures, spinal cord and peripheral nerve stimulation, intrathecal drug delivery systems, minimally invasive lumbar decompression (MILD®), percutaneous endoscopic spinal decompression, and regenerative medicine. In addition, advances are also related to the evidence synthesis of comparative effectiveness research. Expert Commentary: Multiple innovations in interventional pain management and potential innovations may reduce costs and improve care and outcomes with proper evidence synthesis and application of principles of evidence-based medicine. Innovations in interventional pain management in managing chronic low back pain depend on extensive research and appropriate evidence synthesis. Innovations should be developed in conjunction with health care policy based on principles of evidence-based medicine.
Significant association between decreased ALDH2 activity and increased sensitivity to genotoxic effects in workers occupationally exposed to styrene.Wednesday, May 25, 2016
Weng Z, Suda M, Wan M, Zhang X, Guan D, Zhao P, Zheng Y, Miyagawa M, Wang RS,
Oncotarget. 20-May-2016
ALDH2 is involved in the metabolism of styrene, a widely used industrial material, but no data are available regarding the influence of this enzyme on the metabolic fate as well as toxic effects of this chemical. In this study, we recruited 329 workers occupationally exposed to styrene and 152 unexposed controls. DNA strand breaks, DNA-base oxidation in leukocytes and urinary 8-hydroxydeoxyguanosine (8-OH-dG) were assayed as biomarkers to measure genotoxic effects. Meanwhile, we examined the genetic polymorphisms, including ALDH2, EXPH1, GSTM1, GSTT1 and CYP2E1, and also analyzed the levels of styrene exposure through detecting urinary styrene metabolites and styrene concentration in air. In terms of DNA damage, the three genotoxic biomarkers were significantly increased in exposed workers as compared with controls. And the styrene-exposed workers with inactive ALDH2 *2 allele were subjected to genotoxicity in a higher degree than those with ALDH2 *1/*1 genotype. Also, lower levels of urinary styrene metabolites (MA + PGA) were observed in styrene-exposed workers carrying ALDH2 *2 allele, suggesting slower metabolism of styrene. The polymorphisms of other enzymes showed less effect. These results suggested that styrene metabolism and styrene-induced genotoxicity could be particularly modified by ALDH2 polymorphisms. The important role of ALDH2 indicated that the accumulation of styrene glycoaldehyde, a possible genotoxic intermediate of styrene, could account for the genotoxicity observed, and should be taken as an increased risk of cancer.
Expression of transmembrane protein 26 (TMEM26) in breast cancer and its association with drug response.Wednesday, May 25, 2016
Nass N, Dittmer A, Hellwig V, Lange T, Mirjam Beyer J, Leyh B, Ignatov A, Weiβenborn C, Kirkegaard T, Lykkesfeldt AE, Kalinski T, Dittmer J,
Oncotarget. 20-May-2016
We have previously shown that stromal cells desensitize breast cancer cells to the anti-estrogen fulvestrant and, along with it, downregulate the expression of TMEM26 (transmembrane protein 26). In an effort to study the function and regulation of TMEM26 in breast cancer cells, we found that breast cancer cells express non-glycosylated and N-glycosylated isoforms of the TMEM26 protein and demonstrate that N-glycosylation is important for its retention at the plasma membrane. Fulvestrant induced significant changes in expression and in the N-glycosylation status of TMEM26. In primary breast cancer, TMEM26 protein expression was higher in ERα (estrogen receptor α)/PR (progesterone receptor)-positive cancers. These data suggest that ERα is a major regulator of TMEM26. Significant changes in TMEM26 expression and N-glycosylation were also found, when MCF-7 and T47D cells acquired fulvestrant resistance. Furthermore, patients who received aromatase inhibitor treatment tend to have a higher risk of recurrence when tumoral TMEM26 protein expression is low. In addition, TMEM26 negatively regulates the expression of integrin β1, an important factor involved in endocrine resistance. Data obtained by spheroid formation assays confirmed that TMEM26 and integrin β1 can have opposite effects in breast cancer cells. These data are consistent with the hypothesis that, in ERα-positive breast cancer, TMEM26 may function as a tumor suppressor by impeding the acquisition of endocrine resistance. In contrast, in ERα-negative breast cancer, particularly triple-negative cancer, high TMEM26 expression was found to be associated with a higher risk of recurrence. This implies that TMEM26 has different functions in ERα-positive and -negative breast cancer.
DNA Triplexes Guided Assembly of G-Quadruplexes for Constructing Label-free Fluorescent Logic Gates.Wednesday, May 25, 2016
Xu L, Hong S, Shen X, Zhou L, Wang J, Zhang J, Pei R,
Chemistry, an Asian journal. 25-May-2016
Assembly of G-quadruplexes guided by DNA triplexes in a controlled manner is achieved for the first time. The folding of triplex sequences in acid conditions will bring two separated guanine-rich sequences together and subsequently a G-quadruplex structure is formed in the presence of K+. Based on this novel platform, label-free fluorescent logic gates, such as AND, INHIBIT and NOR gates are constructed with ions as input and the fluorescence of a G-quadruplex-specific fluorescent probe NMM as output.
Molecular correlates and prognostic value of tmTNF-α expression in colorectal cancer of 5-Fluorouracil-Based Adjuvant Therapy.Wednesday, May 25, 2016
Li X, Wang S, Ren H, Ma J, Sun X, Li N, Liu C, Huang K, Xu M, Ming L,
Cancer biology & therapy. 25-May-2016
Transmembrane tumor necrosis factor-α (tmTNF-α) is known to induce the activation of NF-κB to protect tumor cells. Upregulation of tmTNF-α leads to resistance to apoptosis and induces drug resistance in breast cancer. However, the expression of tmTNF-α in colorectal cancer (CRC) and its association with clinical outcome in CRC have remained unclear. In this study, we examined the tmTNF-α expression in CRC by immunohistochemistry and western blotting, assessed the prognostic value of tmTNF-α related to the recurrence/metastasis and survival of stage II/III CRC by the Kaplan-Meier survival curve and Cox regression model, and also explored the role of tmTNF-α expression on the chemotherapeutic efficacy of 5-Fluorouracil by flow cytometry assay and cell counting kit-8 (CCK-8) in vitro. Overall, we found that 77 (78.6%) out of 98 patients exhibited higher tmTNF-α expression in the CRC tissues comparing with the adjacent tissues. The tmTNF-α expression was correlated with Differentiation (P = 0.019), TNM stage (P = 0.039), Lymph nodes metastasis (P = 0.024) and Lymphovascular invasion (P = 0.027) but not related with Age (P = 0.617), Gender (P = 0.625), Tumor location (P = 0.138), Perforation/Obstruction (P = 1.000), Depth of invasion (P = 0.327), and microsatellite instability status (P = 0.150). The prognostic analyses showed that high tmTNF-α expression patients was significantly associated with decreased Disease-Free Survival (P = 0.0209) and Overall Survival (P = 0.0163). CCK-8 results suggested that the tmTNF-α influenced the chemotherapeutic effect of 5-Fluorouracil on colon cancer cells. Altogether, these data indicated the stage II/III CRC patients with high tmTNF-α expression were more likely to have a worse prognosis than patients with low tmTNF-α expression and tmTNF-α may influence the chemotherapeutic effect of 5-Fluorouracil. The mechanism for these observations warrants further study.
Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury.Wednesday, May 25, 2016
Mikus M, Drobin K, Gry M, Bachmann J, Lindberg J, Yimer G, Aklillu E, Makonnen E, Aderaye G, Roach J, Fier I, Kampf C, Göpfert J, Perazzo H, Poynard T, Stephens C, Andrade RJ, Lucena MI, Arber N, Uhlén M, Watkins PB, Schwenk JM, Nilsson P, Schuppe-Koistinen I,
Liver international : official journal of the International Association for the Study of the Liver. 25-May-2016
These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers. This article is protected by copyright. All rights reserved.
Therapeutic monitoring of immunosuppressive drugs in pediatric patients: special considerations.Wednesday, May 25, 2016
Weber LT, Doetsch J,
Expert review of clinical pharmacology. 25-May-2016
Combining immunosuppressive drugs may create additive or even synergistic effects. Finding the balance between efficacy and toxicity is a challenge in pediatrics, since consequences are severe if the target range is missed. Underimmunosuppression may result in insufficient disease control, impairment of graft function or even graft loss. Conversely, overimmunosuppression may increase the risk of infections, malignancies and cardiovascular adverse effects. The latter aspect is of particular interest in a young population with an expected long span of life. Cardiovascular adverse effects are triggered for example by dyslipidemia, overweight and arterial hypertension, all of which are known side effects of glucocorticoids and calcineurin inhibitors. Therefore, monitoring the concentrations of immunosuppressive drugs has been a crucial part of patient care for decades. However, clinicians must be familiar with essential constraints including analytical pitfalls just as conceptual limitations for a proper use of therapeutic drug monitoring to improve a patient´s individual therapy.
Protective effects of BMP-7 against tumor necrosis factor α-induced oligodendrocyte apoptosis.Wednesday, May 25, 2016
Wang X, Xu JM, Wang YP, Yang L, Li ZJ,
International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience. 17-May-2016
Bone morphogenic protein-7 (BMP7) is a multifunctional cytokine with demonstrated neurogenic potential. Oligodendrocytes (OLs) death after spinal cord injury (SCI) contributes to demyelination of spared axons, even leading to a permanent neurological deficit. Therefore, therapeutic approaches to prevent OLs death after SCI should be considered. Since the effects of BMP7 on OLs after injury are largely unknown, we demonstrated the effects of BMP7 on TNF-α-induced OLs apoptosis in vitro. The effects of BMP7 on TNF-α-induced OLs apoptosis were verified by flow cytometry, spectrophotometry and western blotting on primary cultures from spinal cord of postnatal day 1 (P1) to P2 rats. As shown by flow cytometry, apoptosis rate was 25.6% for the control group, 59.0% for the TNF-α group, and 33.5% for the BMP7+TNF-α group; spectrophotometry showed caspase-3 and caspase-8 activity were significantly increased in the TNF-α group than in the control group, and BMP7 could reverse the increase. The involvement of cIAP1 in the protection of BMP7 was determined by western blotting and silencing cIAP1. In summary, our results demonstrated that BMP7 could potently inhibite TNF-α-induced OLs apoptosis and identified the cIAP1 expression level, the activity of caspase-3 and caspase-8 as important mediators of OLs survival after cellular stress and cytokine challenge.
A potential biomarker for fatigue: oxidative stress and anti-oxidative activity.Wednesday, May 25, 2016
Fukuda S, Nojima J, Motoki Y, Yamaguti K, Nakatomi Y, Okawa N, Fujiwara K, Watanabe Y, Kuratsune H,
Biological psychology. 17-May-2016
We sought to determine whether oxidative stress and anti-oxidative activity could act as biomarkers that discriminate patients with chronic fatigue syndrome (CFS) from healthy volunteers at acute and sub-acute fatigue and resting conditions. We calculated the oxidative stress index (OSI) from reactive oxygen metabolites-derived compounds (d-ROMs) and the biological antioxidant potential (BAP). We determined changes in d-ROMs, BAP, and OSI in acute and sub-acute fatigue in two healthy groups, and compared their values at rest between patients with CFS (diagnosed by Fukuda 1994 criteria) and another group of healthy controls. Following acute fatigue in healthy controls, d-ROMs and OSI increased, and BAP decreased. Although d-ROMs and OSI were significantly higher after sub-acute fatigue, BAP did not decrease. Resting condition yielded higher d-ROMs, higher OSI, and lower BAP in patients with CFS than in healthy volunteers, but lower d-ROMs and OSI when compared with sub-acute controls. BAP values did not significantly differ between patients with CFS and controls in the sub-acute condition. However, values were significantly higher than in the resting condition for controls. Thus, measured of oxidative stress (d-ROMS) and anti-oxidative activity (BAP) might be useful for discriminating acute, sub-acute, and resting fatigue in healthy people from patients with CFS, or for evaluating fatigue levels in healthy people.
Programming Self-Assembly of DNA Origami Honeycomb Two-Dimensional Lattices and Plasmonic Metamaterials.Wednesday, May 25, 2016
Wang P, Gaitanaros S, Lee S, Bathe M, Shih WM, Ke Y,
Journal of the American Chemical Society. 25-May-2016
Scaffolded DNA origami has proven to be a versatile method for generating functional nanostructures with prescribed sub-100 nm shapes. Programming DNA-origami tiles to form large-scale 2D lattices that span hundreds of nanometers to the micron-scale could provide an enabling platform for diverse applications ranging from metamaterials to surface-based biophysical assays. Toward this end, here we design a family of hexagonal DNA-origami tiles using computer-aided design and demonstrate successful self-assembly of micron-scale 2D honeycomb lattices and tubes by controlling their geometric and mechanical properties including their inter-connecting strands. Our results offer insight into programmed self-assembly of low-defect supra-molecular DNA-origami 2D lattices and tubes. In addition, we demonstrate that these DNA-origami hexagon tiles and honeycomb lattices are versatile platforms for assembling optical metamaterials via programmable spatial arrangement of gold nanoparticles (AuNPs) into cluster and superlattice geometries.
HE4 Serum Levels are Associated with Heart Failure Severity in Patients with Chronic Heart Failure.Wednesday, May 25, 2016
Piek A, Meijers WC, Schroten NF, Gansevoort RT, de Boer RA, Silljé HH,
Journal of cardiac failure. 17-May-2016
HE4 levels are increased in CHF, correlate with HF severity and kidney function, and predict HF outcome.
Dog sperm cryopreservation using one step dilution with glycerol-free tris extender.Wednesday, May 25, 2016
Rahman MA, Park SH, Yu IJ,
Cryo letters. 17-5-2016
Cryopreservation of canine sperm cooled for 50 or 70 min following one step dilution in GFTG yields more viable sperm with lower PS translocation and freezing method using LN2 vapor is more effective on progressive motility.
Comparison of Cox Model Methods in A Low-dimensional Setting with Few Events.Wednesday, May 25, 2016
Ojeda FM, Müller C, Börnigen D, Trégouët DA, Schillert A, Heinig M, Zeller T, Schnabel RB,
Genomics, proteomics & bioinformatics. 17-May-2016
Prognostic models based on survival data frequently make use of the Cox proportional hazards model. Developing reliable Cox models with few events relative to the number of predictors can be challenging, even in low-dimensional datasets, with a much larger number of observations than variables. In such a setting we examined the performance of methods used to estimate a Cox model, including (i) full model using all available predictors and estimated by standard techniques, (ii) backward elimination (BE), (iii) ridge regression, (iv) least absolute shrinkage and selection operator (lasso), and (v) elastic net. Based on a prospective cohort of patients with manifest coronary artery disease (CAD), we performed a simulation study to compare the predictive accuracy, calibration, and discrimination of these approaches. Candidate predictors for incident cardiovascular events we used included clinical variables, biomarkers, and a selection of genetic variants associated with CAD. The penalized methods, i.e., ridge, lasso, and elastic net, showed a comparable performance, in terms of predictive accuracy, calibration, and discrimination, and outperformed BE and the full model. Excessive shrinkage was observed in some cases for the penalized methods, mostly on the simulation scenarios having the lowest ratio of number of events to the number of variables. We conclude that in similar settings, these three penalized methods can be used interchangeably. The full model and backward elimination are not recommended in rare event scenarios.
Systematic Literature Review on the Relationship Between Biomarkers of Sarcopenia and Quality of Life in Older People.Wednesday, May 25, 2016
Woo T, Yu S, Visvanathan R,
The Journal of frailty & aging. 17-5-2016
Sarcopenia is a multi-faceted geriatric syndrome that is prevalent in the older population. It is an independent risk factor for a variety of devastating health outcomes that threaten the independence of older people. Quality of life is also very important to older people. The objective of this systematic review therefore was to determine the relationship between the biomarkers of sarcopenia (or sarcopenia) and health related quality of life in older people. Systematic searches were done using the electronic databases from MEDLINE and EMBASE. Search terms included sarcopenia, biomarkers of sarcopenia (e.g. muscle mass, grip strength, muscle performance), and health related quality of life. A total of 20 studies were finally included in this review. Only four studies were deemed of good quality. Sarcopenia was associated with poor health related quality of life in both genders from the one cross sectional study defining sarcopenia as per consensus definition. One high quality longitudinal study demonstrated that better physical performance and muscle strength was associated with a slower rate of decline in health related quality of life over six years. Muscle performance and strength were associated with health related quality of life but muscle mass was not in cross-sectional studies. Good quality and longitudinal studies where sarcopenia is defined as per consensus guidelines are required if the impact of the disease on quality of life is to be clarified.
Reconstitution of Human Ion Channels into Solvent-free Lipid Bilayers Enhanced by Centrifugal Forces.Wednesday, May 25, 2016
Hirano-Iwata A, Ishinari Y, Yoshida M, Araki S, Tadaki D, Miyata R, Ishibashi K, Yamamoto H, Kimura Y, Niwano M,
Biophysical journal. 24-May-2016
Artificially formed bilayer lipid membranes (BLMs) provide well-defined systems for functional analyses of various membrane proteins, including ion channels. However, difficulties associated with the integration of membrane proteins into BLMs limit the experimental efficiency and usefulness of such BLM reconstitution systems. Here, we report on the use of centrifugation to more efficiently reconstitute human ion channels in solvent-free BLMs. The method improves the probability of membrane fusion. Membrane vesicles containing the human ether-a-go-go-related gene (hERG) channel, the human cardiac sodium channel (Nav1.5), and the human GABAA receptor (GABAAR) channel were formed, and the functional reconstitution of the channels into BLMs via vesicle fusion was investigated. Ion channel currents were recorded in 67% of the BLMs that were centrifuged with membrane vesicles under appropriate centrifugal conditions (14-55 × g). The characteristic channel properties were retained for hERG, Nav1.5, and GABAAR channels after centrifugal incorporation into the BLMs. A comparison of the centrifugal force with reported values for the fusion force revealed that a centrifugal enhancement in vesicle fusion was attained, not by accelerating the fusion process but by accelerating the delivery of membrane vesicles to the surface of the BLMs, which led to an increase in the number of membrane vesicles that were available for fusion. Our method for enhancing the probability of vesicle fusion promises to dramatically increase the experimental efficiency of BLM reconstitution systems, leading to the realization of a BLM-based, high-throughput platform for functional assays of various membrane proteins.
Platinum-Based Drugs and DNA Interactions Studied by Single-Molecule and Bulk Measurements.Wednesday, May 25, 2016
Salerno D, Beretta GL, Zanchetta G, Brioschi S, Cristofalo M, Missana N, Nardo L, Cassina V, Tempestini A, Giovannoni R, Cerrito MG, Zaffaroni N, Bellini T, Mantegazza F,
Biophysical journal. 24-May-2016
Platinum-containing molecules are widely used as anticancer drugs. These molecules exert cytotoxic effects by binding to DNA through various mechanisms. The binding between DNA and platinum-based drugs hinders the opening of DNA, and therefore, DNA duplication and transcription are severely hampered. Overall, impeding the above-mentioned important DNA mechanisms results in irreversible DNA damage and the induction of apoptosis. Several molecules, including multinuclear platinum compounds, belong to the family of platinum drugs, and there is a body of research devoted to developing more efficient and less toxic versions of these compounds. In this study, we combined different biophysical methods, including single-molecule assays (magnetic tweezers) and bulk experiments (ultraviolet absorption for thermal denaturation) to analyze the differential stability of double-stranded DNA in complex with either cisplatin or multinuclear platinum agents. Specifically, we analyzed how the binding of BBR3005 and BBR3464, two representative multinuclear platinum-based compounds, to DNA affects its stability as compared with cisplatin binding. Our results suggest that single-molecule approaches can provide insights into the drug-DNA interactions that underlie drug potency and provide information that is complementary to that generated from bulk analysis; thus, single-molecule approaches have the potential to facilitate the selection and design of optimized drug compounds. In particular, relevant differences in DNA stability at the single-molecule level are demonstrated by analyzing nanomechanically induced DNA denaturation. On the basis of the comparison between the single-molecule and bulk analyses, we suggest that transplatinated drugs are able to locally destabilize small portions of the DNA chain, whereas other regions are stabilized.
Dinosaur: a refined open source peptide MS feature detector.Wednesday, May 25, 2016
Teleman J, Chawade A, Sandin M, Levander F, Malmström J,
Journal of proteome research. 25-May-2016
In bottom-up mass spectrometry (MS) based proteomics, peptide isotopic and chromatographic traces (features) are frequently used for label-free quantification in data-dependent acquisition MS, but can also be used for improved identification of chimeric spectra or sample complexity characterization. Feature detection is difficult because of the high complexity of MS proteomics data from biological samples, which frequently causes features to intermingle. In addition, existing feature detection algorithms commonly suffer from compatibility issues, long computation times or poor performance on high-resolution data. Because of these limitations we developed a new tool, Dinosaur, with increased speed and versatility. Dinosaur has functionality to sample algorithm computations through quality control plots, which we call a plot trail. From evaluation of this plot trail we introduce several algorithmic improvements to further improve robustness and performance of Dinosaur, with detection of features for 98% of MS/MS identifications in a benchmark dataset, while no other algorithm tested in this study passed 96% feature detection. We finally used Dinosaur to re-implement a published workflow for peptide identification in chimeric spectra, increasing chimeric identification from 26% to 32% over the standard workflow. Dinosaur is operating system independent and is freely available as open source on
Idarucizumab for dabigatran overdose.Wednesday, May 25, 2016
Peetermans M, Pollack C, Reilly P, Liesenborghs L, Jacquemin M, Levy JH, Weitz JI, Verhamme P,
Clinical toxicology (Philadelphia, Pa.). 25-May-2016
This case highlights the potential use of idarucizumab for the management of massive dabigatran overdoses.
What's in the Literature?Wednesday, May 25, 2016
Silvestri NJ, Wolfe GI, Bromberg M, Lacomis D,
Journal of clinical neuromuscular disease. Jun-2016
One of the first questions asked by patients and family members when a diagnosis of amyotrophic lateral sclerosis is made is "what about stem cells?" The term "stem cells" has attractiveness to it, with the assumption that stem cell treatment (stem nerve cells) can replace lost nerve cells. There are perhaps 2 types of stem cell trials, those that are vetted by the Food and Drug Administration and those that have no official oversight and whose results are infrequently published. The issue of the latter was discussed in the last edition of this column. The results of one of the formal stem cell trials now in the United States have been reported. Spinal muscular atrophy is a form of motor neuron disease affecting children and has a genetic cause, which has led to a feasibility study giving antisense oligonucleotides, and the results have also been reported. Biomarkers of amyotrophic lateral sclerosis are being sought, and the presence of neurofilaments is promising. Inflammatory neuropathies are an important group because they are treatable. Intravenous immune globulin is a commonly used agent, but a number of questions persist: one is efficacy among brands, another is the probability of a response, and a third is optimum dosing and taper schedules. A number of recent articles address these issues. The predictive value of single-fiber electromyography in determining which patients with ocular myasthenia will develop generalized disease, the risk of crisis after thymectomy, and 2 papers discussing new forms of congenital myasthenic syndrome are discussed. The risk of brain tumors, quality of life, and the assessment of trunk muscle strength in patients with type 1 myotonic dystrophy is reviewed. An article describing the discovery of mutations in SCN4A as a cause of congenital myopathy is discussed, as is one describing the occurrence of rhabdomyolysis in a group of patients subsequently discovered to have various forms of muscular dystrophy. Finally, articles describing the features of patients with inflammatory myopathies and Jo-1 and either 3-hydroxy-3-methylglutaryl-conezymea reductase or to signal recognition particle antibodies are reviewed.
Elongation Factor Tu Prevents Misediting of Gly-tRNA(Gly) Caused by the Design Behind the Chiral Proofreading Site of D-Aminoacyl-tRNA Deacylase.Wednesday, May 25, 2016
Routh SB, Pawar KI, Ahmad S, Singh S, Suma K, Kumar M, Kuncha SK, Yadav K, Kruparani SP, Sankaranarayanan R,
PLoS biology. May-2016
D-aminoacyl-tRNA deacylase (DTD) removes D-amino acids mischarged on tRNAs and is thus implicated in enforcing homochirality in proteins. Previously, we proposed that selective capture of D-aminoacyl-tRNA by DTD's invariant, cross-subunit Gly-cisPro motif forms the mechanistic basis for its enantioselectivity. We now show, using nuclear magnetic resonance (NMR) spectroscopy-based binding studies followed by biochemical assays with both bacterial and eukaryotic systems, that DTD effectively misedits Gly-tRNAGly. High-resolution crystal structure reveals that the architecture of DTD's chiral proofreading site is completely porous to achiral glycine. Hence, L-chiral rejection is the only design principle on which DTD functions, unlike other chiral-specific enzymes such as D-amino acid oxidases, which are specific for D-enantiomers. Competition assays with elongation factor thermo unstable (EF-Tu) and DTD demonstrate that EF-Tu precludes Gly-tRNAGly misediting at normal cellular concentrations. However, even slightly higher DTD levels overcome this protection conferred by EF-Tu, thus resulting in significant depletion of Gly-tRNAGly. Our in vitro observations are substantiated by cell-based studies in Escherichia coli that show that overexpression of DTD causes cellular toxicity, which is largely rescued upon glycine supplementation. Furthermore, we provide direct evidence that DTD is an RNA-based catalyst, since it uses only the terminal 2'-OH of tRNA for catalysis without the involvement of protein side chains. The study therefore provides a unique paradigm of enzyme action for substrate selection/specificity by DTD, and thus explains the underlying cause of DTD's activity on Gly-tRNAGly. It also gives a molecular and functional basis for the necessity and the observed tight regulation of DTD levels, thereby preventing cellular toxicity due to misediting.
Comparison between DNA Detection in Trigeminal Nerve Ganglia and Serology to Detect Cattle Infected with Bovine Herpesviruses Types 1 and 5.Wednesday, May 25, 2016
Puentes R, Campos FS, Furtado A, Torres FD, Franco AC, Maisonnave J, Roehe PM,
PloS one. 25-5-2016
Bovine herpesviruses (BoHVs) types 1 (BoHV-1) and 5 (BoHV-5) are alphaherpesviruses of major importance to the bovine production chain. Such viruses are capable of establishing latent infections in neuronal tissues. Infected animals tend to develop a serological response to infection; however, such response-usually investigated by antibody assays in serum-may eventually not be detected in laboratory assays. Nevertheless, serological tests such as virus neutralization (VN) and various enzyme-linked immunosorbent assays (ELISAs) are widely employed to check individual or herd status of BoHV infections. The correlation between detection of antibodies and the presence of viral nucleic acids as indicatives of infection in infected cattle has not been deeply examined. In order to investigate such correlation, 248 bovine serum samples were tested by VN to BoHV-1 and BoHV-5, as well as in a widely employed (though not type-differential) gB ELISA (IDEXX IBR gB X2 Ab Test) in search for antibodies to BoHVs. Immediately after blood withdrawal, cattle were slaughtered and trigeminal ganglia (TG) excised for DNA extraction and viral nucleic acid detection (NAD) by nested PCR. Neutralizing antibodies to BoHV-1 and/or BoHV-5 were detected in 44.8% (111/248) of sera, whereas the gB ELISA detected antibodies in 51.2% (127/248) of the samples. However, genomes of either BoHV-1, BoHV-5, or both, were detected in TGs of 85.9% (213/248) of the animals. These findings reveal that the assays designed to detect antibodies to BoHV-1 and/or BoHV-5 employed here may fail to detect a significant number of latently infected animals (in this study, 35.7%). From such data, it is clear that antibody assays are poorly correlated with detection of viral genomes in BoHV-1 and BoHV-5-infected animals.
Geographic Distribution of Natural Products Produced by Red Algae Laurencia dendroidea J. Agardh.Wednesday, May 25, 2016
da Silva Machado FL, Duarte HM, de Souza Gestinari LM, Cassano V, Kaiser CR, Soares AR,
Chemistry & biodiversity. 25-May-2016
In order to evaluate the chemical diversity of Laurencia dendroidea J. Agardh, a wide distributed seaweed in Brazilian coast, a phytochemical study was carried out with algae collected from six different locations along Southeast Brazilian coast. Purified compounds were identified by MS and NMR techniques. The chemical profiles of lipophilic extracts were obtained by GC/MS for each population. In total, fifteen compounds were described. The sesquiterpene composition accounted for 49-63% of the GC/MS chromatogram area. The discrimination of three chemotypes was done by the use of HCA on GC/MS chromatograms. They were also analyzed by PCA and, together with peak area analysis, it was possible to discriminate all populations by the main variation of elatol, obtusol, rogiolol and triquinane. The results revealed the high diversity of sesquiterpene composition among populations of L. dendroidea. Curiously, the within and among population variation of elatol and obtusol suggested a biochemical interplay on the content of these compounds. More studies are necessary to understand the patterns of chemical diversity and compound variation within and among populations of L. dendroidea. This article is protected by copyright. All rights reserved.
Medicinal Plants and Natural Products as Potential Sources for Antiparkinson Drugs.Wednesday, May 25, 2016
Ríos JL, Onteniente M, Picazo D, Montesinos MC,
Planta medica. 25-May-2016
Parkinson's disease is a progressive neurodegenerative dysfunction characterized by the loss of pigmented dopaminergic neurons of the nigrostriatal system with a consequent dopamine decrease. The reduction of dopamine levels produces neuronal damage, depigmentation of the substantia nigra, and the presence of intracellular inclusions in dopaminergic neurons. Treatments for Parkinson's disease aim for improving these motor symptoms by increasing the dopaminergic signal in the striatum with levodopa in combination with enzyme inhibitors or anticholinergic drugs. Nevertheless, natural products can act as neuroprotective agents by reducing the progression of the disease and the inflammatory process.In the present review, we have compiled data on the principal medicinal plants and natural products as potential antiparkinsonian agents. They act by different mechanisms, such as the inhibition of α-synuclein condensation, reduction of oxidative stress and neuro-inflammation, increase of dopaminergic neurons survival, or the blockade of the A2 A receptor.
Pregnane Glycosides from Cynanchum marnierianum Stimulate GLP-1 Secretion in STC-1 Cells.Wednesday, May 25, 2016
Tsoukalas M, Muller CD, Lobstein A, Urbain A,
Planta medica. 25-May-2016
In the framework of the search for natural glucagon-like peptide-1 secretagogues, the bioassay-guided fractionation of the ethanolic extract from Cynanchum marnierianum led to the isolation of two new pregnane glycosides named marnieranosides A (1) and B (2). The structures were determined based on spectroscopic data and were established as 12β,20 S-O-dibenzoyl-pregn-6-en-5α,8β,14β,17β-tetraol-3-O-β-D-oleandropyranosyl-(1 → 4)-β-D-cymaropyranoside (1) and 12β,20R-O-dibenzoyl-pregn-6-en-5α,8β,14β-triol-3-O-β-D-oleandropyranosyl-(1 → 4)-β-D-canaropyranosyl-(1 → 4)-β-D-cymaropyranoside (2). They present structural analogies to pregnanes previously described in species known for their appetite suppressant and antihyperglycemic effects, such as P57 from Hoodia gordonii. Lupeol (3), a known dipeptidyl peptidase-4 inhibitor, and the insulinomimetic kaempferol-3-O-neohesperidoside (4) were also identified in C. marnierianum. In an in vitro assay on secretin tumor cell line-1 cells, compounds 1, 2, and P57 were found to stimulate the secretion of GLP-1 by 130 % (all tested at 100 µM). These results suggest that C. marnierianum could be of great interest in the treatment of type 2 diabetes, and that pregnane derivatives should be partly responsible via the stimulation of glucagon-like peptide-1 secretion.
Gamma-Terpinene Modulation of LPS-Stimulated Macrophages is Dependent on the PGE2/IL-10 Axis.Wednesday, May 25, 2016
Ramalho TR, Filgueiras LR, Pacheco de Oliveira MT, Lima AL, Bezerra-Santos CR, Jancar S, Piuvezam MR,
Planta medica. 25-May-2016
Gamma-terpinene is a monoterpene present in the essential oils of several plants, including those from the Eucalyptus genus. This molecule was recently described as anti-inflammatory and microbiocidal, but little is known about the mechanisms behind its effects. The aim of the present study was to investigate the effect of gamma-terpinene on the lipopolysaccharide-induced production of cytokines by murine peritoneal macrophages. Gamma-terpinene treatment was found to reduce the production of proinflammatory cytokines, such as interleukin-1β and interleukin-6, and enhance that of the anti-inflammatory cytokine interleukin-10. This was accompanied by increased levels of the enzyme cycloxygenase-2 and its product, the lipid mediator prostaglandin E2. Inhibition of cycloxygenase-2 with nimesulide abolished the potentiating effect of gamma-terpinene on interleukin-10 production. Moreover, nimesulide treatment also abrogated the inhibitory effect of gamma-terpinene on interleukin-1β and interleukin-6. Furthermore, in macrophages from mice deficient in the interleukin-10 gene, gamma-terpinene failed to inhibit interleukin-1β and interleukin-6 production. These results suggest that this monoterpene promotes the prostaglandin E2/interleukin-10 axis, which inhibits the production of these proinflammatory cytokines.
Liquid Chromatography-Electrospray Ionization Mass Spectrometry Analysis of Limonoids and Flavonoids in Seeds of Grapefruits, Other Citrus Species, and Dietary Supplements.Wednesday, May 25, 2016
Avula B, Sagi S, Wang YH, Wang M, Gafner S, Manthey JA, Khan IA,
Planta medica. 25-May-2016
A selective UHPLC-DAD-QToF-MS method was developed to screen grapefruit seeds, and the seeds of other Citrus species for limonoid aglycones, acids, glucosides, and flavonoids. These classes of compounds were identified in positive and negative ion modes over a mass-to-charge range from 100-1500. Accurate mass values, elution times, and fragmentation patterns obtained by QToF-mass spectrometry were used to identify or tentatively characterize the compounds detected in the sample of this study. Limonin was the major limonoid in most of the seeds of Citrus species, followed by nomilin. This analytical method was successfully applied for the analysis of commercial extracts and dietary supplements claiming to contain grapefruit seed extract, or extracts made from the seed and other fruit parts such as the peel or pulp. Many commercial products contained large numbers of flavonoids, indicating the use of peel, pulp, or seed coat. This method also permitted detection of synthetic preservatives such as benzethonium chloride, methylparaben, and triclosan in commercial grapefruit seed extract products. Out of the 17 commercial products analyzed, two contained the synthetic antimicrobial agent benzethonium chloride.
IL-17A exacerbates fibrosis by promoting the proinflammatory and profibrotic function of orbital fibroblasts in TAO.Wednesday, May 25, 2016
Fang S, Huang Y, Wang S, Zhang Y, Luo X, Liu L, Zhong S, Liu X, Li D, Liang R, Miranda P, Gu P, Zhou H, Fan X, Li B,
The Journal of clinical endocrinology and metabolism. 25-May-2016
Our observations illustrate the potential pathogenic role of IL-17A-producing T cells in the inflammatory response and fibrosis of TAO. The effect of vialinin A on the reduction of RORγt level implicates its potential role as a novel therapeutic agent for TAO and other autoimmune disorders in the future.
Serologic screening of United States blood donors for Babesia microti using an investigational enzyme immunoassay.Wednesday, May 25, 2016
Levin AE, Williamson PC, Bloch EM, Clifford J, Cyrus S, Shaz BH, Kessler D, Gorlin J, Erwin JL, Krueger NX, Williams GV, Penezina O, Telford SR, Branda JA, Krause PJ, Wormser GP, Schotthoefer AM, Fritsche TR, Busch MP,
Transfusion. 25-May-2016
The B. microti EIA detected PCR-positive, potentially infectious blood donors in an endemic population and exhibited high specificity among uninfected and unexposed individuals. The EIA promises to provide an effective tool for blood donor screening for B. microti in a format amenable to high-throughput and cost-effective screening.
Role of Fibroblast Growth Factor-5 on the Proliferation of Human Tonsil-derived Mesenchymal Stem Cells.Wednesday, May 25, 2016
Park GC, Song JS, Park HY, Shin SC, Jang JY, Lee JC, Wang SG, Lee BJ, Jung JS,
Stem cells and development. 25-May-2016
Human mesenchymal stem cells (MSCs) are a promising tool for therapeutic applications in cell-based therapy and regenerative medicine, and MSCs from the human palatine tonsils have recently been used as a new tissue source. However, the understanding of the proliferation and differentiation capacity of T-MSCs is limited. In this study, we compared the proliferative potential of T-MSCs with BM-MSCs and adipose tissue-derived MSCs (A-MSCs). Additionally, we investigated the underlying mechanism of T-MSC function. We showed that T-MSCs proliferated faster than A-MSCs and BM-MSCs in MTT assays, cell count assays, and cell cycle distribution analyses. DNA microarray and real-time PCR analyses revealed that the expression of fibroblast growth factor-5 (FGF5) was significantly elevated in T-MSCs compared with those in A-MSCs and BM-MSCs. Cell growth curves showed a difference in cell growth between untreated cells and siFGF5-treated T-MSCs. The administration of recombinant human FGF5 (rhFGF5) to the cells transfected with siFGF5 led to a significant increase in the proliferation rates. The administration of rhFGF5 to T-MSCs led to an increase in the levels of phosphorylated ERK1/2. However, treatment with siFGF5 resulted in an overall decrease in the level of phosphorylated ERK1/2. The osteogenic differentiation of T-MSCs was reduced following siFGF5 transfection, and it recovered to near-normal levels when rhFGF5 was added. These findings indicate that T-MSCs show significantly higher proliferative potential compared with BM-MSCs and A-MSCs. FGF5 facilitates cell proliferation through ERK1/2 activation, and it influences the osteogenic differentiation of T-MSCs.
Huangkui capsule, an extract from Abelmoschus manihot (L.) medic, improves diabetic nephropathy via activating Peroxisome proliferator-activated receptor (PPAR)-α/γ and attenuating endoplasmic reticulum stress in rats.Wednesday, May 25, 2016
Ge J, Miao JJ, Sun XY, Yu JY,
Journal of ethnopharmacology. 17-May-2016
Our results show that HKC improved lipid metabolic disorders by activating PPARα/γ and attenuating ER stress. HKC could dose-dependently ameliorate renal inflammation and glomerular injury in DN rats. These results suggest that HKC has potential as an anti-DN agent for the treatment of DN in humans.
Poncirin and its metabolite ponciretin attenuate colitis in mice by inhibiting LPS binding on TLR4 of macrophages and correcting Th17/Treg imbalance.Wednesday, May 25, 2016
Kang GD, Kim DH,
Journal of ethnopharmacology. 17-May-2016
Orally administered poncirin is metabolized to ponciretin by gut microbiota and poncirin and ponciretin attenuates colitis by suppressing NF-κB activation through the inhibition of LPS binding on macrophages and correcting Th17/Treg cell imbalance.
Functional proteomic analysis revels that the ethanol extract of Annona muricataL.induces liver cancer cell apoptosis through endoplasmic reticulum stress pathway.Wednesday, May 25, 2016
Liu N, Yang HL, Wang P, Lu YC, Yang YJ, Wang L, Lee SC,
Journal of ethnopharmacology. 17-May-2016
Our results indicate that the ethanol extract of leaves of Annona muricata L. causes apoptosis of liver cancer cells through ER stress pathway, which supports the ethnomedicinal use of this herb as an alternative or complementary therapy for cancer.
Xiaotan Sanjie Decoction Inhibits Angiogenesis in Gastric Cancer through Interleukin-8-linked Regulation of the Vascular Endothelial Growth Factor Pathway.Wednesday, May 25, 2016
Shi J, Lu Y, Wei P,
Journal of ethnopharmacology. 17-May-2016
XTSJ decoction might inhibit angiogenesis in gastric cancer through IL-8-linked regulation of the VEGF pathway.
Gel-Free/Label-Free Proteomic Analysis of Endoplasmic Reticulum Proteins in Soybean Root Tips under Flooding and Drought Stresses.Wednesday, May 25, 2016
Wang X, Komatsu S,
Journal of proteome research. 25-May-2016
Soybean is a widely cultivated crop; however, it is sensitive to flooding and drought stresses. The adverse environmental cues cause the endoplasmic reticulum (ER) stress due to accumulation of unfolded or misfolded proteins. To investigate the mechanisms in response to flooding and drought stresses, ER proteomics was performed in soybean root tips. The enzyme activity of NADH cytochrome c reductase was 2-fold higher in the ER than other fractions, indicating that the ER was isolated with high purity. Protein abundance of ribosomal proteins were decreased under both stresses compared to control condition; however, the percentage of increased ribosomes was 2-fold higher in flooding compared to drought. The ER proteins related to protein glycosylation and signaling were in response to both stresses. Compared to control condition, calnexin was decreased under both stresses; however, protein disulfide isomerase like-proteins and heat shock proteins were markedly decreased under flooding and drought conditions, respectively. Furthermore, fewer glycoproteins and higher levels of cytosolic calcium were identified under both stresses compared to control condition. These results suggest that reduced accumulation of glycoproteins in response to both stresses might be due to dysfunction of protein folding through calnexin/calreticulin cycle. Additionally, the increased cytosolic calcium levels induced by flooding and drought stresses might disturb the ER environment for proper protein folding in soybean root tips.
Staphylococcus aureus Regulatory RNAs as Potential Biomarkers for Bloodstream Infections.Wednesday, May 25, 2016
Bordeau V, Cady A, Revest M, Rostan O, Sassi M, Tattevin P, Donnio PY, Felden B,
Emerging infectious diseases. 15-Sep-2016
Staphylococcus aureus is a commensal bacterium and pathogen. Identifying biomarkers for the transition from colonization to disease caused by this organism would be useful. Several S. aureus small RNAs (sRNAs) regulate virulence. We investigated presence and expression of 8 sRNAs in 83 S. aureus strains from 42 patients with sepsis or septic shock and 41 asymptomatic colonized carriers. Small pathogenicity island sRNAs sprB and sprC were clade specific. Six sRNAs had variable expression not correlated with clinical status. Expression of RNAIII was lower in strains from septic shock patients than in strains from colonized patients. When RNAIII was associated with expression of sprD, colonizing strains could be discriminated from strains in patients with bloodstream infections, including patients with sepsis and septic shock. Isolates associated with colonization might have sRNAs with target expression different from those of disease isolates. Monitoring expression of RNAIII and sprD could help determine severity of bloodstream infections.
Novel Hypomorphic Alleles of the Mouse Tyrosinase Gene Induced by CRISPR-Cas9 Nucleases Cause Non-Albino Pigmentation Phenotypes.Wednesday, May 25, 2016
Challa AK, Boitet ER, Turner AN, Johnson LW, Kennedy D, Downs ER, Hymel KM, Gross AK, Kesterson RA,
PloS one. 15-9-2016
Tyrosinase is a key enzyme in melanin biosynthesis. Mutations in the gene encoding tyrosinase (Tyr) cause oculocutaneous albinism (OCA1) in humans. Alleles of the Tyr gene have been useful in studying pigment biology and coat color formation. Over 100 different Tyr alleles have been reported in mice, of which ≈24% are spontaneous mutations, ≈60% are radiation-induced, and the remaining alleles were obtained by chemical mutagenesis and gene targeting. Therefore, most mutations were random and could not be predicted a priori. Using the CRISPR-Cas9 system, we targeted two distinct regions of exon 1 to induce pigmentation changes and used an in vivo visual phenotype along with heteroduplex mobility assays (HMA) as readouts of CRISPR-Cas9 activity. Most of the mutant alleles result in complete loss of tyrosinase activity leading to an albino phenotype. In this study, we describe two novel in-frame deletion alleles of Tyr, dhoosara (Sanskrit for gray) and chandana (Sanskrit for sandalwood). These alleles are hypomorphic and show lighter pigmentation phenotypes of the body and eyes. This study demonstrates the utility of CRISPR-Cas9 system in generating domain-specific in-frame deletions and helps gain further insights into structure-function of Tyr gene.
SUMO-Modification of the La Protein Facilitates Binding to mRNA In Vitro and in Cells.Wednesday, May 25, 2016
Kota V, Sommer G, Durette C, Thibault P, van Niekerk EA, Twiss JL, Heise T,
PloS one. 25-5-2016
The RNA-binding protein La is involved in several aspects of RNA metabolism including the translational regulation of mRNAs and processing of pre-tRNAs. Besides its well-described phosphorylation by Casein kinase 2, the La protein is also posttranslationally modified by the Small Ubiquitin-like MOdifier (SUMO), but the functional outcome of this modification has not been defined. The objective of this study was to test whether sumoylation changes the RNA-binding activity of La. Therefore, we established an in vitro sumoylation assay for recombinant human La and analyzed its RNA-binding activity by electrophoretic mobility shift assays. We identified two novel SUMO-acceptor sites within the La protein located between the RNA recognition motif 1 and 2 and we demonstrate for the first time that sumoylation facilitates the RNA-binding of La to small RNA oligonucleotides representing the oligopyrimidine tract (TOP) elements from the 5' untranslated regions (UTR) of mRNAs encoding ribosomal protein L22 and L37 and to a longer RNA element from the 5' UTR of cyclin D1 (CCND1) mRNA in vitro. Furthermore, we show by RNA immunoprecipitation experiments that a La mutant deficient in sumoylation has impaired RNA-binding activity in cells. These data suggest that modulating the RNA-binding activity of La by sumoylation has important consequences on its functionality.
Performance of Bio-Rad and Limiting Antigen Avidity Assays in Detecting Recent HIV Infections Using the Quebec Primary HIV-1 Infection Cohort.Wednesday, May 25, 2016
Serhir B, Hamel D, Doualla-Bell F, Routy JP, Beaulac SN, Legault M, Fauvel M, Tremblay C,
PloS one. 25-5-2016
Multiassay algorithms that include the CDC-modified Bio-Rad-Avidity assay and the Sedia-LAg-Avidity assay performed better than each avidity assay alone. Such 2-assay algorithm that starts with the CDC-modified Bio-Rad-Avidity assay followed by the Sedia-LAg-Avidity assay allowed a better classification of HIV-1 infections.
Optimisation of vectorisation property: a comparative study for a secondary amphipathic peptide.Wednesday, May 25, 2016
Konate K, Lindberg M, Vaissiere A, Jourdan C, Aldrian G, Margeat E, Deshayes S, Boisguerin P,
International journal of pharmaceutics. 17-May-2016
RNA interference provides a powerful technology for specific gene silencing. Therapeutic applications of small interfering RNA (siRNA) however require efficient vehicles for stable complexation and intracellular delivery. In order to enhance their cell delivery, short amphipathic peptides called cell-penetrating peptides (CPPs) have been intensively developed for the last two decades. In this context, the secondary amphipathic peptide CADY has shown to form stable siRNA complexes and to improve their cellular uptake independent of the endosomal pathway. In the present work, we have described the parameters influencing CADY nanoparticle formation (buffers, excipients, presence of serum, etc.), and have followed in details the CPP:siRNA self-assembly. Once optimal conditions were determined, we have compared the ability of seven different CADY analogues to form siRNA-loaded nanoparticles compared to CADY:siRNA. First of all, we were able to show by biophysical methods that structural polymorphism (α-helix) is an important prerequisite for stable nanoparticle formation independently of occurring sequence mutations. Luciferase assays revealed that siRNA complexed to CADY-K (shorter version) shows better knock-down efficiency on Neuro2a-Luc(+) and B16-F10-Luc(+) cells compared to CADY:siRNA. Altogether, CADY-K is an ideal candidate for further application especially with regards to ex vivo or in vivo applications.
New metabolites of acteoside identified by ultra-performance liquid chromatography/quadrupole-time-of-flight MS(E) in rat plasma, urine, and feces.Wednesday, May 25, 2016
Su D, Li W, Xu Q, Liu Y, Song Y, Feng Y,
Fitoterapia. 17-May-2016
Acteoside, which belongs to the family of phenylethanoid glycosides (PhGs), has extensive biological activities, including strong antioxidant, anti-inflammatory, hepatoprotect, and cell apoptosis regulation. Like other PhGs compounds, the fate of acteoside in the gut for both parent polyphenols and their degradation products, small phenolic acid and aromatic catabolites cannot be ignored. Therefore, in this work, expanded and systematical investigation for metabolism characteristic profiles of acteoside in vivo by ultra-performance liquid chromatography/ quadrupole-time-of-flight and a new MS(E) data collection technology had been studied. This was equivalent to non-slective MS/MS scans and helpful to explore new metabolites. After oral administration of 200mg/kg acteoside, He et al. (2011) a total of 44 metabolites was detected and identified, and 37 of them were reported for the first time. Among them, 35 were parent drug metabolites classified in 14 groups. Owen et al. (2003) Through the comprehensive metabolites study in plasma, urine and feces, acteoside systemical metabolites profiles and characteristics elaborated firstly. The relative content of metabolites research showed that acteoside could exist stably and the process for biotransformation of acteoside in blood keep extreme short time. Pan and Hori (1996) The significant new transformation of isomerization from acteoside to isoacteoside had been firstly found and confirmed. The results of this work provided new information for the clarification of the metabolism of acteoside and rendered a very valuable theoretical basis for the development of novel ideal dosage forms of acteoside in the future.
Kazinol B from Broussonetia kazinoki Improves Insulin Sensitivity via Akt and AMPK activation in 3T3-L1 Adipocytes.Wednesday, May 25, 2016
Lee H, Li H, Jeong JH, Noh M, Ryu JH,
Fitoterapia. 17-May-2016
In this study, we evaluated the insulin-sensitizing effect of flavans purified from Broussonetia kazinoki Siebold (BK) on 3T3-L1 adipocytes. Among the tested compounds, kazinol B enhanced intracellular lipid accumulation, gene expression of proliferator-activated receptorγ (PPARγ) and CCAAT/enhancer binding protein-alpha (C/EBPα), and consistently induced PPARγ transcriptional activation. To further investigate the insulin-sensitizing effect of kazinol B, we measured glucose analogue uptake by fully differentiated adipocytes and myotubes. Kazinol B increased 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-D-glucose (2-NBDG) uptake by cells by upregulating the gene expression and translocation of glucose transporter 4 (GLUT-4) into the plasma membrane in adipocytes. Kazinol B stimulated the gene expression and secretion of adiponectin, which is associated with a low risk of types 1 and 2 diabetes mellitus. We also suggested the mechanism of the antidiabetic effect of kazinol B by assaying Akt and AMP-activated protein kinase (AMPK) phosphorylation. In conclusion, kazinol B isolated from BK improved insulin sensitivity by enhancing glucose uptake via the insulin-Akt signaling pathway and AMPK activation. These results suggest that kazinol B might be a therapeutic candidate for diabetes mellitus.
Systems Metabolic Engineering of Escherichia coli.Wednesday, May 25, 2016
Choi KR, Shin JH, Cho JS, Yang D, Lee SY,
EcoSal Plus. May-2016
Systems metabolic engineering, which recently emerged as metabolic engineering integrated with systems biology, synthetic biology, and evolutionary engineering, allows engineering of microorganisms on a systemic level for the production of valuable chemicals far beyond its native capabilities. Here, we review the strategies for systems metabolic engineering and particularly its applications in Escherichia coli. First, we cover the various tools developed for genetic manipulation in E. coli to increase the production titers of desired chemicals. Next, we detail the strategies for systems metabolic engineering in E. coli, covering the engineering of the native metabolism, the expansion of metabolism with synthetic pathways, and the process engineering aspects undertaken to achieve higher production titers of desired chemicals. Finally, we examine a couple of notable products as case studies produced in E. coli strains developed by systems metabolic engineering. The large portfolio of chemical products successfully produced by engineered E. coli listed here demonstrates the sheer capacity of what can be envisioned and achieved with respect to microbial production of chemicals. Systems metabolic engineering is no longer in its infancy; it is now widely employed and is also positioned to further embrace next-generation interdisciplinary principles and innovation for its upgrade. Systems metabolic engineering will play increasingly important roles in developing industrial strains including E. coli that are capable of efficiently producing natural and nonnatural chemicals and materials from renewable nonfood biomass.
MicroRNA-197 Mediates the Overgrowth and Anti-Apoptotic Effects by Downregulating Insulin-Like Growth Factor-Binding Protein-3 During Nephroblastoma Tumorigenesis.Wednesday, May 25, 2016
Hu J, Liu G, Zhao Z, Jia W, Xia H,
Fetal and pediatric pathology. 25-May-2016
MiR-197 is frequently upregulated to induce a series of oncogenic effects, which is closely associated with poor survival and prognosis of multiple malignancies. However, the roles of miR-197 in tumorigenesis and the detailed molecular mechanism in Wilms tumor (WT) have rarely been reported. This study aimed to evaluate the expression of miR-197 in WT in vivo and the potential effects of miR-197 on the proliferation and apoptosis in SK-NEP-1 cells. A total of 15 patients with a pathologically confirmed diagnosis of WT and 15 paraneoplastic controls were enrolled. Real-time quantitative PCR (RT-qPCR) identified the upregulation of miR-197 and downregulation of insulin-like growth factors binding protein 3 (IGFBP3) in WT tissues in comparison with adjacent normal tissue (p < 0.001). CCK-8 and flow cytometry assay found that inhibition of miR-197 caused a significantly reduced proliferation along with a dramatically enhanced apoptosis of SK-NEP-1 cells (p < 0.01). IGFBP3 was overexpressed in SK-NEP-1 cells by pEGFP-C1-IGFBP3 plasmid transfection. Overexpression of IGFBP3 suppressed the proliferation and induced the apoptosis of SK-NEP-1 cells (p < 0.01). Further study detected the decreased IGFBP3 expression with miR-197 mimics SK-NEP-1 cells and increased IGFBP3 expression with miR-197 inhibitor SK-NEP-1 cells compared with mock (p < 0.01). Dual luciferase reporter assay revealed a direct interaction between miR-197 and 3'-UTR site of IGFBP3. Overall, the above results indicated that miR-197 targeted IGFBP3 to induce the overgrowth and anti-apoptotic effects of WT cells, which could promote nephroblastoma tumorigenesis. Therefore, miR-197 may be further assessed as a potential target for the treatment of WT.
Serological based monitoring of a cohort of patients with chronic Chagas disease treated with benznidazole in a highly endemic area of northern Argentina.Wednesday, May 25, 2016
Niborski LL, Grippo V, Lafón SO, Levitus G, García-Bournissen F, Ramirez JC, Burgos JM, Bisio M, Juiz NA, Ayala V, Coppede M, Herrera V, López C, Contreras A, Gómez KA, Elean JC, Mujica HD, Schijman AG, Levin MJ, Longhi SA,
Memorias do Instituto Oswaldo Cruz. 24-May-2016
This study aimed to evaluate well-documented diagnostic antigens, named B13, 1F8 and JL7 recombinant proteins, as potential markers of seroconversion in treated chagasic patients. Prospective study, involving 203 patients treated with benznidazole, was conducted from endemic areas of northern Argentina. Follow-up was possible in 107 out of them and blood samples were taken for serology and PCR assays before and 2, 3, 6, 12, 24 and 36 months after treatment initiation. Reactivity against Trypanosoma cruzi lysate and recombinant antigens was measured by ELISA. The rate of decrease of antibody titers showed nonlinear kinetics with an abrupt drop within the first three months after initiation of treatment for all studied antigens, followed by a plateau displaying a low decay until the end of follow-up. At this point, anti-B13, anti-1F8 and anti-JL7 titers were relatively close to the cut-off line, while anti-T. cruzi antibodies still remained positive. At baseline, 60.8% (45/74) of analysed patients tested positive for parasite DNA by PCR and during the follow-up period in 34 out of 45 positive samples (75.5%) could not be detected T. cruzi DNA. Our results suggest that these antigens might be useful as early markers for monitoring antiparasitic treatment in chronic Chagas disease.
Crystal Structures of Putative Sugar Kinases from Synechococcus Elongatus PCC 7942 and Arabidopsis Thaliana.Wednesday, May 25, 2016
Xie Y, Li M, Chang W,
PloS one. 24-5-2016
The genome of the Synechococcus elongatus strain PCC 7942 encodes a putative sugar kinase (SePSK), which shares 44.9% sequence identity with the xylulose kinase-1 (AtXK-1) from Arabidopsis thaliana. Sequence alignment suggests that both kinases belong to the ribulokinase-like carbohydrate kinases, a sub-family of FGGY family carbohydrate kinases. However, their exact physiological function and real substrates remain unknown. Here we solved the structures of SePSK and AtXK-1 in both their apo forms and in complex with nucleotide substrates. The two kinases exhibit nearly identical overall architecture, with both kinases possessing ATP hydrolysis activity in the absence of substrates. In addition, our enzymatic assays suggested that SePSK has the capability to phosphorylate D-ribulose. In order to understand the catalytic mechanism of SePSK, we solved the structure of SePSK in complex with D-ribulose and found two potential substrate binding pockets in SePSK. Using mutation and activity analysis, we further verified the key residues important for its catalytic activity. Moreover, our structural comparison with other family members suggests that there are major conformational changes in SePSK upon substrate binding, facilitating the catalytic process. Together, these results provide important information for a more detailed understanding of the cofactor and substrate binding mode as well as the catalytic mechanism of SePSK, and possible similarities with its plant homologue AtXK-1.
Post-transcriptional regulation of the GASC1 oncogene with active tumor-targeted siRNA-nanoparticle.Wednesday, May 25, 2016
Movassaghian S, Hildebrandt C, Xie Y, Rosati R, Li Y, Kim NH, Conti D, da Rocha SR, Yang ZQ, Merkel OM,
Molecular pharmaceutics. 25-May-2016
Basal-like breast cancer (BLBC) accounts for the most aggressive types of breast cancer, marked by high rates of relapse, visceral metastases, and poor prognoses with no effective clinical therapy yet. Therefore, investigation of new targets and treatment strategies is more than necessary. Here, we identified a receptor that can be targeted in BLBC for efficient and specific siRNA mediated gene knock down of therapeutically relevant genes such as the histone demethylase GASC1 which is involved in multiple signaling pathways leading to tumorigenesis. Breast cancer and healthy breast cell lines were compared regarding transferrin receptor (TfR) expression via flow cytometry and transferrin binding assays. Nanobioconjugates made of low molecular weight polyethylenimine (LMW-PEI) and transferrin (Tf) were synthesized to contain a bioreducible disulfide bond. siRNA complexation was characterized by condensation assays and dynamic light scattering. Cytotoxicity, transfection efficiency and the targeting specificity of the conjugates were investigated in TfR positive and negative healthy breast and breast cancer cell lines by flow cytometry, confocal microscopy, RT-PCR and western blot. Breast cancer cell lines revealed a significantly higher TfR expression than healthy breast cells. The conjugates efficiently condensed siRNA into particles with 45 nm size at low polymer concentrations, showed no apparent toxicity on different breast cancer cell lines and had significantly greater transfection and gene knockdown activity on mRNA and protein levels than PEI/siRNA. The synthesized nanobioconjugates improved the efficiency of gene transfer and targeting specificity in transferrin receptors positive cells but not in cells with basal receptor expression. Therefore, these materials in combination with our newly identified siRNA sequences are promising candidates for therapeutic targeting of hard-to-treat BLBC and are currently further investigated regarding in vivo targeting efficacy and biocompatibility.
High specific genotyping method using short target probe and helper probe.Wednesday, May 25, 2016
Ahn JJ, Song HJ, Hong JY, Kim GW, Hwang SY,
Molecular and cellular probes. 17-May-2016
Differentiating 1-bp differences using real-time PCR often leads to false-positive results. Therefore, we developed a fluorescence melting curve analysis (FMCA) method with a short target probe and helper probe labeled with a fluorophore and quencher, respectively. This fluorophore and quencher were designed to be near each other when the probes were hybridized to template DNA. The target probe was designed with a shorter length to facilitate a dramatic shift in melting temperature (Tm) upon encountering mismatched hybridization. In FMCA, when the temperature approached the target probe Tm, the target probe would begin to denature from the template DNA, and at the target probe Tm, the fluorescence signal increased markedly. Here, we examined 1-bp differences using the developed method with mitochondrial DNA from Larimichthys polyactis and L. crocea. Application of this method permitted specific genotype identification for all cases with no cross-reactivity, even when both templates were added to the same tube.
A simple and efficient method for generating high-quality recombinant Mical enzyme for in vitro assays.Wednesday, May 25, 2016
Wu H, Hung RJ, Terman JR,
Protein expression and purification. 17-May-2016
We have recently identified a new family of multidomain oxidoreductase (redox) enzymes, the MICALs, that directly regulate the actin cytoskeletal elements necessary for the morphology, motility, and trajectory of cells. Our genetic assays reveal that Mical is both necessary and sufficient for actin organization and cellular effects in vivo and our biochemical assays with purified Mical protein reveal that Mical utilizes its redox activity to directly disassemble actin filaments. These results identify Mical proteins as novel actin disassembly factors and uncover a redox signaling mechanism that directly regulates the actin cytoskeleton. These results have also set the stage for in-depth characterization of the Mical enzyme. However, it has been difficult to obtain sufficient amounts of highly-pure Mical protein to conduct further biochemical, structural, imaging, catalytic, and other high-precision studies. Herein, we describe a means for expressing high levels of soluble recombinant Mical protein in bacteria. Likewise, we have designed a new purification strategy that enables the rapid and efficient purification of milligram quantities of highly-pure and >99% active Mical protein. This new strategy for generating large amounts of highly-pure and active Mical protein will aid research objectives designed to characterize the biochemical, enzymology, and structural biology of Mical and its effects on actin filament dynamics.
A Facile Probe Design: Fluorescent Amphiphilic Nucleic Acid Probes without Quencher Providing Telomerase Activity Imaging inside Living Cells.Wednesday, May 25, 2016
Jia Y, Gao P, Zhuang Y, Miao M, Lou X, Xia F,
Analytical chemistry. 25-May-2016
Nowadays, the probe with fluorophore but no quencher is promising for its simple preparation, environmental friendliness and wide application scope. This study designs a new amphiphilic nucleic acid probe (ANAP) based on aggregation-caused quenching (ACQ) effect without any quencher. Upon binding with targets, the dispersion of hydrophobic part (conjugated fluorene, CF) in ANAP is enhanced as a signal-on model for proteins, nucleic acids and small molecules detection, or the aggregation of CF is enhanced as a signal-off model for ion detection. Meanwhile, due to the high specificity of ANAP, a one-step method is developed powerfully for monitoring the telomerase activity not only from the cell extracts but also from 50 clinic urine samples (positive results from 45 patients with bladder cancer and negative results from 5 healthy people). ANAPs can also readily enter into cells and exhibit a good performance for distinguishing natural tumor cells from the tumor cells pretreated by telomerase-related drugs or normal cells. In contrast to our previous results (Anal. Chem. 2015, 87, 3890-3894), the present CF is a monomer which is just the structure unit of the previous fluorescent polymer. Since the accurate molecular structure and high DNA/CF ratio of the present CF, these advanced experiments obtain an easier preparation of probes, an improved sensitivity and specificity, and broader detectable targets.
Targeting Serglycin Prevents Metastasis in Murine Mammary Carcinoma.Wednesday, May 25, 2016
Roy A, Femel J, Huijbers EJ, Spillmann D, Larsson E, Ringvall M, Olsson AK, Åbrink M,
PloS one. 25-5-2016
In hematopoietic cells, serglycin proteoglycans mainly contribute to proper storage and secretion of inflammatory mediators via their negatively charged glycosaminoglycans. Serglycin proteoglycans are also expressed in cancer cells where increased expression has been linked to poor prognosis. However, the serglycin-dependent mediators promoting cancer progression remain to be determined. In the present study we report that genetic ablation of serglycin proteoglycan completely blocks lung metastasis in the MMTV-PyMT-driven mouse breast cancer model, while serglycin-deficiency did not affect primary tumour growth or number of mammary tumours. Although E-cadherin expression was higher in the serglycin-deficient primary tumour tissue, indicating reduced invasiveness, serglycin-deficient tumour cells were still detected in the circulation. These data suggest that serglycin proteoglycans play a role in extravasation as well as colonization and growth of metastatic cells. A microarray expression analysis and functional annotation of differentially expressed genes identified several biological pathways where serglycin may be important. Our results suggest that serglycin and serglycin-dependent mediators are potential drug targets to prevent metastatic disease/dissemination of cancer.
Plasma Levels of the Interleukin-1-Receptor Antagonist Are Lower in Women with Gestational Diabetes Mellitus and Are Particularly Associated with Postpartum Development of Type 2 Diabetes.Wednesday, May 25, 2016
Katra P, Dereke J, Nilsson C, Hillman M,
PloS one. 25-5-2016
Diabetes mellitus is a group of diseases characterized by chronic hyperglycemia. Women who develops hyperglycemia for the first time during pregnancy receive the diagnosis gestational diabetes mellitus (GDM). Presently, there is no consensus about the diagnostic criteria for GDM. A majority of these women subsequently develop postpartum overt diabetes making it important to identify these patients as early as possible. In this study we investigated if plasma levels of the interleukin-1 receptor antagonist (IL-1Ra), an endogenous inhibitor of IL-1 signaling, can be used as a complementary biomarker for diagnosing GDM and predicting postpartum development of overt diabetes mellitus. Patients participating in this study (n = 227) were diagnosed with their first GDM 2004-2013 at Lund University Hospital, Lund, Sweden. Healthy pregnant volunteers (n = 156) were recruited from women's welfare centers in the same region 2014-2015. Levels of IL-1Ra and C-peptide were analyzed in ethylenediaminetetraacetic acid (EDTA)-plasma or serum using enzyme linked immunosorbent assay (ELISA). GDM patients had significantly lower levels of IL-1Ra than the control group (p = 0.012). In addition, GDM patients that had developed impaired glucose tolerance (IGT) or type 2 diabetes mellitus postpartum had significantly lower levels of IL-1Ra, and significantly higher levels of C-peptide than GDM patients that had not developed diabetes mellitus postpartum (p = 0.023) and (p = 0.0011) respectively. An inverse correlation was found between IL-1Ra and serum C-peptide levels in the control group (rs = -0.31 p = 0.0001). Our results show that IL-1Ra might be included in a future panel of biomarkers, both for diagnosing GDM to complement blood glucose, and also identifying GDM patients that are at risk of developing type 2 diabetes mellitus postpartum. However, the ROC curve analysis provided a sensitivity of 52.2% and specificity of 67.1%, which nonetheless may not be sufficient enough to use IL-1Ra as a sole biomarker.
Multifunctional microbeads for drug delivery in TACE.Wednesday, May 25, 2016
Bannerman D, Wan W,
Expert opinion on drug delivery. 25-May-2016
The incorporation of nanoparticles that possess desirable properties into the microbead matrix is a suitable method of creating multifunctional microbeads. The development of these "nano-on-micro" systems is a promising approach to improve TACE therapy and may lead to improved treatment.
cMET exon 14 skipping: from the structure to the clinic.Wednesday, May 25, 2016
Van Der Steen N, Giovannetti E, Pauwels P, Peters GJ, Hong DS, Cappuzzo F, Hirsch FR, Rolfo C,
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 17-May-2016
The abnormal stimulation of the multiple signal transduction pathways downstream of the receptor tyrosine kinase mesenchymal-epithelial transition factor (cMET) promotes cellular transformation, tumor motility and invasion. Therefore, cMET has been the focus of prognostic and therapeutic studies in different tumor types, including non-small cell lung cancer (NSCLC). In particular, several cMET-inhibitors have been developed as innovative therapeutic candidates, and are currently under investigation in clinical trials. However, one of the challenges in establishing effective targeted treatments against cMET, remains the accurate identification of biomarkers for the selection of responsive subsets of patients. Recently, splice site mutations have been discovered in cMET that lead to the skipping of exon 14, impairing the break-down of the receptor. NSCLC-patients carrying this splice variant typically overexpress the cMET receptor and show a response to small molecule inhibitors of cMET. Here, we review the main differences at the structural level between the wild-type and the splice variant of cMET and their influence on cMET signaling. We clarify the reason why this variant responds to small molecule inhibitors, and their prognostic/predictive role.
Plasma microRNA panels to diagnose pancreatic cancer: Results from a multicenter study.Wednesday, May 25, 2016
Cao Z, Liu C, Xu J, You L, Wang C, Lou W, Sun B, Miao Y, Liu X, Wang X, Zhang T, Zhao Y,
Oncotarget. 19-May-2016
Biomarkers for the early diagnosis of pancreatic cancer (PC) are urgent needed. Plasma microRNAs (miRNAs) might be used as biomarkers for the diagnosis of cancer. We analyzed 361 plasma samples from 6 surgical centers in China and performed machine learning approach. We gain insight of the association between the aberrant plasma miRNA expression and pancreatic disease. 671 microRNAs were screened in the discovery phase and 33 microRNAs in the training phase and 13 microRNAs in the validation phase. After the discovery phase and training phase, 2 diagnostic panels were constructed comprising 3 microRNAs in panel I (miR-486-5p, miR-126-3p, miR-106b-3p) and 6 microRNAs in panel II (miR-486-5p, miR-126-3p, miR-106b-3p, miR-938, miR-26b-3p, miR-1285). Panel I and panel II had high accuracy for distinguishing pancreatic cancer from chronic pancreatitis (CP) with area under the curve (AUC) values of 0.891 (Standard Error (SE): 0.097) and 0.889 (SE: 0.097) respectively, in the validation phase. Additionally, we demonstrated that the diagnostic value of the panels in discriminating PC from CP were comparable to that of carbohydrate antigen 19-9 (CA 19-9) 0.775 (SE: 0.053) (P = 0.1 for both). This study identified 2 diagnostic panels based on microRNA expression in plasma with the potential to distinguish PC from CP. These patterns might be developed as biomarkers for pancreatic cancer.
Phamacometabolomics study identifies circulating spermidine and tryptophan as potential biomarkers associated with the complete pathological response to trastuzumab-paclitaxel neoadjuvant therapy in HER-2 positive breast cancer.Wednesday, May 25, 2016
Miolo G, Muraro E, Caruso D, Crivellari D, Ash A, Scalone S, Lombardi D, Rizzolio F, Giordano A, Corona G,
Oncotarget. 19-May-2016
Defining biomarkers that predict therapeutic effects and adverse events is a crucial mandate to guide patient selection for personalized cancer treatments. In the present study, we applied a pharmacometabolomics approach to identify biomarkers potentially associated with pathological complete response to trastuzumab-paclitaxel neoadjuvant therapy in HER-2 positive breast cancer patients. Based on histological response the 34 patients enrolled in the study were subdivided into two groups: good responders (n = 15) and poor responders (n = 19). The pre-treatment serum targeted metabolomics profile of all patients were analyzed by liquid chromatography tandem mass spectrometry and the differences in the metabolomics profile between the two groups was investigated by multivariate partial least squares discrimination analysis. The most relevant metabolites that differentiate the two groups of patients were spermidine and tryptophan. The Good responders showed higher levels of spermidine and lower amounts of tryptophan compared with the poor responders (p < 0.001, q < 0.05). The serum level of these two metabolites identified patients who achieved a pathological complete response with a sensitivity of 90% [0.79-1.00] and a specificity of 0.87% [0.67-1.00]. These preliminary results support the role played by the individual patients' metabolism in determining the response to cancer treatments and may be a useful tool to select patients that are more likely to benefit from the trastuzumab-paclitaxel treatment.
Study of 1550nm Erbium Glass Laser Fractional non-ablative treatment of photoaging: Comparative clinical effects, histopathology, electron microscopy and immunohistochemistry.Wednesday, May 25, 2016
de Sica RC, Rodrigues CJ, Maria DA, Cucé LC,
Journal of cosmetic and laser therapy : official publication of the European Society for Laser Dermatology. 25-May-2016
The histopathology, immunohistochemistry and electron microscopy showed an improvement compatible to the clinical effectiveness after 4 months.
Evaluation of biomarkers for ulcerative colitis comparing two sampling methods: fecal markers reflect colorectal inflammation both macroscopically and on a cellular level.Wednesday, May 25, 2016
Peterson CG, Lampinen M, Hansson T, Lidén M, Hällgren R, Carlson M,
Scandinavian journal of clinical and laboratory investigation. 25-May-2016
The levels of inflammation markers in feces and patch fluid distinctly reflected active inflammation in UC. The degree of disease activity was however best assessed by fecal markers, particularly MPO and IL-1β. Fecal markers reflect colorectal inflammation both macroscopically and on a cellular level, and may be useful for the evaluation of subclinical inflammation. The applicability of patch markers is restricted to rectal inflammation.
Imaging flow cytometry for phytoplankton analysis.Wednesday, May 25, 2016
Dashkova V, Malashenkov D, Poulton N, Vorobjev I, Barteneva NS,
Methods (San Diego, Calif.). 17-May-2016
This review highlights the concepts and instrumentation of imaging flow cytometry technology and in particular its use for phytoplankton analysis. Imaging flow cytometry, a hybrid technology combining speed and statistical capabilities of flow cytometry with imaging features of microscopy, is rapidly advancing as a cell imaging platform that overcomes many of the limitations of current techniques and contributed significantly to the advancement of phytoplankton analysis in recent years. This review presents the various instrumentation relevant to the field and currently used for assessment of complex phytoplankton communities' composition and abundance, size structure determination, biovolume estimation, detection of harmful algal bloom species, evaluation of viability and metabolic activity and other applications. Also we present our data on viability and metabolic assessment of Aphanizomenon sp. cyanobacteria using Imagestream X Mark II imaging cytometer. Herein, we highlight the immense potential of imaging flow cytometry for microalgal research, but also discuss limitations and future developments.
Effect of Chocolate and Yerba Mate Phenolic Compounds on Inflammatory and Oxidative Biomarkers in HIV/AIDS Individuals.Wednesday, May 25, 2016
Petrilli AA, Souza SJ, Teixeira AM, Pontilho PM, Souza JM, Luzia LA, Rondó PH,
Nutrients. 17-5-2016
Flavonoids in cocoa and yerba mate have a beneficial role on inflammation and oxidative disorders. Their effect on HIV individuals has not been studied yet, despite the high cardiovascular risk of this population. This study investigated the role of cocoa and yerba mate consumption on oxidative and inflammatory biomarkers in HIV+ individuals. A cross-over, placebo-controlled, double-blind, randomized clinical trial was conducted in 92 individuals on antiretroviral therapy for at least six months and at viral suppression. Participants were randomized to receive either 65 g of chocolate or chocolate-placebo or 3 g of yerba mate or mate-placebo for 15 days each, alternating by a washout period of 15 days. At baseline, and at the end of each intervention regimen, data regarding anthropometry, inflammatory, oxidative and immunological parameters were collected. High-sensitivity C-reactive protein, fibrinogen, lipid profile, white blood cell profile and thiobarbituric acid reactive substances were assessed. There was a difference between mean concentrations of HDL-c (ANOVA; p ≤ 0.05) among the different regimens: dark chocolate, chocolate-placebo, yerba mate and mate-placebo. When a paired Student t-test was used for comparisons between mean HDL-c at baseline and after each regimen, the mean concentration of HDL-c was higher after supplementation with dark chocolate (p = 0.008).
Factors That Improve RT-QuIC Detection of Prion Seeding Activity.Wednesday, May 25, 2016
Orrú CD, Hughson AG, Groveman BR, Campbell KJ, Anson KJ, Manca M, Kraus A, Caughey B,
Viruses. 23-5-2016
Rapid and sensitive detection of prions is important in managing prion diseases. The real-time quaking-induced conversion (RT-QuIC) assay for prion seeding activity has been applied to many prion diseases and provides for specific antemortem diagnostic testing. We evaluated RT-QuIC's long-term consistency and varied multiple reaction parameters. Repeated assays of a single scrapie sample using multiple plate readers and recombinant prion protein (rPrP(Sen)) substrates gave comparable results. N-terminal truncated hamster rPrP(Sen) (residues 90-231) hastened both prion-seeded and prion-independent reactions but maintained a clear kinetic distinction between the two. Raising temperatures or shaking speeds accelerated RT-QuIC reactions without compromising specificity. When applied to nasal brushings from Creutzfeldt-Jakob disease patients, higher temperatures accelerated RT-QuIC kinetics, and the use of hamster rPrP(Sen) (90-231) strengthened RT-QuIC responses. Elongation of shaking periods reduced scrapie-seeded reaction times, but continuous shaking promoted false-positive reactions. Furthermore, pH 7.4 provided for more rapid RT-QuIC reactions than more acidic pHs. Additionally, we show that small variations in the amount of sodium dodecyl sulfate (SDS) significantly impacted the assay. Finally, RT-QuIC performed in multiplate thermoshakers followed by fluorescence readings in separate plate readers enhanced assay throughput economically. Collectively, these results demonstrate improved speed, efficacy and practicality of RT-QuIC assays and highlight variables to be optimized for future applications.
Aerosol Transmission of Filoviruses.Wednesday, May 25, 2016
Mekibib B, Ariën KK,
Viruses. 23-5-2016
Filoviruses have become a worldwide public health concern because of their potential for introductions into non-endemic countries through international travel and the international transport of infected animals or animal products. Since it was first identified in 1976, in the Democratic Republic of Congo (formerly Zaire) and Sudan, the 2013-2015 western African Ebola virus disease (EVD) outbreak is the largest, both by number of cases and geographical extension, and deadliest, recorded so far in medical history. The source of ebolaviruses for human index case(s) in most outbreaks is presumptively associated with handling of bush meat or contact with fruit bats. Transmission among humans occurs easily when a person comes in contact with contaminated body fluids of patients, but our understanding of other transmission routes is still fragmentary. This review deals with the controversial issue of aerosol transmission of filoviruses.
Domotics Project Housing Block.Wednesday, May 25, 2016
Morón C, Payán A, García A, Bosquet F,
Sensors (Basel, Switzerland). 23-5-2016
This document develops the study of an implementation project of a home automation system in a housing placed in the town of Galapagar, Madrid. This house, which is going to be occupied by a four-member family, consists of 67 constructed square meters distributed in lounge, kitchen, three bedrooms, bath, bathroom and terrace, this being a common arrangement in Spain. Thus, this study will allow extracting conclusions about the adequacy of the home automation in a wide percentage of housing in Spain. In this document, three house automation proposals are developed based on the requirements of the client and the different home automation levels that the Spanish House and Building Automation Association has established, besides two parallel proposals relating to the safety and the technical alarms. The mentioned proposed systems are described by means of product datasheets and descriptions, distribution plans, measurements, budgets and flow charts that describe the functioning of the system in every case. An evaluation of each system is included, based on other studies conclusions on this matter, where expected energy savings from each design, depending on the current cost of lighting, water and gas, as well as the expected economic amortization period is evaluated.
Circulating MicroRNAs as Biomarkers in Biliary Tract Cancers.Wednesday, May 25, 2016
Letelier P, Riquelme I, Hernández AH, Guzmán N, Farías JG, Roa JC,
International journal of molecular sciences. 23-5-2016
Biliary tract cancers (BTCs) are a group of highly aggressive malignant tumors with a poor prognosis. The current diagnosis is based mainly on imaging and intraoperative exploration due to brush cytology havinga low sensitivity and the standard markers, such as carcinoembryonic antigen (CEA) and carbohydrate 19-9 (CA19-9), not having enough sensitivity nor specificity to be used in a differential diagnosis and early stage detection. Thus, better non-invasive methods that can distinguish between normal and pathological tissue are needed. MicroRNAs (miRNAs) are small, single-stranded non-coding RNA molecules of ~20-22 nucleotides that regulate relevant physiological mechanisms and can also be involved in carcinogenesis. Recent studies have demonstrated that miRNAs are detectable in multiple body fluids, showing great stability, either free or trapped in circulating microvesicles, such as exosomes. miRNAs are ideal biomarkers that may be used in screening and prognosis in biliary tract cancers, aiding also in the clinical decisions at different stages of cancer treatment. This review highlights the progress in the analysis of circulating miRNAs in serum, plasma and bile as potential diagnostic and prognostic markers of BTCs.
Selective inhibition of p97 by chlorinated analogues of dehydrocurvularin.Wednesday, May 25, 2016
Tillotson J, Bashyal BP, Kang M, Shi T, De La Cruz F, Gunatilaka AA, Chapman E,
Organic & biomolecular chemistry. 25-May-2016
The ATPase p97 is a ubiquitin targeted segregase that uses the energy of ATP binding and hydrolysis to extract ubiquitylated substrates from biological membranes, from other proteins, or from protein complexes to carry out myriad tasks in eukaryotes. Increased p97 activity has been linked to a poor prognosis in cancer patients, making p97 an anti-neoplastic target. In the present study, we show that dehydrocurvularin (DHC) and its chlorinated variants are covalent inhibitors of p97, interfering with its ATPase activity. Interestingly, cellular studies revealed both DHC and its monochloro analogue interfere with both the proteasome and p97, whereas its dichloro analogue showed p97 specificity.
High Affinity Agonists of the Neuropeptide Y (NPY) Y4 Receptor Derived from the C-terminal Pentapeptide of Human Pancreatic Polypeptide (hPP): Synthesis, Stereochemical Discrimination and Radiolabeling.Wednesday, May 25, 2016
Kuhn KK, Ertl T, Dukorn S, Keller M, Bernhardt G, Reiser O, Buschauer A,
Journal of medicinal chemistry. 25-May-2016
The diastereomeric mixture of D/L-2,7-diaminooctanedioyl-bis(YRLRY-NH2) (BVD-74D, 2) was described in the literature as a high affinity Y4 receptor agonist. Here we report on the synthesis and pharmacological characterization of the pure diastereomers (2R,7R)- and (2S,7S)-2 and a series of homo- and heterodimeric analogues in which octanedioic acid was used as an achiral linker. To investigate the role of the Arg residues, one or two arginines were replaced by Ala. Moreover, N(ω)-(6-aminohexylaminocarbonyl)Arg was introduced as an arginine replacement (17). (2R,7R)-2 was superior to (2S,7S)-2 in binding and functional cellular assays and equipotent with 17. [(3)H]propionylation of one amino group in the linker of (2R,7R)-2 or at the primary amino group in 17 resulted in high affinity Y4R radioligands ([(3)H]-(2R,7R)-10, [(3)H]18) with subnanomolar Kd values.
Black cohosh inhibits 17β-estradiol-induced cell proliferation of endometrial adenocarcinoma cells.Wednesday, May 25, 2016
Park SY, Kim HJ, Lee SR, Choi YH, Jeong K, Chung H,
Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology. 25-May-2016
This study was conducted to investigate the effect of black cohosh (BC) extract on the proliferation and apoptosis of Ishikawa cells. Ishikawa human endometrial adenocarcinoma cells were treated with or without BC (1, 5, 10 and 25 μM) and cell proliferation and cytotoxicity were measured by CCK-8 assays and flow cytometry analysis. Additionally, Ishikawa cells were treated with 17β-estradiol (E2), E2 + progesterone and E2 + BC (5 and 10 μM) and the effect of BC and progesterone on E2-induced cell proliferation was analyzed. BC decreased the proliferation of Ishikawa cells at a dose-dependent rate compared with the control group (p < 0.05). The proliferation of Ishikawa cells increased in the presence of E2, whereas the subsequent addition of progesterone or BC decreased proliferation to the level of the control group (p < 0.05). The inhibitory effect of BC on E2-induced cell proliferation was greater than the inhibitory effect of progesterone. In conclusion, BC induces apoptosis in Ishikawa cells and suppresses E2-induced cell proliferation in Ishikawa cells. BC could be considered a candidate co-treatment agent of estrogen-dependent tumors, especially those involving endometrial cells.
Dual PET and Near-Infrared Fluorescence Imaging Probes as Tools for Imaging in Oncology.Wednesday, May 25, 2016
An FF, Chan M, Kommidi H, Ting R,
AJR. American journal of roentgenology. 25-May-2016
Existing SPECT, PET, fluorescence, and MRI contrast imaging techniques are already deeply integrated into the management of cancer, from initial diagnosis to the observation and management of metastases. Combined positron-emitting fluorescent contrast agents can convey new or substantial benefits that improve on these proven clinical contrast agents.
A new furanocoumarin from the fruits of Scaevola taccada and antifungal activity against Pythium insidiosum.Wednesday, May 25, 2016
Suthiwong J, Thongsri Y, Yenjai C,
Natural product research. 25-May-2016
A new coumarin, scataccanol (1) and 10 known compounds were isolated from the fruits of Scaevola taccada (Gaertn.) Roxb. All compounds were evaluated for antifungal activity against Pythium insidiosum. Compounds 5 and 7 showed strong antifungal activity with minimum inhibitory concentration values of 5 and 10 μg/mL, respectively. Structural determination of all compounds was accomplished by 1D and 2D-NMR, IR and MS.
Use of Metabolomics to Trend Recovery and Therapy After Injury in Critically Ill Trauma Patients.Wednesday, May 25, 2016
Parent BA, Seaton M, Sood RF, Gu H, Djukovic D, Raftery D, O'Keefe GE,
JAMA surgery. 25-May-2016
Metabolomics can function as a serial, comprehensive, and potentially personalized tool to characterize metabolism after injury. A targeted metabolomics approach was associated with ongoing oxidative stress, impaired nucleotide synthesis, and initial suppression of protein metabolism followed by increased nitrogen turnover. This technique may provide new therapeutic and nutrition targets in critically injured patients.
Trabecular and Cortical Bone of Growing C3H Mice Is Highly Responsive to the Removal of Weightbearing.Wednesday, May 25, 2016
Li B, Sankaran JS, Judex S,
PloS one. 25-5-2016
Genetic make-up strongly influences the skeleton's susceptibility to the loss of weight bearing with some inbred mouse strains experiencing great amounts of bone loss while others lose bone at much smaller rates. At young adulthood, female inbred C3H/HeJ (C3H) mice are largely resistant to catabolic pressure induced by unloading. Here, we tested whether the depressed responsivity to unloading is inherent to the C3H genetic make-up or whether a younger age facilitates a robust skeletal response to unloading. Nine-week-old, skeletally immature, female C3H mice were subjected to 3wk of hindlimb unloading (HLU, n = 12) or served as normal baseline controls (BC, n = 10) or age-matched controls (AC, n = 12). In all mice, cortical and trabecular architecture of the femur, as well as levels of bone formation and resorption, were assessed with μCT, histomorphometry, and histology. Changes in bone marrow progenitor cell populations were determined with flow cytometry. Following 21d of unloading, HLU mice had 52% less trabecular bone in the distal femur than normal age-matched controls. Reflecting a loss of trabecular tissue compared to baseline controls, trabecular bone formation rates (BFR/BS) in HLU mice were 40% lower than in age-matched controls. Surfaces undergoing osteoclastic resorption were not significantly different between groups. In the mid-diaphysis, HLU inhibited cortical bone growth leading to 14% less bone area compared to age-matched controls. Compared to AC, BFR/BS of HLU mice were 53% lower at the endo-cortical surface and 49% lower at the periosteal surface of the mid-diaphysis. The enriched osteoprogenitor cell population (OPC) comprised 2% of the bone marrow stem cells in HLU mice, significantly different from 3% OPC in the AC group. These data show that bone tissue in actively growing C3H mice is lost rapidly, or fails to grow, during the removal of functional weight bearing-in contrast to the insignificant response previously demonstrated in female young adult C3H mice. Thus, the attributed low sensitivity of the C3H mouse strain to the loss of mechanical signals is not apparent at a young age and this trait therefore does not reflect a genetic regulation throughout the life span of this strain. These results highlight the significance of age in modulating the contribution of genetics in orchestrating bone's response to unloading and that the skeletal unresponsiveness of young adult C3H mice to the loss of weight bearing is not genetically hard-wired.
Characterization of Electronic Cigarette Aerosol and Its Induction of Oxidative Stress Response in Oral Keratinocytes.Wednesday, May 25, 2016
Ji EH, Sun B, Zhao T, Shu S, Chang CH, Messadi D, Xia T, Zhu Y, Hu S,
PloS one. 25-5-2016
In this study, we have generated and characterized Electronic Cigarette (EC) aerosols using a combination of advanced technologies. In the gas phase, the particle number concentration (PNC) of EC aerosols was found to be positively correlated with puff duration whereas the PNC and size distribution may vary with different flavors and nicotine strength. In the liquid phase (water or cell culture media), the size of EC nanoparticles appeared to be significantly larger than those in the gas phase, which might be due to aggregation of nanoparticles in the liquid phase. By using in vitro high-throughput cytotoxicity assays, we have demonstrated that EC aerosols significantly decrease intracellular levels of glutathione in NHOKs in a dose-dependent fashion resulting in cytotoxicity. These findings suggest that EC aerosols cause cytotoxicity to oral epithelial cells in vitro, and the underlying molecular mechanisms may be or at least partially due to oxidative stress induced by toxic substances (e.g., nanoparticles and chemicals) present in EC aerosols.
Analysis of recent failures of disease modifying therapies in Alzheimer's disease suggesting a new methodology for future studies.Wednesday, May 25, 2016
Amanatkar HR, Papagiannopoulos B, Grossberg GT,
Expert review of neurotherapeutics. 25-May-2016
This contradiction prompted us to review all study phases of Intravenous Immunoglobulin (IVIG), Bapineuzumab, Solanezumab, Avagacestat and Dimebolin to shed more light on these recent failures. We critically analyzed these studies, recommending seven lessons from these failures which should not be overlooked. Expert Commentary: We suggest a new methodology for future treatment research in Alzheimer's disease considering early intervention with more focus on cognitive decline as a screening tool, more sophisticated exclusion criteria with more reliance on biomarkers, stratification of subjects based on the rate of cognitive decline aiming less heterogeneity, and a longer study duration with periodic assessment of cognition and activities of daily living during the study and also after a washout period.
A transferrin-target magnetic/fluorescent dual-mode probe significantly enhances the diagnosis of non-small cell lung cancer.Wednesday, May 25, 2016
Cai J, Gu B, Cao F, Liu S,
Oncotarget. 19-May-2016
To enhance the diagnosis of non-small cell lung cancer (NSCLC), we prepared a dual-modal probe Cy5.5-Tf-Gd-DTPA. Gd-DTPA and near-infrared (NIR) dyes were conjugated to holo-Transferrin (Tf) sequentially, the result of ICP-AES and UV showed 25 Gd ions and 1 Cy5.5 could be loaded per protein, respectively. The calculated longitudinal relaxivity R1 of Cy5.5-Tf-DTPA-Gd was 4.21 mM-1S-1 per Gd while that of Magnevist (Gd-DTPA) was only 4.02 mM-1S-1. Confocal laser scanning microscopy and immunohistochemical analyses revealed that the Cy5.5-Tf-DTPA-Gd was localized and accumulated in cytoplasmic vesicles; the cell toxicity assay showed no apparent toxicity. MR and NIR imaging of mice with subcutaneous H1299 xenografte tumors following intravenous injection of Cy5.5-Tf-DTPA-Gd revealed a strong positive contrast of the tumors, which caused a longer lasting enhancement of the MRI signal and fluorescence signal. Taken together, these studies indicate that Cy5.5-Tf-DTPA-Gd could be a good agent for MR/NIRF dual mode applications to detect both tumor in situ and its metastasis.
MicroRNA-138 acts as a tumor suppressor in non small cell lung cancer via targeting YAP1.Wednesday, May 25, 2016
Xiao L, Zhou H, Li XP, Chen J, Fang C, Mao CX, Cui JJ, Zhang W, Zhou HH, Yin JY, Liu ZQ,
Oncotarget. 19-May-2016
MicroRNA (miR)-138 was found to have suppressive effects on the growth and metastasis of different human cancers. In this study, we aimed to investigate the regulatory mechanism of miR-138 in non-small cell lung cancer (NSCLC). We applied the Quantitative real-time PCR (qRT-PCR) to detect the miR-138 levels in NSCLC tissues (n=21) and cell lines, Bioinformatical predication, luciferase reporter assay and western blot to identify the target gene of miR-138. We also applied Cell transfection, MTT, transwell, and wound healing assays to reveal the role of miR-138 in NSCLC cell proliferation and malignant transformation. We observed that miR-138 expression level was significantly decreased in NSCLC tissues compared to their matched adjacent normal tissues. It was also downregulated in tissues with poor differentiation, advanced stage or lymph nodes metastasis, as well as in several NSCLC cell lines compared to normal lung epithelial cell. We further identified YAP1 as a direct target gene of miR-138, and observed that the protein level of YAP1 was negatively mediated by miR-138 in NSCLC A549 cells. Moreover, overexpression of miR-138 significantly inhibited A549 cell growth, invasion and migration, while knockdown of miR-138 enhanced such capacities. Further investigation showed that the cell proliferation capacity was higher in the miR-138+YAP1 group, when compared with that in the miR-138 group, suggesting that overexpression of YAP1 rescued the suppressive effects of miR-138 upregulation on NSCLC cell proliferation. However, we found no difference of cell invasion and migration capacities between miR-138+YAP1 group and miR-138 group. Finally, YAP1 was markedly upregulated in NSCLC tissues compared to their marched adjacent normal tissues. Its mRNA levels were reversely correlated with the miR-138 levels in NSCLC tissues. In summary, our study suggests that miR-138 may play a suppressive role in the growth and metastasis of NSCLC cells partly at least by targeting YAP1.
Immunotoxic effects of sodium tungstate dihydrate on female B6C3F1/N mice when administered in drinking water.Wednesday, May 25, 2016
Frawley RP, Smith MJ, White KL, Elmore SA, Herbert R, Moore R, Staska LM, Behl M, Hooth MJ, Kissling GE, Germolec DR,
Journal of immunotoxicology. 25-May-2016
Tungsten is a naturally occurring, high-tensile strength element that has been used in a number of consumer products. Tungsten has been detected in soil, waterways, groundwater, and human tissue and body fluids. Elevated levels of tungsten in urine were reported for populations exposed to tungstate in drinking water in areas where natural tungsten formations were prevalent. Published reports indicated that sodium tungstate may modulate hematopoiesis, immune cell populations, and immune responses in rodent models. The objective of this study was to assess potential immunotoxicity of sodium tungstate dihydrate (STD), a drinking water contaminant. Female B6C3F1/N mice received 0-2000 mg STD/L in their drinking water for 28 d, and were evaluated for effects on immune cell populations in spleen and bone marrow, and humoral-mediated, cell-mediated, and innate immunity. Three different parameters of cell-mediated immunity were similarly affected at 1000 mg STD/L. T-cell proliferative responses against allogeneic leukocytes and anti-CD3 were decreased 32%, and 21%, respectively. Cytotoxic T-lymphocyte activity was decreased at all effector:target cell ratios examined. At 2000 mg STD/L, the absolute numbers of CD3(+) T-cell progenitor cells in bone marrow were increased 86%, but the alterations in B-lymphocyte and other progenitor cells were not significant. There were no effects on bone marrow DNA synthesis or colony forming capabilities. STD-induced effects on humoral-mediated immunity, innate immunity, and splenocyte sub-populations were limited. Enhanced histopathology did not detect treatment-related lesions in any of the immune tissues. These data suggest exposure to STD in drinking water may adversely affect cell-mediated immunity.
Determination of amino acids in urine of patients with prostate cancer and benign prostate growth.Wednesday, May 25, 2016
Sroka WD, Boughton BA, Reddy P, Roessner U, Słupski P, Jarzemski P, Dąbrowska A, Markuszewski MJ, Marszałł MP,
European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP). 24-May-2016
Prostate cancer is the leading type of cancer diagnosed in men. Serum prostate-specific antigen levels and digital rectal exam are far from perfect when it comes to differentiation of patients with prostate cancer and benign prostatic hyperplasia. In this study, we attempt to determine whether amino acids can be used as prostate cancer biomarkers. Concentrations of derivatized amino acids and amines were quantified by liquid chromatography tandem mass spectrometry. A total of 100 urine samples from the two groups including samples provided before and after prostate massage were examined quantitatively for amino acid and amine concentrations with 50 urine samples collected from cancer patients and 50 samples from patients diagnosed with benign prostatic hyperplasia. Arginine, homoserine, and proline were more abundant in urine samples of cancer patients compared with arginine, homoserine, and proline levels determined in urine collected from patients with benign growth. We also show that sarcosine is not a definitive indicator of prostate cancer when analyzed in urine samples collected either before or after prostate massage.
Inhibition of Histone Deacetylase 6 Reveals a Potent Immunosuppressant Effect in Models of Transplantation.Wednesday, May 25, 2016
Ellis JD, Neil DA, Inston NG, Jenkinson E, Drayson MT, Hampson P, Shuttleworth SJ, Ready AR, Cobbold M,
Transplantation. 24-May-2016
HDAC6 may represent an optimal target for future immunosuppressant therapeutics with a particular role in transplantation. In this article, we have demonstrated a superior immunosuppressive effect of KA1010 over both CyA and SAHA, in the models of allotransplantation adopted.
Photoreponsive hybrid nanoparticles with inherent FRET activity.Wednesday, May 25, 2016
Achilleos DS, Hatton TA, Vamvakaki M,
Langmuir : the ACS journal of surfaces and colloids. 25-May-2016
The photoactivated inherent fluorescence resonance energy transfer (FRET) properties of a hard-and-soft hybrid nanosystem, comprising poly(1'-(2-methacryloxyethyl)-3',3'-dimethyl-6-nitrospiro-(2H-1-benzopyran-2,2'-indoline))-co-poly[2-(dimethylamino)ethyl methacrylate] (PSPMA-co-PDMAEMA) random copolymer brushes on silica nanoparticles are described. This unique FRET process is switched "on" by the simultaneous generation of isomer X and merocyanine (MC), which are bipolar in nature and comprise donor-acceptor dyads, from a single spiropyran (SP) chromophore upon UV irradiation. These X-MC species exhibit sufficient lifetimes to allow the read-out of the FRET process. The phenomenon is gradually switched "off" due to the thermal relaxation of the bipolar chromophores. This inherent property of the nanoemitters is employed in the development of biosensors of high specificity, by monitoring variations in the FRET efficiency and lifetime of the hybrids in the presence of biological substances. More specifically, bovine serum albumin (BSA) augments the formation of MC species and retards the MC photo-bleaching process leading to the enhancement of the FRET efficiency and lifetime, respectively. On the other hand, the aminoacid L-histidine retards further the MC thermal relaxation and prolongs the FRET process. We envisage that this platform opens new perspectives in the development of novel, optical nanosensors for applications in various fields including healthcare products and environmental monitoring.
Chloride-Mediated Apoptosis-Inducing Activity of bis(Sulfonamide) Anionophores.Wednesday, May 25, 2016
Saha T, Hossain MS, Saha D, Lahiri M, Talukdar P,
Journal of the American Chemical Society. 25-May-2016
Transmembrane anion transport modality is enjoying a renewal interest because of recent advances towards anticancer therapy. Here we show bis(sulfonamides) as efficient receptors for selective Cl(-) ion binding and transport across lipid bilayer membranes. Anion binding studies by (1)H NMR indicate a logical correlation between the acidity of sulfonamide N-H proton and binding strength. Such recognition is influenced further by the lipophilicity of a receptor during the ion transport process. Anion binding and transport activity of a bis(sulfonamide) system are far superior compared to corresponding bis(carboxylic amide) derivative. Fluorescent-based assays confirm the Cl(-)/anion antiport as the operational mechanism of the ion transport by bis(sulfonamides). The disruption of the ionic homeostasis by transported Cl(-) ion, via bis(sulfonamide), is found to impose cell death. Induction of caspase depended intrinsic pathway of apoptosis is confirmed by monitoring the change in mitrochondrial membrane potential, cytochrome c leakage, activation of family of caspases and nuclear fragmentation studies.
Modify workflows and embrace automation to help practices, patients.Wednesday, May 25, 2016
Tennant RM,
MGMA connexion / Medical group Management Association. Apr-2016
Data on sulforaphane treatment mediated suppression of autoreactive, inflammatory M1 macrophages.Wednesday, May 25, 2016
Pal S, Konkimalla VB,
Data in brief. Jun-2016
Any chronic, inflammatory, autoimmune disease (e.g. arthritis) associated pathogenesis directs uncontrolled accumulation of both soluble forms of collagens in the synovial fluids and M1 macrophages around inflamed tissues. Despite of few studies demonstrating efficiency of Sulforaphane (SFN) in suppressing arthritis associated collagen restricted T cells or fibroblasts, its effects on macrophage polarity and plasticity are less understood. Recently, we reported regulation of phenotypic and functional switching by SFN in induced and spontaneously differentiating human monocytes [1]. Here, flow cytometry, western blot and ELISA derived data demonstrated that SFN inhibited in vitro inflammatory responses developed by soluble human collagens (I-IV) induced auto-reactive M1 type monocyte/macrophage model.
Fabrication of molecular tension probes.Wednesday, May 25, 2016
Kim SB, Fujii R,
MethodsX. 2016
A unique bioluminescent imaging probe is introduced for illuminating molecular tension appended by protein-protein interactions (PPIs) of interest. A full-length luciferase is sandwiched between two proteins of interest via minimal flexible linkers. The ligand-activated PPIs append intramolecular tension to the sandwiched luciferase, boosting or dropping the enzymatic activity in a quantitative manner. This method guides construction of a new lineage of bioassays for determining molecular tension appended by ligand-activated PPIs. The summary of the method is: •Molecular tension appended by protein-protein interactions (PPI) is visualized with a luciferase.•Estrogen activities are quantitatively illuminated with the molecular tension probes.•Full-length Renilla luciferase enhances the optical intensities after bending by PPI.
Relationship between MTHFR C677T and A1298C gene polymorphisms and complications of type 2 diabetes mellitus in an Emirati population.Wednesday, May 25, 2016
El Hajj Chehadeh SW, Jelinek HF, Al Mahmeed WA, Tay GK, Odama UO, Elghazali GE, Al Safar HS,
Meta gene. Sep-2016
These findings demonstrate that the MTHFR gene polymorphisms are not related to T2DM in the Emirati population. However, these polymorphisms can be used as risk markers for CVA, nephropathy, high LDL cholesterol and triglycerides in T2DM patients and allow timely treatment.
Transcriptome of the freshwater amphipod Gammarus pulex hepatopancreas.Wednesday, May 25, 2016
Gismondi E, Thomé JP,
Genomics data. Jun-2016
So far, ecotoxicological studies used biomarkers of exposure or of effects in order to investigate the impacts of contaminated areas on biota (Peakall, 1994 [6]). However, although these results are important in the ecotoxicological risk assessment, biomarkers are very specific and only provide information on the biological processes or physiological pathways targeted by the biomarkers experimenters choose to test (Monsinjon and Knigge, 2007 [5]). In recent years, proteomics have become a major tool in ecotoxicology, as they provide a global insight into the mechanism of action of pollutants without the need of hypothesis testing or any preconception on the biological processes likely impacted (Gismondi et al., 2015; Trapp et al., 2015 [7]; Truebano, 2016 [8]). However, the analysis of proteomic results is often limited due to the lack of database, especially for non-model organisms, such as Gammarus sp, commonly used as biological model in ecotoxicology (Sornom et al., 2012 [11]; Vellinger et al., 2013 [9]; Gismondi and Thomé, 2014 [1]; Lebrun et al., 2014 [3]). Here, we performed Illumina HiSeq sequencing to total RNA isolated from the hepatopancreas (i.e. detoxification tissue) of Gammarus pulex males and females coming from uncontaminated river and contaminated river (e.g. PCB, benzo(a)pyrene). Approximately 290 M paired-end reads were assembled, filtered and sorted into 39,801 contigs whose 10.878 were similar of proteins available in databases. The assembled contigs could represent a reference hepatopancreas transcriptome for G. pulex, and constitute an important resource for future investigations on the impacts of pollutants on invertebrate biota, since it would improve the understanding of the mechanisms of action involved in toxicity. In addition, the hepatopancreas transcriptome will also allow the identification of new potential biomarkers for the ecotoxicological risk assessments. Assembled contigs were deposited in the European Nucleotide Archive under the BioProject number PRJEB13055, with accession numbers FJVI01000001-FJVI01039801.
Association between single nucleotide polymorphism in miR-499, miR-196a2, miR-146a and miR-149 and prostate cancer risk in a sample of Iranian population.Wednesday, May 25, 2016
Hashemi M, Moradi N, Ziaee SA, Narouie B, Soltani MH, Rezaei M, Shahkar G, Taheri M,
Journal of advanced research. May-2016
MicroRNAs (miRNAs) play an important role in regulating gene expression at the post-transcriptional level and are involved in numerous physiological processes. Accumulating evidence suggests that single-nucleotide polymorphisms (SNPs) in human miRNA genes may affect miRNA biogenesis pathway and influence the susceptibility to several diseases such as cancer. The present study aimed to evaluate the impact of miR-499 rs3746444, miR-196a2 rs11614913, miR-149 rs2292832, and miR-146a rs2910164 polymorphisms on prostate cancer (PCa) risk in a sample of Iranian population. This case-control study was done on 169 patients with pathologically confirmed PCa and 182 benign prostatic hyperplasia (BPH). The genotyping assays were done using T-ARMS-PCR or PCR-RFLP methods. The findings indicated that CC genotype of miR-499 rs3746444 polymorphism increased the risk of PCa (OR = 1.76, 95% CI = 1.12-2.79, P = 0.019) compared to TT genotype. No statistically significant association was found between miR-196a2 rs11614913, miR-149 rs2292832, and miR-146a rs2910164 polymorphisms and PCa risk. In summary, the findings indicated that miR-499 rs3746444 polymorphism increased the risk of PCa in an Iranian population. Further studies with larger sample sizes and different ethnicities are necessary to verify the findings of the present study.
A survey of FLS2 genes from multiple citrus species identifies candidates for enhancing disease resistance to Xanthomonas citri ssp. citri.Wednesday, May 25, 2016
Shi Q, Febres VJ, Jones JB, Moore GA,
Horticulture research. 2016
Pathogen-associated molecular patterns (PAMPs)-triggered immunity (PTI) is an important component of plant innate immunity. In a previous study, we showed that the PAMP flg22 from Xanthomonas citri ssp. citri (Xflg22), the causal agent of citrus canker, induced PTI in citrus, which correlated with the observed levels of canker resistance. Here, we identified and sequenced two bacterial flagellin/flg22 receptors (FLS2-1 and FLS2-2) from 'Duncan' grapefruit (Citrus paradisi, CpFLS2-1 and CpFLS2-2) and 'Sun Chu Sha' mandarin (C. reticulata, CrFLS2-1 and CrFLS2-2). We were able to isolate only one FLS2 from 'Nagami' kumquat (Fortunella margarita, FmFLS2-1) and gene flanking sequences suggest a rearrangement event that resulted in the deletion of FLS2-2 from the genome. Phylogenetic analysis, gene structure and presence of critical amino acid domains all indicate we identified the true FLS2 genes in citrus. FLS2-2 was more transcriptionally responsive to Xflg22 than FLS2-1, with induced expression levels higher in canker-resistant citrus than in susceptible ones. Interestingly, 'Nagami' kumquat showed the highest FLS2-1 steady-state expression levels, although it was not induced by Xflg22. We selected FmFLS2-1, CrFLS2-2 and CpFLS2-2 to further evaluate their capacity to enhance bacterial resistance using Agrobacterium-mediated transient expression assays. Both FmFLS2-1 and CrFLS2-2, the two proteins from canker-resistant species, conferred stronger Xflg22 responses and reduced canker symptoms in leaves of the susceptible grapefruit genotype. These two citrus genes will be useful resources to enhance PTI and achieve resistance against canker and possibly other bacterial pathogens in susceptible citrus types.
Multidrug-resistant tuberculosis outbreak in an Italian prison: tolerance of pyrazinamide plus levofloxacin prophylaxis and serial interferon gamma release assays.Wednesday, May 25, 2016
Bedini A, Garlassi E, Stentarelli C, Petrella S, Meacci M, Meccugni B, Meschiari M, Franceschini E, Cerri S, Brasacchio A, Rumpianesi F, Richeldi L, Mussini C,
New microbes and new infections. Jul-2016
The optimal treatment for latent tuberculosis infection (LTBI) in subjects exposed to multidrug-resistant (MDR) tuberculosis (TB) remains unclear, and the change in response of the QuantiFERON-TB Gold In-Tube (QTB-IT) test during and after treatment is unknown. Between May 2010 and August 2010, 39 prisoners at the 'Casa Circondariale' of Modena, Italy, were exposed to a patient with active pulmonary MDR TB. All contacts were tested with the tuberculin skin test and QTB-IT. Upon exclusion of active TB, subjects positive to both tests were offered 6 months' treatment with pyrazinamide (PZA) and levofloxacin (LVX). QTB-IT testing was repeated at 3 and 6 months after initial testing in all subjects who were offered LTBI treatment. Seventeen (43.5%) of 39 subjects tested positive to both tuberculin skin test and QTB-IT test, and 12 (70.5%) agreed to receive therapy with PZA and LVX at standard doses. Only five (41.6%) of 12 subjects completed 6 months' treatment. Reasons for discontinuation were asymptomatic hepatitis, gastritis and diarrhoea. The QTB-IT values decreased in all subjects who completed the treatment, in two (33%) of six of those who received treatment for less than 3 months and in one (50%) of two patients who discontinued therapy after 3 months. The QTB-IT test results never turned negative. Despite the small number of subjects, the study confirmed that PZA plus LVX is a poorly tolerated option for MDR LTBI treatment. We observed a large degree of variation in the results of the QTB-IT test results among participants. The study confirmed that the interferon gamma release assay is not a reliable tool for monitoring the treatment of MDR LTBI in clinical practice.
Oxidative Stress Measurement and Prediction of Epileptic Seizure in Children and Adults With Severe Motor and Intellectual Disabilities.Wednesday, May 25, 2016
Morimoto M, Satomura S, Hashimoto T, Ito E, Kyotani S,
Journal of clinical medicine research. Jun-2016
These results indicate that the use of d-ROMs and BAP as biomarkers can provide a tool for predicting the prognosis of epileptic seizures in patients with SMID.
Disagreement between two common biomarkers of global DNA methylation.Wednesday, May 25, 2016
Knothe C, Shiratori H, Resch E, Ultsch A, Geisslinger G, Doehring A, Lötsch J,
Clinical epigenetics. 2016
Although providing partly correlated measurements of DNA methylation, interchangeability of the quantitative results obtained with LINE-1 and LUMA was jeopardized by a consistent bias between the results. Moreover, the present analyses strongly indicate a tissue specificity of the differences between the two methods.
Production of a functional cell wall-anchored minicellulosome by recombinant Clostridium acetobutylicum ATCC 824.Wednesday, May 25, 2016
Willson BJ, Kovács K, Wilding-Steele T, Markus R, Winzer K, Minton NP,
Biotechnology for biofuels. 2016
We have been able to demonstrate the synthesis and in vivo assembly of a four-component minicellulosome by recombinant C. acetobutylicum strains. Furthermore, we have been able to anchor a minicellulosome to the C. acetobutylicum cell wall by the use of the native sortase system. The recombinant strains display an improved growth phenotype on xylan and an increase in released reducing sugar from several substrates including untreated powdered wheat straw. This constitutes an important milestone towards the development of a truly cellulolytic strain suitable for CBP.
The structure and regulation of Cullin 2 based E3 ubiquitin ligases and their biological functions.Wednesday, May 25, 2016
Cai W, Yang H,
Cell division. 2016
Cullin-2 based E3 ubiquitin ligases, using many different substrate recognition receptors, recognize a number of substrates and regulate their protein stability. These complexes play critical roles in biological processes and diseases such as cancer, germline differentiation and viral defense. Through the better understanding of their biology, we can devise and develop new therapeutic strategies to treat cancers, inherited diseases and viral infections.
High Ki67/BCL2 index is associated with worse outcome in early stage breast cancer.Wednesday, May 25, 2016
Min KW, Kim DH, Do SI, Pyo JS, Chae SW, Sohn JH, Kim K, Lee HJ, Kim DH, Oh S, Choi SH, Park YL, Park CH, Kwon MJ, Moon KM,
Postgraduate medical journal. 24-May-2016
The Ki67/BCL2 index should be considered as a prognostic predictor in patients with early stage invasive ductal carcinoma.
Type D personality is related to severity of acute coronary syndrome in patients with recurrent cardiovascular disease.Wednesday, May 25, 2016
Garcia-Retamero R, Petrova D, Arrebola-Moreno A, Catena A, Ramírez-Hernández JA,
British journal of health psychology. 25-May-2016
Type D personality was related to a worse lipid profile and more severe acute coronary syndrome in patients with previous history of CVD. Given the strong relationship between disease severity and subsequent mortality, these results suggest that severity of the myocardial infarction may be a potential mechanism explaining increased mortality in Type D patients with recurrent CVD. Statement of contribution What is already known on this subject? Type D personality has been related to worse outcomes in cardiac patients. However, recent studies show mixed results, suggesting the need to clarify potential mechanisms. What does this study add? Type D personality is related to severity of acute coronary syndrome in patients with previous history of cardiovascular disease. This effect is partially accounted for by lower HDL levels in Type D patients. Disease severity is a potential mechanism by which Type D personality may affect cardiovascular health of patients with recurrent CVD.
CXCR2 and CXCL4 regulate survival and self-renewal of hematopoietic stem/progenitor cells.Wednesday, May 25, 2016
Sinclair A, Park L, Shah M, Drotar M, Calaminus S, Hopcroft LE, Kinstrie R, Guitart AV, Dunn K, Abraham SA, Sansom O, Michie AM, Machesky L, Kranc KR, Graham GJ, Pellicano F, Holyoake TL,
Blood. 24-May-2016
The regulation of hematopoietic stem cell (HSC) survival and self-renewal within the bone marrow (BM) niche is not well understood. We therefore investigated global transcriptomic profiling of normal human hematopoietic stem/progenitor cells, revealing that several chemokine ligands (CXCL1-4, CXCL6, CXCL10, CXCL11, CXCL13) were up-regulated in human quiescent CD34(+)Hoescht(-)Pyronin Y(-) and primitive CD34(+)38(-), as compared to proliferating CD34(+)Hoechst(+)Pyronin Y(+) and CD34(+)38(+) stem/progenitor cells. This suggested that chemokines may play an important role in the homeostasis of HSCs. In human CD34(+) hematopoietic cells, knock-down of CXCL4 or pharmacological inhibition of the chemokine receptor CXCR2, significantly decreased cell viability and colony forming cell (CFC) potential. Studies on Cxcr2(-/-) mice demonstrated enhanced BM and spleen cellularity, with significantly increased numbers of HSC, hematopoietic progenitor cell (HPC)-1, HPC-2 and Lin(-)Sca-1(+)c-Kit(+) sub-populations. Cxcr2(-/-) stem/progenitor cells showed reduced self-renewal capacity as measured in serial transplantation assays. Parallel studies on Cxcl4 demonstrated reduced numbers of CFC in primary and secondary assays following knock-down in murine c-Kit(+) cells and Cxcl4(-/-) mice showed a decrease in HSC and reduced self-renewal capacity after secondary transplantation. These data demonstrate that the CXCR2 network and CXCL4 play a role in the maintenance of normal hematopoietic stem/progenitor cell fates, including survival and self-renewal.
Dietary diversity no longer offsets the mortality risk of hyperhomocysteinaemia in older adults with diabetes: a prospective cohort study.Wednesday, May 25, 2016
Wahlqvist ML, Xiu L, Lee MS, Chen RC, Chen KJ, Li D,
Asia Pacific journal of clinical nutrition. 2016
In non-diabetic hyperhomocysteinaemia, a more diverse diet increases survival prospects independent of B group vitamins, but not in hyperhomocysteinaemic diabetes where the cardiomyopathy may be less responsive.
Intake of added sugar in Malaysia: a review.Wednesday, May 25, 2016
Amarra MS, Khor GL, Chan P,
Asia Pacific journal of clinical nutrition. 2016
The term 'added sugars' refers to sugars and syrup added to foods during processing or preparation, and sugars and syrups added at the table. Calls to limit the daily intakes of added sugars and its sources arose from evidence analysed by WHO, the American Heart Association and other organizations. The present review examined the best available evidence regarding levels of added sugar consumption among different age and sex groups in Malaysia and sources of added sugars. Information was extracted from food balance sheets, household expenditure surveys, nutrition surveys and published studies. Varying results emerged, as nationwide information on intake of sugar and foods with added sugar were obtained at different times and used different assessment methods. Data from the 2003 Malaysian Adult Nutrition Survey (MANS) using food frequency questionnaires suggested that on average, Malaysian adults consumed 30 grams of sweetened condensed milk (equivalent to 16 grams sugar) and 21 grams of table sugar per day, which together are below the WHO recommendation of 50 grams sugar for every 2000 kcal/day to reduce risk of chronic disease. Published studies suggested that, for both adults and the elderly, frequently consumed sweetened foods were beverages (tea or coffee) with sweetened condensed milk and added sugar. More accurate data should be obtained by conducting population-wide studies using biomarkers of sugar intake (e.g. 24-hour urinary sucrose and fructose excretion or serum abundance of the stable isotope 13C) to determine intake levels, and multiple 24 hour recalls to identify major food sources of added sugar.
miR-375 inhibits the invasion and metastasis of colorectal cancer via targeting SP1 and regulating EMT-associated genes.Wednesday, May 25, 2016
Cui F, Wang S, Lao I, Zhou C, Kong H, Bayaxi N, Li J, Chen Q, Zhu T, Zhu H,
Oncology reports. 24-May-2016
Accumulating evidence has shown that aberrantly expressed microRNAs (miRNAs) are associated with tumor development and progression. Our previous study found that microRNA-375 (miR-375) was downregulated in colorectal cancer (CRC), but little is known concerning the role of miR-375 and the related mechanism in CRC development. The proliferation, invasion and migration effects were investigated by Cell Counting Kit-8 (CCK-8), colony formation and Transwell assays with or without Matrigel. In addition, candidate target genes were screened and validated by luciferase reporter and western blot assays. In addition, western blot analysis was performed to explore the molecular mechanisms associated with epithelial‑mesenchymal transition (EMT). It was found that miR-375 inhibited proliferation, invasion and migration in DLD1 and HCT8 cells. In addition, miR-375 negatively regulated Sp1 transcription factor (SP1) protein by directly binding to the 3'-untranslated region (3'-UTR). Furthermore, it was found that miR-375 regulated matrix metalloproteinase 2 (MMP2) and EMT-associated genes, E-cadherin, vimentin, snail, N-cadherin and β-catenin. In conclusion, miR-375 inhibited the proliferation, invasion and migration by directly targeting SP1 and regulating MMP2 and EMT-associated genes.
An eight-long non-coding RNA signature as a candidate prognostic biomarker for lung cancer.Wednesday, May 25, 2016
Tu Z, He D, Deng X, Xiong M, Huang X, Li X, Hao L, Ding Q, Zhang Q,
Oncology reports. 18-May-2016
Cumulative evidence suggests that long non-coding RNAs (lncRNAs) may be good biomarkers in various types of tumors. In the present study, we mined lncRNA expression profiling in 739 lung cancer patients from Gene Expression Omnibus (GEO) datasets. A risk score model was constructed based on the expression data of these eight lncRNAs in the training dataset (GSE30219). The validation for the association was performed in three independent testing sets (GSE31210, GSE37745 and GSE19188). Finally, a set of eight lncRNA genes (AK021595, BC030759, AK000053, AK124307, BC020384, AK022024, CR615992 and AF085995) were identified by the random survival forest algorithm. Using a risk score based on the expression signature of these lncRNAs, we separated the patients into low-risk and high-risk groups with significantly different survival times in the training set. This finding was validated in the other three testing sets. Further study revealed that the eight-lncRNA expression signature was independent of age and gender. Gene Set Enrichment Analysis (GSEA) suggested that lncRNAs were involved in cell cycle and DNA replication signaling pathways. Therefore, the eight lncRNAs may be candidate prognostic biomarkers for lung cancer patients.
Evaluation of the immunogenicity and protective effects of a trivalent chimeric norovirus P particle immunogen displaying influenza HA2 from subtypes H1, H3 and B.Wednesday, May 25, 2016
Gong X, Yin H, Shi Y, He X, Yu Y, Guan S, Kuai Z, Haji NM, Haji NM, Kong W, Shan Y,
Emerging microbes & infections. 2016
The ectodomain of the influenza A virus (IAV) hemagglutinin (HA) stem is highly conserved across strains and has shown promise as a universal influenza vaccine in a mouse model. In this study, potential B-cell epitopes were found through sequence alignment and epitope prediction in a stem fragment, HA2:90-105, which is highly conserved among virus subtypes H1, H3 and B. A norovirus (NoV) P particle platform was used to express the HA2:90-105 sequences from subtypes H1, H3 and B in loops 1, 2 and 3 of the protrusion (P) domain, respectively. Through mouse immunization and microneutralization assays, the immunogenicity and protective efficacy of the chimeric NoV P particle (trivalent HA2-PP) were tested against infection with three subtypes (H1N1, H3N2 and B) of IAV in Madin-Darby canine kidney cells. The protective efficacy of the trivalent HA2-PP was also evaluated preliminarily in vivo by virus challenge in the mouse model. The trivalent HA2-PP immunogen induced significant IgG antibody responses, which could be enhanced by a virus booster vaccination. Moreover, the trivalent HA2-PP immunogen also demonstrated in vitro neutralization of the H3 and B viruses, and in vivo protection against the H3 virus. Our results support the notion that a broadly protective vaccine approach using an HA2-based NoV P particle platform can provide cross-protection against challenge viruses of different IAV subtypes. The efficacy of the immunogen should be further enhanced for practicality, and a better understanding of the protective immune mechanism will be critical for the development of HA2-based multivalent vaccines.
Source: NCBI - Disclaimer and Copyright notice

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