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Showing 100 Latest Publications
TitleDate Created
Multistability analysis of a general class of recurrent neural networks with non-monotonic activation functions and time-varying delays.Monday, May 02, 2016
Liu P, Zeng Z, Wang J,
Neural networks : the official journal of the International Neural Network Society. 12-Apr-2016
This paper addresses the multistability for a general class of recurrent neural networks with time-varying delays. Without assuming the linearity or monotonicity of the activation functions, several new sufficient conditions are obtained to ensure the existence of (2K+1)(n) equilibrium points and the exponential stability of (K+1)(n) equilibrium points among them for n-neuron neural networks, where K is a positive integer and determined by the type of activation functions and the parameters of neural network jointly. The obtained results generalize and improve the earlier publications. Furthermore, the attraction basins of these exponentially stable equilibrium points are estimated. It is revealed that the attraction basins of these exponentially stable equilibrium points can be larger than their originally partitioned subsets. Finally, three illustrative numerical examples show the effectiveness of theoretical results.
Enzymes for N-Glycan Branching and Their Genetic and Nongenetic Regulation in Cancer.Monday, May 02, 2016
Kizuka Y, Taniguchi N,
Biomolecules. 12-4-2016
N-glycan, a fundamental and versatile protein modification in mammals, plays critical roles in various physiological and pathological events including cancer progression. The formation of N-glycan branches catalyzed by specific N-acetylglucosaminyltransferases [GnT-III, GnT-IVs, GnT-V, GnT-IX (Vb)] and a fucosyltransferase, Fut8, provides functionally diverse N-glycosylated proteins. Aberrations of these branches are often found in cancer cells and are profoundly involved in cancer growth, invasion and metastasis. In this review, we focus on the GlcNAc and fucose branches of N-glycans and describe how their expression is dysregulated in cancer by genetic and nongenetic mechanisms including epigenetics and nucleotide sugar metabolisms. We also survey the roles that these N-glycans play in cancer progression and therapeutics. Finally, we discuss possible applications of our knowledge on basic glycobiology to the development of medicine and biomarkers for cancer therapy.
Characterization of a Novel Polerovirus Infecting Maize in China.Monday, May 02, 2016
Chen S, Jiang G, Wu J, Liu Y, Qian Y, Zhou X,
Viruses. 28-4-2016
A novel virus, tentatively named Maize Yellow Mosaic Virus (MaYMV), was identified from the field-grown maize plants showing yellow mosaic symptoms on the leaves collected from the Yunnan Province of China by the deep sequencing of small RNAs. The complete 5642 nucleotide (nt)-long genome of the MaYMV shared the highest nucleotide sequence identity (73%) to Maize Yellow Dwarf Virus-RMV. Sequence comparisons and phylogenetic analyses suggested that MaYMV represents a new member of the genus Polerovirus in the family Luteoviridae. Furthermore, the P0 protein encoded by MaYMV was demonstrated to inhibit both local and systemic RNA silencing by co-infiltration assays using transgenic Nicotiana benthamiana line 16c carrying the GFP reporter gene, which further supported the identification of a new polerovirus. The biologically-active cDNA clone of MaYMV was generated by inserting the full-length cDNA of MaYMV into the binary vector pCB301. RT-PCR and Northern blot analyses showed that this clone was systemically infectious upon agro-inoculation into N. benthamiana. Subsequently, 13 different isolates of MaYMV from field-grown maize plants in different geographical locations of Yunnan and Guizhou provinces of China were sequenced. Analyses of their molecular variation indicate that the 3' half of P3-P5 read-through protein coding region was the most variable, whereas the coat protein- (CP-) and movement protein- (MP-)coding regions were the most conserved.
An Improved Alignment Method for the Strapdown Inertial Navigation System (SINS).Monday, May 02, 2016
Liu M, Gao Y, Li G, Guang X, Li S,
Sensors (Basel, Switzerland). 28-4-2016
In this paper, an innovative inertial navigation system (INS) mechanization and the associated Kalman filter (KF) are developed to implement a fine alignment for the strapdown INS (SINS) on stationary base. The improved mechanization is established in the pseudo-geographic frame, which is rebuilt based on the initial position. The new mechanization eliminates the effects of linear movement errors on the heading by decoupling. Compared with the traditional local-level mechanization, it has more advantages. The proposed algorithm requires lower coarse alignment accuracy in both the open-loop and closed-loop KFs and hence can improve the system reliability and decrease the total alignment time. Moreover, for the closed-loop KF, it can decrease oscillation caused by the system errors and improve the closed-loop system stability. In addition, the proposed algorithm can also be applied to polar alignment. The performance of the proposed algorithm is verified by both simulations and experiments and the results exhibit the superior performance of the proposed approach.
Effective Sensor Selection and Data Anomaly Detection for Condition Monitoring of Aircraft Engines.Monday, May 02, 2016
Liu L, Liu D, Zhang Y, Peng Y,
Sensors (Basel, Switzerland). 29-4-2016
In a complex system, condition monitoring (CM) can collect the system working status. The condition is mainly sensed by the pre-deployed sensors in/on the system. Most existing works study how to utilize the condition information to predict the upcoming anomalies, faults, or failures. There is also some research which focuses on the faults or anomalies of the sensing element (i.e., sensor) to enhance the system reliability. However, existing approaches ignore the correlation between sensor selecting strategy and data anomaly detection, which can also improve the system reliability. To address this issue, we study a new scheme which includes sensor selection strategy and data anomaly detection by utilizing information theory and Gaussian Process Regression (GPR). The sensors that are more appropriate for the system CM are first selected. Then, mutual information is utilized to weight the correlation among different sensors. The anomaly detection is carried out by using the correlation of sensor data. The sensor data sets that are utilized to carry out the evaluation are provided by National Aeronautics and Space Administration (NASA) Ames Research Center and have been used as Prognostics and Health Management (PHM) challenge data in 2008. By comparing the two different sensor selection strategies, the effectiveness of selection method on data anomaly detection is proved.
3-D Imaging Systems for Agricultural Applications-A Review.Monday, May 02, 2016
Vázquez-Arellano M, Griepentrog HW, Reiser D, Paraforos DS,
Sensors (Basel, Switzerland). 29-4-2016
Efficiency increase of resources through automation of agriculture requires more information about the production process, as well as process and machinery status. Sensors are necessary for monitoring the status and condition of production by recognizing the surrounding structures such as objects, field structures, natural or artificial markers, and obstacles. Currently, three dimensional (3-D) sensors are economically affordable and technologically advanced to a great extent, so a breakthrough is already possible if enough research projects are commercialized. The aim of this review paper is to investigate the state-of-the-art of 3-D vision systems in agriculture, and the role and value that only 3-D data can have to provide information about environmental structures based on the recent progress in optical 3-D sensors. The structure of this research consists of an overview of the different optical 3-D vision techniques, based on the basic principles. Afterwards, their application in agriculture are reviewed. The main focus lays on vehicle navigation, and crop and animal husbandry. The depth dimension brought by 3-D sensors provides key information that greatly facilitates the implementation of automation and robotics in agriculture.
Mycoplasma bovis MBOV_RS02825 Encodes a Secretory Nuclease Associated with Cytotoxicity.Monday, May 02, 2016
Zhang H, Zhao G, Guo Y, Menghwar H, Chen Y, Chen H, Guo A,
International journal of molecular sciences. 29-4-2016
This study aimed to determine the activity of one Mycoplasma bovis nuclease encoded by MBOV_RS02825 and its association with cytotoxicity. The bioinformatics analysis predicted that it encodes a Ca(2+)-dependent nuclease based on existence of enzymatic sites in a TNASE_3 domain derived from a Staphylococcus aureus thermonuclease (SNc). We cloned and purified the recombinant MbovNase (rMbovNase), and demonstrated its nuclease activity by digesting bovine macrophage linear DNA and RNA, and closed circular plasmid DNA in the presence of 10 mM Ca(2+) at 22-65 °C. In addition, this MbovNase was localized in membrane and rMbovNase able to degrade DNA matrix of neutrophil extracellular traps (NETs). When incubated with macrophages, rMbovNase bound to and invaded the cells localizing to both the cytoplasm and nuclei. These cells experienced apoptosis and the viability was significantly reduced. The apoptosis was confirmed by activated expression of phosphorylated NF-κB p65 and Bax, and inhibition of Iκβα and Bcl-2. In contrast, rMbovNase(Δ181-342) without TNASE_3 domain exhibited deficiency in all the biological functions. Furthermore, rMbovNase was also demonstrated to be secreted. In conclusion, it is a first report that MbovNase is an active nuclease, both secretory and membrane protein with ability to degrade NETs and induce apoptosis.
Data Interoperability of Whole Exome Sequencing (WES) Based Mutational Burden Estimates from Different Laboratories.Monday, May 02, 2016
Qiu P, Pang L, Arreaza G, Maguire M, Chang KC, Marton MJ, Levitan D,
International journal of molecular sciences. 29-4-2016
Immune checkpoint inhibitors, which unleash a patient's own T cells to kill tumors, are revolutionizing cancer treatment. Several independent studies suggest that higher non-synonymous mutational burden assessed by whole exome sequencing (WES) in tumors is associated with improved objective response, durable clinical benefit, and progression-free survival in immune checkpoint inhibitors treatment. Next-generation sequencing (NGS) is a promising technology being used in the clinic to direct patient treatment. Cancer genome WES poses a unique challenge due to tumor heterogeneity and sequencing artifacts introduced by formalin-fixed, paraffin-embedded (FFPE) tissue. In order to evaluate the data interoperability of WES data from different sources to survey tumor mutational landscape, we compared WES data of several tumor/normal matched samples from five commercial vendors. A large data discrepancy was observed from vendors' self-reported data. Independent data analysis from vendors' raw NGS data shows that whole exome sequencing data from qualified vendors can be combined and analyzed uniformly to derive comparable quantitative estimates of tumor mutational burden.
Proteome Profile and Quantitative Proteomic Analysis of Buffalo (Bubalusbubalis) Follicular Fluid during Follicle Development.Monday, May 02, 2016
Fu Q, Huang Y, Wang Z, Chen F, Huang D, Lu Y, Liang X, Zhang M,
International journal of molecular sciences. 29-4-2016
Follicular fluid (FF) accumulates in the antrum of the ovarian follicle and provides the microenvironment for oocyte development. FF plays an important role in follicle growth and oocyte maturation. The FF provides a unique window to investigate the processes occurring during buffalo follicular development. The observed low quality of buffalo oocytes may arise from the poor follicular microenvironment. Investigating proteins found in buffalo FF (BFF) should provide insight into follicular development processes and provide further understanding of intra-follicular maturation and oocytes quality. Here, a proteomic-based approach was used to analyze the proteome of BFF. SDS-PAGE separation combined with mass spectrometry was used to generate the proteomic dataset. In total, 363 proteins were identified and classified by Gene Ontology terms. The proteins were assigned to 153 pathways, including signaling pathways. To evaluate difference in proteins expressed between BFF with different follicle size (small, <4 mm; and large, >8 mm), a quantitative proteomic analysis based on multi-dimensional liquid chromatography pre-fractionation tandem Orbitrap mass spectrometry identification was performed. Eleven differentially expressed proteins (six downregulated and five upregulated in large BFF) were identified and assigned to a variety of functional processes, including serine protease inhibition, oxidation protection and the complement cascade system. Three differentially expressed proteins, Vimentin, Peroxiredoxin-1 and SERPIND1, were verified by Western blotting, consistent with the quantitative proteomics results. Our datasets offers new information about proteins present in BFF and should facilitate the development of new biomarkers. These differentially expressed proteins illuminate the size-dependent protein changes in follicle microenvironment.
One-Pot Three-Component Synthesis of Novel Diethyl((2-oxo-1,2-dihydroquinolin-3-yl)(arylamino)methyl)phosphonate as Potential Anticancer Agents.Monday, May 02, 2016
Fang YL, Wu ZL, Xiao MW, Tang YT, Li KM, Ye J, Xiang JN, Hu AX,
International journal of molecular sciences. 29-4-2016
With the aim of discovering new anticancer agents, we have designed and synthesized novel α-aminophosphonate derivatives containing a 2-oxoquinoline structure using a convenient one-pot three-component method. The newly synthesized compounds were evaluated for antitumor activities against the A549 (human lung adenocarcinoma cell), HeLa (human cervical carcinoma cell), MCF-7 (human breast cancer cell), and U2OS (human osteosarcoma cell) cancer cell lines in vitro, employing a standard 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. The results of pharmacological screening indicated that many compounds exhibited moderate to high levels of antitumor activities against the tested cancer cell lines and that most compounds showed more potent inhibitory activities comparable to 5-fluorouracil (5-FU) which was used as a positive control. The mechanism of representative compound 4u (diethyl((2-oxo-1,2-dihydroquinolin-3-yl)(phenyl-amino)methyl)phosphonate) indicated that the compound mainly arrested HeLa cells in S and G2 stages and was accompanied by apoptosis in HeLa cells. This action was confirmed by acridine orange/ethidium bromide staining, Hoechst 33342 staining, and flow cytometry.
Photoactivatable Caged Prodrugs of VEGFR-2 Kinase Inhibitors.Monday, May 02, 2016
Pinchuk B, Horbert R, Döbber A, Kuhl L, Peifer C,
Molecules (Basel, Switzerland). 29-4-2016
In this study, we report on the design, synthesis, photokinetic properties and in vitro evaluation of photoactivatable caged prodrugs for the receptor tyrosine kinase VEGFR-2. Highly potent VEGFR-2 inhibitors 1 and 3 were caged by introduction of a photoremovable protecting group (PPG) to yield the caged prodrugs 4 and 5. As expected, enzymatic and cellular proliferation assays showed dramatically diminished efficacy of caged prodrugs in vitro. Upon ultraviolet (UV) irradiation of the prodrugs original inhibitory activity was completely restored and even distinctly reinforced, as was the case for the prodrug 4. The presented results are a further evidence for caging technique being an interesting approach in the protein kinase field. It could enable spatial and temporal control for the inhibition of VEGFR-2. The described photoactivatable prodrugs might be highly useful as biological probes for studying the VEGFR-2 signal transduction.
The Traditional Medicine and Modern Medicine from Natural Products.Monday, May 02, 2016
Yuan H, Ma Q, Ye L, Piao G,
Molecules (Basel, Switzerland). 29-4-2016
Natural products and traditional medicines are of great importance. Such forms of medicine as traditional Chinese medicine, Ayurveda, Kampo, traditional Korean medicine, and Unani have been practiced in some areas of the world and have blossomed into orderly-regulated systems of medicine. This study aims to review the literature on the relationship among natural products, traditional medicines, and modern medicine, and to explore the possible concepts and methodologies from natural products and traditional medicines to further develop drug discovery. The unique characteristics of theory, application, current role or status, and modern research of eight kinds of traditional medicine systems are summarized in this study. Although only a tiny fraction of the existing plant species have been scientifically researched for bioactivities since 1805, when the first pharmacologically-active compound morphine was isolated from opium, natural products and traditional medicines have already made fruitful contributions for modern medicine. When used to develop new drugs, natural products and traditional medicines have their incomparable advantages, such as abundant clinical experiences, and their unique diversity of chemical structures and biological activities.
Nerolidol: A Sesquiterpene Alcohol with Multi-Faceted Pharmacological and Biological Activities.Monday, May 02, 2016
Chan WK, Tan LT, Chan KG, Lee LH, Goh BH,
Molecules (Basel, Switzerland). 29-4-2016
Nerolidol (3,7,11-trimethyl-1,6,10-dodecatrien-3-ol) is a naturally occurring sesquiterpene alcohol that is present in various plants with a floral odor. It is synthesized as an intermediate in the production of (3E)-4,8-dimethy-1,3,7-nonatriene (DMNT), a herbivore-induced volatile that protects plants from herbivore damage. Chemically, nerolidol exists in two geometric isomers, a trans and a cis form. The usage of nerolidol is widespread across different industries. It has been widely used in cosmetics (e.g., shampoos and perfumes) and in non-cosmetic products (e.g., detergents and cleansers). In fact, U.S. Food and Drug Administration (FDA) has also permitted the use of nerolidol as a food flavoring agent. The fact that nerolidol is a common ingredient in many products has attracted researchers to explore more medicinal properties of nerolidol that may exert beneficial effect on human health. Therefore, the aim of this review is to compile and consolidate the data on the various pharmacological and biological activities displayed by nerolidol. Furthermore, this review also includes pharmacokinetic and toxicological studies of nerolidol. In summary, the various pharmacological and biological activities demonstrated in this review highlight the prospects of nerolidol as a promising chemical or drug candidate in the field of agriculture and medicine.
Interaction of Di-2-pyridylketone 2-pyridine Carboxylic Acid Hydrazone and Its Copper Complex with BSA: Effect on Antitumor Activity as Revealed by Spectroscopic Studies.Monday, May 02, 2016
Li C, Huang T, Fu Y, Liu Y, Zhou S, Qi Z, Li C,
Molecules (Basel, Switzerland). 28-4-2016
The drug, di-2-pyridylketone-2-pyridine carboxylic acid hydrazone (DPPCAH) and its copper complex (DPPCAH-Cu) exhibit significant antitumor activity. However, the mechanism of their pharmacological interaction with the biological molecule bovine serum albumin (BSA) remains poorly understood. The present study elucidates the interactions between the drug and BSA through MTT assays, spectroscopic methods and molecular docking analysis. Our results indicate that BSA could attenuate effect on the cytotoxicity of DPPCAH, but not DPPCAH-Cu. Data from fluorescence quenching measurements demonstrated that both DPPCAH and DPPCAH-Cu could bind to BSA, with a reversed effect on the environment of tryptophan residues in polarity. CD spectra revealed that the DPPCAH-Cu exerted a slightly stronger effect on the secondary structure of BSA than DPPCAH. The association constant of DPPCAH with BSA was greater than that of DPPCAH-Cu. Docking studies indicated that the binding of DPPCAH to BSA involved a greater number of hydrogen bonds compared to DPPCAH-Cu. The calculated distances between bound ligands and tryptophans in BSA were in agreement with fluorescence resonance energy transfer results. Thus, the binding affinity of the drug (DPPCAH or DPPCAH-Cu) with BSA partially contributes to its antitumor activity; the greater the drug affinity is to BSA, the less is its antitumor activity.
Gradient Infiltration of Neutrophil Extracellular Traps in Colon Cancer and Evidence for Their Involvement in Tumour Growth.Monday, May 02, 2016
Arelaki S, Arampatzioglou A, Kambas K, Papagoras C, Miltiades P, Angelidou I, Mitsios A, Kotsianidis I, Skendros P, Sivridis E, Maroulakou I, Giatromanolaki A, Ritis K,
PloS one. 28-4-2016
These data support further the role of neutrophils and NETs in cancer biology. We also suggest their involvement on cancer cell growth.
Recommendations for the electronic pre-transfusion check at the bedside.Monday, May 02, 2016
Ohsaka A, Kato H, Kino S, Kawabata K, Kitazawa J, Sugimoto T, Takeshita A, Baba K, Hamaguchi M, Fujii Y, Horiuchi K, Yonemura Y, Hamaguchi I, Handa M,
Blood transfusion = Trasfusione del sangue. 21-Mar-2016
Viral metagenomics applied to blood donors and recipients at high risk for blood-borne infections.Monday, May 02, 2016
Sauvage V, Laperche S, Cheval J, Muth E, Dubois M, Boizeau L, Hébert C, Lionnet F, Lefrère JJ, Eloit M,
Blood transfusion = Trasfusione del sangue. 16-Mar-2016
This study did not identify any new blood-borne virus in high-risk individuals. However, rare and/or viruses present at very low titre could have escaped our protocol. Our results demonstrate the positive contribution of HTS in the detection of viral sequences in blood donations.
Microparticles variability in fresh frozen plasma: preparation protocol and storage time effects.Monday, May 02, 2016
Kriebardis AG, Antonelou MH, Georgatzakou HT, Tzounakas VL, Stamoulis KE, Papassideri IS,
Blood transfusion = Trasfusione del sangue. 22-Feb-2016
The preparation protocol and the duration of storage in the freezer, independently and in combination, influenced the accumulation of microparticles in fresh frozen plasma units. In contrast, storage of thawed units for 24 h at 4 ºC had no significant effect on the concentration of microparticles.
Solving Biology's Iron Chemistry Problem with Ferritin Protein Nanocages.Monday, May 02, 2016
Theil EC, Tosha T, Behera RK,
Accounts of chemical research. 2-May-2016
Ferritins reversibly synthesize iron-oxy(ferrihydrite) biominerals inside large, hollow protein nanocages (10-12 nm, ∼480 000 g/mol); the iron biominerals are metabolic iron concentrates for iron protein biosyntheses. Protein cages of 12- or 24-folded ferritin subunits (4-α-helix polypeptide bundles) self-assemble, experimentally. Ferritin biomineral structures differ among animals and plants or bacteria. The basic ferritin mineral structure is ferrihydrite (Fe2O3·H2O) with either low phosphate in the highly ordered animal ferritin biominerals, Fe/PO4 ∼ 8:1, or Fe/PO4 ∼ 1:1 in the more amorphous ferritin biominerals of plants and bacteria. While different ferritin environments, plant bacterial-like plastid organelles and animal cytoplasm, might explain ferritin biomineral differences, investigation is required. Currently, the physiological significance of plant-specific and animal-specific ferritin iron minerals is unknown. The iron content of ferritin in living tissues ranges from zero in "apoferritin" to as high as ∼4500 iron atoms. Ferritin biomineralization begins with the reaction of Fe(2+) with O2 at ferritin enzyme (Fe(2+)/O oxidoreductase) sites. The product of ferritin enzyme activity, diferric oxy complexes, is also the precursor of ferritin biomineral. Concentrations of Fe(3+) equivalent to 2.0 × 10(-1) M are maintained in ferritin solutions, contrasting with the Fe(3+) Ks ∼ 10(-18) M. Iron ions move into, through, and out of ferritin protein cages in structural subdomains containing conserved amino acids. Cage subdomains include (1) ion channels for Fe(2+) entry/exit, (2) enzyme (oxidoreductase) site for coupling Fe(2+) and O yielding diferric oxy biomineral precursors, and (3) ferric oxy nucleation channels, where diferric oxy products from up to three enzyme sites interact while moving toward the central, biomineral growth cavity (12 nm diameter) where ferric oxy species, now 48-mers, grow in ferric oxy biomineral. High ferritin protein cage symmetry (3-fold and 4-fold axes) and amino acid conservation coincide with function, shown by amino acid substitution effects. 3-Fold symmetry axes control Fe(2+) entry (enzyme catalysis of Fe(2+)/O2 oxidoreduction) and Fe(2+) exit (reductive ferritin mineral dissolution); 3-fold symmetry axes influence Fe(2+)exit from dissolved mineral; bacterial ferritins diverge slightly in Fe/O2 reaction mechanisms and intracage paths of iron-oxy complexes. Biosynthesis rates of ferritin protein change with Fe(2+) and O2 concentrations, dependent on DNA-binding, and heme binding protein, Bach 1. Increased cellular O2 indirectly stabilizes ferritin DNA/Bach 1 interactions. Heme, Fe-protoporphyrin IX, decreases ferritin DNA-Bach 1 binding, causing increased ferritin mRNA biosynthesis (transcription). Direct Fe(2+) binding to ferritin mRNA decreases binding of an inhibitory protein, IRP, causing increased ferritin mRNA translation (protein biosynthesis). Newly synthesized ferritin protein consumes Fe(2+) in biomineral, decreasing Fe(2)(+) and creating a regulatory feedback loop. Ferritin without iron is "apoferritin". Iron removal from ferritin, experimentally, uses biological reductants, for example, NADH + FMN, or chemical reductants, for example, thioglycolic acid, with Fe(2+) chelators; physiological mechanism(s) are murky. Clear, however, is the necessity of ferritin for terrestrial life by conferring oxidant protection (plants, animals, and bacteria), virulence (bacteria), and embryonic survival (mammals). Future studies of ferritin structure/function and Fe(2+)/O2 chemistry will lead to new ferritin uses in medicine, nutrition, and nanochemistry.
Chlorin p6-based Water-soluble Amino Acid Derivatives as Potent Photosensitizers for Photodynamic Therapy.Monday, May 02, 2016
Meng Z, Yu B, Han G, Liu M, Shan B, Dong G, Miao Z, Jia N, Tan Z, Li B, Zhang W, Zhu H, Sheng C, Yao J,
Journal of medicinal chemistry. 2-May-2016
The development of novel photosensitizer with high phototoxicity, low dark-toxicity and good water solubility is a challenging task for photodynamic therapy (PDT). A series of chlorin p6-based water-soluble amino acid conjugates were synthesized and investigated for antitumor activity. Among them, aspartylchlorin p6 dimethylester (7b) showed highest phototoxicity against melanoma cells with weakest dark-toxicity, which was more phototoxic than verteporfin while with less dark-toxicity. It also exhibited better in vivo PDT antitumor efficacy on mice bearing B16-F10 tumor than verteporfin. The biological assays revealed that 7b was localized in multiple subcellular organelles, and could cause both cell necrosis and apoptosis after PDT in a dose dependent manner, resulting in more effective cell destruction. As a result, 7b represents a promising photosensitizer for PDT applications because of its strong absorption in the phototherapeutic window, relatively high singlet oxygen quantum yield, highest dark-toxicity/phototoxicity ratio, good water-solubility and excellent in vivo PDT antitumor efficacy.
Radioprotective Effect of Epigallocatechin-3-Gallate on Salivary Gland Dysfunction After Radioiodine Ablation in a Murine Model.Monday, May 02, 2016
Choi JS, An HY, Park IS, Kim SK, Kim YM, Lim JY,
Clinical and experimental otorhinolaryngology. 2-May-2016
EGCG supplementation before RI therapy could protect from RI-induced SG damage in a manner comparable to amifostine, and thus, offers a possible means of preventing SG damage by RI.
Development and Validation of a Universal High-Throughput UDP-Glycosyltransferase Assay with a Time-Resolved FRET Signal.Monday, May 02, 2016
Zielinski T, Reichman M, Donover PS, Lowery RG,
Assay and drug development technologies. 2-May-2016
Glycosyltransferase enzymes play diverse metabolic and regulatory roles by catalyzing the transfer of sugar molecules to protein, lipid, and carbohydrate acceptors, and they are increasingly of interest as therapeutic targets in a number of diseases, including metabolic disorders, cancer, and infectious diseases. The glycosyltransferases are a challenging target class from an assay development perspective because of the diversity of both donor and acceptor substrates and the lack of suitable glycan detection methods. However, many glycosyltransferases use uridine 5'-diphosphate (UDP) sugars as donor substrates, and detection of the free UDP reaction product provides a generic approach for measuring the activity of those enzymes. To exploit this approach for a broadly applicable high-throughput screening (HTS) assay for discovery of glycosyltransferase inhibitors, we developed a Transcreener(®) assay for immunodetection of UDP with a time-resolved Förster resonance energy transfer (TR-FRET) signal. We optimized the assay for detection of glycosyltransferase activity with nucleotide diphosphate (NDP) sugars at concentrations from 10 μM to 1 mM, achieving Z' values of 0.6 or higher. The assay was validated by orthogonal pooled screening with 8,000 compounds using polypeptide N-acetylgalactosaminyltransferase T3 as the target, and the hits were confirmed using an orthogonal readout. The reagents and signal were both stable for more than 8 h at room temperature, insuring robust performance in automated HTS environments. The TR-FRET-based UDP detection assay provides a broadly applicable approach for screening glycosyltransferases that use a UDP-sugar donor.
Kidney Transplantation With Corticosteroids Alone After Haploidentical HSCT From The Same Donor.Monday, May 02, 2016
Schwarz C, Lawitschka A, Böhmig GA, Dauber EM, Greinix H, Kozakowski N, Mühlbacher F, Berlakovich GA, Wekerle T,
Transplantation. 29-Apr-2016
This is one of the first cases of kidney transplantation from the same donor after previous haploidentical HSCT with a corticosteroid taper alone. Our results suggest that immunosuppression can be avoided in such cases.
Microparticles in sickle cell anaemia: promise and pitfalls.Monday, May 02, 2016
Hebbel RP, Key NS,
British journal of haematology. 2-May-2016
Blood from patients with sickle cell disease contains microparticles (MP) derived from multiple cell sources, including red cells, platelets, monocytes and endothelial cells. MPs are of great interest because of their disease associations, their status as promising biomarkers, and the intercellular communications they mediate. To illustrate the likelihood of their relevance in sickle cell disease, we discuss the nature of MP, their profiling in sickle disease, some caveats relevant to their detection, their roles in supporting coagulation and the disparate influences they may exert upon the pathobiology of sickle cell disease.
Moving Denitrifying Bioreactors beyond Proof of Concept: Introduction to the Special Section.Monday, May 02, 2016
Christianson LE, Schipper LA,
Journal of environmental quality. May-2016
Denitrifying bioreactors are organic carbon-filled excavations designed to enhance the natural process of denitrification for the simple, passive treatment of nitrate-nitrogen. Research on and installation of these bioreactors has accelerated within the past 10 years, particularly in watersheds concerned about high nonpoint-source nitrate loads and also for tertiary wastewater treatment. This special section, inspired by the meeting of the Managing Denitrification in Agronomic Systems Community at the 2014 Annual Meeting of the American Society of Agronomy, Crop Science Society of America, and Soil Science Society of America, aims to firmly establish that denitrifying bioreactors for treatment of nitrate in drainage waters, groundwater, and some wastewaters have moved beyond the proof of concept. This collection of 14 papers expands the peer-reviewed literature of denitrifying bioreactors into new locations, applications, and environmental conditions. There is momentum behind the pairing of wood-based bioreactors with other media (biochar, corn cobs) and in novel designs (e.g., use within treatment trains or use of baffles) to broaden applicability into new kinds of waters and pollutants and to improve performance under challenging field conditions such as cool early season agricultural drainage. Concerns about negative bioreactor by-products (nitrous oxide and hydrogen sulfide emissions, start-up nutrient flushing) are ongoing, but this translates into a significant research opportunity to develop more advanced designs and to fine tune management strategies. Future research must think more broadly to address bioreactor impacts on holistic watershed health and greenhouse gas balances and to facilitate collaborations that allow investigation of mechanisms within the bioreactor "black box."
Prognostic Value of ALDH1, EZH2 and Ki-67 in Astrocytic Gliomas.Monday, May 02, 2016
Ahmed S, Rashed H, Hegazy A, Mohamed AM, Elmesallamy W,
Turk patoloji dergisi. 3-5-2016
Increased expression of ALDH1, EZH2 and KI67 are found to be associated with unfavourable prognosis in patients with astrocytic gliomas and may predict therapeutic modalities.
Pulchrin A, a New Natural Coumarin Derivative of Enicosanthellum pulchrum, Induces Apoptosis in Ovarian Cancer Cells via Intrinsic Pathway.Monday, May 02, 2016
Nordin N, Fadaeinasab M, Mohan S, Mohd Hashim N, Othman R, Karimian H, Iman V, Ramli N, Mohd Ali H, Abdul Majid N,
PloS one. 3-5-2016
Drug resistance presents a challenge in chemotherapy and has attracted research interest worldwide and particular attention has been given to natural compounds to overcome this difficulty. Pulchrin A, a new compound isolated from natural products has demonstrated novel potential for development as a drug. The identification of pulchrin A was conducted using several spectroscopic techniques such as nuclear magnetic resonance, liquid chromatography mass spectrometer, infrared and ultraviolet spectrometry. The cytotoxicity effects on CAOV-3 cells indicates that pulchrin A is more active than cisplatin, which has an IC50 of 22.3 μM. Significant changes in cell morphology were present, such as cell membrane blebbing and formation of apoptotic bodies. The involvement of phosphatidylserine (PS) in apoptosis was confirmed by Annexin V-FITC after a 24 h treatment. Apoptosis was activated through the intrinsic pathway by activation of procaspases 3 and 9 as well as cleaved caspases 3 and 9 and ended at the executioner pathway, with the occurrence of DNA laddering. Apoptosis was further confirmed via gene and protein expression levels, in which Bcl-2 protein was down-regulated and Bax protein was up-regulated. Furthermore, the CAOV-3 cell cycle was disrupted at the G0/G1 phase, leading to apoptosis. Molecular modeling of Bcl-2 proteins demonstrated a high- binding affinity, which inhibited the function of Bcl-2 proteins and led to cell death. Results of the current study can shed light on the development of new therapeutic agents, particularly, human ovarian cancer treatments.
Loss of Pcgf5 Affects Global H2A Monoubiquitination but Not the Function of Hematopoietic Stem and Progenitor Cells.Monday, May 02, 2016
Si S, Nakajima-Takagi Y, Aoyama K, Oshima M, Saraya A, Sugishita H, Nakayama M, Ishikura T, Koseki H, Iwama A,
PloS one. 2-5-2016
Polycomb-group RING finger proteins (Pcgf1-Pcgf6) are components of Polycomb repressive complex 1 (PRC1)-related complexes that catalyze monoubiquitination of histone H2A at lysine 119 (H2AK119ub1), an epigenetic mark associated with repression of genes. Pcgf5 has been characterized as a component of PRC1.5, one of the non-canonical PRC1, consisting of Ring1a/b, Rybp/Yaf2 and Auts2. However, the biological functions of Pcgf5 have not yet been identified. Here we analyzed the impact of the deletion of Pcgf5 specifically in hematopoietic stem and progenitor cells (HSPCs). Pcgf5 is expressed preferentially in hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) compared with committed myeloid progenitors and differentiated cells. We transplanted bone marrow (BM) cells from Rosa::Cre-ERT control and Cre-ERT;Pcgf5fl/fl mice into lethally irradiated recipient mice. At 4 weeks post-transplantation, we deleted Pcgf5 by injecting tamoxifen, however, no obvious changes in hematopoiesis were detected including the number of HSPCs during a long-term observation period following the deletion. Competitive BM repopulating assays revealed normal repopulating capacity of Pcgf5-deficient HSCs. Nevertheless, Pcgf5-deficient HSPCs showed a significant reduction in H2AK119ub1 levels compared with the control. ChIP-sequence analysis confirmed the reduction in H2AK119ub1 levels, but revealed no significant association of changes in H2AK119ub1 levels with gene expression levels. Our findings demonstrate that Pcgf5-containing PRC1 functions as a histone modifier in vivo, but its role in HSPCs is limited and can be compensated by other PRC1-related complexes in HSPCs.
Purification and partial characterization of a fibrinolytic enzyme from the fruiting body of the medicinal and edible mushroom Pleurotus ferulae.Monday, May 02, 2016
Choi JH, Kim DW, Kim S, Kim SJ,
Preparative biochemistry & biotechnology. 2-May-2016
A fibrinolytic metalloprotease with in vitro fibrinolytic effects was purified from the edible mushroom, Pleurotus ferulae using several chromatography steps including anion- and ion-exchange, gel filtration, and fast protein liquid chromatography (FPLC) columns. The molecular mass of the enzyme was estimated to be 20.0 kDa, as determined using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and fibrin zymography. The protease was active at 50 °C, and pH 4.0, 5.0, and 8.0. The fibrinolytic activity of the enzyme was inhibited by EGTA, and strongly inhibited by two metal ions, Cu and Mg. In vitro assays evaluating fibrinolytic activity on a fibrin plate, fibrin turbidity, and thrombolytic activity on fibrin clots using human fibrinogen and human thrombin revealed that the enzyme could hydrolyze fibrin polymers directly and inhibit the formation of fibrin clots. In activated partial thromboplastin time (APTT) and prothrombin time (PT) assays, the enzyme strongly prolonged the APTT, which detects an activity of intrinsic and common pathways. The enzyme showed strong in vivo protective effect against mortality/paralysis from epinephrine plus collagen induced acute thromboembolism in in vivo model. Our findings suggest that the enzyme may have a potential for treatment and prevention of thrombosis-relative disesases.
Digital Three-Dimensional Automation of the Modified Huddart and Bodenham Scoring System for Patients With Cleft Lip and Palate.Monday, May 02, 2016
Ma X, Martin C, McIntyre G, Lin P, Mossey P,
The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association. 2-May-2016
  The automated system facilitates quicker and more reliable outcome assessments by minimizing human errors.
Volatile organic compounds in breath as markers for irritable bowel syndrome: a metabolomic approach.Monday, May 02, 2016
Baranska A, Mujagic Z, Smolinska A, Dallinga JW, Jonkers DM, Tigchelaar EF, Dekens J, Zhernakova A, Ludwig T, Masclee AA, Wijmenga C, van Schooten FJ,
Alimentary pharmacology & therapeutics. 2-May-2016
A set of 16 breath-based biomarkers that distinguishes IBS patients from healthy controls was identified. The VOC-biomarker set correlated significantly with GI symptoms in two independent cohorts. We demonstrate the potential use of breath analysis in the diagnosis and monitoring of IBS, and a possible application of VOC analyses in a general population cohort.
Factors influencing survival among Kenyan children diagnosed with endemic Burkitt lymphoma between 2003 and 2011: A historical cohort study.Monday, May 02, 2016
Buckle G, Maranda L, Skiles J, Ong'echa JM, Foley J, Epstein M, Vik TA, Schroeder A, Lemberger J, Rosmarin A, Remick SC, Bailey JA, Vulule J, Otieno JA, Moormann AM,
International journal of cancer. 2-May-2016
Discovering how to improve survival and establishing clinical reference points for children diagnosed with endemic Burkitt lymphoma (eBL) in resource-constrained settings has recaptured international attention. Using multivariate analyses, we evaluated 428 children with eBL in Kenya for age, gender, tumor stage, nutritional status, hemoglobin, lactate dehydrogenase (LDH), Epstein-Barr virus (EBV) and Plasmodium falciparum prior to induction of chemotherapy (cyclophosphamide, vincristine, methotrexate, and doxorubicin) to identify predictive and prognostic biomarkers of survival. During this ten year prospective study period, 22% died in-hospital and 78% completed six-courses of chemotherapy. Of those, 16% relapsed or died later; 31% achieved event-free-survival; and 31% were lost to follow-up; the overall one-year survival was 45%. After adjusting for co-variates, low hemoglobin (<8g/dL) and high LDH (>400 mU/ml) were associated with increased risk of death (adjusted Hazard Ratio (aHR)=1.57 [0.97 to 2.41]) and aHR=1.84, [0.91 to 3.69], respectively). Anemic children with malaria were 3.55 times more likely to die [1.10 to 11.44] compared to patients without anemia or malarial infection. EBV load did not differ by tumor stage nor was it associated with survival. System-level factors can also contribute to poor outcomes. Children were more likely to die when inadvertently overdosed by more than 115% of the correct dose of cyclophosphamide (a HR=1.43 [0.84 to 2.43]), or doxorubicin (a HR=1.25, [0.66 to 2.35]), compared to those receiving accurate doses of the respective agent in this setting. This study codifies risk factors associated with poor outcomes for eBL patients in Africa and provides a benchmark by which to assess improvements in survival for new chemotherapeutic approaches. This article is protected by copyright. All rights reserved.
The Biomarker GlycA Is Associated with Chronic Inflammation and Predicts Long-Term Risk of Severe Infection.Monday, May 02, 2016
Ritchie SC, Würtz P, Nath AP, Abraham G, Havulinna AS, Fearnley LG, Sarin AP, Kangas AJ, Soininen P, Aalto K, Seppälä I, Raitoharju E, Salmi M, Maksimow M, Männistö S, Kähönen M, Juonala M, Ripatti S, Lehtimäki T, Jalkanen S, Perola M, Raitakari O, Salomaa V, Ala-Korpela M, Kettunen J, Inouye M,
Cell systems. 28-Oct-2015
The biomarker glycoprotein acetylation (GlycA) has been shown to predict risk of cardiovascular disease and all-cause mortality. Here, we characterize biological processes associated with GlycA by leveraging population-based omics data and health records from >10,000 individuals. Our analyses show that GlycA levels are chronic within individuals for up to a decade. In apparently healthy individuals, elevated GlycA corresponded to elevation of myriad inflammatory cytokines, as well as a gene coexpression network indicative of increased neutrophil activity, suggesting that individuals with high GlycA may be in a state of chronic inflammatory response. Accordingly, analysis of infection-related hospitalization and death records showed that increased GlycA increased long-term risk of severe non-localized and respiratory infections, particularly septicaemia and pneumonia. In total, our work demonstrates that GlycA is a biomarker for chronic inflammation, neutrophil activity, and risk of future severe infection. It also illustrates the utility of leveraging multi-layered omics data and health records to elucidate the molecular and cellular processes associated with biomarkers.
L-Glutamate deficiency can trigger proliferation inhibition via down regulation of the mTOR/S6K1 pathway in pig intestinal epithelial cells.Monday, May 02, 2016
Li XG, Sui WG, Gao CQ, Yan HC, Yin YL, Li HC, Wang XQ,
Journal of animal science. Apr-2016
The objective of this study was to investigate the effects of L-glutamate (Glu) deficiency or L-trans pyrrolidine-2,4-dicarboxylic acid (PDC) supplementation on the proliferation of pig intestinal epithelial cells (IPEC-1). First, IPEC-1 cells were cultured in normal growing medium supplemented with 0 (Control), 50, 100, or 200 µmol/L PDC to determine an appropriate concentration of PDC supplementation. Second, IPEC-1 cells were cultured in Glu-deficient medium supplemented with 0 µmol/L Glu (Glu deficiency), 50 µmol/L Glu (Control), or 50 µmol/L Glu plus 100 µmol/L PDC (PDC supplementation). Cell proliferation ( = 24), cell cycle distribution ( = 6), cell apoptosis ( = 6), and expression levels of proteins of interest ( = 4) were determined by MTT assay, flow cytometry, or western blot. The results showed that cell proliferation was inhibited ( < 0.05) by 50, 100, and 200 µmol/L PDC supplementation at 24 and 48 h after treatment. Variance analysis was performed using the GLM procedure, and the results demonstrated that Glu deficiency or PDC supplementation led to the inhibition ( < 0.05) of cell proliferation, a greater ( < 0.05) percentage of cells in the G1 phase, and a lower ( < 0.05) percentage of cells in the S phase. Moreover, Glu deficiency or PDC supplementation reduced ( < 0.05) the expression levels of excitatory AA transporter 3 (EAAT3), phosphor-mammalian target of rapamycin (p-mTOR; Ser2448), p-ribosomal protein S6 kinase 1 (S6K1; Thr389), and p-S6 (Ser235/236). This study demonstrates that Glu deficiency or PDC supplementation inhibits proliferation of IPEC-1 cells via downregulation of the mTOR/S6K1 pathway and EAAT3 expression indicating that Glu deficiency may lead to the disturbances of intestinal epithelial renewal in pigs, particularly in neonates.
Identification of potential serum biomarkers to predict feed efficiency in young pigs.Monday, May 02, 2016
Grubbs JK, Dekkers JC, Huff-Lonergan E, Tuggle CK, Lonergan SM,
Journal of animal science. Apr-2016
Identification of biomarkers for feed efficiency in livestock will aid in the efficient production of high-quality protein to meet the demands of a growing population. The overall objective of this research was to identify biomarkers in serum for swine feed efficiency and to discover pathways affected by divergent selection for residual feed intake (RFI). Serum was collected from young pigs (between 35 and 42 d of age) from 2 lines of pigs that have been genetically selected to be either more efficient (low-RFI) or less efficient (high-RFI). After blood collection, during finishing, pigs from each line were placed on either a low-energy/high-fiber diet or a traditional high-energy/low-fiber diet to test for any diet effects on RFI. Subsets of 6 pigs per line within each diet were used in 3 independent experiments. Pigs with extreme RFI phenotypes from the low-energy/high-fiber diet were used to confirm the results from the first 2 comparisons. Two-dimensional difference in gel electrophoresis and mass spectrometry were used to identify proteins with different abundances between RFI line or finishing diet. Three proteins had consistent and significant ( < 0.05) RFI line differences for both diets: gelsolin, vitronectin, and serine protease inhibitor A3 (serpinA3). Abundance of gelsolin, a protein with roles in actin filament assembly and immune response, was greater in the more efficient low-RFI pigs (9 to 39%). Vitronectin was also more abundant in the low-RFI pigs (39 to 56%) and has known roles in blood homeostasis and may regulate adiposity. SerpinA3 is a member of a very large family of proteins referred to as serine protease inhibitors. A total of 14 spots that were more abundant in the low-RFI line, some at least twice as abundant, were identified as serpinA3. Multiple isoforms of serpinA3 have been reported (serpinA3-1 to serpinA3-4 in pigs and serpinA3-1 to serpinA3-8 in cattle) with serpinA3 having many different functions dependent on isoform. Gelsolin, vitronectin, and serpinA3 are 3 proteins that may play direct and important biological roles in the pathways that control RFI and, ultimately, feed efficiency through energy utilization and homeostasis. These data demonstrate that serum proteins can be a useful source of potential biomarkers for feed efficiency and provide information on pathways with distinct expression patterns between animals that differ in feed efficiency.
Oncogenic Notch signaling in T-cell and B-cell lymphoproliferative disorders.Monday, May 02, 2016
Chiang MY, Radojcic V, Maillard I,
Current opinion in hematology. 28-Apr-2016
Notch signaling is a recurrent oncogenic pathway in multiple T- and B-cell lymphoproliferative disorders. Understanding the complexity and consequences of Notch activation is critical to define optimal therapeutic strategies targeting the Notch pathway.
An unbiased metric of antiproliferative drug effect in vitro.Monday, May 02, 2016
Harris LA, Frick PL, Garbett SP, Hardeman KN, Paudel BB, Lopez CF, Quaranta V, Tyson DR,
Nature methods. 2-May-2016
In vitro cell proliferation assays are widely used in pharmacology, molecular biology, and drug discovery. Using theoretical modeling and experimentation, we show that current metrics of antiproliferative small molecule effect suffer from time-dependent bias, leading to inaccurate assessments of parameters such as drug potency and efficacy. We propose the drug-induced proliferation (DIP) rate, the slope of the line on a plot of cell population doublings versus time, as an alternative, time-independent metric.
Growth rate inhibition metrics correct for confounders in measuring sensitivity to cancer drugs.Monday, May 02, 2016
Hafner M, Niepel M, Chung M, Sorger PK,
Nature methods. 2-May-2016
Drug sensitivity and resistance are conventionally quantified by IC50 or Emax values, but these metrics are highly sensitive to the number of divisions taking place over the course of a response assay. The dependency of IC50 and Emax on division rate creates artefactual correlations between genotype and drug sensitivity, while obscuring valuable biological insights and interfering with biomarker discovery. We derive alternative small molecule drug-response metrics that are insensitive to division number. These are based on estimation of the magnitude of drug-induced growth rate inhibition (GR) using endpoint or time-course assays. We show that GR50 and GRmax are superior to conventional metrics for assessing the effects of small molecule drugs in dividing cells. Moreover, adopting GR metrics requires only modest changes in experimental protocols. We expect GR metrics to improve the study of cell signaling and growth using small molecules and biologics and to facilitate the discovery of drug-response biomarkers and the identification of drugs effective against specific patient-derived tumor cells.
Biomimetic anchors applied to the host-guest antifouling functionalization of titanium substrates.Monday, May 02, 2016
Cai XY, Li NN, Chen JC, Kang ET, Xu LQ,
Journal of colloid and interface science. 21-Apr-2016
A biomimetic strategy was developed for the construction of antifouling titanium oxide (Ti(oxide)) surfaces based on host-guest interactions. Two catecholic derivatives, dopamine 4-(phenylazo)benzamide (AZODopa) and dopamine 1-adamantanecarboxamide (AdaDopa) were synthesized and immobilized onto the Ti(oxide) surfaces. The guest molecules-anchored Ti(oxide) surfaces were further functionalized with zwitterionic heptakis[6-deoxy-6-(N-3-sulfopropyl-N,N-dimethylammonium ethyl sulfanyl)]-β-cyclodextrin (SBCD) and hydrophilic β-CD polymer (CDP). The surface elemental compositions and hydrophobic/hydrophilic properties of the Ti(oxide) surfaces before and after modification were characterized by X-ray photoelectron spectroscopy (XPS) and static water contact angle measurements, respectively. The antifouling properties of the modified Ti(oxide) surfaces were evaluated by the protein adsorption and bacterial adhesion assays. The zwitterionic SBCD- and hydrophilic CDP-functionalized Ti(oxide) surfaces can reduce the adsorption of bovine plasma fibrinogen and adhesion of Escherichia coli, as compared to the pristine and guest molecules-anchored Ti(oxide) surfaces.
Effects of in vitro exposure to butylparaben and di-(2 ethylhexyl) phthalate, alone or in combination, on ovarian function.Monday, May 02, 2016
Guerra MT, Furlong HC, Kempinas WG, Foster WG,
Journal of applied toxicology : JAT. 2-May-2016
Parabens and phthalates are commercial chemicals widely used in the manufacture of industrial and consumer products frequently found as contaminants in biological fluids. We evaluated the effects of di-(2-ethylhexyl) phthalate (DEHP) (ranging from 10(-9) to 10(-7) m [1-100 nm; 0.39-39 ng ml(-1) ]) and butylparaben (BP) (ranging from 10(-8) to 10(-5) m [10 nm-10 μm; 1.9 ng ml(-1) to 1.9 μg ml(-1) ]), alone and in combination, on isolated mouse preantral follicle and human granulosa cell (hGC) cultures to study direct effects on follicle growth and ovarian steroidogenesis. Our results revealed that, in follicle culture, DEHP and BP attenuate estradiol output but only when present together. DEHP decreases progesterone concentrations in the spent media of hGC cultures, an effect that was attenuated when BP was added together with DEHP. Although changes in steroidogenesis were observed, no effects on follicular development or survival were noted in the culture systems. We suggest that BP and DEHP act with additive effect to decrease estradiol production whereas at later stages of follicle development BP blocks the effect of DEHP in hGCs resulting in decreased progesterone output. Taken together our results suggest that DEHP and BP adversely affect steroidogenesis from the preantral stage onward and the effects of these chemicals are both stage-dependent and modified by co-exposure. Copyright © 2016 John Wiley & Sons, Ltd.
Metabolomics for the Authentication of Natural Extracts Used in Flavours and Fragrances: the Case Study of Violet Leaf Absolutes from Viola odorata.Monday, May 02, 2016
Saint-Lary L, Roy C, Paris JP, Martin JF, Thomas OP, Fernandez X,
Chemistry & biodiversity. 2-May-2016
Natural extracts used in fine fragrances (alcoholic perfumes) are rare and precious. As such, they represent an interesting target for fraudulent practices called adulterations. Absolutes, important materials used in the creation of perfumes, are obtained by organic solvent extraction of raw plant materials. Because the non-volatile part of these natural extracts is not normalized and scarcely reported in the literature, highlighting potential adulterations present in this fraction appears highly challenging. For the first time, we investigated the use of non-targeted UHPLC-ToFMS metabolomics for this purpose, considering Viola odorata L., a plant largely used in the perfume industry, as a model. Significant differences in the metabolic fingerprints of the violet leaf absolutes were evidenced according to geographical locations, and/or adulterations. Additionally, markers of the geographical origin were detected through their molecular weight/most probable molecular formula and retention time while adulterations were statistically validated. In this study, we thus clearly demonstrated the efficiency of UHPLC-ToFMS based metabolomics in accelerating both the identification of the origin of raw materials as well as the search for potential adulterations in absolutes, natural products of high added value. This article is protected by copyright. All rights reserved.
The P450 CYP6Z1 confers carbamate/pyrethroid cross-resistance in a major African malaria vector beside a novel carbamate-insensitive N485I acetylcholinesterase-1 mutation.Monday, May 02, 2016
Ibrahim SS, Ndula M, Riveron JM, Irving H, Wondji CS,
Molecular ecology. 2-May-2016
Carbamates are increasingly used for vector control notably in areas with pyrethroid resistance. However, a cross-resistance between these insecticides in major malaria vectors such as Anopheles funestus could severely limit available resistance management options. Unfortunately, the molecular basis of such cross-resistance remains uncharacterized in An. funestus, preventing effective resistance management. Here, using a genome-wide transcription profiling, we revealed that metabolic resistance through up-regulation of cytochrome P450 genes is driving carbamate resistance. The P450s CYP6P9a, CYP6P9b and CYP6Z1 were the most up-regulated detoxification genes in the multiple resistant mosquitoes. However, in silico docking simulations predicted CYP6Z1 to metabolise both pyrethroids and carbamates, whereas CYP6P9a and CYP6P9b were predicted to metabolise only the pyrethroids. Using recombinant enzyme metabolism and inhibition assays we demonstrated that CYP6Z1 metabolizes bendiocarb and pyrethroids, whereas CYP6P9a and CYP6P9b metabolise only the pyrethroids. Other up-regulated gene families in resistant mosquitoes included several cuticular protein genes suggesting a possible reduced penetration resistance mechanism. Investigation of the target-site resistance in acetylcholinesterase 1 (ace-1) gene detected and established the association between the new N485I mutation and bendiocarb resistance (Odds ratio 7.3; P<0.0001). The detection of multiple haplotypes in single mosquitoes after cloning suggested the duplication of ace-1. A TaqMan genotyping of the N485I in nine countries revealed that the mutation is located only in Southern Africa with frequency of 10-15% suggesting its recent occurrence. These findings will help in monitoring the spread and evolution of carbamate resistance and improve the design of effective resistance management strategies to control this malaria vector. This article is protected by copyright. All rights reserved.
Proton transfer dynamics control the mechanism of O2 reduction by a non-precious metal electrocatalyst.Monday, May 02, 2016
Tse EC, Barile CJ, Kirchschlager NA, Li Y, Gewargis JP, Zimmerman SC, Hosseini A, Gewirth AA,
Nature materials. 2-May-2016
Many chemical and biological processes involve the transfer of both protons and electrons. The complex mechanistic details of these proton-coupled electron transfer (PCET) reactions require independent control of both electron and proton transfer. In this report, we make use of lipid-modified electrodes to modulate proton transport to a Cu-based catalyst that facilitates the O2 reduction reaction (ORR), a PCET process important in fuel cells and O2 reduction enzymes. By quantitatively controlling the kinetics of proton transport to the catalyst, we demonstrate that undesired side products such as H2O2 and O2(-) arise from a mismatch between proton and electron transfer rates. Whereas fast proton kinetics induce H2O2 formation and sluggish proton flux produces O2(-), proton transfer rates commensurate with O-O bond breaking rates ensure that only the desired H2O product forms. This fundamental insight aids in the development of a comprehensive framework for understanding the ORR and PCET processes in general.
Nivolumab, anti-programmed death-1 (PD-1) monoclonal antibody immunotherapy: Role in Advanced Cancers.Monday, May 02, 2016
Rajan A, Kim C, Heery CR, Guha U, Gulley JL,
Human vaccines & immunotherapeutics. 2-May-2016
The development of immune checkpoint inhibitors has altered the landscape of treatment of advanced cancers. These drugs are well tolerated and have shown clinical activity against a wide variety of solid tumors and hematological malignancies. The durability of response is particularly impressive when compared to other forms of systemic therapy. Nivolumab (Opdivo) is an IgG4 antibody that causes immune checkpoint blockade by diminishing inhibitory signaling through the programmed death receptor-1 pathway. It is approved for treatment of recurrent non-small cell lung cancer, melanoma, and renal cell carcinoma. Efforts to identify biomarkers of response to nivolumab are ongoing. Clinical trials are also being conducted to determine the benefits of combining nivolumab with other forms of treatment including chemotherapy, molecular-targeted therapy, radiation therapy, and other forms of immune therapy. This review outlines the clinical trials that have led to the emergence of nivolumab as a treatment option for patients with advanced cancers.
Can Signal Abnormalities Detected with MR Imaging in Knee Articular Cartilage Be Used to Predict Development of Morphologic Cartilage Defects? 48-Month Data from the Osteoarthritis Initiative.Monday, May 02, 2016
Schwaiger BJ, Gersing AS, Mbapte Wamba J, Nevitt MC, McCulloch CE, Link TM,
Radiology. 2-May-2016
Purpose To determine the incidence with which morphologic articular cartilage defects develop over 48 months in cartilage with signal abnormalities at baseline magnetic resonance (MR) imaging in comparison with the incidence in articular cartilage without signal abnormalities at baseline. Materials and Methods The institutional review boards of all participating centers approved this HIPAA-compliant study. Right knees of 90 subjects from the Osteoarthritis Initiative (mean age, 55 years ± 8 [standard deviation]; 51% women) with cartilage signal abnormalities but without morphologic cartilage defects at 3.0-T MR imaging and without radiographic osteoarthritis (Kellgren-Lawrence score, 0-1) were frequency matched for age, sex, Kellgren-Lawrence score, and body mass index with right knees in 90 subjects without any signal abnormalities or morphologic defects in the articular cartilage (mean age, 54 years ± 5; 51% women). Individual signal abnormalities (n = 126) on intermediate-weighted fast spin-echo MR images were categorized into four subgrades: subgrade A, hypointense; subgrade B, inhomogeneous; subgrade C, hyperintense; and subgrade D, hyperintense with swelling. The development of morphologic articular cartilage defects (Whole-Organ MR Imaging Score ≥2) at 48 months was analyzed on a compartment level and was compared between groups by using generalized estimating equation logistic regression models. Results Cartilage signal abnormalities were more frequent in the patellofemoral joint than in the tibiofemoral joint (59.5% vs 39.5%). Subgrade A was seen more frequently than were subgrades C and D (36% vs 22%). Incidence of morphologic cartilage defects at 48 months was 57% in cartilage with baseline signal abnormalities, while only 4% of compartments without baseline signal abnormalities developed morphologic defects at 48 months (all compartments combined and each compartment separately, P < .01). The development of morphologic defects was not significantly more likely in any of the subgrades (P = .98) and was significantly associated with progression of bone marrow abnormalities (P = .002). Conclusion Knee cartilage signal abnormalities detected with MR imaging are precursors of morphologic defects with osteoarthritis and may serve as imaging biomarkers with which to assess risk for cartilage degeneration. (©) RSNA, 2016.
Internal Jugular Vein Cross-Sectional Area and Cerebrospinal Fluid Pulsatility in the Aqueduct of Sylvius: A Comparative Study between Healthy Subjects and Multiple Sclerosis Patients.Monday, May 02, 2016
Beggs CB, Magnano C, Belov P, Krawiecki J, Ramasamy DP, Hagemeier J, Zivadinov R,
PloS one. 2-5-2016
In healthy adults, increased CSF pulsatility is associated with increased IJV-CSA in the lower cervix (independent of age and cardiovascular risk factors), suggesting a biomechanical link between the two. This relationship is altered in MS patients.
A Series of microRNA in the Chromosome 14q32.2 Maternally Imprinted Region Related to Progression of Non-Alcoholic Fatty Liver Disease in a Mouse Model.Monday, May 02, 2016
Okamoto K, Koda M, Okamoto T, Onoyama T, Miyoshi K, Kishina M, Kato J, Tokunaga S, Sugihara TA, Hara Y, Hino K, Murawaki Y,
PloS one. 2-5-2016
The expression profiles of seven miRNAs in 14q32.2 mat have high potential as biomarkers for NAFLD and for improving future research on the pathogenesis and treatment of NASH.
Perilipin 5 restores the formation of lipid droplets in activated hepatic stellate cells and inhibits their activation.Monday, May 02, 2016
Lin J, Chen A,
Laboratory investigation; a journal of technical methods and pathology. 2-May-2016
Hepatic stellate cells (HSC) are major effectors during hepatic fibrogenesis. The activation of HSC is coupled to the loss of lipid droplets (LDs), which are specialized organelles composed of neutral lipids surrounded by perilipins. LDs have emerged as a focal point of interest in understanding the metabolic regulation of intrahepatic lipids during lipid-mediated liver fibrogenesis. Perilipin 5 (Plin5) is a newly identified LD protein in the perilipin family, which plays a key role in regulating aspects of intracellular trafficking, signaling, and cytoskeletal organization in hepatocytes. Recent work in Plin5 knockout mice suggests a role in high fat diet-induced hepatic lipotoxicity. The current report is to evaluate the impact of Plin5 on HSC activation and to elucidate the underlying mechanisms. We now show that high fat diet-induced liver fibrosis is accompanied by an approximate 75% reduction in Plin5 in HSC, and that spontaneous activation of primary HSC produces temporally coincident loss of Plin5 expression and LD depletion. As modulating lipid content in HSC is a suggested strategy for inhibition of HSC activation and treatment of hepatic fibrosis, we asked whether exogenous Plin5 expression in primary HSC would reverse the activation phenotype and promote LD formation. Recombinant lentiviral Plin5 expression in primary mouse HSC restored the formation of LDs, increased lipid content by inducing expression of pro-lipogenic genes and suppressing expression of pro-lipolytic genes, and suppressed HSC activation (~two fold reduction in expression of procollagen and α-smooth muscle actin, two unique biomarkers for activated HSC). In addition, the expression of exogenous Plin5 in HSC attenuated cellular oxidative stress by reducing cellular reactive oxygen species, elevating cellular glutathione, and inducing gene expression of glutamate-cysteine ligase. Taken together, our results indicate that expression of Plin5 plays a critical role in the formation of LDs, the elevation of lipid content in HSC, and the inhibition of the activation of HSC.Laboratory Investigation advance online publication, 2 May 2016; doi:10.1038/labinvest.2016.53.
Meroterpenoids with Antiproliferative Activity from a Hawaiian-Plant Associated Fungus Peyronellaea coffeae-arabicae FT238.Monday, May 02, 2016
Li CS, Ren G, Yang BJ, Miklossy G, Turkson J, Fei P, Ding Y, Walker LA, Cao S,
Organic letters. 2-May-2016
Three unusual polyketide-sesquiterpene metabolites peyronellins A-C (1-3), along with the new epoxyphomalin analog 11-dehydroxy epoxyphomalin A (4), have been isolated from the endophytic fungus Peyronellaea coffeae-arabicae FT238, which was isolated from the native Hawaiian plant Pritchardia lowreyana. The structures of compounds 1-4 were characterized based on NMR and MS spectroscopic analysis. The absolute configuration (AC) of the compounds was determined by electronic circular dichroism (ECD). Compound 4 showed antiproliferative activity with an IC50 of 0.5 μM against OVCAR3, and it also strongly inhibited Stat3 at 5 μM.
Psychometric Validation of an Instrument to Measure Family Coping During a Child's Hospitalization for Cancer.Monday, May 02, 2016
Lyu QY, Kong SK, Wong FK, You LM, Yan J, Zhou XZ, Li XW,
Cancer nursing. 29-Apr-2016
The HCS can be used by pediatric oncology nurses to assess the effectiveness of family coping during a hospitalization of their child with cancer and may help pediatric oncology nurses to develop and implement realistic support strategies based on assessments of family coping effectiveness.
Cancer targeted enzymatic theranostic prodrug: Precise diagnosis and chemotherapy.Monday, May 02, 2016
Shin WS, Han J, Verwilst P, Kumar R, Kim JH, Kim JS,
Bioconjugate chemistry. 2-May-2016
The development of targeted and effective theranostic (therapeutic and diagnostic) chemotherapeutic agents is highly desirable for precise diagnosis and treatment of cancer. To realize this goal, we developed a cancer-targeting and enzyme-triggered theranostic prodrug 1, containing 7-ethyl-10-hydroxycamptothecin (SN-38), a well-known anticancer drug, which inhibits topoisomerase I in the cell nucleus; hydroquinone as an enzyme-triggered moiety; and biotin as a cancer targeting unit. Enzyme-triggered theranostic prodrug 1 selectively targets cancer cells and is subsequently activated in the presence of NAD(P)H: quinone oxidoreductase-1 (NQO1), a cytosolic flavoprotein that catalyzes the two-electron reduction of quinone moieties with the concomitant consumption of NADH or NADPH as electron donors. High levels of NQO1 were found in a variety of cancer cell lines compared to healthy cells, and therefore, it is an excellent target for the development of cancer targeted drug delivery systems. Upon preferential cancer cell delivery and uptake, aided by biotin, the enzyme-triggered theranostic prodrug 1 is cleaved by NQO1, with the subsequent release of SN-38, inhibiting topoisomerase I, leading to apoptosis. The drug release and induced apoptosis of cancer cells expressing both biotin receptors and high levels of NQO1 was simultaneously monitored via the innate fluorescence of the released SN-38 by confocal microscopy. In vitro and in vivo studies showed an effective inhibition of cancer growth by the enzyme-triggered theranostic prodrug 1. Thus, this type of enzyme-triggered targeted prodrug therapy is an interesting and promising approach for future cancer treatment.
Tobacco Use Patterns in a Southern US HIV Clinic.Monday, May 02, 2016
Bean MC, Richey LE, Williams K, Wahlquist AE, Kilby JM,
Southern medical journal. May-2016
This study supports that high rates of smoking exist in the south among people living with HIV and AIDS and demonstrated a need for smoking cessation interventions among these patients. These data have potentiated the hiring of a clinical pharmacist to aid in implementation of smoking cessation therapies in a more systematic and formal way.
Cyclic Ketoximes as Estrogen Receptor β Selective Agonists.Monday, May 02, 2016
Granchi C, Lapillo M, Spena CR, Rizzolio F, Tuccinardi T, Martin TA, Carlson KE, Katzenellenbogen JA, Minutolo F,
ChemMedChem. 2-May-2016
The development of estrogen receptor β (ERβ)-selective agonists represents a therapeutic strategy against several kinds of cancers, but the high homology between the two receptor subtypes, ERα and ERβ, makes the achievement of this goal very challenging. In the past, we developed salicylaldoxime- and salicylketoxime-based molecules that proved to bind well to ERβ. In this paper, further structural evolution of the salicylketoximes is presented: two of the newly synthesized five-membered cyclic ketoximes bind with nanomolar affinities to ERβ, and they show selectivity for this subtype over ERα. Their agonist character was confirmed by cell-free coactivator recruitment assays, in which we demonstrated the ability of these compounds to form an active complex with ERβ capable of recruiting coactivator proteins; this indicated their efficacy as agonists. Finally, their potency and selectivity for ERβ binding were rationalized by molecular-modeling studies.
Vacuolin-1 inhibits autophagy by impairing lysosomal maturation via PIKfyve inhibition.Monday, May 02, 2016
Sano O, Kazetani K, Funata M, Fukuda Y, Matsui J, Iwata H,
FEBS letters. 2-May-2016
Lysosomal protein degradation via autophagy strictly regulates cellular protein homeostasis. Herein we performed high-content screening to identify compounds that inhibit autophagy pathways. We obtained 11 hit compounds and performed cluster analysis using cellular morphological information. Vacuolin-1, which induces the formation of giant vacuoles and is a target unknown compound, clustered with the known PIKfyve inhibitor YM201636. We further confirmed that vacuolin-1 is a potent PIKfyve inhibitor, and we finally concluded that PIKfyve inhibitors are novel chemical tools for regulating autophagy. This article is protected by copyright. All rights reserved.
Circulating ceramides are inversely associated with cardiorespiratory fitness in participants aged 54-96 years from the Baltimore Longitudinal Study of Aging.Monday, May 02, 2016
Fabbri E, Yang A, Simonsick EM, Chia CW, Zoli M, Haughey NJ, Mielke MM, Ferrucci L, Coen PM,
Aging cell. 2-May-2016
Cardiorespiratory fitness (VO2 peak) declines with age and is an independent risk factor for morbidity and mortality in older adults. Identifying biomarkers of low fitness may provide insight for why some individuals experience an accelerated decline of aerobic capacity and may serve as clinically valuable prognostic indicators of cardiovascular health. We investigated the relationship between circulating ceramides and VO2 peak in 443 men and women (mean age of 69) enrolled in the Baltimore Longitudinal Study of Aging (BLSA). Individual species of ceramide were quantified by HPLC-tandem mass spectrometry. VO2 peak was measured by a graded treadmill test. We applied multiple regression models to test the associations between ceramide species and VO2 peak, while adjusting for age, sex, blood pressure, serum LDL, HDL, triglycerides, and other covariates. We found that higher levels of circulating C18:0, C20:0, C24:1 ceramides and C20:0 dihydroceramides were strongly associated with lower aerobic capacity (P < 0.001, P < 0.001, P = 0.018, and P < 0.001, respectively). The associations held true for both sexes (with men having a stronger association than women, P value for sex interaction <0.05) and were unchanged after adjusting for confounders and multiple comparison correction. Interestingly, no significant association was found for C16:0, C22:0, C24:0, C26:0, and C22:1 ceramide species, C24:0 dihydroceramide, or total ceramides. Our analysis reveals that specific long-chain ceramides strongly associate with low cardiovascular fitness in older adults and may be implicated in the pathogenesis of low fitness with aging. Longitudinal studies are needed to further validate these associations and investigate the relationship between ceramides and health outcomes.
Does the Chemical Diversity of the Order Haplosclerida (Phylum Porifera: Class Demospongia) Fit with Current Taxonomic Classification?Monday, May 02, 2016
Tribalat MA, Marra MV, McCormack GP, Thomas OP,
Planta medica. 2-May-2016
Sponges and their associated microbiota are well known to produce a large diversity of natural products, also called specialized metabolites. In addition to their potential use in the pharmaceutical industry, these rather species-specific compounds may help in the classification of some particular sponge groups. We review herein compounds isolated from haplosclerid sponges (Class Demospongia, Order Haplosclerida) in order to help in the revision of this large group of marine invertebrates. We focus only on 3-alkylpyridine derivatives and polyacetylenic compounds, as these two groups of natural products are characteristic of haplosclerid species and are highly diverse. A close collaboration between chemists and biologists is required in order to fully apply chemotaxonomical approaches, and whenever possible biological data should include morphological and molecular data and some insight into their microbial abundance.
Embracing the complexity of matricellular proteins: the functional and clinical significance of splice variation.Monday, May 02, 2016
Viloria K, Hill NJ,
Biomolecular concepts. 1-May-2016
Matricellular proteins influence wide-ranging fundamental cellular processes including cell adhesion, migration, growth and differentiation. They achieve this both through interactions with cell surface receptors and regulation of the matrix environment. Many matricellular proteins are also associated with diverse clinical disorders including cancer and diabetes. Alternative splicing is a precisely regulated process that can produce multiple isoforms with variable functions from a single gene. To date, the expression of alternate transcripts for the matricellular family has been reported for only a handful of genes. Here we analyse the evidence for alternative splicing across the matricellular family including the secreted protein acidic and rich in cysteine (SPARC), thrombospondin, tenascin and CCN families. We find that matricellular proteins have double the average number of splice variants per gene, and discuss the types of domain affected by splicing in matricellular proteins. We also review the clinical significance of alternative splicing for three specific matricellular proteins that have been relatively well characterised: osteopontin (OPN), tenascin-C (TNC) and periostin. Embracing the complexity of matricellular splice variants will be important for understanding the sometimes contradictory function of these powerful regulatory proteins, and for their effective clinical application as biomarkers and therapeutic targets.
Rebound Syndrome in Patients With Multiple Sclerosis After Cessation of Fingolimod Treatment.Monday, May 02, 2016
Hatcher SE, Waubant E, Nourbakhsh B, Crabtree-Hartman E, Graves JS,
JAMA neurology. 2-May-2016
These cases provide evidence for a fingolimod rebound syndrome at a clinically relevant frequency, highlighting the need to determine the best methods for sequencing or discontinuing MS therapies. A large prospective registry or population-based study would be helpful to confirm this rebound phenomenon and to determine contributing factors, including immune biomarkers, that increase risk for this syndrome.
Multi-biomarker responses as indication of contaminant effects in Gambusia affinis from impacted rivers by municipal effluents.Monday, May 02, 2016
Huang GY, Liu YS, Liang YQ, Shi WJ, Hu LX, Tian F, Chen J, Ying GG,
The Science of the total environment. 29-Apr-2016
This study investigated toxic effects in mosquitofish from two urban rivers of South China impacted by municipal effluents by using multiple biomarkers including fish morphology, biochemical indicators and transcriptional responses, and explored potential cause-effect relationship with a list of chemicals (metals, polycyclic aromatic hydrocarbons (PAHs) and pesticides). The results showed significant alterations in metallothionein (MT) protein and mRNA expression in mosquitofish collected from the two rivers and a strong association between MT protein and mRNA expression levels and heavy metals in the river water. Both ethoxyresorufin-O-deethylase (EROD) activity and cytochromes P450 1A (CYP1A) mRNA expression were significantly enhanced in mosquitofish at most sampling sites. There existed a strong correlation between EROD activity and CYP1A mRNA expression levels, but no clear correlations between these responses and PAHs in the river water possibly because of the presence of many other agonists of the aryl hydrocarbon receptor in the two rivers. Significant acetylcholinesterase (AChE) inhibition was observed in mosquitofish brain samples. The pesticides in the two rivers showed an influence on the AChE activity, which was also found to be significantly negatively correlated to fipronil concentrations. Moreover, the result also indicates that metals and pesticides present in the two rivers might cause the observed estrogenic and androgenic effects in mosquitofish. The findings from this study clearly showed morphological, biochemical and transcriptional responses in mosquitofish due to chemical contamination of the two urban rivers. This multi-biomarker approach using mosquitofish can be applied to evaluate contamination of riverine environments.
Effects of ocean acidification on the swimming ability, development and biochemical responses of sand smelt larvae.Monday, May 02, 2016
Silva CS, Novais SC, Lemos MF, Mendes S, Oliveira AP, Gonçalves EJ, Faria AM,
The Science of the total environment. 29-Apr-2016
Ocean acidification, recognized as a major threat to marine ecosystems, has developed into one of the fastest growing fields of research in marine sciences. Several studies on fish larval stages point to abnormal behaviours, malformations and increased mortality rates as a result of exposure to increased levels of CO2. However, other studies fail to recognize any consequence, suggesting species-specific sensitivity to increased levels of CO2, highlighting the need of further research. In this study we investigated the effects of exposure to elevated pCO2 on behaviour, development, oxidative stress and energy metabolism of sand smelt larvae, Atherina presbyter. Larvae were caught at Arrábida Marine Park (Portugal) and exposed to different pCO2 levels (control: ~600μatm, pH=8.03; medium: ~1000μatm, pH=7.85; high: ~1800μatm, pH=7.64) up to 15days, after which critical swimming speed (Ucrit), morphometric traits and biochemical biomarkers were determined. Measured biomarkers were related with: 1) oxidative stress - superoxide dismutase and catalase enzyme activities, levels of lipid peroxidation and DNA damage, and levels of superoxide anion production; 2) energy metabolism - total carbohydrate levels, electron transport system activity, lactate dehydrogenase and isocitrate dehydrogenase enzyme activities. Swimming speed was not affected by treatment, but exposure to increasing levels of pCO2 leads to higher energetic costs and morphometric changes, with larger larvae in high pCO2 treatment and smaller larvae in medium pCO2 treatment. The efficient antioxidant response capacity and increase in energetic metabolism only registered at the medium pCO2 treatment may indicate that at higher pCO2 levels the capacity of larvae to restore their internal balance can be impaired. Our findings illustrate the need of using multiple approaches to explore the consequences of future pCO2 levels on organisms.
Toxicity of copper nanoparticles to Daphnia magna under different exposure conditions.Monday, May 02, 2016
Xiao Y, Peijnenburg WJ, Chen G, Vijver MG,
The Science of the total environment. 29-Apr-2016
Although the risks of metallic nanoparticles (NPs) to aquatic organisms have already been studied for >10years, our understanding of the link between the fate of particles in exposure medium and their toxicity is still in its infancy. Moreover, most of the earlier studies did not distinguish the contribution of particles and soluble ions to the toxic effects caused by suspensions of metallic NPs. In this study, the toxicity of CuNPs to Daphnia magna upon modification of the exposure conditions, achieved by aging the suspensions of CuNPs and by altering water chemistry parameters like the pH and levels of dissolved organic carbon (DOC), was investigated. The LC50 values for CuNPs exposure decreased by about 30% after 7days of aging. The LC50 values increased >12-fold upon addition of DOC at concentrations ranging from 0 to 10mg/L to the exposure medium. Changing the pH from 6.5 to 8.5 resulted in a 3-fold higher LC50 value. Furthermore, it was found that during 7days of aging of the exposure medium (without addition of DOC and at pH7.8), the toxicity could be mostly ascribed to the particles present in the suspension (around 70%). However, adding DOC or decreasing the pH of the exposure medium reduced the contribution of the particles to the observed toxicity. We thus found that the effective concentration regarding the toxicity was mainly driven by the contribution of the soluble ions in the presence of DOC or at pH6.5. Our results suggest that the toxicity results of CuNPs obtained from laboratory tests may overestimate the risk of the particles in polluted waters due to the common absence of DOC in laboratory test solutions. Moreover, the role of the ions shedding from CuNPs is very important in explaining the toxicity in natural waters.
A clinician's guide to biosimilars in oncology.Monday, May 02, 2016
Rugo HS, Linton KM, Cervi P, Rosenberg JA, Jacobs I,
Cancer treatment reviews. 21-Apr-2016
Biological agents or "biologics" are widely used in oncology practice for cancer treatment and for the supportive management of treatment-related side effects. Unlike small-molecule generic drugs, exact copies of biologics are impossible to produce because these are large and highly complex molecules produced in living cells. The term "biosimilar" refers to a biological product that is highly similar to a licensed biological product (reference or originator product) with no clinically meaningful differences in terms of safety, purity, or potency. Biosimilars have the potential to provide savings to healthcare systems and to make important biological therapies widely accessible to a global population. As biosimilars for rituximab, trastuzumab, and bevacizumab are expected to reach the market in the near future, clinicians will soon be faced with decisions to consider biosimilars as alternatives to existing reference products. The aim of this article is to inform oncology practitioners about the biosimilar development and evaluation process, and to offer guidance on how to evaluate biosimilar data in order to make informed decisions when integrating these drugs into oncology practice. We will also review several biosimilars that are currently in development for cancer treatment.
A Biomarker Panel to Detect Synchronous Neoplasm in Non-neoplastic Surveillance Biopsies from Patients with Ulcerative Colitis.Monday, May 02, 2016
Garrity-Park MM, Loftus EV, Bryant SC, Smyrk TC,
Inflammatory bowel diseases. 29-Apr-2016
A combined clinical, genetic, and epigenetic model for detecting synchronous neoplasm by testing of non-neoplastic colonic tissue had favorable operating characteristics and could complement current patient care.
Optimizing Treatment with TNF Inhibitors in Inflammatory Bowel Disease by Monitoring Drug Levels and Antidrug Antibodies.Monday, May 02, 2016
Steenholdt C, Bendtzen K, Brynskov J, Ainsworth MA,
Inflammatory bowel diseases. 29-Apr-2016
TDM-guided anti-TNF therapy at treatment failure has been brought from bench to bedside.
Walking exercise simultaneously combined with neuromuscular electrical stimulation of antagonists resistance improved muscle strength, physical function, and knee pain in symptomatic knee osteoarthritis: A single-arm study.Monday, May 02, 2016
Matsuse H, Hashida R, Takano Y, Omoto M, Nago T, Bekki M, Shiba N,
Journal of strength and conditioning research / National Strength & Conditioning Association. 28-Apr-2016
A hybrid training system (HTS) was developed as a way to combine the application of electrical stimulation and voluntary contraction. Moreover we developed a novel training method using HTS during walking (HTSW). This study was designed to evaluate the effect of HTSW on muscle strength, physical function, and knee pain in knee osteoarthritis (KOA). 11 subjects (age: 74.0 ± 8.5 years) participated, and performed HTSW for 30 minutes three times a week for 12 weeks. Isokinetic knee extension/flexion torque (KET/KFT), muscle volume (MV), one-leg standing test (OST), functional reach test, 10-meter maximum gait speed , Timed up & go test , 6-minute walking test , Knee pain using Visual Analog Scale (VAS) and Japan Knee Osteoarthritis Measure (JKOM) were assessed. KET significantly increased from 1.02 ±0.29 Nm/kg pre-training to 1.23 ± 0.33 Nm/kg post- training (P < 0.01, ES = 0.68). KFT significantly increased from 0.65 ± 0.18 Nm/kg pre-training to 0.78 ± 0.17 Nm/kg post-training (p < 0.01). MV significantly increased from 9.00 ± 2.84 mm pre-training to 10.37 ± 3.16 mm at the end of training (p < 0.05). All the physical function except OST was significantly improved. The score of JKOM improved from 26.7 ± 18.30 pre-training to 17.2 ± 14.02 at the end of training (p < 0.01). VAS significantly decreased from 35.4 ± 22.59 pre-training to 16.5 ± 19.73 at the end of training (p < 0.05). HTSW may be an effective training method for the treatment of people with KOA.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.
Biomechanical Analysis of Internal Bracing for Treatment of Medial Knee Injuries.Monday, May 02, 2016
Gilmer BB, Crall T, DeLong J, Kubo T, Mackay G, Jani SS,
Orthopedics. 2-May-2016
The internal brace technique uses a high-strength suture tie to augment injured tissues or a primary repair, allowing early rehabilitation. Anatomic repair with internal bracing is a novel and promising treatment for femoral-sided medial knee avulsion injuries of the medial collateral ligament and posterior oblique ligament. Unfortunately, biomechanical and clinical data are lacking. To evaluate this technique compared with other treatment options, 3 assays of 9 cadaveric matched pairs (54 knees) were tested to failure at 30° under valgus load in a biomechanical testing apparatus. The primary outcome measure was moment at failure (Nm), with secondary outcome measures of stiffness (Nm/°), valgus angulation at 10 Nm (°), and valgus angulation at failure (°). Repair with internal bracing was compared with the intact state, repair alone, and allograft reconstruction. The mean moment to failure (62.5±24.9 Nm) for internal bracing was significantly lower than that for intact specimens (107.2±39.7 Nm) (P=.009). Mean moment to failure and valgus angle at failure were significantly greater for internal bracing (95±31.9 Nm) than for repair (73.4±27.6 Nm) (P=.05). Internal bracing was similar to reconstruction for the primary outcome measure (53.5±26.3 Nm vs 66.9±28.8 Nm) (P=.227) and for all secondary outcome measures. These findings indicate that posteromedial knee repair with internal bracing for femoral-sided avulsions is superior to repair alone and is similar to allograft reconstruction for all parameters measured; however, this technique did not recreate biomechanical properties equivalent to the intact state. [Orthopedics.].
Chiral Phosphoric Acid-Catalyzed Enantioselective Formal [3+2] Cycloaddition of Azomethine Imines with Enecarbamates.Monday, May 02, 2016
Wang Y, Wang Q, Zhu J,
Chemistry (Weinheim an der Bergstrasse, Germany). 2-May-2016
The first catalytic asymmetric inverse electron demand 1,3-dipolar cycloaddition of azomethine imines with enecarbamates has been developed. Isoquinoline-fused pyrazolidines containing two or three contiguous stereogenic centers were obtained in high yields with excellent regio-, diastereo-, and enantioselectivities. The pyrazolidine ring can be opened to install an aminal, α-amino nitrile, or homoallylamine function with an excellent control of the newly generated stereogenic center. Access to aminobenzo[a]quinolizidine is also documented.
Detection of G-Quadruplex Formation via Light Scattering of Defined Gold Nanoassemblies Modulated by Molecular Hairpins.Monday, May 02, 2016
Seow N, Kirk Y, Yung LL,
Bioconjugate chemistry. 2-May-2016
G-quadruplexes are of great scientific interest, as these unique DNA structures play key regulatory roles in cell replication, such as safeguarding against uncontrolled cellular divisions. The quadruplexes have also been applied for detecting DNA and protein biomarkers via methods like fluorescence resonance energy transfer (FRET) and gold nanoparticle (AuNP) aggregation. As an alternative and complementary platform to the established molecular techniques for the study of quadruplexes, we have developed a strategy coupling poly-G (PG)-mediated quadruplex formation with AuNP assembly detectable via dynamic light scattering (DLS). The presence of quadruplex-forming sequences also uniquely modifies the AuNP nanoassembly readout on DLS. In addition, molecular hairpins co-attached onto the AuNP together with PG successfully modulated the quadruplex-induced nanoassembly. Through molecular beacon-based fluorescence restoration and light scattering signal changes, the open/closed conformations of the hairpins are leveraged to tune the size of the quadruplex-mediated nanoassembly.
Multi-site clinical evaluation of the Xpert(®) HIV-1 viral load assay.Monday, May 02, 2016
Jordan JA, Plantier JC, Templeton K, Wu AH,
Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 26-Apr-2016
Very good correlation was seen between the Xpert HIV-1 VL and Abbott RealTime HIV-1 assays, with added benefits for Xpert HIV-1 VL of: (1) lot-to-lot consistency traceable to WHO International Standard, (2) requiring both high and low level internal controls to be in range to have a valid result, (3) use of a single HIV-1 target for PCR and (4) faster turn-around-time for results, no need to wait to do batch testing of specimens. In summary, Xpert HIV-1 VL generated accurate VL results that if implemented could allow for actionable and timely treatment decisions during the same clinic visit. This scenario could reduce the loss to follow up often seen when these test results take days to weeks to become available to the clinician and patient.
Metabolic Network Prediction of Drug Side Effects.Monday, May 02, 2016
Shaked I, Oberhardt MA, Atias N, Sharan R, Ruppin E,
Cell systems. 23-Mar-2016
Drug side effects levy a massive cost on society through drug failures, morbidity, and mortality cases every year, and their early detection is critically important. Here, we describe the array of model-based phenotype predictors (AMPP), an approach that leverages medical informatics resources and a human genome-scale metabolic model (GSMM) to predict drug side effects. AMPP is substantially predictive (AUC > 0.7) for >70 drug side effects, including very serious ones such as interstitial nephritis and extrapyramidal disorders. We evaluate AMPP's predictive signal through cross-validation, comparison across multiple versions of a side effects database, and co-occurrence analysis of drug side effect associations in scientific abstracts (hypergeometric p value = 2.2e-40). AMPP outperforms a previous biochemical structure-based method in predicting metabolically based side effects (aggregate AUC = 0.65 versus 0.59). Importantly, AMPP enables the identification of key metabolic reactions and biomarkers that are predictive of specific side effects. Taken together, this work lays a foundation for future detection of metabolically grounded side effects during early stages of drug development.
Plasma Proteome Profiling to Assess Human Health and Disease.Monday, May 02, 2016
Geyer PE, Kulak NA, Pichler G, Holdt LM, Teupser D, Mann M,
Cell systems. 23-Mar-2016
Proteins in the circulatory system mirror an individual's physiology. In daily clinical practice, protein levels are generally determined using single-protein immunoassays. High-throughput, quantitative analysis using mass-spectrometry-based proteomics of blood, plasma, and serum would be advantageous but is challenging because of the high dynamic range of protein abundances. Here, we introduce a rapid and robust "plasma proteome profiling" pipeline. This single-run shotgun proteomic workflow does not require protein depletion and enables quantitative analysis of hundreds of plasma proteomes from 1 μl single finger pricks with 20 min gradients. The apolipoprotein family, inflammatory markers such as C-reactive protein, gender-related proteins, and >40 FDA-approved biomarkers are reproducibly quantified (CV <20% with label-free quantification). Furthermore, we functionally interpret a 1,000-protein, quantitative plasma proteome obtained by simple peptide pre-fractionation. Plasma proteome profiling delivers an informative portrait of a person's health state, and we envision its large-scale use in biomedicine.
Targeting the dopamine D3 receptor: an overview of drug design strategies.Monday, May 02, 2016
Cortés A, Moreno E, Rodríguez-Ruiz M, Canela EI, Casadó V,
Expert opinion on drug discovery. 2-May-2016
Dopamine is a neurotransmitter widely distributed in both the periphery and the central nervous system (CNS). Its physiological effects are mediated by five closely related G protein-coupled receptors (GPCRs) that are divided into two major subclasses: the D1-like (D1, D5) and the D2-like (D2, D3, D4) receptors. D3 receptors (D3Rs) have the highest density in the limbic areas of the brain, which are associated with cognitive and emotional functions. These receptors are therefore attractive targets for therapeutic management. Areas covered. This review summarizes the functional and pharmacological characteristics of D3Rs, including the design and clinical relevance of full agonists, partial agonists and antagonists, as well as the capacity of these receptors to form active homodimers, heterodimers or higher order receptor complexes as pharmacological targets in several neurological and neurodegenerative disorders. Expert opinion. The high sequence homology between D3R and the D2-type challenges the development of D3R-selective compounds. The design of new D3R-preferential ligands with improved physicochemical properties should provide a better pharmacokinetic/bioavailability profile and lesser toxicity than is found with existing D3R ligands. It is also essential to optimize D3R affinity and, especially, D3R vs. D2-type binding and functional selectivity ratios. Developing allosteric and bitopic ligands should help to improve the D3R selectivity of these drugs. As most evidence points to the ability of GPCRs to form homomers and heteromers, the most promising therapeutic strategy in the future is likely to involve the application of heteromer-selective drugs. These selective ligands would display different affinities for a given receptor depending on the receptor partners within the heteromer. Therefore, designing novel compounds that specifically target and modulate D1R-D3R heteromers would be an interesting approach for the treatment of levodopa (L-DOPA)-induced dyskinesias.
Transcriptional Dysregulation of Upstream Signaling of IFN Pathway in Chronic HCV Type 4 Induced Liver Fibrosis.Monday, May 02, 2016
Ibrahim MK, Salum GM, Bader El Din NG, Dawood RM, Barakat A, Khairy A, El Awady MK,
PloS one. 2-5-2016
IFN orchestrates the expression of various genes to halt hepatitis C virus (HCV) replication with the possibility of either reduced or increased liver fibrosis; due to controlled viral replication or overproduction of inflammatory mediators, repectively. In this study, we examined the transcriptional profiling of type I IFN related genes in HCV-chronically infected patients with varying degrees of liver fibrosis. PCR array was used to examine the expression of 84 type I IFN related genes in peripheral blood mononuclear cells (PBMCs) RNA from 12 treatment-naïve chronic HCV patients (5 F0-F1 and 7 F2-F4) and 5 healthy subjects. We further validated our results by quantitative real time PCR (qRT-PCR) in 103 treatment-naïve chronic HCV patients (43 F0-F1 and 60 F2-F4) and 15 controls. PCR array data revealed dysregulation in TLR7 pathway. The expression of TLR7 was decreased by 4 folds and MyD88 was increased by 3 folds in PBMCs of F2-F4 patients when compared to the healthy volunteers (p = 0.03 and 0.002, respectively). In addition, IRF7 and TLR7 showed dramatic downregulation (6 and 8 folds, respectively) in F2-F4 patients when compared to F0-F1 ones. qRT-PCR confirmed the altered expression patterns of TLR7 and MyD88 in F2-F4 patients when compared to either controls or F0-F1 patients. However, by qRT-PCR, IRF7 and NF-κB1 (TLR7 pathway transcription factors) exhibited similar mRNA abundance among F2-F4 and F0-F1 patients. These results suggest that TLR7 and MyD88 are possible candidates as biomarkers for the progression of HCV-induced liver fibrosis and/ or targets for therapeutic intervention.
Circulating Serum miRNAs as Diagnostic Markers for Colorectal Cancer.Monday, May 02, 2016
Zekri AN, Youssef AS, Lotfy MM, Gabr R, Ahmed OS, Nassar A, Hussein N, Omran D, Medhat E, Eid S, Hussein MM, Ismail MY, Alenzi FQ, Bahnassy AA,
PloS one. 2-5-2016
Aberrant miRNA expressions are highly involved in the cascade of colorectal carcinogenesis. We have found that (miR-17, miR-19a, miR-20a and miR-223) could be used as diagnostic biomarkers for CRC. On the other hand, miR-19b and miR-18a could be used as diagnostic biomarkers for CP and IBD respectively.
Breaking BRAF(V600E)-drug resistance by stressing mitochondria.Monday, May 02, 2016
Luo C, Puigserver P, Widlund HR,
Pigment cell & melanoma research. 2-May-2016
Until recently, advanced stage melanoma was considered an untreatable disease. However, tangible hope for patients has now become attached to small molecule inhibitors targeting the melanoma oncogene BRAF(V600E) and approaches to unleash the immune system against these tumors. Still, not every patient will be given respite by these treatments, and the ultimate goal of durable disease remission remains elusive. While the barriers to achieving durable responses remain incompletely understood, eventual relapse is likely a consequence of a variable degree of cancer heterogeneity that enables selective outgrowth of treatment resistant tumor clones. However, identification of alternative molecular targets that could be harnessed for combinatorial use hold promise to extend these initial responses, and may afford sustainable treatment. This article is protected by copyright. All rights reserved.
A difficult case of recurrent hypoglycaemia: role of insulin assays in establishing the diagnosis.Monday, May 02, 2016
Joshi T, Caswell A, Acharya S,
Diabetic medicine : a journal of the British Diabetic Association. 2-May-2016
Factitious hypoglycemia is difficult to diagnose and treat. A low blood glucose level, suppressed C-peptide level and an inappropriately elevated insulin level is the classic finding. We were able to make a diagnosis in the present case after discordant insulin levels were detected on the two different insulin assays, signifying cross-reactivities of the recombinant insulin with the assays. A multidisciplinary team approach with psychiatric input is needed to treat such cases. This article is protected by copyright. All rights reserved.
Nanocontainers in and onto Nanofibers.Monday, May 02, 2016
Jiang S, Lv LP, Landfester K, Crespy D,
Accounts of chemical research. 2-May-2016
Hierarchical structure is a key feature explaining the superior properties of many materials in nature. Fibers usually serve in textiles, for structural reinforcement, or as support for other materials, whereas spherical micro- and nanoobjects can be either highly functional or also used as fillers to reinforce structure materials. Combining nanocontainers with fibers in one single object has been used to increase the functionality of fibers, for example, antibacterial and thermoregulation, when the advantageous properties given by the encapsulated materials inside the containers are transferred to the fibers. Herein we focus our discussion on how the hierarchical structure composed of nanocontainers in nanofibers yields materials displaying advantages of both types of materials and sometimes synergetical effects. Such materials can be produced by first carefully designing nanocontainers with defined morphology and chemistry and subsequently electrospinning them to fabricate nanofibers. This method, called colloid-electrospinning, allows for marrying the properties of nanocontainers and nanofibers. The obtained fibers could be successfully applied in different fields such as catalysis, optics, energy conversion and production, and biomedicine. The miniemulsion process is a convenient approach for the encapsulation of hydrophobic or hydrophilic payloads in nanocontainers. These nanocontainers can be embedded in fibers by the colloid-electrospinning technique. The combination of nanocontainers with nanofibers by colloid-electrospinning has several advantages. (1) The fiber matrix serves as support for the embedded nanocontainers. For example, through combining catalysts nanoparticles with fiber networks, the catalysts can be easily separated from the reaction media and handled visually. This combination is beneficial for the reuse of the catalyst and the purification of products. (2) Electrospun nanofibers containing nanocontainers offer the active agents inside the nanocontainers a double protection by both the fiber matrix and the nanocontainers. Since the polymer of the fibers and the polymer of the nanocontainers have usually opposite polarities, the encapsulated substance, for example, catalysts, dyes, or drugs, can be protected against a large variety of environmental influences. (3) Electrospun nanofibers exhibit unique advantages for tissue engineering and drug delivery that are a structural similarity to the extracellular matrix of biological tissues, large specific surface area, high and interconnected porosity which enhances cell adhesion, proliferation, drug loading, and mass transfer properties, as well as the flexibility in selecting the raw materials. Moreover, the nanocontainer-in-nanofiber structure allows multidrug loading and programmable release of each drug, which are very important to achieve synergistic effects in tissue engineering and disease therapy. The advantages offered by these materials encourage us to further understand the relationship between colloidal properties and fibers, to predict the morphology and properties of the fibers obtained by colloid-electrospinning, and to explore new possible combination of properties offered by nanoparticles and nanofibers.
Endothelial ROS and Impaired Myocardial Oxygen Consumption in Sepsis-induced Cardiac Dysfunction.Monday, May 02, 2016
Potz BA, Sellke FW, Abid MR,
Journal of intensive and critical care. 2-5-2016
Sepsis is known as the presence of a Systemic Inflammatory Response Syndrome (SIRS) in response to an infection. In the USA alone, 750,000 cases of severe sepsis are diagnosed annually. More than 70% of sepsis-related deaths occur due to organ failure and more than 50% of septic patients demonstrate cardiac dysfunction. Patients with sepsis who develop cardiac dysfunction have significantly higher mortality, and thus cardiac dysfunction serves as a predictor of survival in sepsis. We have very little understanding about the mechanisms that result in cardiac dysfunction in the setting of sepsis. At present, the factors involved in sepsis-related cardiac dysfunction are believed to include the following: persistent inflammatory changes in the vascular endothelium and endocardium leading to circulatory and micro vascular changes, increase in endothelial reactive oxygen species (ROS), abnormal endothelium-leukocyte interaction resulting in a feed-forward loop for inflammatory cytokines and ROS, contractile dysfunction of the heart due to autonomic dysregulation, metabolic changes in myocardium leading to impaired oxygen delivery and increased oxygen consumption, mitochondrial dysfunction, and persistent inflammatory signaling. In this review article, we will briefly discuss the clinical challenges and our current understanding of cardiac dysfunction in sepsis. Major focus will be on the pathological changes that occur in vascular endothelium, with an emphasis on endocardium, and how endothelial ROS, impaired endothelium-leukocyte interaction, and microcirculatory changes lead to cardiac dysfunction in sepsis. The importance of the ongoing quest for the clinical biomarkers for cardiac dysfunction will also be discussed.
Cytokine-Stimulated Phosphoflow of Whole Blood Using CyTOF Mass Cytometry.Monday, May 02, 2016
Fernandez R, Maecker H,
Bio-protocol. 5-Jun-2015
The ability to assess the function of a range of cytokine, antigen receptor, and Toll-like receptor (TLR) signaling pathways in a range of immune cells could provide a kind of fingerprint of the state of the human immune system. The mass cytometry or CyTOF, platform allows for the parallel application of about 40 labeled antibodies to a single sample, creating the possibility to read out many cell types and signaling pathways in a single small blood sample. We developed such a mass cytometry panel, consisting of 22 antibodies to cell surface lineage markers and 8 antibodies to phospho-specific epitopes of signaling proteins. These antibodies were chosen to discriminate all major white blood cell lineages, to a level of detail that includes subsets such as naïve, central memory, effector memory, and late effector CD4+ and CD8+T cells, naïve, transitional, and switched memory B cells, plasmablasts, myeloid and plasmacytoid dendritic cells, CD16+ and CD16+CD56+ NK cells, CD16+ and classical monocytes etc. 32 such cell subsets are defined in our standard gating scheme. The eight phospho-specific antibodies were chosen to represent major signaling nodes responsive to cytokine, TLR, and antigen receptor signaling. This antibody panel is used with 8 standard stimulation conditions (unstimulated, IFNa, IL-6, IL-7, IL-10, IL-21, LPS, PMA+ ionomycin), although other stimuli can be added. Comparison of healthy controls to subjects with immune deficiencies of unknown etiology may help elucidate the mechanisms of such deficiencies. Phosphorylation of tyrosine, serine, and threonine residues is critical for the control of protein activity involved in various cellular events. An assortment of kinases and phosphatases regulate intracellular protein phosphorylation in many different cell signaling pathways, such as T and B cell signaling, those regulating apoptosis, growth and cell cycle control, plus those involved with cytokine, chemokine, and stress responses. Phosphoflow assays combine phospho-specific antibodies with the power of flow cytometry to enhance phospho protein study. In our assay, peripheral blood mononuclear cells are stimulated by cytokines, fixed, surface-stained with a cocktail of antibodies labeled with MAXPAR (Brand Name) metal-chelating polymers and permeabilized with methanol. They are then stained with intracellular phospho-specific antibodies. We use a CyTOF™ mass cytometer to acquire the ICP-MS data. The current mass window selected is approximately AW 103-203, which includes the lanthanides used for most antibody labeling, as well as iridium and rhodium for DNA intercalators. Subsequent analysis of the dual count signal data using FlowJo software allows for cell types to be analyzed based on the dual count signal in each mass channel. The percentage of each cell type is determined and reported as a percent of the parent cell type. Median values are reported to quantitate the level of phosphorylation of each protein in response to stimulation. Comparing the level of phosphorylation between samples can offer insight to the status of the immune system. Whole blood stimulation is the closest to the in vivo condition and it allows for assessment of granulocyte population as well as lymphocytes and monocytes.
Natural T Regulatory Cells (n Treg) in the Peripheral Blood of Healthy Subjects and Subjects with Chronic Periodontitis - A Pilot Study.Monday, May 02, 2016
Sabarish R, Rao SR, Lavu V,
Journal of clinical and diagnostic research : JCDR. Mar-2016
A higher proportion of nTreg in the peripheral blood sample of chronic periodontitis subjects were observed as compared to that of healthy individuals.
Correlation of Salivary pH, Incidence of Dental Caries and Periodontal Status in Diabetes Mellitus Patients: A Cross-sectional Study.Monday, May 02, 2016
Seethalakshmi C, Reddy RC, Asifa N, Prabhu S,
Journal of clinical and diagnostic research : JCDR. Mar-2016
The results of the present study concluded that there was a significant relationship between the diabetes mellitus and increased incidence of dental caries and periodontitis and there was also a significant reduction in the salivary pH in diabetes mellitus patients, compared to that of non diabetic subjects.
Antioxidant and Nephroprotective Activities of Aconitum heterophyllum Root in Glycerol Induced Acute Renal Failure in Rats.Monday, May 02, 2016
Konda VG, Eerike M, Raghuraman LP, Rajamanickam MK,
Journal of clinical and diagnostic research : JCDR. Mar-2016
The present study revealed that Aconitum heterophyllum root has shown antioxidant and nephroprotective activities.
Virtual Screening of Phytochemicals to Novel Target (HAT) Rtt109 in Pneumocystis Jirovecii using Bioinformatics Tools.Monday, May 02, 2016
Sugumar R, Adithavarman AP, Dakshinamoorthi A, David DC, Ragunath PK,
Journal of clinical and diagnostic research : JCDR. Mar-2016
Baicalin has good binding with Rtt 109 in Pneumocystis jirovecii and can be considered as a novel and valuable treatment option for Pneumocystis pneumonia patients after subjecting it to invivo and invitro studies.
Cell Culture, Technology: Enhancing the Culture of Diagnosing Human Diseases.Monday, May 02, 2016
Hudu SA, Alshrari AS, Syahida A, Sekawi Z,
Journal of clinical and diagnostic research : JCDR. Mar-2016
Cell culture involves a complex of processes of cell isolation from their natural environment (in vivo) and subsequent growth in a controlled environmental artificial condition (in vitro). Cells from specific tissues or organs are cultured as short term or established cell lines which are widely used for research and diagnosis, most specially in the aspect of viral infection, because pathogenic viral isolation depends on the availability of permissible cell cultures. Cell culture provides the required setting for the detection and identification of numerous pathogens of humans, which is achieved via virus isolation in the cell culture as the "gold standard" for virus discovery. In this review, we summarized the views of researchers on the current role of cell culture technology in the diagnosis of human diseases. The technological advancement of recent years, starting with monoclonal antibody development to molecular techniques, provides an important approach for detecting presence of viral infection. They are also used as a baseline for establishing rapid tests for newly discovered pathogens. A combination of virus isolation in cell culture and molecular methods is still critical in identifying viruses that were previously unrecognized. Therefore, cell culture should be considered as a fundamental procedure in identifying suspected infectious viral agent.
Global serum glycoform profiling for the investigation of dystroglycanopathies & Congenital Disorders of Glycosylation.Monday, May 02, 2016
Heywood WE, Bliss E, Mills P, Yuzugulen J, Carreno G, Clayton PT, Muntoni F, Worthington VC, Torelli S, Sebire NJ, Mills K, Grunewald S,
Molecular genetics and metabolism reports. Jun-2016
The Congenital Disorders of Glycosylation (CDG) are an expanding group of genetic disorders which encompass a spectrum of glycosylation defects of protein and lipids, including N- & O-linked defects and among the latter are the muscular dystroglycanopathies (MD). Initial screening of CDG is usually based on the investigation of the glycoproteins transferrin, and/or apolipoprotein CIII. These biomarkers do not always detect complex or subtle defects present in older patients, therefore there is a need to investigate additional glycoproteins in some cases. We describe a sensitive 2D-Differential Gel Electrophoresis (DIGE) method that provides a global analysis of the serum glycoproteome. Patient samples from PMM2-CDG (n = 5), CDG-II (n = 7), MD and known complex N- & O-linked glycosylation defects (n = 3) were analysed by 2D DIGE. Using this technique we demonstrated characteristic changes in mass and charge in PMM2-CDG and in charge in CDG-II for α1-antitrypsin, α1-antichymotrypsin, α2-HS-glycoprotein, ceruloplasmin, and α1-acid glycoproteins 1&2. Analysis of the samples with known N- & O-linked defects identified a lower molecular weight glycoform of C1-esterase inhibitor that was not observed in the N-linked glycosylation disorders indicating the change is likely due to affected O-glycosylation. In addition, we could identify abnormal serum glycoproteins in LARGE and B3GALNT2-deficient muscular dystrophies. The results demonstrate that the glycoform pattern is varied for some CDG patients not all glycoproteins are consistently affected and analysis of more than one protein in complex cases is warranted. 2D DIGE is an ideal method to investigate the global glycoproteome and is a potentially powerful tool and secondary test for aiding the complex diagnosis and sub classification of CDG. The technique has further potential in monitoring patients for future treatment strategies. In an era of shifting emphasis from gel- to mass-spectral based proteomics techniques, we demonstrate that 2D-DIGE remains a powerful method for studying global changes in post-translational modifications of proteins.
Natural Agents Used in Chemoprevention of Aerodigestive and GI Cancers.Monday, May 02, 2016
Morris J, Fang Y, De Mukhopdhyay K, Wargovich MJ,
Current pharmacology reports. Feb-2016
Aerodigestive cancers are on an increasing level in both occurrence and mortality. A major cause in many of these cancers is disruption of the inflammatory pathway, leading to increased cell proliferation, and epigenetic silencing of normal regulatory genes. Here we review the research on several natural products: silibinin, silymarin, quercetin, neem & nimbolide, gingerol, epigallatecatechin-3- gallate, curcumin, genistein and resveratrol conducted on aerodigestive cancers. These types of cancers are primarily those from oral cavity, esophagus/windpipe, stomach, small and large intestine, colon/rectum and bile/pancreas tissues. We report on the utilization in vivo and in vitro systems to research these dose effects on the inflammatory and epigenetic pathway components within the aerodigestive cancer. To follow up on the basic research we will discuss remaining research questions and future directions involving these natural products as putative stand alone or in combination with clinical agents.
Diaphragm assessment in mice overexpressing phospholamban in slow-twitch type I muscle fibers.Monday, May 02, 2016
Fajardo VA, Smith IC, Bombardier E, Chambers PJ, Quadrilatero J, Tupling AR,
Brain and behavior. 22-Apr-2016
Therefore, the effects of PLN overexpression on skeletal muscle phenotype differ between diaphragm and the postural soleus and gluteus minimus muscles. Our findings here point to differences in SLN expression and type I fiber distribution as potential contributing factors.
Traditional Therapies for Skin Wound Healing.Monday, May 02, 2016
Pereira RF, Bártolo PJ,
Advances in wound care. 1-May-2016
Significance: The regeneration of healthy and functional skin remains a huge challenge due to its multilayer structure and the presence of different cell types within the extracellular matrix in an organized way. Despite recent advances in wound care products, traditional therapies based on natural origin compounds, such as plant extracts, honey, and larvae, are interesting alternatives. These therapies offer new possibilities for the treatment of skin diseases, enhancing the access to the healthcare, and allowing overcoming some limitations associated to the modern products and therapies, such as the high costs, the long manufacturing times, and the increase in the bacterial resistance. This article gives a general overview about the recent advances in traditional therapies for skin wound healing, focusing on the therapeutic activity, action mechanisms, and clinical trials of the most commonly used natural compounds. New insights in the combination of traditional products with modern treatments and future challenges in the field are also highlighted. Recent Advances: Natural compounds have been used in skin wound care for many years due to their therapeutic activities, including anti-inflammatory, antimicrobial, and cell-stimulating properties. The clinical efficacy of these compounds has been investigated through in vitro and in vivo trials using both animal models and humans. Besides the important progress regarding the development of novel extraction methods, purification procedures, quality control assessment, and treatment protocols, the exact mechanisms of action, side effects, and safety of these compounds need further research. Critical Issues: The repair of skin lesions is one of the most complex biological processes in humans, occurring throughout an orchestrated cascade of overlapping biochemical and cellular events. To stimulate the regeneration process and prevent the wound to fail the healing, traditional therapies and natural products have been used with promising results. Although these products are in general less expensive than the modern treatments, they can be sensitive to the geographic location and season, and exhibit batch-to-batch variation, which can lead to unexpected allergic reactions, side effects, and contradictory clinical results. Future Directions: The scientific evidence for the use of traditional therapies in wound healing indicates beneficial effects in the treatment of different lesions. However, specific challenges remain unsolved. To extend the efficacy and the usage of natural substances in wound care, multidisciplinary efforts are necessary to prove the safety of these products, investigate their side effects, and develop standard controlled trials. The development of good manufacturing practices and regulatory legislation also assume a pivotal role in order to improve the use of traditional therapies by the clinicians and to promote their integration into the national health system. Current trends move to the development of innovative wound care treatments, combining the use of traditional healing agents and modern products/practices, such as nanofibers containing silver nanoparticles, Aloe vera loaded into alginate hydrogels, propolis into dressing films, and hydrogel sheets containing honey.
Cellular Endocytosis and Trafficking of Cholera Toxin B-Modified Mesoporous Silica Nanoparticles.Monday, May 02, 2016
Walker WA, Tarannum M, Vivero-Escoto JL,
Journal of materials chemistry. B, Materials for biology and medicine. 21-Feb-2016
In this study, mesoporous silica nanoparticles (MSNs) were functionalized with Cholera toxin subunit B (CTxB) protein to influence their intracellular trafficking pathways. The CTxB-MSN carrier was synthesized, and its chemical and structural properties were characterized. Endocytic pathway inhibition assays showed that the uptake of CTxB-MSNs in human cervical cancer (HeLa) cells was partially facilitated by both chlatrin- and caveolae-mediated endocytosis mechanisms. Laser scanning confocal microscopy (LSCM) experiments demonstrated that CTxB-MSNs were taken up by the cells and partially trafficked through the trans-Golgi network into to the endoplasmic reticulum in a retrograde fashion. The delivery abilities of CTxB-MSNs were evaluated using propidium iodide, an impermeable cell membrane dye. LSCM images depicted the release of propidium iodide in the endoplasmic reticulum and cell nucleus of HeLa cells.
Recent advances in understanding and managing cholestasis.Monday, May 02, 2016
Wagner M, Trauner M,
F1000Research. 2016
Cholestatic liver diseases are hereditary or acquired disorders with impaired hepatic excretion and enterohepatic circulation of bile acids and other cholephiles. The distinct pathological mechanisms, particularly for the acquired forms of cholestasis, are not fully revealed, but advances in the understanding of the molecular mechanisms and identification of key regulatory mechanisms of the enterohepatic circulation of bile acids have unraveled common and central mechanisms, which can be pharmacologically targeted. This overview focuses on the central roles of farnesoid X receptor, fibroblast growth factor 19, and apical sodium-dependent bile acid transporter for the enterohepatic circulation of bile acids and their potential as new drug targets for the treatment of cholestatic liver disease.
Open drug discovery for the Zika virus.Monday, May 02, 2016
Ekins S, Mietchen D, Coffee M, Stratton TP, Freundlich JS, Freitas-Junior L, Muratov E, Siqueira-Neto J, Williams AJ, Andrade C,
F1000Research. 2016
The Zika virus (ZIKV) outbreak in the Americas has caused global concern that we may be on the brink of a healthcare crisis. The lack of research on ZIKV in the over 60 years that we have known about it has left us with little in the way of starting points for drug discovery. Our response can build on previous efforts with virus outbreaks and lean heavily on work done on other flaviviruses such as dengue virus. We provide some suggestions of what might be possible and propose an open drug discovery effort that mobilizes global science efforts and provides leadership, which thus far has been lacking. We also provide a listing of potential resources and molecules that could be prioritized for testing as in vitro assays for ZIKV are developed. We propose also that in order to incentivize drug discovery, a neglected disease priority review voucher should be available to those who successfully develop an FDA approved treatment. Learning from the response to the ZIKV, the approaches to drug discovery used and the success and failures will be critical for future infectious disease outbreaks.
Associations between joint effusion in the knee and gene expression levels in the circulation: a meta-analysis.Monday, May 02, 2016
Peters MJ, Ramos YF, den Hollander W, Schiphof D, Hofman A, Uitterlinden AG, Oei EH, Slagboom PE, Kloppenburg M, Bloem JL, Bierma-Zeinstra SM, Meulenbelt I, van Meurs JB,
F1000Research. 2016
Meta-analyses and subsequent enriched biological pathways resulted in interesting candidate genes associated with joint effusion that require further characterization. Associations were not transcriptome-wide significant most likely due to limited power. Additional studies are required to replicate our findings in more samples, which will greatly help in understanding the pathophysiology of OA and its relation to inflammation, and may result in biomarkers urgently needed to diagnose OA at an early stage.
Diagnostic workup and management of patients with suspected Niemann-Pick type C disease.Monday, May 02, 2016
Papandreou A, Gissen P,
Therapeutic advances in neurological disorders. May-2016
Niemann-Pick type C (NP-C) disease is a neurovisceral disorder caused by mutations in the NPC1 and NPC2 genes. It is characterized by lysosomal storage of a broad range of lipids as a result of abnormal intracellular lipid trafficking. Typically patients develop neurodegeneration; however, the speed of disease progression is variable. The exact functions of NPC1 and NPC2 proteins have not been determined and therefore the molecular pathophysiology of NP-C is still not clearly understood. Due to the disease's rarity and clinical heterogeneity, delays from symptom onset to diagnosis and treatment initiation are common. Current therapeutic approaches focus on multidisciplinary symptom control and deceleration (rather than reversal) of disease progression. Thus identification of cases at early stages of disease is particularly important. Recent advances in genetic and biochemical testing have resulted in the generation of relatively non-invasive, quick and cost-effective laboratory assays that are highly sensitive and specific and have the capacity to enhance the clinicians' ability to reach a diagnosis earlier. Miglustat is a compound recently licensed in many countries for the treatment of NP-C that has been shown to decelerate neurological regression, whereas many other promising drugs are currently being trialled in preclinical models or human studies. This review summarizes key clinical, genetic and biochemical features of NP-C, suggests a simple diagnostic investigation strategy and gives an overview of available therapeutic options as well as potential novel treatments currently under development.
A pilot study on the benefit of cognitive rehabilitation in Parkinson's disease.Monday, May 02, 2016
Adamski N, Adler M, Opwis K, Penner IK,
Therapeutic advances in neurological disorders. May-2016
The efficacy of the applied computerized cognitive training tool BrainStim could be verified in patients with PD and healthy age-matched controls. The preliminary findings highlighted the suitability of a specific cognitive intervention to improve cognitive inefficiencies in patients with PD as well as in healthy older people. Further research on cognitive training in combination with PD drug therapy is needed to better understand the mutual interaction and to offer optimal therapeutic approaches to patients.
Novel bile acid therapeutics for the treatment of chronic liver diseases.Monday, May 02, 2016
Hegade VS, Speight RA, Etherington RE, Jones DE,
Therapeutic advances in gastroenterology. May-2016
Recent developments in understanding the role of bile acids (BAs) as signalling molecules in human metabolism and inflammation have opened new avenues in the field of hepatology research. BAs are no longer considered as simple molecules helping in fat digestion but as agents with real therapeutic value in treating complex autoimmune and metabolic liver diseases. BAs and their receptors such as farnesoid X receptor, transmembrane G protein-coupled receptor 5 and peroxisome proliferator-activated receptor have been identified as novel targets for drug development. Some of these novel pharmaceuticals are already in clinical evaluation with the most advanced drugs having reached phase III trials. Chronic liver diseases such as primary biliary cholangitis, primary sclerosing cholangitis and nonalcoholic fatty liver disease, for which there is no or limited pharmacotherapy, are most likely to gain from these developments. In this review we discuss recent and the most relevant basic and clinical research findings related to BAs and their implications for novel therapy for chronic liver diseases.
Karyotype features of trematode Himasthla elongata.Monday, May 02, 2016
Solovyeva AI, Stefanova VN, Podgornaya OI, Demin SIu,
Molecular cytogenetics. 2016
Himasthla elongata chromosomes variations presented as image bank. Differential chromosome staining with fluorochromes and FISH used for 18S rDNA mapping let us to conclude: (1) Himasthla elongata karyotype is 2n = 24; (2) chromosome number deviates from the previously studied echinostomatids (2n = 14-22); (3). Chromosome 10 possesses the main rDNA cluster with the minor ones existing on chromosomes 3 and 6.
Anti-inflammatory activities of Ganoderma lucidum (Lingzhi) and San-Miao-San supplements in MRL/lpr mice for the treatment of systemic lupus erythematosus.Monday, May 02, 2016
Cai Z, Wong CK, Dong J, Jiao D, Chu M, Leung PC, Lau CB, Lau CP, Tam LS, Lam CW,
Chinese medicine. 2016
LZ-SMS treatment led to significant increases in the percentages of CD4(+)CD25(+)Foxp3(+) Treg and IL-10(+) Breg cells, together with a reduction in the plasma concentrations of several inflammatory cytokines and the down-regulated expression of the corresponding cytokine related genes in SLE mice. The clinical characteristics of the LZ-SMS-treated SLE mice also improved significantly.
Characterization of new eye drops with choline salicylate and assessment of their irritancy by in vitro short time exposure tests.Monday, May 02, 2016
Wroblewska K, Kucinska M, Murias M, Lulek J,
Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society. Sep-2015
The aim of our study was to examine the irritation potential of new eye drops containing 2% choline salicylate (CS) as an active pharmaceutical ingredient (API) and various polymers increasing eye drop viscosity (hydroxyethylcellulose, hydroxypropyl methylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone). The standard method for assessing the potential of irritating substances has been the Draize rabbit eye test. However the European Centre for Validation of Alternative Methods and the Coordinating Committee for Validation of Alternative Methods recommend, short time exposure (STE) in vitro tests as an alternative method for assessing eye irritation. The eye irritation potential was determined using cytotoxicity test methods for rabbit corneal cell line (SIRC) after 5 min exposure. The viability of cells was determined using two cytotoxicity assays: MTT and Neutral Red Uptake. According to the irritation rankings for the short time exposure test, all tested eye drops are classified as non-irritating (cell viability >70%).
Hydrolysable core crosslinked particle for receptor-mediated pH-sensitive anticancer drug delivery.Monday, May 02, 2016
Liu X, Miller AL, Waletzki BE, Mamo TK, Yaszemski MJ, Lu L,
New journal of chemistry = Nouveau journal de chimie. 1-Nov-2015
Biodegradable micelle systems with both extracellular stabilities and specific targeting properties are highly desirable for anti-cancer drug delivery. Here, we report a biodegradable and crosslinkable poly(propylene fumarate)-co-poly(lactide-co-glycolide)-co-poly(ethylene glycol) (PPF-PLGA-PEG) copolymer conjugated with folate (FA) molecules for receptor-mediated delivery of doxorubicin. Micelles with folate ligands on surface and fumarate bonds within the core were self-assembled and crosslinked, which exhibited better stability against potential physiological conditions during and after drug administration. A pH sensitive drug release profile was observed showing robust release at acidic environment due to the ester hydrolysis of PLGA (50:50). Further, micelles with folate ligands on surface showed strong targeting ability and therapeutic efficacy through receptor-mediated endocytosis, as evidenced by efficacious cancer killing and fatal DNA damage. These results imply promising potential for ligand-conjugated core crosslinked PPF-PLGA-PEG-FA micelles as carrier system for targeted anti-cancer drug delivery.
Dynamics of urinary oxidative stress biomarkers: 8-hydroxy-2'-deoxyguanosine and 8-isoprostane in uterine leiomyomas.Monday, May 02, 2016
Asare GA, Akuffo G, Doku D, Asiedu B, Santa S,
Journal of mid-life health. 3-9-2015
Oxidative damage was absent in the control group but was very much present in the test group on day 14 and day 21 with progesterone and estrogen acting in concert with oxidative damage biomarkers. An inverse pattern of biomarkers was observed between control and fibroid groups. Oxidative stress biomarkers influenced hormonal levels and pattern of the fibroid group.
Source: NCBI - Disclaimer and Copyright notice
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