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Showing 100 Latest Publications
TitleDate Created
Spectrometer-free vibrational imaging by retrieving stimulated Raman signal from highly scattered photons.Tuesday, November 24, 2015
Liao CS, Wang P, Wang P, Li J, Lee HJ, Eakins G, Cheng JX,
Science advances. Oct-2015
In vivo vibrational spectroscopic imaging is inhibited by relatively slow spectral acquisition on the second scale and low photon collection efficiency for a highly scattering system. Recently developed multiplex coherent anti-Stokes Raman scattering and stimulated Raman scattering techniques have improved the spectral acquisition time down to microsecond scale. These methods using a spectrometer setting are not suitable for turbid systems in which nearly all photons are scattered. We demonstrate vibrational imaging by spatial frequency multiplexing of incident photons and single photodiode detection of a stimulated Raman spectrum within 60 μs. Compared to the spectrometer setting, our method improved the photon collection efficiency by two orders of magnitude for highly scattering specimens. We demonstrated in vivo imaging of vitamin E distribution on mouse skin and in situ imaging of human breast cancerous tissues. The reported work opens new opportunities for spectroscopic imaging in a surgical room and for development of deep-tissue Raman spectroscopy toward molecular level diagnosis.
Optogenetic pacing in Drosophila melanogaster.Tuesday, November 24, 2015
Alex A, Li A, Tanzi RE, Zhou C,
Science advances. Oct-2015
Electrical stimulation is currently the gold standard for cardiac pacing. However, it is invasive and nonspecific for cardiac tissues. We recently developed a noninvasive cardiac pacing technique using optogenetic tools, which are widely used in neuroscience. Optogenetic pacing of the heart provides high spatial and temporal precisions, is specific for cardiac tissues, avoids artifacts associated with electrical stimulation, and therefore promises to be a powerful tool in basic cardiac research. We demonstrated optogenetic control of heart rhythm in a well-established model organism, Drosophila melanogaster. We developed transgenic flies expressing a light-gated cation channel, channelrhodopsin-2 (ChR2), specifically in their hearts and demonstrated successful optogenetic pacing of ChR2-expressing Drosophila at different developmental stages, including the larva, pupa, and adult stages. A high-speed and ultrahigh-resolution optical coherence microscopy imaging system that is capable of providing images at a rate of 130 frames/s with axial and transverse resolutions of 1.5 and 3.9 μm, respectively, was used to noninvasively monitor Drosophila cardiac function and its response to pacing stimulation. The development of a noninvasive integrated optical pacing and imaging system provides a novel platform for performing research studies in developmental cardiology.
Kinetics of small molecule interactions with membrane proteins in single cells measured with mechanical amplification.Tuesday, November 24, 2015
Guan Y, Shan X, Zhang F, Wang S, Chen HY, Tao N,
Science advances. Oct-2015
Measuring small molecule interactions with membrane proteins in single cells is critical for understanding many cellular processes and for screening drugs. However, developing such a capability has been a difficult challenge. We show that molecular interactions with membrane proteins induce a mechanical deformation in the cellular membrane, and real-time monitoring of the deformation with subnanometer resolution allows quantitative analysis of small molecule-membrane protein interaction kinetics in single cells. This new strategy provides mechanical amplification of small binding signals, making it possible to detect small molecule interactions with membrane proteins. This capability, together with spatial resolution, also allows the study of the heterogeneous nature of cells by analyzing the interaction kinetics variability between different cells and between different regions of a single cell.
Self-propelled particles that transport cargo through flowing blood and halt hemorrhage.Tuesday, November 24, 2015
Baylis JR, Yeon JH, Thomson MH, Kazerooni A, Wang X, St John AE, Lim EB, Chien D, Lee A, Zhang JQ, Piret JM, Machan LS, Burke TF, White NJ, Kastrup CJ,
Science advances. Oct-2015
Delivering therapeutics deep into damaged tissue during bleeding is challenging because of the outward flow of blood. When coagulants cannot reach and clot blood at its source, uncontrolled bleeding can occur and increase surgical complications and fatalities. Self-propelling particles have been proposed as a strategy for transporting agents upstream through blood. Many nanoparticle and microparticle systems exhibiting autonomous or collective movement have been developed, but propulsion has not been used successfully in blood or used in vivo to transport therapeutics. We show that simple gas-generating microparticles consisting of carbonate and tranexamic acid traveled through aqueous solutions at velocities of up to 1.5 cm/s and delivered therapeutics millimeters into the vasculature of wounds. The particles transported themselves through a combination of lateral propulsion, buoyant rise, and convection. When loaded with active thrombin, these particles worked effectively as a hemostatic agent and halted severe hemorrhage in multiple animal models of intraoperative and traumatic bleeding. Many medical applications have been suggested for self-propelling particles, and the findings of this study show that the active self-fueled transport of particles can function in vivo to enhance drug delivery.
Boramino acid as a marker for amino acid transporters.Tuesday, November 24, 2015
Liu Z, Chen H, Chen K, Shao Y, Kiesewetter DO, Niu G, Chen X,
Science advances. Sep-2015
Amino acid transporters (AATs) are a series of integral channels for uphill cellular uptake of nutrients and neurotransmitters. Abnormal expression of AATs is often associated with cancer, addiction, and multiple mental diseases. Although methods to evaluate in vivo expression of AATs would be highly useful, efforts to develop them have been hampered by a lack of appropriate tracers. We describe a new class of AA mimics-boramino acids (BAAs)-that can serve as general imaging probes for AATs. The structure of a BAA is identical to that of the corresponding natural AA, except for an exotic replacement of the carboxylate with -BF3 (-). Cellular studies demonstrate strong AAT-mediated cell uptake, and animal studies show high tumor-specific accumulation, suggesting that BAAs hold great promise for the development of new imaging probes and smart AAT-targeting drugs.
Fractal circuit sensors enable rapid quantification of biomarkers for donor lung assessment for transplantation.Tuesday, November 24, 2015
Sage AT, Besant JD, Mahmoudian L, Poudineh M, Bai X, Zamel R, Hsin M, Sargent EH, Cypel M, Liu M, Keshavjee S, Kelley SO,
Science advances. Aug-2015
Biomarker profiling is being rapidly incorporated in many areas of modern medical practice to improve the precision of clinical decision-making. This potential improvement, however, has not been transferred to the practice of organ assessment and transplantation because previously developed gene-profiling techniques require an extended period of time to perform, making them unsuitable in the time-sensitive organ assessment process. We sought to develop a novel class of chip-based sensors that would enable rapid analysis of tissue levels of preimplantation mRNA markers that correlate with the development of primary graft dysfunction (PGD) in recipients after transplant. Using fractal circuit sensors (FraCS), three-dimensional metal structures with large surface areas, we were able to rapidly (<20 min) and reproducibly quantify small differences in the expression of interleukin-6 (IL-6), IL-10, and ATP11B mRNA in donor lung biopsies. A proof-of-concept study using 52 human donor lungs was performed to develop a model that was used to predict, with excellent sensitivity (74%) and specificity (91%), the incidence of PGD for a donor lung. Thus, the FraCS-based approach delivers a key predictive value test that could be applied to enhance transplant patient outcomes. This work provides an important step toward bringing rapid diagnostic mRNA profiling to clinical application in lung transplantation.
Structural basis for recognition of diverse transcriptional repressors by the TOPLESS family of corepressors.Tuesday, November 24, 2015
Ke J, Ma H, Gu X, Thelen A, Brunzelle JS, Li J, Xu HE, Melcher K,
Science advances. Jul-2015
TOPLESS (TPL) and TOPLESS-related (TPR) proteins comprise a conserved family of plant transcriptional corepressors that are related to Tup1, Groucho, and TLE (transducin-like enhancer of split) corepressors in yeast, insects, and mammals. In plants, TPL/TPR corepressors regulate development, stress responses, and hormone signaling through interaction with small ethylene response factor-associated amphiphilic repression (EAR) motifs found in diverse transcriptional repressors. How EAR motifs can interact with TPL/TPR proteins is unknown. We confirm the amino-terminal domain of the TPL family of corepressors, which we term TOPLESS domain (TPD), as the EAR motif-binding domain. To understand the structural basis of this interaction, we determined the crystal structures of the TPD of rice (Os) TPR2 in apo (apo protein) state and in complexes with the EAR motifs from Arabidopsis NINJA (novel interactor of JAZ), IAA1 (auxin-responsive protein 1), and IAA10, key transcriptional repressors involved in jasmonate and auxin signaling. The OsTPR2 TPD adopts a new fold of nine helices, followed by a zinc finger, which are arranged into a disc-like tetramer. The EAR motifs in the three different complexes adopt a similar extended conformation with the hydrophobic residues fitting into the same surface groove of each OsTPR2 monomer. Sequence alignments and structure-based mutagenesis indicate that this mode of corepressor binding is highly conserved in a large set of transcriptional repressors, thus providing a general mechanism for gene repression mediated by the TPL family of corepressors.
Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline.Tuesday, November 24, 2015
Preiss L, Langer JD, Yildiz Ö, Eckhardt-Strelau L, Guillemont JE, Koul A, Meier T,
Science advances. May-2015
Multidrug-resistant tuberculosis (MDR-TB) is more prevalent today than at any other time in human history. Bedaquiline (BDQ), a novel Mycobacterium-specific adenosine triphosphate (ATP) synthase inhibitor, is the first drug in the last 40 years to be approved for the treatment of MDR-TB. This bactericidal compound targets the membrane-embedded rotor (c-ring) of the mycobacterial ATP synthase, a key metabolic enzyme required for ATP generation. We report the x-ray crystal structures of a mycobacterial c9 ring without and with BDQ bound at 1.55- and 1.7-Å resolution, respectively. The structures and supporting functional assays reveal how BDQ specifically interacts with the rotor ring via numerous interactions and thereby completely covers the c-ring's ion-binding sites. This prevents the rotor ring from acting as an ion shuttle and stalls ATP synthase operation. The structures explain how diarylquinoline chemicals specifically inhibit the mycobacterial ATP synthase and thus enable structure-based drug design of next-generation ATP synthase inhibitors against Mycobacterium tuberculosis and other bacterial pathogens.
Screening system for drug-induced arrhythmogenic risk combining a patch clamp and heart simulator.Tuesday, November 24, 2015
Okada JI, Yoshinaga T, Kurokawa J, Washio T, Furukawa T, Sawada K, Sugiura S, Hisada T,
Science advances. May-2015
To save time and cost for drug discovery, a paradigm shift in cardiotoxicity testing is required. We introduce a novel screening system for drug-induced arrhythmogenic risk that combines in vitro pharmacological assays and a multiscale heart simulator. For 12 drugs reported to have varying cardiotoxicity risks, dose-inhibition curves were determined for six ion channels using automated patch clamp systems. By manipulating the channel models implemented in a heart simulator consisting of more than 20 million myocyte models, we simulated a standard electrocardiogram (ECG) under various doses of drugs. When the drug concentrations were increased from therapeutic levels, each drug induced a concentration-dependent characteristic type of ventricular arrhythmia, whereas no arrhythmias were observed at any dose with drugs known to be safe. We have shown that our system combining in vitro and in silico technologies can predict drug-induced arrhythmogenic risk reliably and efficiently.
PlGF-induced VEGFR1-dependent vascular remodeling determines opposing antitumor effects and drug resistance to Dll4-Notch inhibitors.Tuesday, November 24, 2015
Iwamoto H, Zhang Y, Seki T, Yang Y, Nakamura M, Wang J, Yang X, Torimura T, Cao Y,
Science advances. Apr-2015
Inhibition of Dll4 (delta-like ligand 4)-Notch signaling-mediated tumor angiogenesis is an attractive approach in cancer therapy. However, inhibition of Dll4-Notch signaling has produced different effects in various tumors, and no biomarkers are available for predicting the anti-Dll4-Notch-associated antitumor activity. We show that human and mouse tumor cell-derived placental growth factor (PlGF) is a key determinant of the Dll4-Notch-induced vascular remodeling and tumor growth. In natural PlGF-expressing human tumors, inhibition of Dll4-Notch signaling markedly accelerated tumor growth by increasing blood perfusion in nonleaking tumor vasculatures. Conversely, in PlGF-negative tumors, Dll4 inhibition suppressed tumor growth by the formation of nonproductive and leaky vessels. Surprisingly, genetic inactivation of vascular endothelial growth factor receptor 1 (VEGFR1) completely abrogated the PlGF-modulated vascular remodeling and tumor growth, indicating a crucial role for VEGFR1-mediated signals in modulating Dll4-Notch functions. These findings provide mechanistic insights on PlGF-VEGFR1 signaling in the modulation of the Dll4-Notch pathway in angiogenesis and tumor growth, and have therapeutic implications of PlGF as a biomarker for predicting the antitumor benefits of Dll4 and Notch inhibitors.
Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia.Tuesday, November 24, 2015
Tada K, Kobayashi M, Takiuchi Y, Iwai F, Sakamoto T, Nagata K, Shinohara M, Io K, Shirakawa K, Hishizawa M, Shindo K, Kadowaki N, Hirota K, Yamamoto J, Iwai S, Sasanuma H, Takeda S, Takaori-Kondo A,
Science advances. Apr-2015
Adult T cell leukemia (ATL) is an aggressive T cell malignancy caused by human T cell leukemia virus type 1 (HTLV-1) and has a poor prognosis. We analyzed the cytotoxic effects of various nucleoside analog reverse transcriptase inhibitors (NRTIs) for HIV-1 on ATL cells and found that abacavir potently and selectively kills ATL cells. Although NRTIs have minimal genotoxicities on host cells, the therapeutic concentration of abacavir induced numerous DNA double-strand breaks (DSBs) in the chromosomal DNA of ATL cells. DSBs persisted over time in ATL cells but not in other cell lines, suggesting impaired DNA repair. We found that the reduced expression of tyrosyl-DNA phosphodiesterase 1 (TDP1), a repair enzyme, is attributable to the cytotoxic effect of abacavir on ATL cells. We also showed that TDP1 removes abacavir from DNA ends in vitro. These results suggest a model in which ATL cells with reduced TDP1 expression are unable to excise abacavir incorporated into genomic DNA, leading to irreparable DSBs. On the basis of the above mechanism, we propose abacavir as a promising chemotherapeutic agent for ATL.
Silver(I) as a widely applicable, homogeneous catalyst for aerobic oxidation of aldehydes toward carboxylic acids in water-"silver mirror": From stoichiometric to catalytic.Tuesday, November 24, 2015
Liu M, Wang H, Zeng H, Li CJ,
Science advances. Mar-2015
The first example of a homogeneous silver(I)-catalyzed aerobic oxidation of aldehydes in water is reported. More than 50 examples of different aliphatic and aromatic aldehydes, including natural products, were tested, and all of them successfully underwent aerobic oxidation to give the corresponding carboxylic acids in extremely high yields. The reaction conditions are very mild and greener, requiring only a very low silver(I) catalyst loading, using atmospheric oxygen as the oxidant and water as the solvent, and allowing gram-scale oxidation with only 2 mg of our catalyst. Chromatography is completely unnecessary for purification in most cases.
Pathologically confirmed autoimmune encephalitis in suspected Creutzfeldt-Jakob disease.Tuesday, November 24, 2015
Maat P, de Beukelaar JW, Jansen C, Schuur M, van Duijn CM, van Coevorden MH, de Graaff E, Titulaer M, Rozemuller AJ, Sillevis Smitt P,
Neurology(R) neuroimmunology & neuroinflammation. Dec-2015
It is important to consider immune-mediated disorders in the differential diagnosis of rapidly progressive neurologic deficits.
Effect of Experimental Thyrotoxicosis onto Blood Coagulation: A Proteomics Study.Tuesday, November 24, 2015
Engelmann B, Bischof J, Dirk AL, Friedrich N, Hammer E, Thiele T, Führer D, Homuth G, Brabant G, Völker U,
European thyroid journal. Sep-2015
The results suggest that experimental thyrotoxicosis exerts selective and specific thyroxine-induced effects on coagulation markers. Our study design allows assessment of thyroid hormone effects on plasma protein levels without secondary effects of other diseases or therapies.
The Multitarget Ligand 3-Iodothyronamine Modulates β-Adrenergic Receptor 2 Signaling.Tuesday, November 24, 2015
Dinter J, Khajavi N, Mühlhaus J, Wienchol CL, Cöster M, Hermsdorf T, Stäubert C, Köhrle J, Schöneberg T, Kleinau G, Mergler S, Biebermann H,
European thyroid journal. Sep-2015
The presented data support that 3-T1AM directly modulates β-adrenergic receptor signaling. The relationship between 3-T1AM and β-adrenergic signaling also reveals a potential therapeutic value for suppressing Ca(2+) channel-mediated inflammation processes, occurring in eye diseases such as conjunctivitis.
Evolutionary Conservation of 3-Iodothyronamine as an Agonist at the Trace Amine-Associated Receptor 1.Tuesday, November 24, 2015
Cöster M, Biebermann H, Schöneberg T, Stäubert C,
European thyroid journal. Sep-2015
The high structural conservation of Taar1 throughout vertebrate evolution highlights the physiological relevance of Taar1, but species-specific differences in T1AM potency at Taar1 orthologs suggest a specialization of rat Taar1 for T1AM recognition. In contrast, β-PEA and p-Tyr potencies were rather conserved throughout all tested Taar1 orthologs. We provide evidence that the observed differences in potency are related to differences in constraint during Taar1 evolution.
Experience with targeted next generation sequencing for the care of lung cancer: insights into promises and limitations of genomic oncology in day-to-day practice.Tuesday, November 24, 2015
Rangachari D, VanderLaan PA, Le X, Folch E, Kent MS, Gangadharan SP, Majid A, Haspel RL, Joseph LJ, Huberman MS, Costa DB,
Cancer treatment communications. 29-5-2015
Targeted NGS can identify a significant number of therapeutically-relevant driver events in lung ACs; particularly in never or light smokers. For SC lung cancers, NGS is less likely to alter current practice. Further research into the cost effectiveness and optimal use of NGS and improved provider training in genomic oncology are warranted.
Label-free assessment of replicative senescence in mesenchymal stem cells by Raman microspectroscopy.Tuesday, November 24, 2015
Bai H, Li H, Han Z, Zhang C, Zhao J, Miao C, Yan S, Mao A, Zhao H, Han Z,
Biomedical optics express. 1-Nov-2015
Here, Raman microspectroscopy was employed to assess replicative senescence of mesenchymal stem cells (MSC). A regular spectral change related to the cell senescence was found in the ratio of two peaks at 1157 cm(-1) and 1174 cm(-1), which are assigned to C-C, C-N stretching vibrations in proteins and C-H bending vibrations in tyrosine and phenylalanine, respectively. With the cell aging, the ratio I1157 / I1174 exhibited a monotonic decline and showed small standard deviations, so that it can statistically distinguish between cells having slight changes in terms of aging. We propose that I1157 / I1174 can act as a characteristic spectral signature for label-free assessment of MSC senescence.
Label-free near-infrared reflectance microscopy as a complimentary tool for two-photon fluorescence brain imaging.Tuesday, November 24, 2015
Mascaro AL, Costantini I, Margoni E, Iannello G, Bria A, Sacconi L, Pavone FS,
Biomedical optics express. 1-Nov-2015
In vivo two-photon imaging combined with targeted fluorescent indicators is currently extensively used for attaining critical insights into brain functionality and structural plasticity. Additional information might be gained from back-scattered photons from the near-infrared (NIR) laser without introducing any exogenous labelling. Here, we describe a complimentary and versatile approach that, by collecting the reflected NIR light, provides structural details on axons and blood vessels in the brain, both in fixed samples and in live animals under a cranial window. Indeed, by combining NIR reflectance and two-photon imaging of a slice of hippocampus from a Thy1-GFPm mouse, we show the presence of randomly oriented axons intermingled with sparsely fluorescent neuronal processes. The back-scattered photons guide the contextualization of the fluorescence structure within brain atlas thanks to the recognition of characteristic hippocampal structures. Interestingly, NIR reflectance microscopy allowed the label-free detection of axonal elongations over the superficial layers of mouse cortex under a cranial window in vivo. Finally, blood flow can be measured in live preparations, thus validating label free NIR reflectance as a tool for monitoring hemodynamic fluctuations. The prospective versatility of this label-free technique complimentary to two-photon fluorescence microscopy is demonstrated in a mouse model of photothrombotic stroke in which the axonal degeneration and blood flow remodeling can be investigated.
Non-invasive manipulation of Drosophila behavior by two-photon excited red-activatable channelrhodopsin.Tuesday, November 24, 2015
Hsiao PY, Tsai CL, Chen MC, Lin YY, Yang SD, Chiang AS,
Biomedical optics express. 1-Nov-2015
Scattering and absorption limit light penetration through inhomogeneous tissue. To reduce scattering, biochemists have shifted the wavelengths of excitation light for optogenetic actuators and fluorescent proteins to the orange-red range, while physicists have developed multiphoton technologies for deep tissue stimulation. We have built a rapid multiphoton spectroscopic screening system of genetically encoded red-activatable channelrhodopsin (ReaChR), and considered specific behaviors in transgenic Drosophila melanogaster as readouts to optimize the laser parameters for two-photon optogenetic activation. A wavelength-tunable optical parametric amplifier was adopted as the major light source for widefield two-photon excitation (TPE) of ReaChR. Our assays suggest that the optimized TPE wavelength of ReaChR is 1250 nm. Exploiting its capacity for optogenetic manipulation to induce macroscopic behavioral change, we realized rapid spectroscopic screening of genetically encoded effectors or indicators in vivo, and used modulation of ReaChR in the fly as a successful demonstration of such a system.
Reflectance confocal microscopy of red blood cells: simulation and experiment.Tuesday, November 24, 2015
Zeidan A, Yelin D,
Biomedical optics express. 1-Nov-2015
Measuring the morphology of red blood cells is important for clinical diagnosis, providing valuable indications on a patient's health. In this work, we have simulated the appearance of normal red blood cells under a reflectance confocal microscope and discovered unique relations between the morphological parameters and the resulting characteristic interference patterns of the cell. The simulation results showed good agreement with in vitro reflectance confocal images of red blood cells, acquired using spectrally encoded flow cytometry that imaged the cells in a linear flow without artificial staining. By matching the simulated patterns to confocal images of the cells, this method could be used for measuring cell morphology in three dimensions and for studying their physiology.
Influence of a skin status on the light interaction with dermis.Tuesday, November 24, 2015
Kamshilin AA, Mamontov OV, Koval VT, Zayats GA, Romashko RV,
Biomedical optics express. 1-Nov-2015
We present experimental evidence that the parameters of green light remitted from a human tissue in-vivo strongly depend on skin contact status. In case when the skin is free of any contact, simultaneous recording of imaging photoplethysmogram (iPPG) and electrocardiogram revealed that contactless iPPG fails in correct estimates of the heart rate in almost half of the cases. Meanwhile, the number of successful correlations between ECG and iPPG is significantly increased when the skin is in contact with a glass plate. These observations are in line with the recently proposed model in which pulsatile arteries deform the connective-tissue components of the dermis thus resulting in temporal modulation of the capillary density interacting with slightly penetrating light.
Faecal calprotectin: Management in inflammatory bowel disease.Tuesday, November 24, 2015
Benítez JM, García-Sánchez V,
World journal of gastrointestinal pathophysiology. 15-Nov-2015
Inflammatory bowel disease (IBD) is a chronic and relapsing disorder which leads to an inflammation of the gastrointestinal tract. A tailored therapy to achieve mucosal healing with the less adverse events has become a key issue in the management of IBD. In the past, the clinical remission was the most important factor to consider for adapting diagnostic procedures and therapeutic strategies. However, there is no a good correlation between symptoms and intestinal lesions, so currently the goals of treatment are to achieve not only the control of symptoms, but deep remission, which is related with a favourable prognosis. Thus, the determination of biological markers or biomarkers of intestinal inflammation play a crucial role. Many biomarkers have been extensively evaluated in IBD showing significant correlation with endoscopic lesions, risk of recurrence and response to treatment. One of the most important markers is faecal calprotectin (FC). Despite calprotectin limitations, this biomarker represents a reliable and noninvasive alternative to reduce the need for endoscopic procedures. FC has demonstrated its performance for regular monitoring of IBD patients, not only to the diagnosis for discriminating IBD from non-IBD diagnosis, but for assessing disease activity, relapse prediction and response to therapy. Although, FC provides better results than other biomarkers such as C-reactive protein and erythrocyte sedimentation rate, these surrogate markers of intestinal inflammation should not be used isolation but in combination with other clinical, endoscopic, radiological or/and histological parameters enabling a comprehensive assessment of IBD patients.
Magnetic resonance imaging biomarkers of gastrointestinal motor function and fluid distribution.Tuesday, November 24, 2015
Khalaf A, Hoad CL, Spiller RC, Gowland PA, Moran GW, Marciani L,
World journal of gastrointestinal pathophysiology. 15-Nov-2015
Magnetic resonance imaging (MRI) is a well established technique that has revolutionized diagnostic radiology. Until recently, the impact that MRI has had in the assessment of gastrointestinal motor function and bowel fluid distribution in health and in disease has been more limited, despite the novel insights that MRI can provide along the entire gastrointestinal tract. MRI biomarkers include intestinal motility indices, small bowel water content and whole gut transit time. The present review discusses new developments and applications of MRI in the upper gastrointestinal tract, the small bowel and the colon reported in the literature in the last 5 years.
Novel therapy for advanced gastric cancer.Tuesday, November 24, 2015
Zhang Y, Wu S,
World journal of gastrointestinal oncology. 15-Nov-2015
Gastric cancer (GC) is a common lethal malignancy. Gastroesophageal junction and gastric cardia tumors are the fastest rising malignancies due to increasing prevalence of obesity and acid reflex in the United States. Traditional chemotherapy remains the main treatment with trastuzumab targeting human epidermal growth factor receptor 2 positive disease. The median overall survival (OS) is less than one year for advanced GC patients; thus, there is an urgent unmet need to develop novel therapy for GC. Although multiple targeted agents were studied, only the vascular endothelial growth factor receptor inhibitor ramucirumab was approved recently by the United States Food and Drug Administration because of its 1.4 mo OS benefit (5.2 mo vs 3.8 mo, P = 0.047) as a single agent; 2.2 mo improvement of survival (9.6 mo vs 7.4 mo, P = 0.017) when combined with paclitaxel in previously treated advanced GC patients. It is the first single agent approved for previously treated GC and the second biologic agent after trastuzumab. Even with limited success, targeted therapy may be improved by developing new biomarkers. Immune therapy is changing the paradigm of cancer treatment and is presently under active investigation for GC in clinical trials. More evidence supports GC stem cells existence and early stage studies are looking for its potential therapeutic possibilities.
A semipolar fraction of petroleum ether extract of Artemisia aucheri induces apoptosis and enhances the apoptotic response to doxorubicin in human neuroblastoma SKNMC cell line.Tuesday, November 24, 2015
Ahmadi F, Mojarrab M, Ghazi-Khansari M, Hosseinzadeh L,
Research in pharmaceutical sciences. 18-6-2015
Artemisia is an important genus of Iranian flora whose potent anti-proliferative effect has been demonstrated previously on human cancerous cell lines. In the current study, further fractionation was carried out on the petroleum ether extract of A. aucheri and their cytotoxic effects were evaluated on three human cancer cell lines. Cell viability was determined by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide assay. Real time polymerase chain reaction (RT-PCR) was used to evaluate the expression of apoptotic related genes. Activation of caspases and detection of intracellular doxorubicin (DOX) accumulation were evaluated using a spectrophotometer. Mitochondrial membrane potential (MMP) was measured using flow cytometry. The fraction NO-7 (F7) of petroleum ether extract showed the highest anti-proliferative effect, especially against SKNMC cells. Therefore, we focused on a description of the cytotoxic mechanism of the most potent fraction on SKNMC cells. The results indicated that F7 was able to induce apoptosis through MMP disruption, activation of caspases and increament of proapoptotic genes Bax and Smac/DIABLO. Moreover, our observation indicated that F7 is able to increase the cytotoxicity of DOX in SKNMC cells. The combination of F7+DOX significantly increased the intracellular accumulation of DOX. These results indicated that F7 induces apoptosis in SKNMC cells. Moreover, it might enhance the antitumor activity of DOX, through modulating the activity of multidrug resistant cancer cells and inducing apoptosis.
Saffron ethanolic extract attenuates oxidative stress, spatial learning, and memory impairments induced by local injection of ethidium bromide.Tuesday, November 24, 2015
Ghaffari S, Hatami H, Dehghan G,
Research in pharmaceutical sciences. 25-11-2015
Cognitive deficits have been observed in patients with multiple sclerosis (MS) because of hippocampal insults. Oxidative stress plays a key role in the pathophysiology of MS. The aim of this study was to evaluate the effects of Crocus sativus L., commonly known as saffron, on learning and memory loss and the induction of oxidative stress in the hippocampus of toxic models of MS. One week after MS induction by intrahippocampal injection of ethidium bromide (EB), animals were treated with two doses of saffron extract (5 and 10 μg/rat) for a week. Learning and spatial memory status was assessed using Morris Water Maze. After termination of behavioral testing days, animals were decapitated and the bilateral hippocampi dissected to measure some of the oxidative stress markers including the level of hippocampi thiobarbituric acid reactive substances and the activity of antioxidant enzymes such as glutathione peroxidase and superoxide dismutase. Treatment with saffron extract ameliorated spatial learning and memory impairment (P<0.05). Total antioxidant reactivity capacity, lipid peroxidation products and antioxidant enzymes activity in the hippocampus homogenates of EB treated group were significantly higher than those of all other groups (P<0.01). Indeed, treatment with a saffron extract for 7 consecutive days significantly restored the antioxidant status to the normal levels (P<0.01). These observations reveal that saffron extract can ameliorate the impairment of learning and memory as well as the disturbances in oxidative stress parameters in the hippocampus of experimental models of MS.
Evaluation of the effect of ethanolic extract of fruit pulp of Cassia fistula Linn. on forced swimming induced chronic fatigue syndrome in mice.Tuesday, November 24, 2015
Sarma P, Borah M, Das S,
Research in pharmaceutical sciences. 25-11-2015
The fruit of Cassia fistula Linn. is a legume, has antioxidant and lots of other medicinal properties. As oxidants are involved in the pathogenesis of chronic fatigue syndrome, the present study was done to evaluate the effect of ethanolic extract of fruit pulp of C. fistula Linn. (EECF) on forced swimming induced chronic fatigue syndrome (CFS). Albino mice of 25-40 grams were grouped into five groups (n=5). Group A served as naive control and group B served as stress control. Group C received EECF 200 mg/kg and group D received EECF 400 mg/kg respectively. Group E received imipramine 20 mg/kg (standard). All animals were treated with their respective agent orally daily for 7 days. Except for group A, animals in other groups were subjected to force swimming 6 min daily for 7 days to induce a state of chronic fatigue. Duration of immobility was assessed on day 1(st), 3(rd), 5(th) and 7(th). Anxiety level (by elevated plus maze and mirrored chamber) and loco-motor activity (by open field test) were assessed 24 h after last force swimming followed by biochemical estimations of oxidative biomarkers in brain homogenate at the end of study. Treatment with EECF resulted in significant reduction in the duration of immobility, reduced anxiety and increased loco-motor activity. Malondialdehyde level was also reduced and catalase level was increased in the extract treated group and standard group compared to stress control group. The study indicates that EECF has protective effect against experimentally induced CFS.
Stereospecific quantitation of 6-prenylnaringenin in commercially available H. lupulus-containing natural health products and dietary supplements.Tuesday, November 24, 2015
Martinez SE, Davies NM,
Research in pharmaceutical sciences. 25-11-2015
6-Prenylnaringenin (6PN) is a chiral prenylflavonoid found most prevalently in hops (Humulus lupulus) and present in hops and hop products. It is an isomer of the potent phytoestrogen, 8-prenylnaringenin. An enantiospecific method for quantitation 6PN by LC-ESI-MS has been developed. Baseline enantiomeric resolution of 6PN was attained on a Chiralpak(®) AD-RH column with an isocratic mobile phase consisting of acetonitrile and 10 mM ammonium formate (pH 8.5) (39:61, v/v) and a flow rate of 1.25 mL/min. Quantitative MS data were obtained by selected ion monitoring of the [M-H](-)-ion of both enantiomers of 6PN (m/z 339.10) and the internal standard, 4-acetamidobenzoic acid (m/z 178.05). The method was found to be accurate and precise for enantiospecific quantification of 6PN. The method was successfully applied to the content analysis of 39 commercially available natural health products and dietary supplements reported to contain H. lupulus plant material, extracts and label claims of 6PN. 6PN was present in 25 of 34 products containing plant material or extracts of H. lupulus. Of the five products with claimed amounts of 6PN, all were found to possess <50% of label claims. Results of the content analysis indicated a lack of uniformity in botanical nutraceuticals claiming 6PN content.
Molecular mechanisms of etoposide.Tuesday, November 24, 2015
Montecucco A, Zanetta F, Biamonti G,
EXCLI journal. 25-11-2015
Etoposide derives from podophyllotoxin, a toxin found in the American Mayapple. It was first synthesized in 1966 and approved for cancer therapy in 1983 by the U.S. Food and Drug Administration (Hande, 1998[25]). Starting from 1980s several studies demonstrated that etoposide targets DNA topoisomerase II activities thus leading to the production of DNA breaks and eliciting a response that affects several aspects of cell metabolisms. In this review we will focus on molecular mechanisms that account for the biological effect of etoposide.
Effects of fermented Cordyceps sinensis on oxidative stress in doxorubicin treated rats.Tuesday, November 24, 2015
Wu R, Gao JP, Wang HL, Gao Y, Wu Q, Cui XH,
Pharmacognosy magazine. 19-1-2015
Fermented CS can inhibit DOX-induced OS reactions, and the anti-OS effects have high selectivity to heart and liver, especially to heart. Thus, fermented CS may be a candidate used for the prevention against various cardiac diseases induced by OS.
Phenolic alkaloids from Menispermum dauricum inhibits BxPC-3 pancreatic cancer cells by blocking of Hedgehog signaling pathway.Tuesday, November 24, 2015
Zhou ZG, Zhang CY, Fei HX, Zhong LL, Bai Y,
Pharmacognosy magazine. 25-11-2015
The treatment of PAMD displayed Hh signaling pathway blockade through decreasing the protein and mRNA levels of Shh and its downstream transcription factor Gli-1, suggesting a promising strategy in treating human PC.
Phytochemicals of Salacia oblonga responsible for free radical scavenging and antiproliferative activity against breast cancer cell lines (MDA-MB-231).Tuesday, November 24, 2015
Musini A, Rao JP, Giri A,
Physiology and molecular biology of plants : an international journal of functional plant biology. Oct-2015
Salacia oblonga, an inhabitant of tropical regions has been used in traditional Indian medicinal systems. Phytochemicals were extracted in methanol from the plant and analyzed for various biological activities. The results of biochemical tests for total phenolics (297 ± 0.005 and 275 ± 0.006) and flavonoids (95 ± 0.004 and 61.6 ± 0.004) in the aerial and root parts were indicated as Gallic acid and quercetin equivalents respectively. The Aerial and root extracts showed strong reducing ability based on reducing power and FRAP assays. The extracts exhibited significant IC50 values in DPPH, super oxide and nitric oxide radical scavenging assays. The extracts displayed low IC50 values (<50 μg/ml) when assessed for antiproliferative activity against breast cancer cell lines using the MTT assay. GC-MS analysis of methanolic extracts have revealed the presence of compounds viz. n-Hexadecanoic acid, N-Methoxy-N-methylacetamide, Ursa-9(11), 12-dien-3-ol, Gamma-sitosterol etc., that might be potential candidates for the biological activity exhibited by the extract.
Critical review of Ayurvedic Varṇya herbs and their tyrosinase inhibition effect.Tuesday, November 24, 2015
Sharma K, Joshi N, Goyal C,
Ancient science of life. 4-9-2015
All the twenty herbs reviewed are found to act as varṇya directly (citation as varṇya) or indirectly (alleviation of pitta and rakta) as per Ayurveda and to interfere in melanogenesis pathway through tyrosinase inhibition as per biomedicine. This shows their potential to act as good skin whitening agents. Śuṇṭhi being a part of many varṇya formulations, is the only herb among all reviewed in the present study found to exhibit tyrosinase inhibition without any Ayurvedic citation of varṇya property.
The imidazoline receptors and ligands in pain modulation.Tuesday, November 24, 2015
Bektas N, Nemutlu D, Arslan R,
Indian journal of pharmacology. 25-11-2015
Pain is an unpleasant experience and effects daily routine negatively. Although there are various drugs, many of them are not entirely successful in relieving pain, since pain modulation is a complex process involving numerous mediators and receptors. Therefore, it is a rational approach to identify the factors involved in the complex process and develop new agents that act on these pain producing mechanisms. In this respect, the involvement of the imidazoline receptors in pain modulation has drawn attention in recent years. In this review, it is aimed to focus on the imidazoline receptors and their ligands which contribute to the pain modulation. It is demonstrated that imidazoline-2 (I2) receptors are steady new drug targets for analgesics. Even if the mechanism of I2 receptor is not well known in the modulation of pain, it is known that it plays a role in tonic and chronic pain but not in acute phasic pain. Moreover, the I2 receptor ligands increase the analgesic effects of opioids in both acute and chronic pain and prevent the development of opioid tolerance. So, they are valuable for the chronic pain treatment and also therapeutic coadjuvants in the management of chronic pain with opiate drugs due to the attenuation of opioid tolerance and addiction. Thus, the use of the ligands which bind to the imidazoline receptors is an effective strategy for relieving pain. This educational forum exhibits the role of imidazoline receptors and ligands in pain process by utilizing experimental studies.
A systematic review of observational studies on oxidative/nitrosative stress involvement in dengue pathogenesis.Tuesday, November 24, 2015
Castro R, Pinzón HS, Alvis-Guzman N,
Colombia medica (Cali, Colombia). 25-11-2015
Based on published data found in peer-reviewed literature, oxidative and nitrosative stress are demonstrated by changes in plasma levels of nitric oxide, antioxidants, lipid peroxidation and protein oxidation markers in patients with dengue infection. Additionally, elevated serum protein carbonyls and malondialdehyde levels appear to be associated with dengue disease severity.
Do SADQ and AUDIT identify independent impacts of alcohol abuse - clinical and biochemical markers respectively?Tuesday, November 24, 2015
Pradeep RJ, Dhilip AM, Mysore A,
Indian journal of psychiatry. 30-9-2015
Our data suggests that the two scales, AUDIT and SADQ may be tapping into two different outcomes of increased alcohol use namely clinical and biochemical markers, respectively. SADQ could be useful in studies looking at withdrawal related severity and clinical aspects of alcoholism; while AUDIT could be more suitable for studies looking at alcoholism-related medical morbidity. This needs to be confirmed in larger unselected samples from different community and clinical settings.
Propofol induces apoptosis and inhibits the proliferation of rat embryonic neural stem cells via gamma-aminobutyric acid type A receptor.Tuesday, November 24, 2015
Wang JW, Cheng WW, Xu T, Yang ZY,
Genetics and molecular research : GMR. 25-11-2015
We investigated the effect of propofol on the proliferation and viability of rat embryonic neural stem cells (rENSCs) and the potential mechanisms involved. rENSCs were isolated and cultured in vitro and treated with 1, 10, or 50 μM propofol, while the control group was treated with 0.1 μM dimethyl sulfoxide. The effect of propofol on the proliferation and viability of rENSCs was examined by proliferation and apoptosis assays. Real-time polymerase chain reaction was employed to analyze the mRNA expression of checkpoint kinase 1 (Chk1) and p53 in rENSCs exposed to propofol. Immunoprecipitation assay and western blotting analysis were performed to analyze the effect of propofol on Chk1 and p53 activity. The gamma-aminobutyric acid type A (GABAA) receptor antagonist securinine was added to the rENSCs before being treated with propofol to investigate the role of the GABAA receptor in propofol-triggered effects on rENSCs. rENSCs specifically expressing nestin protein were successfully isolated and cultured for experiments. The inhibitory effect of propofol on rENSCs increased dose-dependently. The percentage of apoptotic cells increased to 11.7% and the activity of Chk1 and p53 enhanced after treatment with 50 μM propofol. However, addition of securinine abrogated propofol-induced apoptosis and activation of Chk1. The GABAA receptor mediates propofol-induced apoptosis and proliferation inhibition of rENSCs, possibly by modulating the Chk1/p53 signaling pathway.
Effects of Tripterygium wilfordii glycosides on regulatory T cells and Th17 in an IgA nephropathy rat model.Tuesday, November 24, 2015
Chen F, Ma YL, Ding H, Chen BP,
Genetics and molecular research : GMR. 23-11-2015
In this study, we examined the effects of Tripterygium wilfordii glycosides (TWGs) on Th17 and regulatory T cells (Tregs) in an immunoglobulin A nephropathy (IgAN) rat model. IgAN model rats were randomly divided into the model group, TWG treatment group, and prednisone group. Normal rats were included as controls. There were 6 rats in each group. The urine protein levels and the number of red blood cells in urine were analyzed at 24 h. IgA deposition in renal tissue was detected by fluorescence microscopy. The concentration of interleukin-17 in serum was detected by an enzyme-linked immunosorbent assay and the number of Tregs in blood was analyzed by flow cytometry. TWGs and prednisone significantly reduced urine protein levels and urine red blood cells at 24 h in IgAN model rats (P < 0.01), but prednisone had a greater effect than did TWGs (P < 0.05). TWGs and prednisone reduced IgA deposition in renal tissue, but prednisone had a greater effect than TWGs. T. wilfordii glycosides and prednisone significantly decreased the serum IL-17 level in an IgAN rat model and increased the number of Tregs in the blood (P < 0.01). There was no significant difference between prednisone and TWGs  (P > 0.05). In conclusion, TWGs had therapeutic effects on IgAN model rats and may regulate the immune balance of Th17 and Tregs.
KDR gene silencing inhibits proliferation of A549cells and enhancestheir sensitivity to docetaxel.Tuesday, November 24, 2015
Wei R, Zang JP,
Genetics and molecular research : GMR. 23-11-2015
We investigated the effects of kinase-domain insert containing receptor (KDR) gene silencing on the proliferation of A549 cells and their sensitivity to docetaxel. After designing and synthesizing the KDR siRNA sequence, the sequence was transfected into A549 cells using Lipofectamine 2000. The expression of KDR mRNA and protein after KDR gene silencing was detected by reverse transcription-polymerase chain reaction and western blotting; A549 cell cycle was detected by flow cytometry. An MTT assay and colony formation was performed to determine the sensitivity of A549 cells to docetaxel after KDR gene silencing. After 48-h KDR gene silencing, KDR gene and protein expression significantly decreased (P < 0.05). A549 cell cycle was significantly arrested in G0/G1 phase, and the number of cells in S phase was reduced; the difference was statistically significant (P < 0.05) in the KDR gene silencing group, sensitivity of A549 cells to docetaxel showed a significant enhancement (P < 0.05). KDR siRNA can significantly silence KDR gene and protein expression in A549 cells, inhibit the proliferation of A549 cells, and enhance their sensitivity to docetaxel.
Effect of ABCE1-silencing gene, transfected by electrotransfer, on the proliferation, invasion, and migration of human thyroid carcinoma SW579 cells.Tuesday, November 24, 2015
Qu X, Zhang L,
Genetics and molecular research : GMR. 23-11-2015
We investigated the effect of an ABCE1-silencing gene on the proliferation, invasion, and migration of human thyroid carcinoma SW579 cells. We designed and synthesized targeted ABCE1-siRNA sequences and a negative control sequence (NC-siRNA), and transfected them into human thyroid cancer SW579 cells by electrotransfer to obtain ABCE1-SW579 and NC-siRNA-SW579 cells (siRNA is small interfering RNA). Through reverse transcription polymerase chain reaction and western blotting analysis, ABCE1 mRNA and protein expression levels in the electrotransferred cells were detected, and flow cytometry was used to detect cell cycle and apoptosis. The cell counting kit-8 (CCK-8) proliferation assay, the scratch healing assay, and the cell invasion assay were used to measure cell proliferation, migration, and invasion capabilities, respectively. Compared with NC-siRNA-SW579 and Ctrl-SW579 groups, ABCE1 mRNA and protein expression levels in the ABCE1-SW579 cells were significantly reduced. The growth rate of ABCE1-SW579 cells was significantly inhibited, the cell cycle was arrested in the G0/G1 phase, and the number of cells in the S phase was reduced. Compared with the Ctrl-SW579 group, the cell apoptosis rate in the ABCE1-SW579 group was significantly higher (P < 0.01), and proliferation, migration, and invasion were significantly reduced (P < 0.05). Expression of the ABCE1-silencing gene, transfected by electrotransfer, could inhibit the proliferation, invasion, and migration of thyroid cancer cells.
Quantitative trait locus analysis for kernel width using maize recombinant inbred lines.Tuesday, November 24, 2015
Hui GQ, Wen GQ, Liu XH, Yang HP, Luo Q, Song HX, Wen L, Sun Y, Zhang HM,
Genetics and molecular research : GMR. 23-11-2015
Maize (Zea mays L.) kernel width is one of the most important traits that is related to yield and appearance. To understand its genetic mechanisms more clearly, a recombinant inbred line (RIL) segregation population consisting of 239 RILs was used for quantitative trait locus (QTL) mapping for kernel width. We found four QTLs on chromosomes 3 (one), 5 (two), and 10 (one). The QTLs were close to their adjacent markers, with a range of 0-23.8 cM, and explained 6.2-19.7% of the phenotypic variation. The three QTLs on chromosomes 3 and 5 had positive additive effects, and to a certain extent increased kernel width, whereas the one on chromosome 10 exhibited negative additive effects and decreased kernel width. These results can be used for gene cloning and marker-assisted selection in maize-breeding programs.
Regulatory role of microRNA184 in osteosarcoma cells.Tuesday, November 24, 2015
Yin GR, Wang Q, Zhang XB, Wang SJ,
Genetics and molecular research : GMR. 19-11-2015
Osteosarcoma is a highly malignant cancer that often appears in teenagers. It is the most frequently occurring primary bone tumor, and can easily metastasize, resulting in high mortality. MicroRNAs express abnormally in osteosarcoma, and may function as oncogenes or tumor suppressors. Recent studies showed that microRNA184 (miR-184) is abnormally expressed in multiple tumors, and is involved in tumor cell growth, differentiation, invasion, and metastasis. Nevertheless, the role of miR-184 in osteosarcoma cells remains unknown. We evaluated the expression and function of microRNA184 in osteosarcoma cells. SOSP-M osteosarcoma cells were divided into normal control, miR-184 mimic, and miR-184 inhibitor groups. Real-time PCR was applied to detect miR-184 expression. The 3-(4,5-dimethylthaizol-2-yl)-2,5-diphenyltetrazolium bromide assay was used to evaluate cell proliferation. Transwell assays were performed to detect changes in cell invasion ability. Compared with the control group, miR-184 expression was significantly increased in the miR-184 mimic group (P < 0.05). After miR-184 inhibitor transfection, miR-184 expression was obviously reduced (P < 0.05). Tumor cell proliferation was enhanced in the miR-184 mimic group (P < 0.05), whereas miR-184 inhibition suppressed cell proliferation (P < 0.05). Furthermore, tumor cell invasion increased after miR-184 mimic transfection (P < 0.05), and decreased after inhibiting miR-184 (P < 0.05). MiR-184 promotes tumor cell proliferation and invasion, and may represent a new biological target for osteosarcoma.
A Model of Drosophila Larva Chemotaxis.Tuesday, November 24, 2015
Davies A, Louis M, Webb B,
PLoS computational biology. Nov-2015
Detailed observations of larval Drosophila chemotaxis have characterised the relationship between the odour gradient and the runs, head casts and turns made by the animal. We use a computational model to test whether hypothesised sensorimotor control mechanisms are sufficient to account for larval behaviour. The model combines three mechanisms based on simple transformations of the recent history of odour intensity at the head location. The first is an increased probability of terminating runs in response to gradually decreasing concentration, the second an increased probability of terminating head casts in response to rapidly increasing concentration, and the third a biasing of run directions up concentration gradients through modulation of small head casts. We show that this model can be tuned to produce behavioural statistics comparable to those reported for the larva, and that this tuning results in similar chemotaxis performance to the larva. We demonstrate that each mechanism can enable odour approach but the combination of mechanisms is most effective, and investigate how these low-level control mechanisms relate to behavioural measures such as the preference indices used to investigate larval learning behaviour in group assays.
Serial Changes of Cytokines and Growth Factors in Peripheral Circulation after Right Lobe Donor Hepatectomy.Tuesday, November 24, 2015
Sasturkar SV, David P, Sharma S, Sarin SK, Trehanpati N, Pamecha V,
Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 24-Nov-2015
Cytokines and growth factors have prominent role in liver regeneration. Aim of this study was to evaluate the biological markers of liver regeneration in healthy donors undergoing right lobe donor hepatectomy for living donor liver transplantation (LDLT). Twenty five voluntary liver donors were enrolled. Peripheral blood samples were taken at day before the operation and on postoperative day (POD) 1, 3, 7, 14 and 42. Levels of hepatocytes growth factor (HGF), interleukin 6 (IL6), tumor necrosis factor α (TNFα), thrombopoietin (TPO), transforming growth factor β1 (TGFβ1), interferon α (IFNα) and interferon γ (IFNγ) were monitored. The remnant liver volume (RLV) before surgery and regeneration liver volume (RgV) on POD14 were calculated on computed tomography (CT). RgV/RLV ratio was correlated with the ratio of the RLV to the body weight (RLVBWR). Inverse correlation was observed between RgV/RLV and RLVBWR (r(2) = 0.61; P < 0.001). There was significant rise of HGF on POD1 (p= 0.001), POD7 (p= 0.049) and POD14 (p= 0.04). TNFα was elevated on POD1 (P = 0.004). The levels of IL6 (P < 0.001) and TPO (P < 0.001) were higher from POD1 to POD42. IFNα was higher on POD14 (P = 0.003) and POD42 (P = 0.001). There was significant fall of IFNγ on POD1 (P = 0.01) and increased on POD14 (P = 0.04). The levels of TGFβ1 were higher on POD14 (P = 0.008) and on POD42 (P = 0.002). In conclusion, HGF, IL6, TNFα and TPO are involved in the early phase while TGFβ1 and interferon are involved in termination phase of liver regeneration. Liver regeneration was observed to be higher in donors with low RLVBWR. This article is protected by copyright. All rights reserved.
Comparative Study of a Real-Time PCR Assay Targeting senX3-regX3 versus Other Molecular Strategies Commonly Used in the Diagnosis of Tuberculosis.Tuesday, November 24, 2015
Sanjuan-Jimenez R, Toro-Peinado I, Bermudez P, Colmenero JD, Morata P,
PloS one. 24-11-2015
Real-time PCR assays targeting IS6110 lack the desired specificity. The Xpert MTB/RIF and in-house senX3-regX3 assays are both sensitive and specific for the detection of MTBC in both pulmonary and extrapulmonary samples. Therefore, the real time PCR senX3-regX3 based assay could be a useful and complementary tool in the diagnosis of tuberculosis.
Enzyme-operated DNA-based nanodevices.Tuesday, November 24, 2015
Del Grosso E, Dallaire AM, Vallée-Bélisle A, Ricci F,
Nano letters. 24-Nov-2015
Functional molecular nanodevices and nanomachines have attracted a growing interest for their potential use in life science and nanomedicine. In particular, due to their versatility and modularity, DNA-based nanodevices appear extremely promising. However, a limitation of such devices is represented by the limited number of molecular stimuli and cues that can be used to control and regulate their function. Here we demonstrate the possibility to rationally control and regulate DNA-based nanodevices using biocatalytic reactions catalyzed by different enzymes. To demonstrate the versatility of our approach we have employed three model DNA-based systems and three different enzymes (belonging to several classes, i.e. transferases and hydrolases). The possibility to use enzymes and enzymatic substrates as possible cues to operate DNA-based molecular nanodevices will allow to expand the available toolbox of molecular stimuli to be used in the field of DNA nanotechnology and could open the door to many applications including enzyme-induced drug delivery and enzyme-triggered nanostructures assembly.
Changes in Blood B Cell-Activating Factor (BAFF) Levels in Multiple Sclerosis: A Sign of Treatment Outcome.Tuesday, November 24, 2015
Kannel K, Alnek K, Vahter L, Gross-Paju K, Uibo R, Kisand KV,
PloS one. 24-11-2015
Multiple sclerosis (MS) is mediated primarily by autoreactive T cells. However, evidence suggesting the involvement of humoral immunity in brain diseases has increased interest in the role of B cells and their products during MS pathogenesis. The major survival factor for B cells, BAFF has been shown to play a role in several autoimmune conditions. Elevated BAFF levels have been reported in MS animal model and during MS relapse in patients. Moreover, disease-modifying treatments (DMT) reportedly influence blood BAFF levels in MS patients, but the significance of these changes remains unclear. The present study addresses how blood BAFF levels are associated with the clinical course of relapsing-remitting MS and the effectiveness of DMT and short-term steroid treatment. During a prospective longitudinal follow-up of 2.3 years, BAFF was measured in the blood of 170 MS patients in the stable phase and within 186 relapses. BAFF levels were significantly higher in MS patients compared to healthy controls. However, stable MS patients without relapses exhibited significantly higher BAFF levels than relapsing patients. Treatment with interferon-β and immunosuppressants raised BAFF blood levels. Interestingly, a similar effect was not seen in patients treated with glatiramer acetate. Short-term treatment with high doses of intravenous methylprednisolone did not significantly alter plasma BAFF levels in 65% of relapsing-remitting MS patients. BAFF were correlated weakly but significantly with monocyte and basophil counts, but not with other blood cell types (neutrophils, lymphocytes, or eosinophils) or inflammatory biomarkers. To our knowledge, this is the first report demonstrating that higher blood BAFF levels may reflect a more stable and effective MS treatment outcome. These results challenge hypotheses suggesting that elevated blood BAFF levels are associated with more severe disease presentation and could explain the recent failure of pharmaceutical trials targeting BAFF with soluble receptor for MS treatment.
Association Between IL-17A +197 G/A Polymorphism and Cancer Risk: A Meta-analysis.Tuesday, November 24, 2015
Lu Y, Gu J, Lu H, Zhu Q, Zhang F, Wang X, Lu L, Zhang C,
Genetic testing and molecular biomarkers. 24-Nov-2015
Our present study indicates that the IL-17A +197 G/A/T polymorphism (rs2275913) is associated with the risk of cancer in Asian populations and nongastrointestinal cancers. Hence, rs2275913 might be useful as a diagnostic biomarker of cancer in these populations.
Fibrogenic Lung Injury Induces Non-Cell-Autonomous Fibroblast Invasion.Tuesday, November 24, 2015
Ahluwalia N, Grasberger PE, Mugo BM, Feghali-Bostwick C, Pardo A, Selman M, Lagares D, Tager AM,
American journal of respiratory cell and molecular biology. 24-Nov-2015
Pathologic accumulation of fibroblasts in pulmonary fibrosis appears to depend on their invasion through basement membranes and extracellular matrices. Fibroblasts from the fibrotic lungs of patients with idiopathic pulmonary fibrosis (IPF) have been demonstrated to acquire a phenotype characterized by increased cell-autonomous invasion. Here, we investigated whether fibroblast invasion is further stimulated by soluble mediators induced by lung injury. We found that bronchoalveolar lavage (BAL) fluids from bleomycin-challenged mice or patients with IPF contain mediators that dramatically increase the matrix invasion of primary lung fibroblasts. Further characterization of this non-cell-autonomous fibroblast invasion suggested that the mediators driving this process are produced locally following lung injury and are preferentially produced by fibrogenic (e.g. bleomycin-induced) rather than non-fibrogenic (e.g. LPS-induced) lung injury. Comparison of invasion and migration induced by a series of fibroblast-active mediators indicated that these two forms of fibroblast movement are directed by distinct sets of stimuli. Finally, knockdown of multiple different membrane receptors, including PDGFRβ, LPA1, EGFR, and FGFR2, mitigated the non-cell-autonomous fibroblast invasion induced by BAL from bleomycin-injured mice, suggesting that multiple different mediators drive fibroblast invasion in pulmonary fibrosis. The magnitude of this mediator-driven fibroblast invasion suggests that its inhibition could be a novel therapeutic strategy for pulmonary fibrosis. Further elaboration of the molecular mechanisms that drive non-cell-autonomous fibroblast invasion consequently may provide a rich set of novel drug targets for the treatment of IPF and other fibrotic lung diseases.
Long-and Short-Term Exposure To Air Pollution and Inflammatory/Hemostatic Markers in Midlife Women.Tuesday, November 24, 2015
Green R, Broadwin R, Malig B, Basu R, Gold EB, Qi L, Sternfeld B, Bromberger JT, Greendale GA, Kravitz HM, Tomey K, Matthews K, Derby C, Jackson EA, Green R, Ostro B,
Epidemiology (Cambridge, Mass.). 23-Nov-2015
Our findings suggest that prior year exposures to PM2.5 and ozone are associated with adverse effects on inflammatory and hemostatic pathways for cardiovascular outcomes in midlife women.
VEGFR2 Gene Polymorphism Correlates with Deep Venous Thrombosis Risk in Chinese Han Population.Tuesday, November 24, 2015
Wang X, Wang HQ, Jian T, Qin WW, Xu F, Xin ZL, Wang YH, Zhang M, Lu HJ,
Genetic testing and molecular biomarkers. 24-Nov-2015
Our findings suggest that the VEGFR2 gene -604T>C polymorphism and TAC haplotype are associated with DVT, and the TAC haplotype might affect the efficacy of long-term treatment of DVT patients.
Genome-Wide Association Study Identifies That the ABO Blood Group System Influences Interleukin-10 Levels and the Risk of Clinical Events in Patients with Acute Coronary Syndrome.Tuesday, November 24, 2015
Johansson Å, Alfredsson J, Eriksson N, Wallentin L, Siegbahn A,
PloS one. 24-11-2015
Our results suggest that the ABO antigens play important roles, not only for the immunological response in ACS patients, but also for the outcome of the disease.
TRPM2 channels in alveolar epithelial cells mediate bleomycin-induced lung inflammation.Tuesday, November 24, 2015
Yonezawa R, Yamamoto S, Takenaka M, Kage Y, Negoro T, Toda T, Ohbayashi M, Numata T, Nakano Y, Yamamoto T, Mori Y, Ishii M, Shimizu S,
Free radical biology & medicine. 17-Nov-2015
Lung inflammation is a major adverse effect of therapy with the antitumor drug bleomycin (BLM). Transient receptor potential melastatin 2 (TRPM2) is a Ca(2+)-permeable channel that is activated by oxidative stress through the production of ADP-ribose. We herein investigated whether TRPM2 channels contributed to BLM-induced lung inflammation. The intratracheal instillation of BLM into wild-type (WT) mice increased the number of polymorphonuclear leukocytes (PMNs) and inflammatory cytokine levels in the lung. Increases in inflammatory markers in WT mice were markedly reduced in trpm2 knockout (KO) mice, which demonstrated that the activation of TRPM2 channels was involved in BLM-induced lung inflammation. The expression of TRPM2 mRNA was observed in alveolar macrophages, alveolar epithelial cells, and lung fibroblasts. Actually, TRPM2 protein was expressed in lung tissues. Of these, TRPM2 channels in epithelial cells were activated by the addition of H2O2 following a BLM pretreatment, resulting in the secretion of macrophage inflammatory protein-2 (MIP-2). The H2O2-induced activation of TRPM2 by the BLM pretreatment was blocked by the poly(ADP-ribose) polymerase (PARP) inhibitors PJ34 and 3-aminobenzamide. The accumulation of poly(ADP-ribose) in the nucleus, a marker for ADP-ribose production, was strongly induced by H2O2 following the BLM pretreatment. Furthermore, administration of PRAP inhibitors into WT mice markedly reduced recruitment of inflammatory cells and MIP-2 secretion induced by BLM instillation. These results suggest that the induction of MIP-2 secretion through the activation of TRPM2 channels in alveolar epithelial cells is an important mechanism in BLM-induced lung inflammation, and the TRPM2 activation is likely to be mediated by ADP-ribose production via PARP pathway. TRPM2 channels may be new therapeutic target for BLM-induced lung inflammation.
The 3rd China Bioanalysis Forum annual meeting.Tuesday, November 24, 2015
Tang D, Zhong D, Dong K,
Bioanalysis. Nov-2015
The third China Bioanalysis Forum conference was successfully held in Shanghai in June 2015. This year's conference focused on biologics, biomarkers and regulated bioanalytical challenges. More than 150 delegates from pharmaceutical/biotech industry, CRO, clinical research centers, research institutes and regulatory agencies attended. This report summarizes the major discussion topics at the conference. 3rd China Bioanalysis Forum, Shanghai, China, 13-14 June 2015.
miR-17 and -20a Target the Neuron-Derived Orphan Receptor-1 (NOR-1) in Vascular Endothelial Cells.Tuesday, November 24, 2015
Sambri I, Crespo J, Aguiló S, Ingrosso D, Rodríguez C, Martínez González J,
PloS one. 13-11-2015
Neuron-derived orphan receptor-1 (NOR-1) plays a major role in vascular biology by controlling fibroproliferative and inflammatory responses. Because microRNAs (miRNAs) have recently emerged as key players in the regulation of gene expression in the vasculature, here we have investigated the regulation of NOR-1 by miRNAs in endothelial cells. Computational algorithms suggest that NOR-1 could be targeted by members of the miR-17 family. Accordingly, ectopic over-expression of miR-17 or miR-20a in endothelial cells using synthetic premiRNAs attenuated the up-regulation of NOR-1 expression induced by VEGF (as evidenced by real time PCR, Western blot and immunocitochemistry). Conversely, the antagonism of these miRNAs by specific antagomirs prevented the down-regulation of NOR-1 promoted by miR-17 or miR-20a in VEGF-stimulated cells. Disruption of the miRNA-NOR-1 mRNA interaction using a custom designed target protector evidenced the selectivity of these responses. Further, luciferase reporter assays and seed-sequence mutagenesis confirmed that miR-17 and -20a bind to NOR-1 3'-UTR. Finally, miR-17 and -20a ameliorated the up-regulation of VCAM-1 mediated by NOR-1 in VEGF-stimulated cells. Therefore, miR-17 and -20a target NOR-1 thereby regulating NOR-1-dependent gene expression.
Assembly of Primary (Hetero)Arylamines via CuI/Oxalic Diamide-Catalyzed Coupling of Aryl Chlorides and Ammonia.Tuesday, November 24, 2015
Fan M, Zhou W, Jiang Y, Ma D,
Organic letters. 24-Nov-2015
A general and practical catalytic system for aryl amination of aryl chlorides with aqueous or gaseous ammonia has been developed, with CuI as the catalyst and bisaryl oxalic diamides as the ligands. The reaction proceeds at 105-120 °C to provide a diverse set of primary (hetero)aryl amines in high yields with various functional groups.
Higher serum dehydroepiandrosterone sulfate protects against the onset of depression in the elderly: Findings from the English Longitudinal Study of Aging (ELSA).Tuesday, November 24, 2015
Souza-Teodoro LH, de Oliveira C, Walters K, Carvalho LA,
Psychoneuroendocrinology. 12-Nov-2015
Depression is one of the major causes of disability worldwide, but the complete etiology of depression is not fully understood. Dehydroepiandrosterone (DHEA) and its sulphated form DHEA(S) have been associated with mood and healthy aging. Associations with mental illness over the middle to late years of life have not yet been extensively investigated in large, western community-dwelling samples. The aim of this study was to investigate whether low DHEA(S) levels are associated with the development of depressive symptoms in a large longitudinal cohort study of older men and women. We assessed data from English Longitudinal Study of Aging (ELSA) to evaluate the association of DHEA(S) levels and depressive symptoms measured by Center for Epidemiologic Studies Scale (CES-D) at baseline (n=3083) and at 4-year follow-up (n=3009). At baseline, there was an inverse association between DHEA(S) and depressive symptoms (B=-0.252, p=0.014). Adjustments for physical illnesses, impairments in cognitive function and health behaviors abolished this association (p=0.109) at baseline. Decreased DHEA(S) levels at baseline also predicted incident depression at 4-year follow-up (B=-0.332, p<0.001). In conclusion, higher DHEA(S) levels were associated with reduced risk of developing depressive symptoms in both men and women.
Characterization of microRNA expression profiles in blood and saliva using the Ion Personal Genome Machine(®) System (Ion PGM™ System).Tuesday, November 24, 2015
Wang Z, Zhou D, Cao Y, Hu Z, Zhang S, Bian Y, Hou Y, Li C,
Forensic science international. Genetics. 1-Nov-2015
MicroRNA (miRNA) expression profiling is gaining interest in the forensic community because the intrinsically short fragment and tissue-specific expression pattern enable miRNAs as a useful biomarker for body fluid identification. Measuring the quantity of miRNAs in forensically relevant body fluids is an important step to screen specific miRNAs for body fluid identification. The recent introduction of massively parallel sequencing (MPS) has the potential for screening miRNA biomarkers at the genome-wide level, which allows both the detection of expression pattern and miRNA sequences. In this study, we employed the Ion Personal Genome Machine(®) System (Ion PGM™ System, Thermo Fisher) to characterize the distribution and expression of 2588 human mature miRNAs (miRBase v21) in 5 blood samples and 5 saliva samples. An average of 1,885,000 and 1,356,000 sequence reads were generated in blood and saliva respectively. Based on miRDong, a Perl-based tool developed for semi-automated miRNA distribution designations, and manually ascertained, 6 and 19 miRNAs were identified respectively as potentially blood and saliva-specific biomarkers. Herein, this study describes a complete and reliable miRNA workflow solution based on Ion PGM™ System, starting from efficient RNA extraction, followed by small RNA library construction and sequencing. With this workflow solution and miRDong analysis it will be possible to measure miRNA expression pattern at the genome-wide level in other forensically relevant body fluids.
Multiparameter analysis of stimulated human peripheral blood mononuclear cells: A comparison of mass and fluorescence cytometry.Tuesday, November 24, 2015
Nicholas KJ, Greenplate AR, Flaherty DK, Matlock BK, Juan JS, Smith RM, Irish JM, Kalams SA,
Cytometry. Part A : the journal of the International Society for Analytical Cytology. 24-Nov-2015
Mass and fluorescence cytometry are quantitative single cell flow cytometry approaches that are powerful tools for characterizing diverse tissues and cellular systems. Here mass cytometry was directly compared with fluorescence cytometry by studying phenotypes of healthy human peripheral blood mononuclear cells (PBMC) in the context of superantigen stimulation. One mass cytometry panel and five fluorescence cytometry panels were used to measure 20 well-established lymphocyte markers of memory and activation. Comparable frequencies of both common and rare cell subpopulations were observed with fluorescence and mass cytometry using biaxial gating. The unsupervised high-dimensional analysis tool viSNE was then used to analyze data sets generated from both mass and fluorescence cytometry. viSNE analysis effectively characterized PBMC using eight features per cell and identified similar frequencies of activated CD4+ T cells with both technologies. These results suggest combinations of unsupervised analysis programs and extended multiparameter cytometry will be indispensable tools for detecting perturbations in protein expression in both health and disease. © 2015 International Society for Advancement of Cytometry.
Design, Synthesis and In Vitro Activity of Anticancer Styrylquinolines. The p53 Independent Mechanism of Action.Tuesday, November 24, 2015
Mrozek-Wilczkiewicz A, Spaczynska E, Malarz K, Cieslik W, Rams-Baron M, Kryštof V, Musiol R,
PloS one. 24-11-2015
A group of styrylquinolines were synthesized and tested for their anti-proliferative activity. Anti-proliferative activity was evaluated against the human colon carcinoma cell lines that had a normal expression of the p53 protein (HCT116 p53+/+) and mutants with a disabled TP53 gene (HCT116 p53-/-) and against the GM 07492 normal human fibroblast cell line. A SAR study revealed the importance of Cl and OH as substituents in the styryl moiety. Several of the compounds that were tested were found to have a marked anti-proliferative activity that was similar to or better than doxorubicin and were more active against the p53 null than the wild type cells. The cellular localization tests and caspase activity assays suggest a mechanism of action through the mitochondrial pathway of apoptosis in a p53-independent manner. The activity of the styrylquinoline compounds may be associated with their DNA intercalating ability.
Do persistent organic pollutants interact with the stress response? Individual compounds, and their mixtures, interaction with the glucocorticoid receptor.Tuesday, November 24, 2015
Wilson J, Friis Berntsen H, Elisabeth Zimmer K, Verhaegen S, Frizzell C, Ropstad E, Connolly L,
Toxicology letters. 17-Nov-2015
Persistent organic pollutants (POPs) are toxic substances, highly resistant to environmental degradation, which can bio-accumulate and have long-range atmospheric transport potential (UNEP 2001). The majority of studies on endocrine disruption have focused on interferences on the sexual steroid hormones and so have overlooked disruption to glucocorticoid hormones. Here the endocrine disrupting potential of individual POPs and their mixtures has been investigated in vitro to identify any disruption to glucocorticoid nuclear receptor transcriptional activity. POP mixtures were screened for glucocorticoid receptor (GR) translocation using a GR redistribution assay (RA) on a CellInsight(TM) NXT High Content Screening (HCS) platform. A mammalian reporter gene assay (RGA) was then used to assess the individual POPs, and their mixtures, for effects on glucocorticoid nuclear receptor transactivation. POP mixtures did not induce GR translocation in the GR RA or produce an agonist response in the GR RGA. However, in the antagonist test, in the presence of cortisol, an individual POP, p,p'-dichlorodiphenyldichloroethylene (DDE), was found to decrease glucocorticoid nuclear receptor transcriptional activity to 72.5% (in comparison to the positive cortisol control). Enhanced nuclear transcriptional activity, in the presence of cortisol, was evident for the two lowest concentrations of perfluorodecanoic acid (PFOS) potassium salt (0.0147mg/ml and 0.0294mg/ml), the two highest concentrations of perfluorodecanoic acid (PFDA) (0.0025mg/ml and 0.005mg/ml) and the highest concentration of 2,2',4,4'-tetrabromodiphenyl ether (BDE 47) (0.0000858mg/ml). It is important to gain a better understanding of how POPs can interact with GRs as the disruption of glucocorticoid action is thought to contribute to complex diseases.
Identification of the Key Fields and Their Key Technical Points of Oncology by Patent Analysis.Tuesday, November 24, 2015
Zhang T, Chen J, Jia X,
PloS one. 17-11-2015
The results of this study could provide guidance on the development direction of oncology, and also help researchers broaden innovative ideas and discover new technological opportunities.
Combining in Vitro Diagnostics with in Vivo Imaging for Earlier Detection of Pancreatic Ductal Adenocarcinoma: Challenges and Solutions.Tuesday, November 24, 2015
Laeseke PF, Chen R, Jeffrey RB, Brentnall TA, Willmann JK,
Radiology. Dec-2015
Pancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer-related death in the United States and is associated with a dismal prognosis, particularly when diagnosed at an advanced stage. Overall survival is significantly improved if PDAC is detected at an early stage prior to the onset of symptoms. At present, there is no suitable screening strategy for the general population. Available diagnostic serum markers are not sensitive or specific enough, and clinically available imaging modalities are inadequate for visualizing early-stage lesions. In this article, the role of currently available blood biomarkers and imaging tests for the early detection of PDAC will be reviewed. Also, the emerging biomarkers and molecularly targeted imaging agents being developed to improve the specificity of current imaging modalities for PDAC will be discussed. A strategy incorporating blood biomarkers and molecularly targeted imaging agents could lead to improved screening and earlier detection of PDAC in the future. (©) RSNA, 2015.
A COI Nonsynonymous Mutation as Diagnostic Tool for Intraspecific Discrimination in the European Anchovy Engraulis encrasicolus (Linnaeus).Tuesday, November 24, 2015
Pappalardo AM, Federico C, Sabella G, Saccone S, Ferrito V,
PloS one. 25-11-2015
The European anchovy, Engraulis encrasicolus, is currently one of the principal target species for commercial fisheries in Europe. In this study, the mitochondrial Control Region (CR) and the Cytochrome Oxidase I (COI) mitochondrial gene were analyzed in 74 specimens of E. encrasicolus from four localities in the central Mediterranean. In both populations, the two markers revealed the presence of two main haplogroups, A and B, already detected in previous investigations of different classes of molecular markers. Both CR and COI markers consistently identified two haplogroups. The COI sequence analysis identified a non-synonymous transversion (T to G) at position 116 of the translated sequence, resulting in an amino acid change. All COI sequences of haplogroup A had an amino acid sequence with alanine in this position, while serine was present in the same position in haplogroup B. The two haplogroups A and B were also discriminated by the variable number of TACA elements at the 5'-end of the mitochondrial CR. The selection tests applied to the COI dataset revealed that codon 116 was not under positive selection, that seven amino acid changes were under purifying selection, and that two amino acids were under episodic positive selection.
Characterization of gene expression in mouse embryos at the 1-cell stage.Tuesday, November 24, 2015
Yamamoto R, Abe KI, Suzuki Y, Suzuki MG, Aoki F,
The Journal of reproduction and development. 22-Nov-2015
In mice, transcription from the zygotic genome is initiated at the mid-1-cell stage after fertilization. Although a recent high-throughput sequencing (HTS) analysis revealed that this transcription occurs promiscuously throughout almost the entire genome in 1-cell stage embryos, a detailed investigation of this process has yet to be conducted using protein-coding genes. Thus, the present study utilized previous RNA sequencing (RNAseq) data to determine the characteristics and regulatory regions of genes transcribed at the 1-cell stage. While the expression patterns of protein-coding genes of mouse embryos were very different at the 1-cell stage than at other stages and in various tissues, an analysis for the upstream and downstream regions of actively expressed genes did not reveal any elements that were specific to 1-cell stage embryos. Therefore, the unique gene expression pattern observed at the 1-cell stage in mouse embryos appears to be governed by mechanisms independent of a specific promoter element.
Symptomatic Management of Fever in Children: A National Survey of Healthcare Professionals' Practices in France.Tuesday, November 24, 2015
Bertille N, Pons G, Khoshnood B, Fournier-Charrière E, Chalumeau M,
PloS one. 22-11-2015
Despite the production and dissemination of recommendations related to managing fever in children, this symptom saturates the practices of primary healthcare professionals (HPs). Data on parent practices related to fever are available, but data on HPs' practices are limited. We studied HPs' practices, determinants of practices and concordance with recommendations in France. We conducted a national cross-sectional observational study between 2007 and 2008 among French general practitioners, primary care pediatricians and pharmacists. HPs were asked to include 5 consecutive patients aged 1 month to 12 years with acute fever. HPs completed a questionnaire about their practices for the current fever episode. We used a multilevel logistic regression model to assess the joint effects of patient- and HP-level variables associated with this behavior. In all, 1,534 HPs (participation rate 13%) included 6,596 children (mean age 3.7 ± 2.7 years). Physicians measured the temperature of 40% of children. Primary HPs recommended drug treatment for 84% of children (including monotherapy for 92%) and physical treatment for 62% (including all recommended physical treatments for 7%). HPs gave written advice or a pamphlet for 13% of children. Significant practice variations were associated with characteristics of the child (age, fever level and diagnosis) and HP (profession and experience). In France, despite the production and dissemination of national recommendations for managing fever in children, primary HPs' observed practices differed greatly from current recommendations, which suggests potential targets for continuing medical education.
The Hidden Sexuality of Alexandrium Minutum: An Example of Overlooked Sex in Dinoflagellates.Tuesday, November 24, 2015
Figueroa RI, Dapena C, Bravo I, Cuadrado A,
PloS one. 23-11-2015
Dinoflagellates are haploid eukaryotic microalgae in which rapid proliferation causes dense blooms, with harmful health and economic effects to humans. The proliferation mode is mainly asexual, as the sexual cycle is believed to be rare and restricted to stressful environmental conditions. However, sexuality is key to explaining the recurrence of many dinoflagellate blooms because in many species the fate of the planktonic zygotes (planozygotes) is the formation of resistant cysts in the seabed (encystment). Nevertheless, recent research has shown that individually isolated planozygotes in the lab can enter other routes besides encystment, a behavior of which the relevance has not been explored at the population level. In this study, using imaging flow cytometry, cell sorting, and Fluorescence In Situ Hybridization (FISH), we followed DNA content and nuclear changes in a population of the toxic dinoflagellate Alexandrium minutum that was induced to encystment. Our results first show that planozygotes behave like a population with an "encystment-independent" division cycle, which is light-controlled and follows the same Light:Dark (L:D) pattern as the cycle governing the haploid mitosis. Resting cyst formation was the fate of just a small fraction of the planozygotes formed and was restricted to a period of strongly limited nutrient conditions. The diploid-haploid turnover between L:D cycles was consistent with two-step meiosis. However, the diel and morphological division pattern of the planozygote division also suggests mitosis, which would imply that this species is not haplontic, as previously considered, but biphasic, because individuals could undergo mitotic divisions in both the sexual (diploid) and the asexual (haploid) phases. We also report incomplete genome duplication processes. Our work calls for a reconsideration of the dogma of rare sex in dinoflagellates.
Locked Nucleic Acid Probe-Based Real-Time PCR Assay for the Rapid Detection of Rifampin-Resistant Mycobacterium tuberculosis.Tuesday, November 24, 2015
Zhao Y, Li G, Sun C, Li C, Wang X, Liu H, Zhang P, Zhao X, Wang X, Jiang Y, Yang R, Wan K, Zhou L,
PloS one. 23-11-2015
Drug-resistant Mycobacterium tuberculosis can be rapidly diagnosed through nucleic acid amplification techniques by analyzing the variations in the associated gene sequences. In the present study, a locked nucleic acid (LNA) probe-based real-time PCR assay was developed to identify the mutations in the rpoB gene associated with rifampin (RFP) resistance in M. tuberculosis. Six LNA probes with the discrimination capability of one-base mismatch were designed to monitor the 23 most frequent rpoB mutations. The target mutations were identified using the probes in a "probe dropout" manner (quantification cycle = 0); thus, the proposed technique exhibited superiority in mutation detection. The LNA probe-based real-time PCR assay was developed in a two-tube format with three LNA probes and one internal amplification control probe in each tube. The assay showed excellent specificity to M. tuberculosis with or without RFP resistance by evaluating 12 strains of common non-tuberculosis mycobacteria. The limit of detection of M. tuberculosis was 10 genomic equivalents (GE)/reaction by further introducing a nested PCR method. In a blind validation of 154 clinical mycobacterium isolates, 142/142 (100%) were correctly detected through the assay. Of these isolates, 88/88 (100%) were determined as RFP susceptible and 52/54 (96.3%) were characterized as RFP resistant. Two unrecognized RFP-resistant strains were sequenced and were found to contain mutations outside the range of the 23 mutation targets. In conclusion, this study established a sensitive, accurate, and low-cost LNA probe-based assay suitable for a four-multiplexing real-time PCR instrument. The proposed method can be used to diagnose RFP-resistant tuberculosis in clinical laboratories.
Genotoxic potential of montmorillonite clay mineral and alteration in the expression of genes involved in toxicity mechanisms in the human hepatoma cell line HepG2.Tuesday, November 24, 2015
Maisanaba S, Hercog K, Filipic M, Jos Á, Zegura B,
Journal of hazardous materials. 27-Oct-2015
Montmorillonite, also known as Cloisite(®)Na(+) (CNa(+)), is a natural clay with a wide range of well-documented and novel applications, such as pharmaceutical products or food packaging. Although considered a low toxic product, the expected increased exposure to CNa(+) arises concern on the potential consequences on human and environmental health especially as its genotoxicity has scarcely been investigated so far. Thus, we investigated, for the first time, the influence of non-cytotoxic concentrations of CNa(+) (15.65, 31.25 and 62.5μg/mL) on genomic instability of human hepatoma cell line (HepG2) by determining the formation of micronuclei (MNi), nucleoplasmic bridges (NPBs) and nuclear buds (NBUDs) with the Cytokinesis block micronucleus cytome assay. Further on we studied the influence of CNa(+) on the expression of several genes involved in toxicity mechanisms using the real-time quantitative PCR. The results showed that CNa(+) increased the number of MNi, while the numbers of NBUDs and NPBs were not affected. In addition it deregulated genes in all the groups studied, mainly after longer time of exposure. These findings provide the evidence that CNa(+) is potentially genotoxic. Therefore further studies that will elucidate the molecular mechanisms involved in toxic activity of CNa(+) are needed for hazard identification and human safety assessment.
Evaluation of DNA damage induced by norcantharidin in human cultured lymphocytes.Tuesday, November 24, 2015
Khabour OF, Enaya FM, Alzoubi K, Al-Azzam SI,
Drug and chemical toxicology. 24-Nov-2015
Norcantharidin (NCTD) is currently used in the treatment of several cancers such as leukemia, melanoma and hepatoma. The mechanism of action of NCTD is suggested to involve induction of apoptosis of cancer cells via production of reactive oxygen species. In this study, the genotoxic effect of different concentrations of NCTD (1, 10 and 20 μm) in human lymphocytes was investigated using sister chromatid exchanges (SCEs) and chromosomal aberrations (CAs) assays. The results revealed that NCTD significantly increased the rate of SCEs (p < 0.05) in a dose-dependent manner. In addition, NCTD significantly increased the number of high-frequency cells (SCEs ≥ 8, p < 0.05). However, NCTD did not have any significant effect on the rate of CAs (p > 0.05). In addition, no significant differences were detected in the mitotic index or proliferative index at examined doses (up to 20 μm). In conclusion, NCTD is genotoxic to human cultured lymphocytes as measured by SCE assay.
Glycoprotein Nonmetastatic Melanoma B (Gpnmb)-Positive Macrophages Contribute to the Balance between Fibrosis and Fibrolysis during the Repair of Acute Liver Injury in Mice.Tuesday, November 24, 2015
Kumagai K, Tabu K, Sasaki F, Takami Y, Morinaga Y, Mawatari S, Hashimoto S, Tanoue S, Kanmura S, Tamai T, Moriuchi A, Uto H, Tsubouchi H, Ido A,
PloS one. 24-11-2015
Gpnmb-positive macrophages infiltrate the liver during the recovery phase of CCl4-induced acute liver injury and contribute to the balance between fibrosis and fibrolysis in the repair process following acute liver injury.
Genomic Landscape of Primary Mediastinal B-Cell Lymphoma Cell Lines.Tuesday, November 24, 2015
Dai H, Ehrentraut S, Nagel S, Eberth S, Pommerenke C, Dirks WG, Geffers R, Kalavalapalli S, Kaufmann M, Meyer C, Faehnrich S, Chen S, Drexler HG, MacLeod RA,
PloS one. 23-11-2015
Primary mediastinal B-Cell lymphoma (PMBL) is a recently defined entity comprising ~2-10% non-Hodgkin lymphomas (NHL). Unlike most NHL subtypes, PMBL lacks recurrent gene rearrangements to serve as biomarkers or betray target genes. While druggable, late chemotherapeutic complications warrant the search for new targets and models. Well characterized tumor cell lines provide unlimited material to serve as preclinical resources for verifiable analyses directed at the discovery of new biomarkers and pathological targets using high throughput microarray technologies. The same cells may then be used to seek intelligent therapies directed at clinically validated targets. Four cell lines have emerged as potential PMBL models: FARAGE, KARPAS-1106P, MEDB-1 and U-2940. Transcriptionally, PMBL cell lines cluster near c(lassical)-HL and B-NHL examples showing they are related but separate entities. Here we document genomic alterations therein, by cytogenetics and high density oligonucleotide/SNP microarrays and parse their impact by integrated global expression profiling. PMBL cell lines were distinguished by moderate chromosome rearrangement levels undercutting cHL, while lacking oncogene translocations seen in B-NHL. In total 61 deletions were shared by two or more cell lines, together with 12 amplifications (≥4x) and 72 homozygous regions. Integrated genomic and transcriptional profiling showed deletions to be the most important class of chromosome rearrangement. Lesions were mapped to several loci associated with PMBL, e.g. 2p15 (REL/COMMD1), 9p24 (JAK2, CD274), 16p13 (SOCS1, LITAF, CIITA); plus new or tenuously associated loci: 2p16 (MSH6), 6q23 (TNFAIP3), 9p22 (CDKN2A/B), 20p12 (PTPN1). Discrete homozygous regions sometimes substituted focal deletions accompanied by gene silencing implying a role for epigenetic or mutational inactivation. Genomic amplifications increasing gene expression or gene-activating rearrangements were respectively rare or absent. Our findings highlight biallelic deletions as a major class of chromosomal lesion in PMBL cell lines, while endorsing the latter as preclinical models for hunting and testing new biomarkers and actionable targets.
Design and synthesis of a C7-aryl piperlongumine derivative with potent antimicrotubule and mutant p53-reactivating properties.Tuesday, November 24, 2015
Punganuru SR, Madala HR, Venugopal SN, Samala R, Mikelis C, Srivenugopal KS,
European journal of medicinal chemistry. 2-Nov-2015
Small molecules that can restore biological function to the p53 mutants found in human cancers have been highly sought to increase the anticancer efficacy. In efforts to generate hybrid anticancer drugs that can impact two or more targets simultaneously, we designed and developed piperlongumine (PL) derivatives with an aryl group inserted at the C-7 position. This insertion bestowed a combretastatin A4 (CA4, an established microtubule disruptor) like structure while retaining the piperlongumine configuration. The new compounds exhibited potent antiproliferative activities against eight cancer cell lines, in particular, were more cytotoxic against the SKBR-3 breast cancer cells which harbor a R175H mutation in p53 suppressor. KSS-9, a representative aryl PL chosen for further studies induced abundant ROS generation and protein glutathionylation. KSS-9 strongly disrupted the tubulin polymerization in vitro, destabilized the microtubules in cells and induced a potent G2/M cell cycle block. More interestingly, KSS-9 showed the ability to reactivate the p53 mutation and restore biological activity to the R175H mutant protein present in SKBR3 cells. Several procedures, including immunocytochemistry using conformation-specific antibodies for p53, immunoprecipitation combined with western blotting, electrophoretic shift mobility shift assays showed a reciprocal loss of mutant protein and generation of wild-type like protein. p53 reactivation was accompanied by the induction of the target genes, MDM2, p21cip1 and PUMA. Mechanistically, the redox-perturbation in cancer cells by the hybrid drug appears to underlie the p53 reactivation process. This anticancer drug approach merits further development.
Formulation Design Space: a proven approach to maximize flexibility and outcomes within early clinical development.Tuesday, November 24, 2015
McDermott J, Scholes P,
Therapeutic delivery. 24-Nov-2015
Traditional formulation development studies involve expensive and time-consuming screening of prototypes in preclinical species to select 'lead' systems for evaluation in human clinical pharmacokinetic studies. A new paradigm, Translational Pharmaceutics, has emerged to integrate pharmaceutical development, manufacturing and clinical functions to address these restrictions. Rapid Formulation development and Clinical Testing (RapidFACT) is applied to exploit the benefits of Translational Pharmaceutics in the clinical screening and optimization of drug products. Benefits are maximized by the adapted utilization of the concept of 'formulation design space'. This article presents the experience of the application of design space within RapidFACT and is supported by data from over 200 formulations studied to date, including case studies on how the approach has been applied.
Membrane-anchored Serine Protease Matriptase is a Trigger of Pulmonary Fibrogenesis.Tuesday, November 24, 2015
Bardou O, Menou A, François C, Duitman JW, von der Thüsen JH, Borie R, Sales KU, Mutze K, Castier Y, Sage E, Liu L, Bugge TH, Fairlie DP, Königshoff M, Crestani B, Borensztajn KS,
American journal of respiratory and critical care medicine. 24-Nov-2015
These results implicate increased matriptase expression and activity in the pathogenesis of pulmonary fibrosis in human IPF and in an experimental mouse model. Overall, targeting matriptase, or treatment by camostat mesilate, which is already in clinical use for other diseases, may represent potential therapies for IPF.
The Multi-allelic Genetic Architecture of a Variance-Heterogeneity Locus for Molybdenum Concentration in Leaves Acts as a Source of Unexplained Additive Genetic Variance.Tuesday, November 24, 2015
Forsberg SK, Andreatta ME, Huang XY, Danku J, Salt DE, Carlborg Ö,
PLoS genetics. Nov-2015
Genome-wide association (GWA) analyses have generally been used to detect individual loci contributing to the phenotypic diversity in a population by the effects of these loci on the trait mean. More rarely, loci have also been detected based on variance differences between genotypes. Several hypotheses have been proposed to explain the possible genetic mechanisms leading to such variance signals. However, little is known about what causes these signals, or whether this genetic variance-heterogeneity reflects mechanisms of importance in natural populations. Previously, we identified a variance-heterogeneity GWA (vGWA) signal for leaf molybdenum concentrations in Arabidopsis thaliana. Here, fine-mapping of this association reveals that the vGWA emerges from the effects of three independent genetic polymorphisms that all are in strong LD with the markers displaying the genetic variance-heterogeneity. By revealing the genetic architecture underlying this vGWA signal, we uncovered the molecular source of a significant amount of hidden additive genetic variation or "missing heritability". Two of the three polymorphisms underlying the genetic variance-heterogeneity are promoter variants for Molybdate transporter 1 (MOT1), and the third a variant located ~25 kb downstream of this gene. A fourth independent association was also detected ~600 kb upstream of MOT1. Use of a T-DNA knockout allele highlights Copper Transporter 6; COPT6 (AT2G26975) as a strong candidate gene for this association. Our results show that an extended LD across a complex locus including multiple functional alleles can lead to a variance-heterogeneity between genotypes in natural populations. Further, they provide novel insights into the genetic regulation of ion homeostasis in A. thaliana, and empirically confirm that variance-heterogeneity based GWA methods are a valuable tool to detect novel associations of biological importance in natural populations.
Genotypic Diversity and Population Structure of Vibrio vulnificus Strains Isolated in Taiwan and Korea as Determined by Multilocus Sequence Typing.Tuesday, November 24, 2015
Kim HJ, Cho JC,
PloS one. 23-11-2015
The genetic diversity and population structure of Vibrio vulnificus isolates from Korea and Taiwan were investigated using PCR-based assays targeting putative virulence-related genes and multilocus sequence typing (MLST). BOX-PCR genomic fingerprinting identified 52 unique genotypes in 84 environmental and clinical V. vulnificus isolates. The majority (> 50%) of strains had pathogenic genotypes for all loci tested; moreover, many environmental strains had pathogenic genotypes. Although significant (p < 0.05) inter-relationships among the genotypes were observed, the association between genotype and strain source (environmental or clinical) was not significant, indicating that genotypic characteristics alone are not sufficient to predict the isolation source or the virulence of a given V. vulnificus strain and vice versa. MLST revealed 23-35 allelic types per locus analyzed, resulting in a total of 44 unique sequence types (STs). Two major monophyletic groups (lineages A and B) corresponding to the two known lineages of V. vulnificus were observed; lineage A had six STs that were exclusively environmental, whereas lineage B had STs from both environmental and clinical sources. Pathogenic and nonpathogenic genotypes predominated in MLST lineages B and A, respectively. In addition, V. vulnificus was shown to be in linkage disequilibrium (p < 0.05), although two different recombination tests (PHI and Sawyer's tests) detected significant evidence of recombination. Tajima's D test also indicated that V. vulnificus might be comprised of recently sub-divided lineages. These results suggested that the two lineages revealed by MLST correspond to two distinct ecotypes of V. vulnificus.
Integration of an optical CMOS sensor with a microfluidic channel allows a sensitive readout for biological assays in point-of-care tests.Tuesday, November 24, 2015
Van Dorst B, Brivio M, Van Der Sar E, Blom M, Reuvekamp S, Tanzi S, Groenhuis R, Adojutelegan A, Lous EJ, Frederix F, Stuyver LJ,
Biosensors & bioelectronics. 11-Nov-2015
In this manuscript, a microfluidic detection module, which allows a sensitive readout of biological assays in point-of-care (POC) tests, is presented. The proposed detection module consists of a microfluidic flow cell with an integrated Complementary Metal-Oxide-Semiconductor (CMOS)-based single photon counting optical sensor. Due to the integrated sensor-based readout, the detection module could be implemented as the core technology in stand-alone POC tests, for use in mobile or rural settings. The performance of the detection module was demonstrated in three assays: a peptide, a protein and an antibody detection assay. The antibody detection assay with readout in the detection module proved to be 7-fold more sensitive that the traditional colorimetric plate-based ELISA. The protein and peptide assay showed a lower limit of detection (LLOD) of 200fM and 460fM respectively. Results demonstrate that the sensitivity of the immunoassays is comparable with lab-based immunoassays and at least equal or better than current mainstream POC devices. This sensitive readout holds the potential to develop POC tests, which are able to detect low concentrations of biomarkers. This will broaden the diagnostic capabilities at the clinician's office and at patient's home, where currently only the less sensitive lateral flow and dipstick POC tests are implemented.
Quantitative evaluation of alternatively spliced mRNA isoforms by label-free real-time plasmonic sensing.Tuesday, November 24, 2015
Huertas CS, Carrascosa LG, Bonnal S, Valcárcel J, Lechuga LM,
Biosensors & bioelectronics. 10-Nov-2015
Alternative splicing of mRNA precursors enables cells to generate different protein outputs from the same gene depending on their developmental or homeostatic status. Its deregulation is strongly linked to disease onset and progression. Current methodologies for monitoring alternative splicing demand elaborate procedures and often present difficulties in discerning between closely related isoforms, e.g. due to cross-hybridization during their detection. Herein, we report a general methodology using a Surface Plasmon Resonance (SPR) biosensor for label-free monitoring of alternative splicing events in real-time, without any cDNA synthesis or PCR amplification requirements. We applied this methodology to RNA isolated from HeLa cells for the quantification of alternatively spliced isoforms of the Fas gene, involved in cancer progression through regulation of programmed cell death. We demonstrate that our methodology is isoform-specific, with virtually no cross-hybridization, achieving limits of detection (LODs) in the picoMolar (pM) range. Similar results were obtained for the detection of the BCL-X gene mRNA isoforms. The results were independently validated by RT-qPCR, with excellent concordance in the determination of isoform ratios. The simplicity and robustness of this biosensor technology can greatly facilitate the exploration of alternative splicing biomarkers in disease diagnosis and therapy.
Steer by ear: Myoelectric auricular control of powered wheelchairs for individuals with spinal cord injury.Tuesday, November 24, 2015
Schmalfuß L, Rupp R, Tuga MR, Kogut A, Hewitt M, Meincke J, Klinker F, Duttenhoefer W, Eck U, Mikut R, Reischl M, Liebetanz D,
Restorative neurology and neuroscience. 18-Nov-2015
With the ACS we can exploit the untapped potential of the PAMs by assigning them a new, complex function. The inherent advantages of the ACS, such as not interfering with oral communication, robustness, stability over time and proportional and continuous signal generation, meet the specific needs of wheelchair users and render it a realistic alternative to currently available assistive technologies.
Correction: Identification and Validation of Protein Biomarkers of Response to Neoadjuvant Platinum Chemotherapy in Muscle Invasive Urothelial Carcinoma.Tuesday, November 24, 2015
Baras AS, Gandhi N, Munari E, Faraj S, Shultz L, Marchionni L, Schoenberg M, Hahn N, Hoque MO, Berman D, Bivalacqua TJ, Netto G,
PloS one. 18-11-2015
[This corrects the article DOI: 10.1371/journal.pone.0131245.].
Polymer-based vehicles for therapeutic peptide delivery.Tuesday, November 24, 2015
Zhang J, Desale SS, Bronich TK,
Therapeutic delivery. 24-Nov-2015
During the last decades increasing attention has been paid to peptides as potential therapeutics. However, clinical applications of peptide drugs suffer from susceptibility to degradation, rather short circulation half-life, limited ability to cross physiological barriers and potential immunogenicity. These challenges can be addressed by using polymeric materials as peptide delivery systems, owing to their versatile structures and properties. A number of polymer-based vehicles have been developed to stabilize the peptides and to control their release rates. Unfortunately, no single polymer or formulation strategy has been considered ideal for all types of peptide drugs. In this review, currently used and potential polymer-based systems for the peptide delivery will be discussed.
A Methodology for Concomitant Isolation of Intimal and Adventitial Endothelial Cells from the Human Thoracic Aorta.Tuesday, November 24, 2015
Leclercq A, Veillat V, Loriot S, Spuul P, Madonna F, Roques X, Génot E,
PloS one. 24-11-2015
This simple and highly reproducible method allows the simultaneous preparation of reasonably pure primary cultures of intimal and adventitial human endothelial cells, thus providing a reliable source for investigating their biology and involvement in both thoracic aneurysms and other aortic diseases.
Identification of Putative Nuclear Receptors and Steroidogenic Enzymes in Murray-Darling Rainbowfish (Melanotaenia fluviatilis) Using RNA-Seq and De Novo Transcriptome Assembly.Tuesday, November 24, 2015
Bain PA, Papanicolaou A, Kumar A,
PloS one. 24-11-2015
Murray-Darling rainbowfish (Melanotaenia fluviatilis [Castelnau, 1878]; Atheriniformes: Melanotaeniidae) is a small-bodied teleost currently under development in Australasia as a test species for aquatic toxicological studies. To date, efforts towards the development of molecular biomarkers of contaminant exposure have been hindered by the lack of available sequence data. To address this, we sequenced messenger RNA from brain, liver and gonads of mature male and female fish and generated a high-quality draft transcriptome using a de novo assembly approach. 149,742 clusters of putative transcripts were obtained, encompassing 43,841 non-redundant protein-coding regions. Deduced amino acid sequences were annotated by functional inference based on similarity with sequences from manually curated protein sequence databases. The draft assembly contained protein-coding regions homologous to 95.7% of the complete cohort of predicted proteins from the taxonomically related species, Oryzias latipes (Japanese medaka). The mean length of rainbowfish protein-coding sequences relative to their medaka homologues was 92.1%, indicating that despite the limited number of tissues sampled a large proportion of the total expected number of protein-coding genes was captured in the study. Because of our interest in the effects of environmental contaminants on endocrine pathways, we manually curated subsets of coding regions for putative nuclear receptors and steroidogenic enzymes in the rainbowfish transcriptome, revealing 61 candidate nuclear receptors encompassing all known subfamilies, and 41 putative steroidogenic enzymes representing all major steroidogenic enzymes occurring in teleosts. The transcriptome presented here will be a valuable resource for researchers interested in biomarker development, protein structure and function, and contaminant-response genomics in Murray-Darling rainbowfish.
Usefulness of antineutrophil cytoplasmic autoantibodies in diagnosing and managing systemic vasculitis.Tuesday, November 24, 2015
Kallenberg CG,
Current opinion in rheumatology. Jan-2016
The techniques for ANCA testing improve further but new tests should be standardized and validated. Their diagnostic value in the right clinical context is undisputed. Their value for the follow-up of patients is still under discussion.
Systematic review of biochemical biomarkers for neck and upper-extremity musculoskeletal disorders.Tuesday, November 24, 2015
Gold JE, Hallman DM, Hellström F, Björklund M, Crenshaw AG, Djupsjobacka M, Heiden M, Mathiassen SE, Piligian G, Barbe MF,
Scandinavian journal of work, environment & health. 24-Nov-2015
While some MSD biomarkers were identified, limitations in the articles examined included possible selection bias, confounding, spectrum effect (potentially heterogeneous biomarker associations in populations according to symptom severity or duration), and insufficient attention to comorbid conditions. A list of recommendations for future studies is provided.
Reduction of Adipose Tissue Mass by the Angiogenesis Inhibitor ALS-L1023 from Melissa officinalis.Tuesday, November 24, 2015
Park BY, Lee H, Woo S, Yoon M, Kim J, Hong Y, Lee HS, Park EK, Hahm JC, Kim JW, Shin SS, Kim MY, Yoon M,
PloS one. 24-11-2015
It has been suggested that angiogenesis modulates adipogenesis and obesity. This study was undertaken to determine whether ALS-L1023 (ALS) prepared by a two-step organic solvent fractionation from Melissa leaves, which exhibits antiangiogenic activity, can regulate adipose tissue growth. The effects of ALS on angiogenesis and extracellular matrix remodeling were measured using in vitro assays. The effects of ALS on adipose tissue growth were investigated in high fat diet-induced obese mice. ALS inhibited VEGF- and bFGF-induced endothelial cell proliferation and suppressed matrix metalloproteinase (MMP) activity in vitro. Compared to obese control mice, administration of ALS to obese mice reduced body weight gain, adipose tissue mass and adipocyte size without affecting appetite. ALS treatment decreased blood vessel density and MMP activity in adipose tissues. ALS reduced the mRNA levels of angiogenic factors (VEGF-A and FGF-2) and MMPs (MMP-2 and MMP-9), whereas ALS increased the mRNA levels of angiogenic inhibitors (TSP-1, TIMP-1, and TIMP-2) in adipose tissues. The protein levels of VEGF, MMP-2 and MMP-9 were also decreased by ALS in adipose tissue. Metabolic changes in plasma lipids, liver triglycerides, and hepatic expression of fatty acid oxidation genes occurred during ALS-induced weight loss. These results suggest that ALS, which has antiangiogenic and MMP inhibitory activities, reduces adipose tissue mass in nutritionally obese mice, demonstrating that adipose tissue growth can be regulated by angiogenesis inhibitors.
Optimization of human dose prediction by using quantitative and translational pharmacology in drug discovery.Tuesday, November 24, 2015
Bueters T, Gibson C, G Visser SA,
Future medicinal chemistry. 24-Nov-2015
In this perspective article, we explain how quantitative and translational pharmacology, when well-implemented, is believed to lead to improved clinical candidates and drug targets that are differentiated from current treatment options. Quantitative and translational pharmacology aims to build and continuously improve the quantitative relationship between drug exposure, target engagement, efficacy, safety and its interspecies relationship at every phase of drug discovery. Drug hunters should consider and apply these concepts to develop compounds with a higher probability of interrogating the clinical biological hypothesis. We offer different approaches to set an initial effective concentration or pharmacokinetic-pharmacodynamic target in man and to predict human pharmacokinetics that determine together the predicted human dose and dose schedule. All concepts are illustrated with ample literature examples.
Associations between Cerebrospinal Fluid Biomarkers and Cognition in Early Untreated Parkinson's Disease.Tuesday, November 24, 2015
Skogseth RE, Bronnick K, Pereira JB, Mollenhauer B, Weintraub D, Fladby T, Aarsland D,
Journal of Parkinson's disease. 23-Nov-2015
The association between reduced CSF α-synuclein concentrations and cognition suggests that α-synuclein pathology contributes to early cognitive impairment in PD, in particular to executive-attentional dysfunction. Longitudinal analyses are needed to determine if this and other CSF biomarkers in early Parkinson's disease are associated with the risk of future cognitive decline and dementia.
Optimizing Western Blots for the Detection of Endogenous α-Synuclein in the Enteric Nervous System.Tuesday, November 24, 2015
Preterre C, Corbillé AG, Balloy G, Letournel F, Neunlist M, Derkinderen P,
Journal of Parkinson's disease. 22-Nov-2015
Our results demonstrate that the detection of α-synuclein in the gut by Western Blot can be optimized by using methods for enhanced membrane retention of the protein along with the appropriate antibody. Such an optimized protocol opens the way to the development of novel biomarkers for PD that will enable a quantification of α-synuclein in gastrointestinal biopsies.
Pheochromocytoma and paraganglioma: molecular testing and personalized medicine.Tuesday, November 24, 2015
Burnichon N, Buffet A, Gimenez-Roqueplo AP,
Current opinion in oncology. 21-Nov-2015
In the near future, extended molecular testing of PPGL could be used to determine therapeutic approaches and assess diagnosis and prognosis biomarkers. Considering the current development of next-generation sequencing-based genetic screening, this technology appears as a good option to improve both PPGL molecular diagnosis and patient management.
Applications in high-content functional protein microarrays.Tuesday, November 24, 2015
Moore CD, Ajala OZ, Zhu H,
Current opinion in chemical biology. 18-Nov-2015
Protein microarray technology provides a versatile platform for characterization of hundreds to thousands of proteins in a parallel and high-throughput manner. Over the last decade, applications of functional protein microarrays in particular have flourished in studying protein function at a systems level and have led to the construction of networks and pathways describing these functions. Relevant areas of research include the detection of various binding properties of proteins, the study of enzyme-substrate relationships, the analysis of host-microbe interactions, and profiling antibody specificity. In addition, discovery of novel biomarkers in autoimmune diseases and cancers is emerging as a major clinical application of functional protein microarrays. In this review, we will summarize the recent advances of functional protein microarrays in both basic and clinical applications.
Maternal Smoking and Metabolic Health Biomarkers in Newborns.Tuesday, November 24, 2015
Fang F, Luo ZC, Dejemli A, Delvin E, Zhang J,
PloS one. 18-11-2015
Maternal smoking was associated with decreased fetal IGF-I levels, and borderline lower fetal β-cell function. Larger cohort studies are required to confirm the latter finding. The preliminary findings prompt the hypothesis that these early life metabolic changes may be involved in the impact of maternal smoking on future risk of metabolic syndrome related disorders in the offspring.
Enzymatic hydrolysis of polyester thin films: real-time analysis of film mass changes and dissipation dynamics.Tuesday, November 24, 2015
Zumstein MT, Kohler HE, McNeill K, Sander M,
Environmental science & technology. 24-Nov-2015
Cleavage of ester bonds by extracellular microbial hydrolases is considered a key step during the breakdown of biodegradable polyester materials in natural and engineered systems. Here, we present a novel analytical approach for simultaneous detection of changes in the masses and rigidities of polyester thin films during enzymatic hydrolysis using a Quartz Crystal Microbalance with Dissipation monitoring (QCM-D). In experiments with poly(butylene succinate) (PBS) and the lipase of Rhizopus oryzae (RoL), we detected complete hydrolysis of PBS thin films at pH 5 and 40 °C that proceeded through soft and water-rich film intermediates. Increasing the temperature from 20 to 40 °C resulted in a larger increase of the enzymatic hydrolysis rates of PBS than that of non-polymeric dibutyl adipate. This finding was ascribed to elevated accessibility of ester bonds to the catalytic site of RoL due to increasing polyester chain mobility. When the pH of the solution was changed from 5 to 7, initial hydrolysis rates were little affected, while a softer film intermediate that lead to incomplete film hydrolysis was formed. Hydrolysis dynamics of PBS, poly(butylene adipate), poly(lactic acid), and poly(ethylene terephthalate) in assays with RoL showed distinct differences that we attribute to differences in the polyester structure.
Potential risks associated with traditional herbal medicine use in cancer care: A study of MiddleEastern oncology health care professionals.Tuesday, November 24, 2015
Ben-Arye E, Samuels N, Goldstein LH, Mutafoglu K, Omran S, Schiff E, Charalambous H, Dweikat T, Ghrayeb I, Bar-Sela G, Turker I, Hassan A, Hassan E, Saad B, Nimri O, Kebudi R, Silbermann M,
Cancer. 24-Nov-2015
Herbal medicine use, which is prevalent in Middle Eastern countries, has several potentially negative effects that include direct toxic effects, negative interactions with anticancer drugs, and increased chemosensitivity of cancer cells, requiring a reduction in dosedensity. Oncology HCPs working in countries in which herbal medicine use is prevalent need to better understand the implications of this practice. The presence of integrative physicians with training in complementary and traditional medicine can help patients and their HCPs reach an informed decision regarding the safety and effective use of these products. Cancer 2015. © 2015 American Cancer Society.
Empirical fitness models for hepatitis C virus immunogen design.Tuesday, November 24, 2015
Hart GR, Ferguson AL,
Physical biology. 24-11-2015
HCV-hepatitis C virus, HLA-human leukocyte antigen, CTL-cytotoxic T lymphocyte, NS5B-nonstructural protein 5B, MSA-multiple sequence alignment, PEG-IFN-pegylated interferon.
Differences in tolerance to anthropogenic stress between invasive and native bivalves.Tuesday, November 24, 2015
Bielen A, Bošnjak I, Sepčić K, Jaklič M, Cvitanić M, Lušić J, Lajtner J, Simčič T, Hudina S,
The Science of the total environment. 18-Nov-2015
Tolerance towards environmental stress has been frequently considered as one of the key determinants of invasion success. However, empirical evidence supporting the assumption that invasive species can better endure unfavorable conditions compared with native species is limited and has yielded opposing results. In this study, we examined the tolerance to different stress conditions (thermal stress and trace metal zinc pollution stress) in two phylogenetically related and functionally similar freshwater bivalve species, the native Anodonta anatina and the invasive Sinanodonta woodiana. We assessed potential differences in response to stress conditions using several cellular response assays: efficiency of the multixenobiotic resistance mechanism, respiration estimate (INT reduction capacity), and enzymatic biomarkers. Our results demonstrated that the invasive species overall coped much better with unfavorable conditions. The higher tolerance of S. woodiana was evident from (i) significantly decreased Rhodamine B accumulation indicating more efficient multixenobiotic resistance mechanism; (ii) significantly higher INT reduction capacity and (iii) less pronounced alterations in the activity of stress-related enzymes (glutathione-S-transferase, catalase) and of a neurotoxicity biomarker (cholinesterase) in the majority of treatment conditions in both stress trials. Higher tolerance to thermal extremes may provide physiological benefit for further invasion success of S. woodiana in European freshwaters, especially in the context of climate change.
Anti-cn1a antibodies in south australian patients with inclusion body myositis.Tuesday, November 24, 2015
Limaye VS, Lester S, Blumbergs P, Greenberg SA,
Muscle & nerve. 24-Nov-2015
Random sampling of the Central European bat fauna reveals the existence of numerous hitherto unknown adenoviruses.Tuesday, November 24, 2015
Vidovszky M, Kohl C, Boldogh S, Görföl T, Wibbelt G, Kurth A, Harrach B,
Acta veterinaria Hungarica. Dec-2015
From over 1250 extant species of the order Chiroptera, 25 and 28 are known to occur in Germany and Hungary, respectively. Close to 350 samples originating from 28 bat species (17 from Germany, 27 from Hungary) were screened for the presence of adenoviruses (AdVs) using a nested PCR that targets the DNA polymerase gene of AdVs. An additional PCR was designed and applied to amplify a fragment from the gene encoding the IVa2 protein of mastadenoviruses. All German samples originated from organs of bats found moribund or dead. The Hungarian samples were excrements collected from colonies of known bat species, throat or rectal swab samples, taken from live individuals that had been captured for faunistic surveys and migration studies, as well as internal organs of dead specimens. Overall, 51 samples (14.73%) were found positive. We detected 28 seemingly novel and six previously described bat AdVs by sequencing the PCR products. The positivity rate was the highest among the guano samples of bat colonies. In phylogeny reconstructions, the AdVs detected in bats clustered roughly, but not perfectly, according to the hosts' families (Vespertilionidae, Rhinolophidae, Hipposideridae, Phyllostomidae and Pteropodidae). In a few cases, identical sequences were derived from animals of closely related species. On the other hand, some bat species proved to harbour more than one type of AdV. The high prevalence of infection and the large number of chiropteran species worldwide make us hypothesise that hundreds of different yet unknown AdV types might circulate in bats.
Source: NCBI - Disclaimer and Copyright notice

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