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Find video protocols related to scientific articles indexed in Pubmed.
Intraoperative transesophageal echocardiography assessment of right atrial myxoma resulting in a change of the surgical plan.
Ann Card Anaesth
PUBLISHED: 10-05-2014
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Transesophageal echocardiography (TEE) is an important diagnostic tool. It provides structural and functional assessment of cardiac structures which can improve the overall outcome of the patient. We present a case with right atrial myxoma in which TEE helped to find the attachment of the mass so that overall surgical plan was changed.
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A model approach to calculate cancer prevalence from 5 years survival data for selected cancer sites in India--part II.
Asian Pac. J. Cancer Prev.
PUBLISHED: 08-02-2014
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Prevalence is a statistic of primary interest in public health. In the absence of good follow-up facilities, it is often difficult to assess the complete prevalence of cancer for a given registry area. An attempt is made to arrive at the complete prevalence including limited duration prevalence with respect of selected sites of cancer for India by fitting appropriate models to 1, 3 and 5 year cancer survival data available for selected registries of India.
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In vivo anti-diabetic, antioxidant and molecular docking studies of 1, 2, 8-trihydroxy-6-methoxy xanthone and 1, 2-dihydroxy-6-methoxyxanthone-8-O-?-D-xylopyranosyl isolated from Swertia corymbosa.
Phytomedicine
PUBLISHED: 07-22-2014
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1, 2, 8-trihydroxy-6-methoxy xanthone (1) and 1, 2- dihydroxy-6-methoxyxanthone-8-O-?-d-xylopyranosyl (2) are the main constituents of petroleum ether and ethyl acetate extracts from Swertia corymbosa (Gentinaceae), a medicinal plant used in Indian traditional system for the treatment of diabetes. The present study was designed to examine the antihypoglycemic, antihyperlipidemic and antioxidant effect of compounds 1 and 2 in streptozotocin (STZ) induced diabetic rats. Diabetes was induced in male Wistar rats by a single intraperitoneal injection of STZ (60 mg/kg b.w.). The isolated compounds 1 and 2 at a dose of 50 mg/kg b.w., produced the maximum fall of 83% in the blood glucose level in the diabetic rats after 3h of the treatment. The administration of 1 and 2 (50 mg/kgb.w.) daily for 28 days in STZ induced diabetic rats, resulted in a significant decrease in blood glucose, glycosylated hemoglobin, SGOT, SGPT, ALP serum urea and creatinine with significant rise in plasma insulin level. Test compounds 1 and 2 showed antihyperlipidemic activities as evidenced by significant decrease in serum TC, TG, LDL-C, VLDL-C levels coupled together with elevation of HDL-C level in diabetic treated rats when compared to diabetic untreated rats, indicate the protective role against liver and kidney damage. The results of histopathology also showed 1 and 2 protected tissues (pancreas, liver and kidney) against peroxidation damage and maintained tissue integrity. Further, the molecular interaction study of the ligands 1, 2 and glibenclamide with various diabetes mellitus related protein targets like glucokinase (PDB ID: 1V4S), fructose-1, 6-bisphosphatase 1 (PDB ID: 2JJK) 11-?-hydroxysteroid dehydrogenase (PDB ID: 2BEL) and modeled protein sulfonylurea receptor 1 (SUR1) showed that ligand 1 and 2 possess binding affinity with all protein targets except for 2BEL target protein for which ligand 1 has no interaction. The ligand pose with 2BEL and SUR1 protein target of ligand 2 gave the best binding conformation. Hence 1 and 2 can be considered for developing into a potent antidiabetic drug.
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Unusual presentation of PRES in the postnatal period.
BMJ Case Rep
PUBLISHED: 07-11-2014
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Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological entity, associated with a vast array of medical conditions and a variety of presenting symptoms. There is a characteristic pattern of radiographic features alongside suggestive clinical manifestations, which lead to a diagnosis of PRES. This report describes the case of a 39 years old, previously normotensive woman, who presented on day 7 postpartum with generalised tonic clonic seizures, reduced conscious level and a history of blurred vision and headache. She was treated immediately as eclamptic and transferred to the intensive care unit for stabilisation. Following an inconclusive CT result, an MRI was performed 2 days after presentation, which demonstrated white matter changes consistent with those found in PRES. She made a full recovery and a repeat MRI scan 7 weeks later showed no progression of the lesions noted on the original scan.
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Antibacterial Efficacy of Iron-Oxide Nanoparticles against Biofilms on Different Biomaterial Surfaces.
Int J Biomater
PUBLISHED: 06-23-2014
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Biofilm growth on the implant surface is the number one cause of the failure of the implants. Biofilms on implant surfaces are hard to eliminate by antibiotics due to the protection offered by the exopolymeric substances that embed the organisms in a matrix, impenetrable for most antibiotics and immune cells. Application of metals in nanoscale is considered to resolve biofilm formation. Here we studied the effect of iron-oxide nanoparticles over biofilm formation on different biomaterial surfaces and pluronic coated surfaces. Bacterial adhesion for 30?min showed significant reduction in bacterial adhesion on pluronic coated surfaces compared to other surfaces. Subsequently, bacteria were allowed to grow for 24?h in the presence of different concentrations of iron-oxide nanoparticles. A significant reduction in biofilm growth was observed in the presence of the highest concentration of iron-oxide nanoparticles on pluronic coated surfaces compared to other surfaces. Therefore, combination of polymer brush coating and iron-oxide nanoparticles could show a significant reduction in biofilm formation.
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Molecular mechanism of selective binding of peptides to silicon surface.
J Chem Inf Model
PUBLISHED: 06-17-2014
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Despite extensive recent research efforts on material-specific peptides, the fundamental problem to be explored yet is the molecular interactions between peptides and inorganic surfaces. Here we used computer simulations (density functional theory and classical molecular dynamics) to investigate the adsorption mechanism of silicon-binding peptides and the role of individual amino acids in the affinity of peptides for an n-type silicon (n(+)-Si) semiconductor. Three silicon binding 12-mer peptides previously elaborated using phage display technology have been studied. The peptides' conformations close to the surface have been determined and the best-binding amino acids have been identified. Adsorption energy calculations explain the experimentally observed different degrees of affinity of the peptides for n(+)-Si. Our residual scanning analysis demonstrates that the binding affinity relies on both the identity of the amino acid and its location in the peptide sequence.
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FOXO3-mTOR metabolic cooperation in the regulation of erythroid cell maturation and homeostasis.
Am. J. Hematol.
PUBLISHED: 06-07-2014
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Ineffective erythropoiesis is observed in many erythroid disorders including ?-thalassemia and anemia of chronic disease in which increased production of erythroblasts that fail to mature exacerbate the underlying anemias. As loss of the transcription factor FOXO3 results in erythroblast abnormalities similar to the ones observed in ineffective erythropoiesis, we investigated the underlying mechanisms of the defective Foxo3(-/-) erythroblast cell cycle and maturation. Here we show that loss of Foxo3 results in overactivation of the JAK2/AKT/mTOR signaling pathway in primary bone marrow erythroblasts partly mediated by redox modulation. We further show that hyperactivation of mTOR signaling interferes with cell cycle progression in Foxo3 mutant erythroblasts. Importantly, inhibition of mTOR signaling, in vivo or in vitro enhances significantly Foxo3 mutant erythroid cell maturation. Similarly, in vivo inhibition of mTOR remarkably improves erythroid cell maturation and anemia in a model of ?-thalassemia. Finally we show that FOXO3 and mTOR are likely part of a larger metabolic network in erythroblasts as together they control the expression of an array of metabolic genes some of which are implicated in erythroid disorders. These combined findings indicate that a metabolism-mediated regulatory network centered by FOXO3 and mTOR control the balanced production and maturation of erythroid cells. They also highlight physiological interactions between these proteins in regulating erythroblast energy. Our results indicate that alteration in the function of this network might be implicated in the pathogenesis of ineffective erythropoiesis.
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Synthesis of 2-alkoxy and 2-benzyloxy analogues of estradiol as anti-breast cancer agents through microtubule stabilization.
Eur J Med Chem
PUBLISHED: 06-04-2014
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2-Methoxyestradiol (2ME2) is an investigational anticancer drug. In the present study, 2-alkoxyesters/acid and 2-benzyloxy analogues of estradiol have been synthesized as analogues of 2ME2. Three of the derivatives exhibited significant anticancer activity against human breast cancer cell lines. The best analogue of the series i.e. 24 showed stabilization of tubulin polymerisation process. It was substantiated by confocal microscopy and molecular docking studies where 24 occupied 'paclitaxel binding pocket' to stabilize the polymerisation process. Compound 24 significantly inhibited MDA-MB-231 cells (IC50: 7 ?M) and induced arrest of cell cycle and apoptosis in MDA-MB-231 cells. In acute oral toxicity, 24 was found to be non-toxic and well tolerated in Swiss albino mice up to 1000 mg/kg dose.
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5-Aminosalicylic Acid attenuates allergen-induced airway inflammation and oxidative stress in asthma.
Pulm Pharmacol Ther
PUBLISHED: 05-05-2014
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Pro-inflammatory cytokines regulate the magnitude of allergic reactions during asthma. Tumor necrosis factor - alpha (TNF-?), interleukin-6 (IL-6) and interleukin-13 (IL-13) play a crucial role in aggravating the inflammatory conditions during allergic asthma. In addition, oxidative stress contributes to the pathogenesis of asthma by altering the physiological condition resulting in the development of status asthmaticus. Anti-inflammatory corticosteroids are being widely used for treating allergic asthma. In the present study 5-aminosalicylic acid (5-ASA), a salicylic acid derivative, was evaluated, in vivo for its potential to suppress TNF-?, IL-6 and IL-13 using ovalbumin (OVA) induced allergic asthma in Balb/C mice. Oral administration of 65, 130 and 195 mg/kg 5-ASA significantly reduced the OVA induced total and differential leucocyte count, TNF-?, IL-6, IL-13, nitrite, nitrate, MDA, MPO and TPL levels in the lung lavage samples. Collectively, these findings suggest that 5-ASA is a potent immunomodulator and suppresses key Th2 cytokines production and oxidative stress in OVA-induced asthma.
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Characteristics of mobile MOSFET dosimetry system for megavoltage photon beams.
J Med Phys
PUBLISHED: 05-04-2014
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The characteristics of a mobile metal oxide semiconductor field effect transistor (mobile MOSFET) detector for standard bias were investigated for megavoltage photon beams. This study was performed with a brass alloy build-up cap for three energies namely Co-60, 6 and 15 MV photon beams. The MOSFETs were calibrated and the performance characteristics were analyzed with respect to dose rate dependence, energy dependence, field size dependence, linearity, build-up factor, and angular dependence for all the three energies. A linear dose-response curve was noted for Co-60, 6 MV, and 15 MV photons. The calibration factors were found to be 1.03, 1, and 0.79 cGy/mV for Co-60, 6 MV, and 15 MV photon energies, respectively. The calibration graph has been obtained to the dose up to 600 cGy, and the dose-response curve was found to be linear. The MOSFETs were found to be energy independent both for measurements performed at depth as well as on the surface with build-up. However, field size dependence was also analyzed for variable field sizes and found to be field size independent. Angular dependence was analyzed by keeping the MOSFET dosimeter in parallel and perpendicular orientation to the angle of incidence of the radiation with and without build-up on the surface of the phantom. The maximum variation for the three energies was found to be within ± 2% for the gantry angles 90° and 270°, the deviations without the build-up for the same gantry angles were found to be 6%, 25%, and 60%, respectively. The MOSFET response was found to be independent of dose rate for all three energies. The dosimetric characteristics of the MOSFET detector make it a suitable in vivo dosimeter for megavoltage photon beams.
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Childhood-onset Takayasu arteritis -- experience from a tertiary care center in South India.
J. Rheumatol.
PUBLISHED: 05-01-2014
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To study the clinical profile and outcome of Asian Indian children with childhood-onset Takayasu arteritis (c-TA).
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Phytochemical Analysis, Antioxidant, Antistress, and Nootropic Activities of Aqueous and Methanolic Seed Extracts of Ladies Finger (Abelmoschus esculentus L.) in Mice.
ScientificWorldJournal
PUBLISHED: 04-29-2014
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Abelmoschus esculentus L. (ladies finger, okra) is a well-known tropical vegetable, widely planted from Africa to Asia and from South Europe to America. In the present study, we investigated the in vitro antioxidant capacity and in vivo protective effect of the aqueous and methanolic seed extracts of Abelmoschus esculentus against scopolamine-induced cognitive impairment using passive avoidance task and acute restraining stress-induced behavioural and biochemical changes using elevated plus maze (EPM) and forced swimming test (FST) in mice. Our results demonstrated that the pretreatment of mice with aqueous and methanolic seed extracts of Abelmoschus esculentus (200?mg/kg, p.o.) for seven days significantly (P < 0.01) attenuated scopolamine-induced cognitive impairment in the passive avoidance test. In addition, these extracts significantly reduced the blood glucose, corticosterone, cholesterol, and triglyceride levels elevated by acute restraint stress and also significantly increased the time spent in open arm in EPM and decreased the immobility time in FST. It has also been revealed that these extracts showed a significant antioxidant activity and no signs of toxicity or death up to a dose of 2000?mg/kg, p.o. These results suggest that the seed extracts of Abelmoschus esculentus L. possess antioxidant, antistress, and nootropic activities which promisingly support the medicinal values of ladies finger as a vegetable.
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Saturated free fatty acids induce cholangiocyte lipoapoptosis.
Hepatology
PUBLISHED: 04-16-2014
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Recent studies have identified a cholestatic variant of nonalcoholic fatty liver disease (NAFLD) with portal inflammation and ductular reaction. Based on reports of biliary damage, as well as increased circulating free fatty acids (FFAs) in NAFLD, we hypothesized the involvement of cholangiocyte lipoapoptosis as a mechanism of cellular injury. Here, we demonstrate that the saturated FFAs palmitate and stearate induced robust and rapid cell death in cholangiocytes. Palmitate and stearate induced cholangiocyte lipoapoptosis in a concentration-dependent manner in multiple cholangiocyte-derived cell lines. The mechanism of lipoapoptosis relied on the activation of caspase 3/7 activity. There was also a significant up-regulation of the proapoptotic BH3-containing protein, PUMA. In addition, palmitate-induced cholangiocyte lipoapoptosis involved a time-dependent increase in the nuclear localization of forkhead family of transcription factor 3 (FoxO3). We show evidence for posttranslational modification of FoxO3, including early (6 hours) deacetylation and dephosphorylation that coincide with localization of FoxO3 in the nuclear compartment. By 16 hours, nuclear FoxO3 is both phosphorylated and acetylated. Knockdown studies confirmed that FoxO3 and its downstream target, PUMA, were critical for palmitate- and stearate-induced cholangiocyte lipoapoptosis. Interestingly, cultured cholangiocyte-derived cells did not accumulate appreciable amounts of neutral lipid upon FFA treatment. Conclusion: Our data show that the saturated FFAs palmitate and stearate induced cholangiocyte lipoapoptosis by way of caspase activation, nuclear translocation of FoxO3, and increased proapoptotic PUMA expression. These results suggest that cholangiocyte injury may occur through lipoapoptosis in NAFLD and nonalcoholic steatohepatitis patients. (Hepatology 2014).
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Quorum sensing peptides mediating interspecies bacterial cell death as a novel class of antimicrobial agents.
Curr. Opin. Microbiol.
PUBLISHED: 04-06-2014
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mazEF is a toxin-antitoxin stress-induced module which is abundant on the chromosome of most bacteria including pathogens and most extensively studied in Escherichia coli. E. coli mazEF mediated cell death is a population phenomenon requiring the quorum-sensing (QS) 'Extracellular Death Factor' (EDF), the E. coli peptide NNWNN. E. coli mazEF-mediated cell death can also be triggered by different QS peptides secreted by the Gram positive bacterium Bacillus subtilis and the Gram negative bacterium Pseudomonas aeruginosa. Thus, the different EDFs belong to a family of QS peptides that mediates interspecies cell death. We suggest that members of the EDF family may become the basis for a novel class of antimicrobial agents to trigger death from outside the bacterial cells.
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Turn plasticity distinguishes different modes of amyloid-? aggregation.
J. Am. Chem. Soc.
PUBLISHED: 03-21-2014
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Pathogenesis of Alzheimer's disease (AD) is associated with aggregation of the amyloid-? (A?) peptide into oligomeric and fibrillar assemblies; however, little is known about the molecular basis of aggregation of A? into distinct assembly states. Here we demonstrate that phosphorylation at serine 26 (S26) impairs A? fibrillization while stabilizing its monomers and nontoxic soluble assemblies of nonfibrillar morphology. NMR spectroscopy and replica-exchange molecular dynamics indicate that introduction of a phosphate group or phosphomimetic at position 26 diminishes A?'s propensity to form a ?-hairpin, rigidifies the region around the modification site, and interferes with formation of a fibril-specific salt bridge between aspartic acid 23 and lysine 28. The combined data demonstrate that phosphorylation of S26 prevents a distinct conformational rearrangement that is required for progression of A? aggregation toward fibrils and provide a basis for a possible role of phosphorylation at serine 26 in AD.
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Intra-Abdominal Desmoid Tumour (DT) with Pelvic Extension-A Case Report.
J Clin Diagn Res
PUBLISHED: 03-06-2014
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Desmoid Tumour (DT) is a rare benign, myofibroblastic tumour originating from muscle fascia with tendency to recur but, it rarely metastasizes. We are reporting here a case of DT that presented as an intra-abdominal mass with pelvic extension in a patient who underwent hysterectomy for fibroid uterus seventeen years ago. A clinical diagnosis of ovarian malignancy was made. Ovarian tumour markers for surface epithelial and germ cell tumours were negative. Imaging studies suggested DT and the same was excised surgically. A histopathological diagnosis of DT was made and confirmed with immunohistochemistry (IHC) markers. DT should always be considered especially in female patients with previous history of surgery. A complete surgical excision is the treatment of choice with recurrent cases requiring radiotherapy. A differential diagnosis like sarcoma and further toxic chemotherapy can be avoided with careful histopathological evaluation and IHC confirmation of DTs.
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Pattern of reproductive cancers in India.
Asian Pac. J. Cancer Prev.
PUBLISHED: 02-27-2014
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Reproductive cancers are those that affect the human organs that are involved in producing offspring. An attempt is made in the present communication to assess the magnitude and pattern of reproductive cancers, including their treatment modalities, in India. The cancer incidence data related to reproductive cancers collected by five population-based urban registries, namely Bangalore, Bhopal, Chennai, Delhi and Mumbai, for the years 2006-08 were utilized. The reproductive cancers among females constituted around 25% of the total and around 9% among males. Among females, the three major contributors were cervix (55.5%), ovary (26.1%) and corpus uteri (12.4%). Similarly among males, the three major contributors were prostate (77.6%), penis (11.6%) and testis (10.5%). For females, the AAR of reproductive cancers varied between 30.5 in the registry of Mumbai to 37.3 in the registry of Delhi. In males, it ranged between 6.5 in the registry of Bhopal to 14.7 in the registry of Delhi. For both males and females, the individual reproductive cancer sites showed increasing trends with age. The leading treatment provided was: radio-therapy in combination with chemo-therapy for cancers of cervix (48.3%) and vagina (43.9%); surgery in combination with chemo-therapy (54.9%) for ovarian cancer; and surgery in combination with radio-therapy for the cancers of the corpus uteri (39.8%). In males, the leading treatment provided was hormone-therapy for prostate cancer (39.6%), surgery for penile cancer (81.3%) and surgery in combination with chemo-therapy for cancer of the testis (57.6%).
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Bioassay directed isolation and biological evaluation of compounds isolated from Rubus fairholmianus Gard.
Biomed Res Int
PUBLISHED: 02-13-2014
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The in vitro and in silico analysis of Rubus fairholmianus acetone extract for antioxidant, antiproliferative, and anti-inflammatory activity led to the isolation of six compounds. Amongst all the six isolated compounds tested, 1-(2-hydroxyphenyl)-4-methylpentan-1-one (compound 1) and 2-[(3-methylbutoxy) carbonyl] benzoic acid (compound 2) were found to be more active in inhibiting BRCA and COX target proteins, which also showed the better results for DPPH and ABTS radical scavenging assays. The promising results of this investigation emphasize the importance of using R. fairholmianus in the treatment of radical generated disorders mainly cancer and other inflammatory diseases.
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Biochemical stages of amyloid-? peptide aggregation and accumulation in the human brain and their association with symptomatic and pathologically preclinical Alzheimer's disease.
Brain
PUBLISHED: 02-10-2014
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Alzheimer's disease is characterized by the deposition of amyloid-? peptide in the brain. N-terminal truncation resulting in the formation of A?N3pE and phosphorylation at serine 8 have been reported to modify aggregation properties of amyloid-?. Biochemically, soluble, dispersible, membrane-associated, and insoluble, plaque-associated amyloid-? aggregates have been distinguished. Soluble and dispersible amyloid-? aggregates are both in mixture with the extracellular or intracellular fluid but dispersible aggregates can be cleared from proteins in solution by ultracentrifugation. To clarify the role of phosphorylated amyloid-? and A?N3pE in soluble, dispersible, membrane-associated, and plaque-associated amyloid-? aggregates in the pathogenesis of Alzheimer's disease we studied brains from 21 cases with symptomatic Alzheimer's disease, 33 pathologically preclinical Alzheimer's disease cases, and 20 control cases. Western blot analysis showed that soluble, dispersible, membrane-associated and plaque-associated amyloid-? aggregates in the earliest preclinical stage of Alzheimer's disease did not exhibit detectable amounts of A?N3pE and phosphorylated amyloid-?. This stage was referred to as biochemical stage 1 of amyloid-? aggregation and accumulation. In biochemical amyloid-? stage 2, A?N3pE was additionally found whereas phosphorylated amyloid-? was restricted to biochemical amyloid-? stage 3, the last stage of amyloid-? aggregation. Phosphorylated amyloid-? was seen in the dispersible, membrane-associated, and plaque-associated fraction. All cases with symptomatic Alzheimer's disease in our sample fulfilled biochemical amyloid-? stage 3 criteria, i.e. detection of phosphorylated amyloid-?. Most, but not all, cases with pathologically preclinical Alzheimer's disease had biochemical amyloid-? stages 1 or 2. Immunohistochemistry confirmed the hierarchical occurrence of amyloid-?, A?N3pE, and phosphorylated amyloid-? in amyloid plaques. Phosphorylated amyloid-? containing plaques were, thereby, seen in all symptomatic cases with Alzheimer's disease but only in a few non-demented control subjects. The biochemical amyloid-? stages correlated with the expansion of amyloid-? plaque deposition and with that of neurofibrillary tangle pathology. Taken together, we demonstrate that A?N3pE and phosphorylated amyloid-? are not only detectable in plaques, but also in soluble and dispersible amyloid-? aggregates outside of plaques. They occur in a hierarchical sequence that allows the distinction of three stages. In light of our findings, it is tempting to speculate that this hierarchical, biochemical sequence of amyloid-? aggregation and accumulation is related to disease progression and may be relevant for an increasing toxicity of amyloid-? aggregates.
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Hepatitis a virus infection-associated hemophagocytic lymphohistiocytosis in two children.
Indian J Hematol Blood Transfus
PUBLISHED: 01-15-2014
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Hemophagocytic lymphohistiocytosis (HLH) is a syndrome characterized by high fever, maculopapular rash, neurological symptoms, abnormal liver functions and coagulopathy. Primary HLH is due to an underlying genetic abnormality. Secondary HLH are due to an underlying infection, autoimmune disease or malignancy. Secondary HLH due to viral infections are commonly due to the herpes group commonest of which is the Ebstein Barr virus (EBV). We describe two children with virus associated hemophagocytic lymphohistiocytosis (VAHLH) secondary to hepatitis A infection.
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Cryosupernatant and Immunosuppression as Effective Alternative Therapies for TTP in Three Pediatric SLE Patients.
Indian J Hematol Blood Transfus
PUBLISHED: 01-15-2014
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Thrombotic thrombocytopenic purpura (TTP) and systemic lupus erythematosus (SLE) very rarely present simultaneously and pose a diagnostic and therapeutic dilemma to the physician. Prompt diagnosis and management with plasma exchange and immunosuppression is life-saving. To describe the effectiveness of cryosupernatant and steroids in pediatric SLE with TTP. We describe three children aged 12-14 years with SLE who were diagnosed with TTP based on fever, CNS manifestations, ANA, anti-dsDNA, anti-sm positivity, hypocomplementemia, and microangiopathic anemia with thrombocytopenia. All three children were managed with cryosupernatant and steroids without plasmapheresis. All children improved with cryosupernatant and steroids. All attained remission within 10 days. They were doing well at last follow up without relapse or flare. Cryosupernatant and steroids may be an effective therapy for Thrombotic thrombocytopenic purpura with systemic lupus erythematosus.
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Posterior reversible encephalopathy syndrome unmasking acute glomerulonephritis.
J Clin Diagn Res
PUBLISHED: 01-12-2014
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Posterior reversible encephalopathy syndrome (PRES) is a recently described condition, wherein there is vasogenic oedema, seen on neuroimaging, predominantly over the parieto occipital regions of the cerebrum. Though, as the name implies, the condition is reversible, there may be fatalities and neurological sequelae. We are reporting a 9-year-old female child in whom the typical clinical and neurological findings of PRES were caused by an atypical presentation of acute glomerulonephritis.
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Synthesis of neolignans as microtubule stabilisers.
Bioorg. Med. Chem.
PUBLISHED: 01-09-2014
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Tubulin is a well established target for anticancer drug development. Lignans and neolignans were synthesized as tubulin interacting agents. Neolignans 10 and 19 exhibited significant anticancer activity against MCF-7 and MDAMB-231 human breast cancer cell lines. Both the compounds effectively induced stabilization of microtubule at 4 and 20 ?M concentrations respectively. Neolignan 10 induced G2/M phase arrest in MCF-7 cells. Docking experiments raveled that 10 and 19 occupied the same binding pocket of paclitaxel with some difference in active site amino acids and good bioavailability of both the compounds. In in vivo acute oral toxicity 10 was well tolerated up to 300 mg/kg dose in Swiss-albino mice.
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DNA Cleavage, Cytotoxic Activities, and Antimicrobial Studies of Ternary Copper(II) Complexes of Isoxazole Schiff Base and Heterocyclic Compounds.
Bioinorg Chem Appl
PUBLISHED: 01-07-2014
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Novel mixed ligand bivalent copper complexes [Cu. L. A. ClO 4 ] and [Cu. L. A] where "L" is Schiff bases, namely 2-((3,4-dimethylisoxazol-5-ylimino)methyl)-4-bromophenol (DMIIMBP)/2-((3,4-dimethylisoxazol-5-ylimino)methyl)-4-chlorophenol (DMIIMCP), and "A" is heterocyclic compound, such as 1,10-phenanthroline (phen)/2,2(1)-bipyridyl (bipy)/8-hydroxyquinoline (oxine)/5-chloro-8-hydroxyquinoline (5-Cl-oxine), have been synthesized. These complexes have been characterized by IR, UV-Vis, ESR, elemental analysis, magnetic moments, TG, and DTA. On the basis of spectral studies and analytical data, five-coordinated square pyramidal/four-coordinated square planar geometry is assigned to all complexes. The ligands and their ternary complexes with Cu(II) have been screened for antimicrobial activity against bacteria and fungi by paper disc method. The antimicrobial studies of Schiff bases and their metal complexes showed significant activity and further it is observed that the metal complexes showed more activity than corresponding Schiff bases. In vitro antitumor activity of Cu(II) complexes was assayed against human cervical carcinoma (HeLa) cancer cells and it was observed that few complexes exhibit good antitumor activity on HeLa cell lines. The DNA cleavage studies have also been carried out on pBR 322 and it is observed that these Cu(II) complexes are capable of cleaving supercoiled plasmid DNA in the presence of H2O2 and UV light.
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CNX-012-570, a direct AMPK activator provides strong glycemic and lipid control along with significant reduction in body weight; studies from both diet-induced obese mice and db/db mice models.
Cardiovasc Diabetol
PUBLISHED: 01-07-2014
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AMP activated protein kinase (AMPK) regulates the coordination of anabolic and catabolic processes and is an attractive therapeutic target for T2DM, obesity and metabolic syndrome. We report the anti-hyperglycemic and anti-hyperlipidemic effects of CNX-012-570 is an orally bioavailable small molecule (molecular weight of 530 Daltons) that directly activates AMPK in DIO and db/db animal models of diabetes.
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Synthesis and characterization of curcumin loaded polymer/lipid based nanoparticles and evaluation of their antitumor effects on MCF-7 cells.
Biochim. Biophys. Acta
PUBLISHED: 01-07-2014
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Hybrid materials are synthesized using hydrophilic polymer and lipids which ensure their long term systemic circulation through intravenous administration and enhance loading of hydrophobic drugs. The purpose of this study is to prepare, characterize and evaluate the in vitro efficacy of curcumin loaded poly-hydroxyethyl methacrylate/stearic acid nanoparticles in MCF-7.
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Extraction process optimization of polyphenols from Indian Citrus sinensis - as novel antiglycative agents in the management of diabetes mellitus.
J Diabetes Metab Disord
PUBLISHED: 01-07-2014
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Diabetes mellitus is a chronic metabolic disorder characterized by increased blood glucose level. It has become an epidemic disease in the 21st century where, India leads the world with largest number of diabetic subjects. Non-enzymatic glycosylation (glycation) is severe form of diabetes, occurs between reducing sugar and proteins which results in the formation of advanced glycation end products (AGEs) that leads to the other complicated secondary disorders. In this context, Mangifera indica (Mango), Syzygium cumini (Jambul), Vitis vinifera (Grapes), Citrus sinensis (Orange), Artocarpus heterophyllus (Jackfruit), Manilkara zapota (Sapodilla) seeds were evaluated for their antiglyation activity. Attempts were made to isolate the polyphenols in the seeds that have recorded the maximum activity.
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Characterization, analysis, and application of fabricated Fe3O4-chitosan-pectinase nanobiocatalyst.
Appl. Biochem. Biotechnol.
PUBLISHED: 01-02-2014
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The investigation on fabrication of Fe3O4-chitosan-pectinase nanobiocatalyst was performed by covalently binding the pectinase onto carboxyl group activated chitosan-coated magnetic nanoparticles (CMNPs). The morphological and size distribution analysis of the different magnetic nanoparticles (MNPs) was done using transmission electron microscopy (TEM), and the average diameter was 11.07 ± 3.04, 11.55 ± 3.16, and 11.59 ± 3.16 nm for MNPs, CMNPs, and fabricated nanobiocatalyst, respectively, suggesting that there was no significant change in the size of MNPs after coating and binding. The characteristic peaks occurred at 2? of 30.39, 35.43, 43.37, 57.22, and 62.9, and their corresponding indices 220, 311, 400, 520, and 441 for different MNPs from the X-ray diffraction (XRD) studies confirmed the presence of Fe3O4 with the spinel structure, and there was no phase change even after coating and binding. The various required characteristic absorption peaks (575, 585, 1,563, 1,614, 1,651, and 1,653 cm(-1)) from Fourier transform infrared (FT-IR) spectroscopy confirmed the surface modifications and binding of pectinase onto the MNPs. At the weight ratio of about 19.8 × 10(-3) mg bound pectinase/mg activated CMNPs, the activity of fabricated nanobiocatalyst was found to be maximum. In order to monitor their improved activity, the pH, temperature, reusability, storage ability, and kinetic studies were established.
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XIAP antagonist embelin inhibited proliferation of cholangiocarcinoma cells.
PLoS ONE
PUBLISHED: 01-01-2014
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Cholangiocarcinoma cells are dependent on antiapoptotic signaling for survival and resistance to death stimuli. Recent mechanistic studies have revealed that increased cellular expression of the E3 ubiquitin-protein ligase X-linked inhibitor of apoptosis (XIAP) impairs TRAIL- and chemotherapy-induced cytotoxicity, promoting survival of cholangiocarcinoma cells. This study was undertaken to determine if pharmacologic antagonism of XIAP protein was sufficient to sensitize cholangiocarcinoma cells to cell death. We employed malignant cholangiocarcinoma cell lines and used embelin to antagonize XIAP protein. Embelin treatment resulted in decreased XIAP protein levels by 8 hours of treatment with maximal effect at 16 hours in KMCH and Mz-ChA-1 cells. Assessment of nuclear morphology demonstrated a concentration-dependent increase in nuclear staining. Interestingly, embelin induced nuclear morphology changes as a single agent, independent of the addition of TNF-related apoptosis inducing ligand (TRAIL). However, caspase activity assays revealed that increasing embelin concentrations resulted in slight inhibition of caspase activity, not activation. In addition, the use of a pan-caspase inhibitor did not prevent nuclear morphology changes. Finally, embelin treatment of cholangiocarcinoma cells did not induce DNA fragmentation or PARP cleavage. Apoptosis does not appear to contribute to the effects of embelin on cholangiocarcinoma cells. Instead, embelin caused inhibition of cell proliferation and cell cycle analysis indicated that embelin increased the number of cells in S and G2/M phase. Our results demonstrate that embelin decreased proliferation in cholangiocarcinoma cell lines. Embelin treatment resulted in decreased XIAP protein expression, but did not induce or enhance apoptosis. Thus, in cholangiocarcinoma cells the mechanism of action of embelin may not be dependent on apoptosis.
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Insights on the Facet Specific Adsorption of Amino Acids and Peptides toward Platinum.
J Chem Inf Model
PUBLISHED: 12-06-2013
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Engineering shape-controlled bionanomaterials requires comprehensive understanding of interactions between biomolecules and inorganic surfaces. We explore the origin of facet-selective binding of peptides adsorbed onto Pt(100) and Pt(111) crystallographic planes. Using molecular dynamics simulations, we show that upon adsorption the peptides adopt a predictable conformation. We compute the binding energies of the amino acids constituting two adhesion peptides for Pt, S7, and T7 and demonstrate that peptides surface recognition behavior that makes them unique among populations originates from differential adsorption of their building blocks. We find that the degree of peptide binding is mainly due to polar amino acids and the molecular architecture of the peptides close to the Pt facets. Our analysis is a first step in the prediction of enhanced affinity between inorganic materials and a peptides, toward the synthesis of novel nanomaterials with programmable shape, structure, and properties.
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The type of A?-related neuronal degeneration differs between amyloid precursor protein (APP23) and amyloid ?-peptide (APP48) transgenic mice.
Acta Neuropathol Commun
PUBLISHED: 11-02-2013
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The deposition of the amyloid ?-peptide (A?) in the brain is one of the hallmarks of Alzheimers disease (AD). It is not yet clear whether A? always leads to similar changes or whether it induces different features of neurodegeneration in relation to its intra- and/or extracellular localization or to its intracellular trafficking routes. To address this question, we have analyzed two transgenic mouse models: APP48 and APP23 mice. The APP48 mouse expresses A?1-42 with a signal sequence in neurons. These animals produce intracellular A? independent of amyloid precursor protein (APP) but do not develop extracellular A? plaques. The APP23 mouse overexpresses human APP with the Swedish mutation (KM670/671NL) in neurons and produces APP-derived extracellular A? plaques and intracellular A? aggregates.
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Rapid control of disease activity by tocilizumab in 10 difficult-to-treat cases of Takayasu arteritis.
Int J Rheum Dis
PUBLISHED: 10-29-2013
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To assess outcome of 10 difficult to treat patients with Takayasu arteritis (TA) treated with tocilizumab.
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The C terminus of p53 regulates gene expression by multiple mechanisms in a target- and tissue-specific manner in vivo.
Genes Dev.
PUBLISHED: 09-10-2013
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The p53 tumor suppressor is a transcription factor that mediates varied cellular responses. The C terminus of p53 is subjected to multiple and diverse post-translational modifications. An attractive hypothesis is that differing sets of combinatorial modifications therein determine distinct cellular outcomes. To address this in vivo, a Trp53(?CTD/?CTD) mouse was generated in which the endogenous p53 is targeted and replaced with a truncated mutant lacking the C-terminal 24 amino acids. These Trp53(?CTD/?CTD) mice die within 2 wk post-partum with hematopoietic failure and impaired cerebellar development. Intriguingly, the C terminus acts via three distinct mechanisms to control p53-dependent gene expression depending on the tissue. First, in the bone marrow and thymus, the C terminus dampens p53 activity. Increased senescence in the Trp53(?CTD/?CTD) bone marrow is accompanied by up-regulation of Cdkn1 (p21). In the thymus, the C-terminal domain negatively regulates p53-dependent gene expression by inhibiting promoter occupancy. Here, the hyperactive p53(?CTD) induces apoptosis via enhanced expression of the proapoptotic Bbc3 (Puma) and Pmaip1 (Noxa). In the liver, a second mechanism prevails, since p53(?CTD) has wild-type DNA binding but impaired gene expression. Thus, the C terminus of p53 is needed in liver cells at a step subsequent to DNA binding. Finally, in the spleen, the C terminus controls p53 protein levels, with the overexpressed p53(?CTD) showing hyperactivity for gene expression. Thus, the C terminus of p53 regulates gene expression via multiple mechanisms depending on the tissue and target, and this leads to specific phenotypic effects in vivo.
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(Methanol-?O)-cis-dioxido{(4Z,NE)-N-[(Z)-4-oxido-4-phenyl-but-3-en-2-yl-idene]iso-nicotino-hydrazidato}molybdenum(VI).
Acta Crystallogr Sect E Struct Rep Online
PUBLISHED: 08-01-2013
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In the title complex, [Mo(C16H13N3O2)O2(CH3OH)], the deprotonated Schiff base (E)-N-[(Z)-4-oxido-4-phenyl-but-3-en-2-yl-idene]isonicotinohydrazide coordinates in a meridional fashion through the enolate O-, imine N- and amidate O-atom donors to the Mo atom of a cis-[MoO2](2+) core. The sixth coordination site of molybdenum is occupied by the O atom of a methanol mol-ecule. In this complex, the NO5 coordination sphere adopts a distorted octa-hedral coordination geometry. The metal atom is shifted by 0.335?(1)?Å from the square plane defined by the three donor atoms of the Schiff base ligand and one oxide group towards the second oxide group in the cis position. In the crystal, the complex forms inversion dimers through a pair of O-H?N hydrogen bonds involving the methanol -OH group and the pyridine N atom. Additional C-H?O contacts stack the mol-ecules along the b axis.
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?-Catenin-independent activation of TCF1/LEF1 in human hematopoietic tumor cells through interaction with ATF2 transcription factors.
PLoS Genet.
PUBLISHED: 08-01-2013
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The role of Wnt signaling in embryonic development and stem cell maintenance is well established and aberrations leading to the constitutive up-regulation of this pathway are frequent in several types of human cancers. Upon ligand-mediated activation, Wnt receptors promote the stabilization of ?-catenin, which translocates to the nucleus and binds to the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors to regulate the expression of Wnt target genes. When not bound to ?-catenin, the TCF/LEF proteins are believed to act as transcriptional repressors. Using a specific lentiviral reporter, we identified hematopoietic tumor cells displaying constitutive TCF/LEF transcriptional activation in the absence of ?-catenin stabilization. Suppression of TCF/LEF activity in these cells mediated by an inducible dominant-negative TCF4 (DN-TCF4) inhibited both cell growth and the expression of Wnt target genes. Further, expression of TCF1 and LEF1, but not TCF4, stimulated TCF/LEF reporter activity in certain human cell lines independently of ?-catenin. By a complementary approach in vivo, TCF1 mutants, which lacked the ability to bind to ?-catenin, induced Xenopus embryo axis duplication, a hallmark of Wnt activation, and the expression of the Wnt target gene Xnr3. Through generation of different TCF1-TCF4 fusion proteins, we identified three distinct TCF1 domains that participate in the ?-catenin-independent activity of this transcription factor. TCF1 and LEF1 physically interacted and functionally synergized with members of the activating transcription factor 2 (ATF2) family of transcription factors. Moreover, knockdown of ATF2 expression in lymphoma cells phenocopied the inhibitory effects of DN-TCF4 on the expression of target genes associated with the Wnt pathway and on cell growth. Together, our findings indicate that, through interaction with ATF2 factors, TCF1/LEF1 promote the growth of hematopoietic malignancies in the absence of ?-catenin stabilization, thus establishing a new mechanism for TCF1/LEF1 transcriptional activity distinct from that associated with canonical Wnt signaling.
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Tumor cell entry into the lymph node is controlled by CCL1 chemokine expressed by lymph node lymphatic sinuses.
J. Exp. Med.
PUBLISHED: 07-22-2013
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Lymphatic vessels are thought to contribute to metastasis primarily by serving as a transportation system. It is widely believed that tumor cells enter lymph nodes passively by the flow of lymph. We demonstrate that lymph node lymphatic sinuses control tumor cell entry into the lymph node, which requires active tumor cell migration. In human and mouse tissues, CCL1 protein is detected in lymph node lymphatic sinuses but not in the peripheral lymphatics. CCR8, the receptor for CCL1, is strongly expressed by human malignant melanoma. Tumor cell migration to lymphatic endothelial cells (LECs) in vitro is inhibited by blocking CCR8 or CCL1, and recombinant CCL1 promotes migration of CCR8(+) tumor cells. The proinflammatory mediators TNF, IL-1?, and LPS increase CCL1 production by LECs and tumor cell migration to LECs. In a mouse model, blocking CCR8 with the soluble antagonist or knockdown with shRNA significantly decreased lymph node metastasis. Notably, inhibition of CCR8 led to the arrest of tumor cells in the collecting lymphatic vessels at the junction with the lymph node subcapsular sinus. These data identify a novel function for CCL1-CCR8 in metastasis and lymph node LECs as a critical checkpoint for the entry of metastases into the lymph nodes.
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Copper catalyzed oxidative coupling of amines with formamides: a new approach for the synthesis of unsymmetrical urea derivatives.
Chem. Commun. (Camb.)
PUBLISHED: 06-17-2013
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Direct access to unsymmetrical urea derivatives via copper catalysed C-H/N-H coupling of formamides with amines has been developed at room temperature. This protocol is also applied to the synthesis of chiral urea derivatives.
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Novel quorum-sensing peptides mediating interspecies bacterial cell death.
MBio
PUBLISHED: 06-06-2013
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ABSTRACT Escherichia coli mazEF is a toxin-antitoxin stress-induced module mediating cell death. It requires the quorum-sensing signal (QS) "extracellular death factor" (EDF), the penta-peptide NNWNN (EcEDF), enhancing the endoribonucleolytic activity of E. coli toxin MazF. Here we discovered that E. coli mazEF-mediated cell death could be triggered by QS peptides from the supernatants (SN) of the Gram-positive bacterium Bacillus subtilis and the Gram-negative bacterium Pseudomonas aeruginosa. In the SN of B. subtilis, we found one EDF, the hexapeptide RGQQNE, called BsEDF. In the SN of P. aeruginosa, we found three EDFs: the nonapeptide INEQTVVTK, called PaEDF-1, and two hexadecapeptides, VEVSDDGSGGNTSLSQ, called PaEDF-2, and APKLSDGAAAGYVTKA, called PaEDF-3. When added to a diluted E. coli cultures, each of these peptides acted as an interspecies EDF that triggered mazEF-mediated death. Furthermore, though their sequences are very different, each of these EDFs amplified the endoribonucleolytic activity of E. coli MazF, probably by interacting with different sites on E. coli MazF. Finally, we suggest that EDFs may become the basis for a new class of antibiotics that trigger death from outside the bacterial cells. IMPORTANCE Bacteria communicate with one another via quorum-sensing signal (QS) molecules. QS provides a mechanism for bacteria to monitor each others presence and to modulate gene expression in response to population density. Previously, we added E. coli EDF (EcEDF), the peptide NNWNN, to this list of QS molecules. Here we extended the group of QS peptides to several additional different peptides. The new EDFs are produced by two other bacteria, Bacillus subtilis and Pseudomonas aeruginosa. Thus, in this study we established a "new family of EDFs." This family provides the first example of quorum-sensing molecules participating in interspecies bacterial cell death. Furthermore, each of these peptides provides the basis of a new class of antibiotics triggering death by acting from outside the cell.
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Fluorescent prey traps in carnivorous plants.
Plant Biol (Stuttg)
PUBLISHED: 05-23-2013
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Carnivorous plants acquire most of their nutrients by capturing ants, insects and other arthropods through their leaf-evolved biological traps. So far, the best-known attractants in carnivorous prey traps are nectar, colour and olfactory cues. Here, fresh prey traps of 14 Nepenthes, five Sarracenia, five Drosera, two Pinguicula species/hybrids, Dionaea muscipula and Utricularia stellaris were scanned at UV 366 nm. Fluorescence emissions of major isolates of fresh Nepenthes khasiana pitcher peristomes were recorded at an excitation wavelength of 366 nm. N. khasiana field pitcher peristomes were masked by its slippery zone extract, and prey capture rates were compared with control pitchers. We found the existence of distinct blue fluorescence emissions at the capture spots of Nepenthes, Sarracenia and Dionaea prey traps at UV 366 nm. These alluring blue emissions gradually developed with the growth of the prey traps and diminished towards their death. On excitation at 366 nm, N. khasiana peristome 3:1 CHCl3–MeOH extract and its two major blue bands showed strong fluorescence emissions at 430–480 nm. Masking of blue emissions on peristomes drastically reduced prey capture in N. khasiana pitchers. We propose these molecular emissions as a critical factor attracting arthropods and other visitors to these carnivorous traps. Drosera, Pinguicula and Utricularia prey traps showed only red chlorophyll emissions at 366 nm.
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Proline mechanisms of stress survival.
Antioxid. Redox Signal.
PUBLISHED: 05-23-2013
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The imino acid proline is utilized by different organisms to offset cellular imbalances caused by environmental stress. The wide use in nature of proline as a stress adaptor molecule indicates that proline has a fundamental biological role in stress response. Understanding the mechanisms by which proline enhances abiotic/biotic stress response will facilitate agricultural crop research and improve human health.
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Cytogenetic and molecular aberrations of multiple myeloma patients: a single-center study in Singapore.
Chin. Med. J.
PUBLISHED: 05-16-2013
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Much is known about the cytogenetic lesions that characterize multiple myeloma (MM) patients from the USA, Europe, and East Asia. However, little has been published about the disease among Southeast Asians. The aim of this study was to determine the chromosomal abnormalities of MM patients in our Singapore population.
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Salmonella Typhimurium TTSS-2 deficient mig-14 mutant shows attenuation in immunocompromised mice and offers protection against wild-type Salmonella Typhimurium infection.
BMC Microbiol.
PUBLISHED: 05-14-2013
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Development of Salmonella enterica serovar Typhimurium (S. Typhimurium) live attenuated vaccine carrier strain to prevent enteric infections has been a subject of intensive study. Several mutants of S. Typhimurium have been proposed as an effective live attenuated vaccine strain. Unfortunately, many such mutant strains failed to successfully complete the clinical trials as they were suboptimal in delivering effective safety and immunogenicity. However, it remained unclear, whether the existing live attenuated S. Typhimurium strains can further be attenuated with improved safety and immune efficacy or not.
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Molecular characterization of patient-derived human pancreatic tumor xenograft models for preclinical and translational development of cancer therapeutics.
Neoplasia
PUBLISHED: 05-06-2013
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Preclinical evaluation of novel cancer agents requires models that accurately reflect the biology and molecular characteristics of human tumors. Molecular profiles of eight pancreatic ductal adenocarcinoma patient tumors were compared to corresponding passages of xenografts obtained by grafting tumor fragments into immunocompromised mice. Molecular characterization was performed by copy number analysis, gene expression and microRNA microarrays, mutation analysis, short tandem repeat (STR) profiling, and immunohistochemistry. Xenografts were found to be highly representative of their respective tumors, with a high degree of genetic stability observed by STR profiling and mutation analysis. Copy number variation (CNV) profiles of early and late xenograft passages were similar, with recurrent losses on chromosomes 1p, 3p, 4q, 6, 8p, 9, 10, 11q, 12p, 15q, 17, 18, 20p, and 21 and gains on 1q, 5p, 8q, 11q, 12q, 13q, 19q, and 20q. Pearson correlations of gene expression profiles of tumors and xenograft passages were above 0.88 for all models. Gene expression patterns between early and late passage xenografts were highly stable for each individual model. Changes observed in xenograft passages largely corresponded to human stromal compartment genes and inflammatory processes. While some differences exist between the primary tumors and corresponding xenografts, the molecular profiles remain stable after extensive passaging. Evidence for stability in molecular characteristics after several rounds of passaging lends confidence to clinical relevance and allows for expansion of models to generate the requisite number of animals required for cohorts used in drug screening and development studies.
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Current status on development of steroids as anticancer agents.
J. Steroid Biochem. Mol. Biol.
PUBLISHED: 04-25-2013
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Steroids are important biodynamic agents. Their affinities for various nuclear receptors have been an interesting feature to utilize them for drug development particularly for receptor mediated diseases. Steroid biochemistry and its crucial role in human physiology, has attained importance among the researchers. Recent years have seen an extensive focus on modification of steroids. The rational modifications of perhydrocyclopentanophenanthrene nucleus of steroids have yielded several important anticancer lead molecules. Exemestane, SR16157, fulvestrant and 2-methoxyestradiol are some of the successful leads emerged on steroidal pharmacophores. The present review is an update on some of the steroidal leads obtained during past 25 years. Various steroid based enzyme inhibitors, antiestrogens, cytotoxic conjugates and steroidal cytotoxic molecules of natural as well as synthetic origin have been highlighted. This article is part of a Special Issue entitled "Synthesis and biological testing of steroid derivatives as inhibitors".
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Chromatin modifications sequentially enhance ErbB2 expression in ErbB2-positive breast cancers.
Cell Rep
PUBLISHED: 03-29-2013
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ErbB2 gene amplification occurs in 20%-25% of breast cancers, and its therapeutic targeting has markedly improved survival of patients with breast cancer in the adjuvant setting. However, resistance to these therapies can develop. Because epigenetic mechanisms can importantly influence oncogene expression and be druggable as well, we investigated histone modifications that influence ErbB2 overexpression, independent of gene amplification. We demonstrate here that ErbB2-overexpressing breast carcinomas acquire the H3K4me3 mark on the erbB2 promoter and that receptor-amplified tumors further acquire the H3K9ac mark, which is dependent on H3K4me3 mark acquisition. Targeting WD repeat domain 5 (Wdr5), which is absolutely required for H3K4me3 enrichment, decreased ErbB2 overexpression, associated with a decrease in the H3K4me3 mark on the erbB2 promoter. Of note, Wdr5 silencing cooperated with trastuzumab or chemotherapy in specifically inhibiting the growth of ErbB2-positive breast tumor cells. Thus, our studies illuminate epigenetic steps in the selection for ErbB2 activation.
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Curcumin loaded poly(2-hydroxyethyl methacrylate) nanoparticles from gelled ionic liquid--in vitro cytotoxicity and anti-cancer activity in SKOV-3 cells.
Eur J Pharm Sci
PUBLISHED: 03-26-2013
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The main focus of this study is to encapsulate hydrophobic drug curcumin in hydrophilic polymeric core such as poly(2-hydroxyethyl methacrylate) [PHEMA] nanoparticles from gelled ionic liquid (IL) to improve its efficacy. We have achieved 26.4% drug loading in a biocompatible hydrophilic polymer. Curcumin loaded PHEMA nanoparticles (C-PHEMA-NPs) were prepared by nano-precipitation method. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) analysis showed that the prepared nanoparticles were spherical in shape and free from aggregation. The size and zeta potential of prepared C-PHEMA-NPs were about 300 nm and -33.4 mV respectively. C-PHEMA-NPs were further characterized by FT-IR spectroscopy which confirmed the existence of curcumin in the nanoparticles. X-ray diffraction and differential scanning calorimetry studies revealed that curcumin present in the PHEMA nanoparticles were found to be amorphous in nature. The anticancer activity of C-PHEMA-NPs was measured in ovarian cancer cells (SKOV-3) in vitro, and the results revealed that the C-PHEMA-NPs had better tumor cells regression activity than free curcumin. Flow cytometry showed the significant reduction in G0/G1 cells after treatment with C-PHEMA-NPs and molecular level of apoptosis were also studied using western blotting. Toxicity of PHEMA nanoparticles were studied in zebrafish embryo model and results revealed the material to be highly biocompatible. The present study demonstrates the curcumin loaded PHEMA nanoparticles have potential therapeutic values in the treatment of cancer.
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Gene therapy in oral cancer: a review.
J Clin Diagn Res
PUBLISHED: 03-16-2013
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Gene therapy is the use of DNA as an agent to treat disease. Gene therapy aims at the insertion of a functional gene into the cells of a patient for the correction of an inborn error of metabolism, to alter or repair an acquired genetic abnormality, and to provide new function to the cell. Many experiments have been done with respect to its application in various diseases.Today, most of the gene therapy studies are aimed at cancer and hereditary diseases which are linked to genetic defects. Cancer usually occurs due to the production of multiple mutations in a single cell which cause it to proliferate out of control. Several methods such as surgery, radiation therapy and chemotherapy have been used widely to treat cancers. But, the cancer patients who are not helped by these therapies can be treated by gene therapy. The purpose of this article is to review the use and purpose of gene therapy in oral cancer.
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Safety and efficacy of hepatitis B vaccination in cirrhosis of liver.
Adv Virol
PUBLISHED: 03-14-2013
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Introduction. Patients with chronic liver disease (CLD) are more likely to have severe morbidity and fatality rate due to superimposed acute or chronic hepatitis B (HBV) infection. The literature has shown that hepatitis B vaccines are safe and effective in patients with CLD, but the data in cirrhosis liver is lacking. We assessed the safety and immunogenicity of HBV vaccine in patients with cirrhosis liver. Methods. CTP classes A and B CLD patients negative for hepatitis B surface antigen and antibody to hepatitis B core antigen were included. All patients received three doses of hepatitis B vaccine 20?mcg intramuscularly at 0, 30, and 60 days. Anti-HBs antibody was measured after 120 days. Results. 52 patients with mean age 47.48 ± 9.37 years were studied. Response rates in CTP classes A and B were 88% and 33.3%. We observed that the alcoholic chronic liver disease had less antibody response (44%) than other causes of chronic liver disease such as cryptogenic 69% and HCV 75%. Conclusions. Patients with cirrhosis liver will have low antibody hepatitis B titers compared to general population. As the age and liver disease progress, the response rate for hepatitis B vaccination will still remain to be weaker.
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Management of mandibular first molar with four canals in mesial root.
J Conserv Dent
PUBLISHED: 03-03-2013
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Successful root canal treatment depends on adequate cleaning, shaping, and filling of the root canal system. The presence of middle mesial (MM) root canal of mandibular molars has been reported by various authors. But incidence of four canals in mesial root of mandibular molar is very rare. The aim of this case report is to present and describe the identification and management of a mandibular first molar with four canals in the mesial root and single canal in the distal root.
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Targeted modifications in adeno-associated virus serotype 8 capsid improves its hepatic gene transfer efficiency in vivo.
Hum Gene Ther Methods
PUBLISHED: 02-28-2013
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Recombinant adeno-associated virus vectors based on serotype 8 (AAV8) have shown significant promise for liver-directed gene therapy. However, to overcome the vector dose dependent immunotoxicity seen with AAV8 vectors, it is important to develop better AAV8 vectors that provide enhanced gene expression at significantly low vector doses. Since it is known that AAV vectors during intracellular trafficking are targeted for destruction in the cytoplasm by the host-cellular kinase/ubiquitination/proteasomal machinery, we modified specific serine/threonine kinase or ubiquitination targets on the AAV8 capsid to augment its transduction efficiency. Point mutations at specific serine (S)/threonine (T)/lysine (K) residues were introduced in the AAV8 capsid at the positions equivalent to that of the effective AAV2 mutants, generated successfully earlier. Extensive structure analysis was carried out subsequently to evaluate the structural equivalence between the two serotypes. scAAV8 vectors with the wild-type (WT) and each one of the S/T?Alanine (A) or K-Arginine (R) mutant capsids were evaluated for their liver transduction efficiency in C57BL/6 mice in vivo. Two of the AAV8-S?A mutants (S279A and S671A), and a K137R mutant vector, demonstrated significantly higher enhanced green fluorescent protein (EGFP) transcript levels (~9- to 46-fold) in the liver compared to animals that received WT-AAV8 vectors alone. The best performing AAV8 mutant (K137R) vector also had significantly reduced ubiquitination of the viral capsid, reduced activation of markers of innate immune response, and a concomitant two-fold reduction in the levels of neutralizing antibody formation in comparison to WT-AAV8 vectors. Vector biodistribution studies revealed that the K137R mutant had a significantly higher and preferential transduction of the liver (106 vs. 7.7 vector copies/mouse diploid genome) when compared to WT-AAV8 vectors. To further study the utility of the K137R-AAV8 mutant in therapeutic gene transfer, we delivered human coagulation factor IX (h.FIX) under the control of liver-specific promoters (LP1 or hAAT) into C57BL/6 mice. The circulating levels of h.FIX:Ag were higher in all the K137R-AAV8 treated groups up to 8 weeks post-hepatic gene transfer. These studies demonstrate the feasibility of the use of this novel AAV8 vectors for potential gene therapy of hemophilia B.
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Fabrication, characterization and application of pectin degrading Fe3O4-SiO2 nanobiocatalyst.
Mater Sci Eng C Mater Biol Appl
PUBLISHED: 01-22-2013
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The covalent binding of pectinase onto amino functionalized silica-coated magnetic nanoparticles (CSMNPs) through glutaraldehyde activation was investigated for nanobiocatalyst fabrication. The average particle size and morphology of the nanoparticles were characterized using transmission electron microscopy (TEM). The statistical analysis for TEM image suggests that the coating and binding process did not cause any significant change in size of MNPs. The morphological and phase change of the magnetic nanoparticles (MNPs) after various coatings and immobilization were characterized by X-ray diffraction (XRD) studies. The various surface modifications and pectinase binding onto nanoparticles were confirmed by Fourier transform infrared (FT-IR) spectroscopy. The maximum activity of immobilized pectinase was obtained at its weight ratio of 19.0×10(-3) mg bound pectinase/mg CSMNPs. The pH, temperature, reusability, storage ability and kinetic studies were established to monitor their improved stability and activity of the fabricated nanobiocatalyst. Furthermore, the application was extended in the clarification of Malus domestica juice.
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Sunlight-enhanced calcareous deposition on cathodic stainless steel in natural seawater.
Biofouling
PUBLISHED: 01-22-2013
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In replicate series of experiments in natural seawater, one in full darkness and the other in a 1:1 diurnal cycle with as little as ~5% of natural solar illumination, sunlight promoted calcareous deposition on cathodic stainless steel surfaces. As exemplified by scanning electron microscopy, the deposit that formed under the natural diurnal cycle, in the presence of photosynthetic biofilms, was composed of finer calcareous crystals that provided more compact and more uniform surface coverage than the one formed in the dark. The light-enhanced deposit also possessed better scale properties, as suggested by X-ray analysis and electrochemical measurements. Sunlight enhancement of calcareous deposition looked all the more conspicuous when day and night regimes were examined independently. These results not only bear important implications for cathodic protection in marine waters, but also provide an intriguing analogy to coral reef calcification.
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Early intraneuronal accumulation and increased aggregation of phosphorylated Abeta in a mouse model of Alzheimers disease.
Acta Neuropathol.
PUBLISHED: 01-09-2013
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The progressive accumulation of extracellular amyloid plaques in the brain is a common hallmark of Alzheimers disease (AD). We recently identified a novel species of A? phosphorylated at serine residue 8 with increased propensity to form toxic aggregates as compared to non-phosphorylated species. The age-dependent analysis of A? depositions using novel monoclonal phosphorylation-state specific antibodies revealed that phosphorylated A? variants accumulate first inside of neurons in a mouse model of AD already at 2 month of age. At higher ages, phosphorylated A? is also abundantly detected in extracellular plaques. Besides a large overlap in the spatiotemporal deposition of phosphorylated and non-phosphorylated A? species, fractionized extraction of A? from brains revealed an increased accumulation of phosphorylated A? in oligomeric assemblies as compared to non-phosphorylated A? in vivo. Thus, phosphorylated A? could represent an important species in the formation and stabilization of neurotoxic aggregates, and might be targeted for AD therapy and diagnosis.
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Accidental ingestion of molar band and its management: maintenance is better than management.
Case Rep Dent
PUBLISHED: 01-06-2013
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Ingestion of a broken part of fixed orthodontic appliance is a potential complication during orthodontic treatment. We report a case of accidental ingestion of molar band and its subsequent diagnosis followed by endoscopic retrieval method. Although prevention of such incidence is the best method at the same time management of such an event is also crucial. The objective of this paper is to draw attention to the potentially serious complications that can occur if preventive techniques are not practiced and also the management of such event.
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The effect of gold and iron-oxide nanoparticles on biofilm-forming pathogens.
ISRN Microbiol
PUBLISHED: 01-01-2013
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Microbial biofilms on biomaterial implants or devices are hard to eliminate by antibiotics due to their protection by exopolymeric substances that embed the organisms in a matrix, impenetrable for most antibiotics and immune-cells. Application of metals in their nanoparticulated form is currently considered to resolve bacterial infections. Gold and iron-oxide nanoparticles are widely used in different medical applications, but their utilisation to eradicate biofilms on biomaterials implants is novel. Here, we studied the effect of gold and iron oxide nanoparticles on Staphylococcus aureus and Pseudomonas aeruginosa biofilms. We report that biofilm growth was reduced at higher concentrations of gold and iron-oxide nanoparticles compared to absence of nanoparticles. Thus nanoparticles with appropriate concentration could show significant reduction in biofilm formation.
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The application of vizilite in oral cancer.
J Clin Diagn Res
PUBLISHED: 01-01-2013
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This article depicts the various applications of Vizilite plus in oral cancer. The oral cavity demonstrates a variety of red and white, pigmented and vesiculo- bullous lesions. Oral cancer still happens to carry the highest mortality worldwide, especially in India. In India, the prime focus is on the downstreaming of oral cancer from an advanced stage to an early diseased state. The techniques that are promoted to facilitate an earlier detection and diagnosis of an oral malignancy include Toluidine blue, ViziLite Plus with TBlue, ViziLite, Microlux DL, Orascoptic DK, VEL scope, Oral CDx and brush biopsy.
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Colorimetric sensing of fluoride ion by new expanded calix[4]pyrrole through anion-? interaction.
Org. Lett.
PUBLISHED: 12-29-2011
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Three new expanded calix[4]pyrroles were synthesized, where the two dialkylldipyrromethane units are linked via C-C double bonds. One of them, calix[2]bispyrrolylethene, colorimetrically senses fluoride ion only, owing to anion-? interaction in polar aprotic solvents.
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p53 serves as a host antiviral factor that enhances innate and adaptive immune responses to influenza A virus.
J. Immunol.
PUBLISHED: 11-21-2011
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Several direct target genes of the p53 tumor suppressor have been identified within pathways involved in viral sensing, cytokine production, and inflammation, suggesting a potential role of p53 in antiviral immunity. The increasing need to identify immune factors to devise host-targeted therapies against pandemic influenza A virus (IAV) led us to investigate the role of endogenous wild-type p53 on the immune response to IAV. We observed that the absence of p53 resulted in delayed cytokine and antiviral gene responses in lung and bone marrow, decreased dendritic cell activation, and reduced IAV-specific CD8(+) T cell immunity. Consequently, p53(-/-) mice showed a more severe IAV-induced disease compared with their wild-type counterparts. These findings establish that p53 influences the antiviral response to IAV, affecting both innate and adaptive immunity. Thus, in addition to its established functions as a tumor suppressor gene, p53 serves as an IAV host antiviral factor that might be modulated to improve anti-IAV therapy and vaccines.
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Natural host-range and experimental transmission of Laem-Singh virus (LSNV).
Dis. Aquat. Org.
PUBLISHED: 10-14-2011
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Slow growth caused by viral diseases has become a major constraint in shrimp aquaculture. Laem-Singh virus (LSNV), a positive-sense single-stranded RNA (ssRNA) virus, has been identified in Penaeus monodon showing slow growth syndrome. To examine the host-range and transmission modes of the virus, 6 species of penaeid shrimp of varying life stages, sourced from the wild and from farms, as well as juvenile mud crabs Scylla serrata, were screened using RT-nested PCR. LSNV was detected in P. monodon, Fenneropenaeus merguiensis, Metapenaeus dobsoni, and Litopenaeus vannamei, but not in E indicus, Marsupenaeus japonicus or S. serrata. LSNV was most prevalent in P. monodon followed by M. dobsoni, F. merguiensis, and L. vannamei, and real-time quantitative RT-PCR (qRT-PCR) showed that LSNV infection loads were highest in P. monodon, followed by L. vannamei, M. dobsoni, and E merguiensis. The nucleotide sequence of the LSNV RdRP gene fragment amplified by RT-nested PCR was highly conserved (99% identity) across these 4 penaeid species. LSNV was detected in both small and normal-sized P. monodon collected from the same pond. In experimental infections of both P. monodon and S. serrata, LSNV infection loads increased over time. The present study extends the known natural penaeid host-range and geographical distribution of LSNV and shows for the first time the potential susceptibility of S. serrata.
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Chronic calcific pancreatitis presenting as an isolated left perinephric abscess: a case report and review of the literature.
JOP
PUBLISHED: 09-10-2011
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Acute and chronic pancreatitis may present with pseudocysts in atypical locations. Activated pancreatic enzymes track along anatomic fascial planes causing digestion of the surrounding tissues and resulting in distant pseudocysts. Pseudocysts at atypical locations pose significant diagnostic as well as therapeutic challenges.
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Phosphorylation of amyloid beta (A?) peptides - a trigger for formation of toxic aggregates in Alzheimers disease.
Aging (Albany NY)
PUBLISHED: 08-27-2011
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Alzheimers disease (AD) is the most common form of dementia and associated with the progressive accumulation of amyloid ?-peptides (A?) in form of extracellular amyloid plaques in the human brain. A critical role of A? in the pathogenesis of AD is strongly supported by gene mutations that cause early-onset familial forms of the disease. Such mutations have been identified in the APP gene itself and in presenilin 1 and 2. Importantly, all the identified mutations commonly lead to early deposition of extracellular plaques likely by increasing the generation and/or aggregation of A?. However, such mutations are very rare and molecular mechanisms that might trigger aggregation and deposition of A?, in the most common late onset AD are largely unknown. We recently demonstrated that extracellular A? undergoes phosphorylation by a cell surface-localized or secreted form of protein kinase A. The phosphorylation of serine residue 8 promotes aggregation by stabilization of ?-sheet conformation of A? and increased formation of oligomeric A? aggregates that represent nuclei for fibrillization. Phosphorylated A? was detected in the brains of transgenic mice and human AD brains and showed increased toxicity in Drosophila models as compared with non-phosphorylated A?. Together, these findings demonstrate a novel molecular mechanism that triggers aggregation and toxicity of A?. Thus, phosphorylation of A? could be relevant in the pathogenesis of late onset AD. The identification of extracellular protein kinase A should also stimulate pharmacological approaches to decrease A? phosphorylation in the therapy and/or prevention of AD.
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BRI2 protein regulates ?-amyloid degradation by increasing levels of secreted insulin-degrading enzyme (IDE).
J. Biol. Chem.
PUBLISHED: 08-26-2011
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The amyloid precursor protein (APP) is one of the major proteins involved in Alzheimer disease (AD). Proteolytic cleavage of APP gives rise to amyloid-? (A?) peptides that aggregate and deposit extensively in the brain of AD patients. Although the increase in levels of aberrantly folded A? peptide is considered to be important to disease pathogenesis, the regulation of APP processing and A? metabolism is not fully understood. Recently, the British precursor protein (BRI2, ITM2B) has been implicated in influencing APP processing in cells and A? deposition in vivo. Here, we show that the wild type BRI2 protein reduces plaque load in an AD mouse model, similar to its disease-associated mutant form, ADan precursor protein (ADanPP), and analyze in more detail the mechanism of how BRI2 and ADanPP influence APP processing and A? metabolism. We find that overexpression of either BRI2 or ADanPP reduces extracellular A? by increasing levels of secreted insulin-degrading enzyme (IDE), a major A?-degrading protease. This effect is also observed with BRI2 lacking its C-terminal 23-amino acid peptide sequence. Our results suggest that BRI2 might act as a receptor protein that regulates IDE levels that in turn influences APP metabolism in a previously unrecognized way. Targeting the regulation of IDE may be a promising therapeutic approach to sporadic AD.
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Roles of the 15-kDa selenoprotein (Sep15) in redox homeostasis and cataract development revealed by the analysis of Sep 15 knockout mice.
J. Biol. Chem.
PUBLISHED: 07-18-2011
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The 15-kDa selenoprotein (Sep15) is a thioredoxin-like, endoplasmic reticulum-resident protein involved in the quality control of glycoprotein folding through its interaction with UDP-glucose:glycoprotein glucosyltransferase. Expression of Sep15 is regulated by dietary selenium and the unfolded protein response, but its specific function is not known. In this study, we developed and characterized Sep15 KO mice by targeted removal of exon 2 of the Sep15 gene coding for the cysteine-rich UDP-glucose:glycoprotein glucosyltransferase-binding domain. These KO mice synthesized a mutant mRNA, but the shortened protein product could be detected neither in tissues nor in Sep15 KO embryonic fibroblasts. Sep15 KO mice were viable and fertile, showed normal brain morphology, and did not activate endoplasmic reticulum stress pathways. However, parameters of oxidative stress were elevated in the livers of these mice. We found that Sep15 mRNA was enriched during lens development. Further phenotypic characterization of Sep15 KO mice revealed a prominent nuclear cataract that developed at an early age. These cataracts did not appear to be associated with severe oxidative stress or glucose dysregulation. We suggest that the cataracts resulted from an improper folding status of lens proteins caused by Sep15 deficiency.
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Nitration of tyrosine 10 critically enhances amyloid ? aggregation and plaque formation.
Neuron
PUBLISHED: 07-01-2011
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Part of the inflammatory response in Alzheimers disease (AD) is the upregulation of the inducible nitric oxide synthase (NOS2) resulting in increased NO production. NO contributes to cell signaling by inducing posttranslational protein modifications. Under pathological conditions there is a shift from the signal transducing actions to the formation of protein tyrosine nitration by secondary products like peroxynitrite and nitrogen dioxide. We identified amyloid ? (A?) as an NO target, which is nitrated at tyrosine 10 (3NTyr(10)-A?). Nitration of A? accelerated its aggregation and was detected in the core of A? plaques of APP/PS1 mice and AD brains. NOS2 deficiency or oral treatment with the NOS2 inhibitor L-NIL strongly decreased 3NTyr(10)-A?, overall A? deposition and cognitive dysfunction in APP/PS1 mice. Further, injection of 3NTyr(10)-A? into the brain of young APP/PS1 mice induced ?-amyloidosis. This suggests a disease modifying role for NOS2 in AD and therefore represents a potential therapeutic target.
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Gold and iron oxide nanoparticle-based ethylcellulose nanocapsules for Cisplatin drug delivery.
Iran J Pharm Res
PUBLISHED: 07-01-2011
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The present study is aimed at the overall improvement in the efficacy, reduced toxicity and enhancement of therapeutic index of cisplatin. Nanocapsules of cisplatin containing ethylcellulose have been prepared using solvent evaporation technique under ambient conditions. The prepared nanocapsules were used for controlled drug release of anticancer agents with gold and iron oxide nanoparticles. The drug-entrapped nanocapsules were characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Fourier transform infrared (FTIR) studies indicated the absence of chemical interactions between the drug, polymer and metal nanoparticles. The drug loaded nanoparticles are spherical in shape and had average diameter in the range of 100-300 nm. Drug release study showed that the acidic media provided a faster release than the phosphate buffer media. These findings were also compared statistically through calculating mean, standard deviation and coefficient of variation for various polymer nanocapsules. However, the drug release for gold nanoparticles/anticancer drug (Au-cis) incorporated ethylcellulose nanocapsules was controlled and slow compared to iron oxide nanoparticles-cisplatin incorporated ethylcellulose nanocapsules. Hence, gold nanoparticles act as good trapping agents which slow down the rate of drug release from nanocapsules.
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Effect of apoptosis-inducing antitumor agents on endocardial endothelial cells.
Cardiovasc. Toxicol.
PUBLISHED: 06-15-2011
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Chemotherapy is one of the common treatment modalities for cancer. Some of the antineoplastic drugs have, however, been found to be toxic for vascular endothelium, resulting in complications such as endothelial dysfunction, thromboembolism, heart failure, and cardiomyopathy. In this study, we investigated the cytotoxic effect of widely used antitumor agents doxorubicin, camptothecin, and thapsigargin on primary and immortalized porcine endocardial endothelial cells and compared with the effects of these agents on human umbilical vein endothelial cells, human aortic endothelial cells, and EA.hy926 cells. Our study revealed that endocardial endothelial cells are relatively resistant to apoptosis induced by these drugs. Interestingly, our study indicates that response to antitumor agents greatly differs depending on the site of origin of endothelial cells. Doxorubicin, camptothecin, and thapsigargin induce mitochondrial-dependent cell death following loss of mitochondrial membrane potential (MMP) in vascular endothelial cells, with subsequent increase in sub-G0 population. In endocardial endothelial cells, there was no MMP loss; and only cell cycle arrest either at G1 or S phases was observed when the cells were treated with doxorubicin, camptothecin, and thapsigargin.
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FOXO1 is an essential regulator of pluripotency in human embryonic stem cells.
Nat. Cell Biol.
PUBLISHED: 06-06-2011
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Pluripotency of embryonic stem cells (ESCs) is defined by their ability to differentiate into three germ layers and derivative cell types and is established by an interactive network of proteins including OCT4 (also known as POU5F1; ref. 4), NANOG (refs 5, 6), SOX2 (ref. 7) and their binding partners. The forkhead box O (FoxO) transcription factors are evolutionarily conserved regulators of longevity and stress response whose function is inhibited by AKT protein kinase. FoxO proteins are required for the maintenance of somatic and cancer stem cells; however, their function in ESCs is unknown. We show that FOXO1 is essential for the maintenance of human ESC pluripotency, and that an orthologue of FOXO1 (Foxo1) exerts a similar function in mouse ESCs. This function is probably mediated through direct control by FOXO1 of OCT4 and SOX2 gene expression through occupation and activation of their respective promoters. Finally, AKT is not the predominant regulator of FOXO1 in human ESCs. Together these results indicate that FOXO1 is a component of the circuitry of human ESC pluripotency. These findings have critical implications for stem cell biology, development, longevity and reprogramming, with potentially important ramifications for therapy.
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Synthesis of gold nanoparticles: an ecofriendly approach using Hansenula anomala.
ACS Appl Mater Interfaces
PUBLISHED: 05-04-2011
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This work describes a bioassisted approach for the preparation of metal nanoparticles using yeast species Hansenula anomala. Gold nanoparticles were prepared using gold salt as the precursor, amine-terminated polyamidoamine dendrimer as the stabilizer, and the extracellular material from H. anomala as the bioreductant. It could also be demonstrated that, using our approach, small molecules such as cysteine can act as stabilizers as well. This synthetic approach offers a greener alternative route to the preparation of gold sols that are devoid of cellular and toxic chemical components. The ability of as-synthesized gold sol to function as biological ink for producing patterns for the analysis of fingerprints and to act as an antimicrobial reagent is evaluated. The generality of this toxin-free synthetic approach to other metals was assessed using palladium and silver.
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Extracellular phosphorylation of the amyloid ?-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimers disease.
EMBO J.
PUBLISHED: 04-04-2011
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Alzheimers disease (AD) is the most common form of dementia and associated with progressive deposition of amyloid ?-peptides (A?) in the brain. A? derives by sequential proteolytic processing of the amyloid precursor protein by ?- and ?-secretases. Rare mutations that lead to amino-acid substitutions within or close to the A? domain promote the formation of neurotoxic A? assemblies and can cause early-onset AD. However, mechanisms that increase the aggregation of wild-type A? and cause the much more common sporadic forms of AD are largely unknown. Here, we show that extracellular A? undergoes phosphorylation by protein kinases at the cell surface and in cerebrospinal fluid of the human brain. Phosphorylation of serine residue 8 promotes formation of oligomeric A? assemblies that represent nuclei for fibrillization. Phosphorylated A? was detected in the brains of transgenic mice and human AD brains and showed increased toxicity in Drosophila models as compared with non-phosphorylated A?. Phosphorylation of A? could represent an important molecular mechanism in the pathogenesis of the most common sporadic form of AD.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.