Corporate Banner
Satellite Banner
Biomolecular Screening
Scientific Community
Become a Member | Sign in
Home>Resources>Latest Publications
  Latest Publications
Advanced Search


Showing 100 Latest Publications
TitleDate Created
The Diagnostic Ability of Follow-Up Imaging Biomarkers after Treatment of Glioblastoma in the Temozolomide Era: Implications from Proton MR Spectroscopy and Apparent Diffusion Coefficient Mapping.Thursday, October 08, 2015
Bulik M, Kazda T, Slampa P, Jancalek R,
BioMed research international.
Objective. To prospectively determine institutional cut-off values of apparent diffusion coefficients (ADCs) and concentration of tissue metabolites measured by MR spectroscopy (MRS) for early differentiation between glioblastoma (GBM) relapse and treatment-related changes after standard treatment. Materials and Methods. Twenty-four GBM patients who received gross total resection and standard adjuvant therapy underwent MRI examination focusing on the enhancing region suspected of tumor recurrence. ADC maps, concentrations of N-acetylaspartate, choline, creatine, lipids, and lactate, and metabolite ratios were determined. Final diagnosis as determined by biopsy or follow-up imaging was correlated to the results of advanced MRI findings. Results. Eighteen (75%) and 6 (25%) patients developed tumor recurrence and pseudoprogression, respectively. Mean time to radiographic progression from the end of chemoradiotherapy was 5.8 ± 5.6 months. Significant differences in ADC and MRS data were observed between those with progression and pseudoprogression. Recurrence was characterized by N-acetylaspartate ≤ 1.5 mM, choline/N-acetylaspartate ≥ 1.4 (sensitivity 100%, specificity 91.7%), N-acetylaspartate/creatine ≤ 0.7, and ADC ≤ 1300 × 10(-6) mm(2)/s (sensitivity 100%, specificity 100%). Conclusion. Institutional validation of cut-off values obtained from advanced MRI methods is warranted not only for diagnosis of GBM recurrence, but also as enrollment criteria in salvage clinical trials and for reporting of outcomes of initial treatment.
Long Noncoding RNA Expression Signatures of Metastatic Nasopharyngeal Carcinoma and Their Prognostic Value.Thursday, October 08, 2015
Zhang W, Wang L, Zheng F, Zou R, Xie C, Guo Q, Hu Q, Chen J, Yang X, Yao H, Song E, Xiang Y,
BioMed research international. 13-9-2015
Long noncoding RNAs (lncRNAs) have recently been found to play important roles in various cancer types. The elucidation of genome-wide lncRNA expression patterns in metastatic nasopharyngeal carcinoma (NPC) could reveal novel mechanisms underlying NPC carcinogenesis and progression. In this study, lncRNA expression profiling was performed on metastatic and primary NPC tumors, and the differentially expressed lncRNAs between these samples were identified. A total of 33,045 lncRNA probes were generated for our microarray based on authoritative data sources, including RefSeq, UCSC Knowngenes, Ensembl, and related literature. Using these probes, 8,088 lncRNAs were found to be significantly differentially expressed (≥2-fold). To identify the prognostic value of these differentially expressed lncRNAs, four lncRNAs (LOC84740, ENST00000498296, AL359062, and ENST00000438550) were selected; their expression levels were measured in an independent panel of 106 primary NPC samples via QPCR. Among these lncRNAs, ENST00000438550 expression was demonstrated to be significantly correlated with NPC disease progression. A survival analysis showed that a high expression level of ENST00000438550 was an independent indicator of disease progression in NPC patients (P = 0.01). In summary, this study may provide novel diagnostic and prognostic biomarkers for NPC, as well as a novel understanding of the mechanism underlying NPC metastasis and potential targets for future treatment.
Metastatic Salivary Gland Tumors: A Single-Center Study Demonstrating the Feasibility and Potential Clinical Benefit of Molecular-Profiling-Guided Therapy.Thursday, October 08, 2015
Popovtzer A, Sarfaty M, Limon D, Marshack G, Perlow E, Dvir A, Soussan-Gutman L, Stemmer SM,
BioMed research international. 13-9-2015
We evaluated the use of molecular profiling (MP) for metastatic salivary gland adenoid cystic carcinoma (SACC), for which there is no standard treatment. MP (Caris Molecular Intelligence) was performed on biopsy samples from all metastatic SACC patients attending a tertiary medical center between 2010 and 2013 (n = 14). Treatment was selected according to the biomarkers identified. Findings were compared with all similarly diagnosed patients treated in the same center between 1996 and 2009 (n = 9). For each patient, MP identified 1-13 biomarkers associated with clinical benefit for specific therapies (most commonly low/negative TS, low ERCC1). Eleven patients (79%) received MP-guided treatment (2 died prior to treatment initiation, 1 opted not to be treated), with complete response in 1, partial response (PR) in 3, and stable disease in 4. In the historical controls, 2 patients (22%) were treated (1 had PR). Median (range) progression-free survival in the first line after MP was 8.2 months (1.4-49.5+). Median (range) overall survival from diagnosis of metastatic disease was 31.3 (1.4-71.1+) versus 14.0 (1.5-116) months in the historical controls. In conclusion, MP expands treatment options and may improve clinical outcomes for metastatic SACC. In orphan diseases where randomized trials cannot be performed, MP could become a standard clinical tool.
The Emergent Landscape of Detecting EGFR Mutations Using Circulating Tumor DNA in Lung Cancer.Thursday, October 08, 2015
Huang WL, Wei F, Wong DT, Lin CC, Su WC,
BioMed research international. 13-9-2015
The advances in targeted therapies for lung cancer are based on the evaluation of specific gene mutations especially the epidermal growth factor receptor (EGFR). The assays largely depend on the acquisition of tumor tissue via biopsy before the initiation of therapy or after the onset of acquired resistance. However, the limitations of tissue biopsy including tumor heterogeneity and insufficient tissues for molecular testing are impotent clinical obstacles for mutation analysis and lung cancer treatment. Due to the invasive procedure of tissue biopsy and the progressive development of drug-resistant EGFR mutations, the effective initial detection and continuous monitoring of EGFR mutations are still unmet requirements. Circulating tumor DNA (ctDNA) detection is a promising biomarker for noninvasive assessment of cancer burden. Recent advancement of sensitive techniques in detecting EGFR mutations using ctDNA enables a broad range of clinical applications, including early detection of disease, prediction of treatment responses, and disease progression. This review not only introduces the biology and clinical implementations of ctDNA but also includes the updating information of recent advancement of techniques for detecting EGFR mutation using ctDNA in lung cancer.
Long Noncoding RNAs as New Architects in Cancer Epigenetics, Prognostic Biomarkers, and Potential Therapeutic Targets.Thursday, October 08, 2015
Meseure D, Drak Alsibai K, Nicolas A, Bieche I, Morillon A,
BioMed research international. 13-9-2015
Recent advances in genome-wide analysis have revealed that 66% of the genome is actively transcribed into noncoding RNAs (ncRNAs) while less than 2% of the sequences encode proteins. Among ncRNAs, high-resolution microarray and massively parallel sequencing technologies have identified long ncRNAs (>200 nucleotides) that lack coding protein function. LncRNAs abundance, nuclear location, and diversity allow them to create in association with protein interactome, a complex regulatory network orchestrating cellular phenotypic plasticity via modulation of all levels of protein-coding gene expression. Whereas lncRNAs biological functions and mechanisms of action are still not fully understood, accumulating data suggest that lncRNAs deregulation is pivotal in cancer initiation and progression and metastatic spread through various mechanisms, including epigenetic effectors, alternative splicing, and microRNA-like molecules. Mounting data suggest that several lncRNAs expression profiles in malignant tumors are associated with prognosis and they can be detected in biological fluids. In this review, we will briefly discuss characteristics and functions of lncRNAs, their role in carcinogenesis, and their potential usefulness as diagnosis and prognosis biomarkers and novel therapeutic targets.
Molecular Biology in Pediatric High-Grade Glioma: Impact on Prognosis and Treatment.Thursday, October 08, 2015
Rizzo D, Ruggiero A, Martini M, Rizzo V, Maurizi P, Riccardi R,
BioMed research international. 13-9-2015
High-grade gliomas are the main cause of death in children with brain tumours. Despite recent advances in cancer therapy, their prognosis remains poor and the treatment is still challenging. To date, surgery followed by radiotherapy and temozolomide is the standard therapy. However, increasing knowledge of glioma biology is starting to impact drug development towards targeted therapies. The identification of agents directed against molecular targets aims at going beyond the traditional therapeutic approach in order to develop a personalized therapy and improve the outcome of pediatric high-grade gliomas. In this paper, we critically review the literature regarding the genetic abnormalities implicated in the pathogenesis of pediatric malignant gliomas and the current development of molecularly targeted therapies. In particular, we analyse the impact of molecular biology on the prognosis and treatment of pediatric high-grade glioma, comparing it to that of adult gliomas.
MET Expression in Primary and Metastatic Clear Cell Renal Cell Carcinoma: Implications of Correlative Biomarker Assessment to MET Pathway Inhibitors.Thursday, October 08, 2015
Shuch B, Falbo R, Parisi F, Adeniran A, Kluger Y, Kluger HM, Jilaveanu LB,
BioMed research international. 13-9-2015
Aims. Inhibitors of the MET pathway hold promise in the treatment for metastatic kidney cancer. Assessment of predictive biomarkers may be necessary for appropriate patient selection. Understanding MET expression in metastases and the correlation to the primary site is important, as distant tissue is not always available. Methods and Results. MET immunofluorescence was performed using automated quantitative analysis and a tissue microarray containing matched nephrectomy and distant metastatic sites from 34 patients with clear cell renal cell carcinoma. Correlations between MET expressions in matched primary and metastatic sites and the extent of heterogeneity were calculated. The mean expression of MET was not significantly different between primary tumors when compared to metastases (P = 0.1). MET expression weakly correlated between primary and matched metastatic sites (R = 0.5) and a number of cases exhibited very high levels of discordance between these tumors. Heterogeneity within nephrectomy specimens compared to the paired metastatic tissues was not significantly different (P = 0.39). Conclusions. We found that MET expression is not significantly different in primary tumors than metastatic sites and only weakly correlates between matched sites. Moderate concordance of MET expression and significant expression heterogeneity may be a barrier to the development of predictive biomarkers using MET targeting agents.
The Fine LINE: Methylation Drawing the Cancer Landscape.Thursday, October 08, 2015
Miousse IR, Koturbash I,
BioMed research international. 13-9-2015
LINE-1 (L1) is the most abundant mammalian transposable element that comprises nearly 20% of the genome, and nearly half of the mammalian genome has stemmed from L1-mediated mobilization. Expression and retrotransposition of L1 are suppressed by complex mechanisms, where the key role belongs to DNA methylation. Alterations in L1 methylation may lead to aberrant expression of L1 and have been described in numerous diseases. Accumulating evidence clearly indicates that loss of global DNA methylation observed in cancer development and progression is tightly associated with hypomethylation of L1 elements. Significant progress achieved in the last several years suggests that such parameters as L1 methylation status can be potentially utilized as clinical biomarkers for determination of the disease stage and in predicting the disease-free survival in cancer patients. In this paper, we summarize the current knowledge on L1 methylation, with specific emphasis given to success and challenges on the way of introduction of L1 into clinical practice.
Thalamocortical relationship in epileptic patients with generalized spike and wave discharges - A multimodal neuroimaging study.Thursday, October 08, 2015
Zhang CH, Sha Z, Mundahl J, Liu S, Lu Y, Henry TR, He B,
NeuroImage. Clinical. 13-9-2015
Unlike focal or partial epilepsy, which has a confined range of influence, idiopathic generalized epilepsy (IGE) often affects the whole or a larger portion of the brain without obvious, known cause. It is important to understand the underlying network which generates epileptic activity and through which epileptic activity propagates. The aim of the present study was to investigate the thalamocortical relationship using non-invasive imaging modalities in a group of IGE patients. We specifically investigated the roles of the mediodorsal nuclei in the thalami and the medial frontal cortex in generating and spreading IGE activities. We hypothesized that the connectivity between these two structures is key in understanding the generation and propagation of epileptic activity in brains affected by IGE. Using three imaging techniques of EEG, fMRI and EEG-informed fMRI, we identified important players in generation and propagation of generalized spike-and-wave discharges (GSWDs). EEG-informed fMRI suggested multiple regions including the medial frontal area near to the anterior cingulate cortex, mediodorsal nuclei of the thalamus, caudate nucleus among others that related to the GSWDs. The subsequent seed-based fMRI analysis revealed a reciprocal cortical and bi-thalamic functional connection. Through EEG-based Granger Causality analysis using (DTF) and adaptive DTF, within the reciprocal thalamocortical circuitry, thalamus seems to serve as a stronger source in driving cortical activity from initiation to the propagation of a GSWD. Such connectivity change starts before the GSWDs and continues till the end of the slow wave discharge. Thalamus, especially the mediodorsal nuclei, may serve as potential targets for deep brain stimulation to provide more effective treatment options for patients with drug-resistant generalized epilepsy.
Perceived Immune Status and Sleep: A Survey among Dutch Students.Thursday, October 08, 2015
Donners AA, Tromp MD, Garssen J, Roth T, Verster JC,
Sleep disorders. 04-8-2015
Reduced immune functioning may have a negative impact on sleep and health, and vice versa. A survey among Dutch young adults (18-35 years old) was administered to collect information on perception of reduced immunity and its relationship to sleep disorders, sleep duration, and quality. Sleep disorders were assessed with the SLEEP-50 questionnaire subscales of sleep apnea, insomnia, circadian rhythm disorder, and daily functioning. Dutch young adults (N = 574) completed the survey. Among them, subjects (N = 209; 36.4%) reported perceived reduced immunity. Relative to those with a normal immune status, subjects reporting reduced immunity had significantly higher scores (p = 0.0001) on sleep apnea (2.6 versus 3.6), insomnia (5.1 versus 6.8), and circadian rhythm disorder (2.1 versus 2.7). Subjects reporting reduced immunity also had significantly poorer daily functioning scores (5.4 versus 7.6, p = 0.0001). No differences were observed in total sleep time, but those reporting reduced immunity had significantly poorer ratings of sleep quality (6.8 versus 7.2, p = 0.0001). Our findings suggest that perceived reduced immunity is associated with sleep disturbances, impaired daily functioning, and a poorer sleep quality. Experimental studies including the assessment of immune biomarkers and objective measures of sleep (polysomnography) should confirm the current observations.
Effects of Eccentric and Concentric Emphasized Resistance Exercise on IL-15 Serum Levels and Its Relation to Inflammatory Markers in Athletes and Non-Athletes.Thursday, October 08, 2015
Bazgir B, Salesi M, Koushki M, Amirghofran Z,
Asian journal of sports medicine. Sep-2015
These results indicated that fitness level and RE could modulate circulating levels of IL-15 and suggest the potential anti-inflammatory effects of IL-15 during RE.
Computer Decision Support Changes Physician Practice But Not Knowledge Regarding Autism Spectrum Disorders.Thursday, October 08, 2015
Bauer NS, Carroll AE, Saha C, Downs SM,
Applied clinical informatics. 28-9-2015
A CDSS module to improve primary care management of ASD in pediatric practice led to significant improvements in physician-reported use of validated screening tools to screen for ASDs. However it did not lead to corresponding changes in physician knowledge or attitudes.
Identification and characterization of a minisatellite contained within a novel miniature inverted-repeat transposable element (MITE) of Porphyromonas gingivalis.Thursday, October 08, 2015
Klein BA, Chen T, Scott JC, Koenigsberg AL, Duncan MJ, Hu LT,
Mobile DNA. 15-7-2015
We performed a bioinformatic analysis of BrickBuilt utilizing existing whole genome sequencing, microarray and RNAseq data, as well as performing in vitro promoter probe assays to determine potential roles, mechanisms and regulation of the expression of these elements and their affect on surrounding loci. The multiplicity, localization and limited host range nature of MITEs and MITE-like elements in P. gingivalis suggest that these elements may play an important role in facilitating genome evolution as well as modulating the transcriptional regulatory system.
Hyaluronan Synthesis, Catabolism, and Signaling in Neurodegenerative Diseases.Thursday, October 08, 2015
Sherman LS, Matsumoto S, Su W, Srivastava T, Back SA,
International journal of cell biology. 6-10-2015
The glycosaminoglycan hyaluronan (HA), a component of the extracellular matrix, has been implicated in regulating neural differentiation, survival, proliferation, migration, and cell signaling in the mammalian central nervous system (CNS). HA is found throughout the CNS as a constituent of proteoglycans, especially within perineuronal nets that have been implicated in regulating neuronal activity. HA is also found in the white matter where it is diffusely distributed around astrocytes and oligodendrocytes. Insults to the CNS lead to long-term elevation of HA within damaged tissues, which is linked at least in part to increased transcription of HA synthases. HA accumulation is often accompanied by elevated expression of at least some transmembrane HA receptors including CD44. Hyaluronidases that digest high molecular weight HA into smaller fragments are also elevated following CNS insults and can generate HA digestion products that have unique biological activities. A number of studies, for example, suggest that both the removal of high molecular weight HA and the accumulation of hyaluronidase-generated HA digestion products can impact CNS injuries through mechanisms that include the regulation of progenitor cell differentiation and proliferation. These studies, reviewed here, suggest that targeting HA synthesis, catabolism, and signaling are all potential strategies to promote CNS repair.
Deep Neural Networks with Multistate Activation Functions.Thursday, October 08, 2015
Cai C, Xu Y, Ke D, Su K,
Computational intelligence and neuroscience. 10-9-2015
We propose multistate activation functions (MSAFs) for deep neural networks (DNNs). These MSAFs are new kinds of activation functions which are capable of representing more than two states, including the N-order MSAFs and the symmetrical MSAF. DNNs with these MSAFs can be trained via conventional Stochastic Gradient Descent (SGD) as well as mean-normalised SGD. We also discuss how these MSAFs perform when used to resolve classification problems. Experimental results on the TIMIT corpus reveal that, on speech recognition tasks, DNNs with MSAFs perform better than the conventional DNNs, getting a relative improvement of 5.60% on phoneme error rates. Further experiments also reveal that mean-normalised SGD facilitates the training processes of DNNs with MSAFs, especially when being with large training sets. The models can also be directly trained without pretraining when the training set is sufficiently large, which results in a considerable relative improvement of 5.82% on word error rates.
Analysis of the expression of PHTF1 and related genes in acute lymphoblastic leukemia.Thursday, October 08, 2015
Huang X, Geng S, Weng J, Lu Z, Zeng L, Li M, Deng C, Wu X, Li Y, Du X,
Cancer cell international. 10-9-2015
PHTF1 overexpression is responsible for regulating cell proliferation and apoptosis in T-ALL cell lines. PHTF1 may be a tumor-suppressor like gene and a therapeutic target for triggering the PHTF1-FEM1b-Apaf-1 apoptosis pathway.
Mixed Phenotype Acute Leukemia with Two Immunophenotypically Distinct B and T Blasts Populations, Double Ph (+) Chromosome and Complex Karyotype: Report of an Unusual Case.Thursday, October 08, 2015
Kohla SA, Sabbagh AA, Omri HE, Ibrahim FA, Otazu IB, Alhajri H, Yassin MA,
Clinical medicine insights. Blood disorders. 5-10-2015
Mixed phenotype acute leukemia (MPAL) is considered as a rare type of leukemia with an incidence of less than 4% of all acute leukemia based on the most recent 2008 WHO classification. Common subtypes are the B/myeloid and T/myeloid; B/T and trilineage MPAL being extremely rare. We present a case of a male in his 20s, whose peripheral blood smears showed 34% blast cells and bone marrow with 70% blasts. Immunophenotyping by multiparametric flow cytometry showed two populations of blasts, the major one with B-lineage and the minor one with T-lineage. Conventional karyotyping revealed complex karyotype with the presence of double Philadelphia chromosome (Ph (+)). BCR/ABL1 rearrangement was confirmed by fluorescent in situ hybridization (FISH) analysis. The BCR/ABL1 ES probe on interphase cells indicated p190 minor m-BCR/ABL fusion in 46% and a second abnormal clone with double Ph (+) in 16% of the cells analyzed confirmed by reverse transcription-PCR (RT-PCR). The case was diagnosed as MPAL with double Philadelphia chromosome Ph (+). The patient was treated with dasatinib, four cycle hyper CVAD/methotrexate cytarabin protocol, and allogeneic transplant. He is still alive in complete hematological, cytogenetic, and molecular remission. Mixed phenotype B/T acute leukemia is an extremely rare disease, particularly those with double Philadelphia chromosomes and clinically presents challenges in diagnosis and treatment.
Distribution of Angiotensin-1 Converting Enzyme Insertion/Deletion and α-Actinin-3 Codon 577 Polymorphisms in Turkish Male Soccer Players.Thursday, October 08, 2015
Ulucan K, Sercan C, Biyikli T,
Genetics & epigenetics. 21-9-2015
Angiotensin-1 converting enzyme (ACE) gene and α-actinin-3 (ACTN3) gene polymorphisms are considered to be the most important candidate genes for genetic predisposition to human athletic performance. In the present study, we aimed to analyze the distribution of ACE and ACTN3 polymorphisms for the first time in male Turkish soccer players. In this prospective study, our cohort consisted of 25 professional players, all with Turkish ancestry. Polymerase chain reaction (PCR)-restriction length polymorphism was used for the characterization of the genotype of ACTN3 and single PCR for ACE. For ACE genotype, 16%, 44%, and 40% of the players had insertion/insertion (II), insertion/deletion (ID), and deletion/deletion (DD) genotypes, respectively, whereas 20% had XX, 36% had RX, and 44% had RR genotypes for ACTN3. When we examined the allelic percentages, for ACE, D allele was recorded as 62 and I as 38, and for ACTN3, R allele was 62 and X was 38. Our results were in agreement with the previous reports, indicating the presence of ACTN3 D and ACE X allele in soccer players. We suggest that ACE and ACTN3 genotypes are important biomarkers for genetic counseling for the individuals who are prone to be successful soccer players.
Optimal first trimester preeclampsia prediction: a comparison of multi marker algorithm, risk profiles and their sequential application.Thursday, October 08, 2015
Gabbay-Benziv R, Oliveira N, Baschat AA,
Prenatal diagnosis. 8-Oct-2015
Sequential application of a multimarker algorithm followed by determination of treatable risk factors in screen positive women is the optimal approach for first trimester preeclampsia prediction and identification of women that may benefit from targeted metabolic or cardiovascular treatment.
Mitochondrial DNA and Toll-Like Receptor-9 Are Associated With Mortality in Critically Ill Patients.Thursday, October 08, 2015
Krychtiuk KA, Ruhittel S, Hohensinner PJ, Koller L, Kaun C, Lenz M, Bauer B, Wutzlhofer L, Draxler DF, Maurer G, Huber K, Wojta J, Heinz G, Niessner A, Speidl WS,
Critical care medicine. 7-Oct-2015
Circulating levels of mitochondrial DNA at ICU admission predict mortality in critically ill patients. This association was in particular present in patients with elevated toll-like receptor-9 expression.
RhoA Ambivalently Controls Prominent Myofibroblast Characteritics by Involving Distinct Signaling Routes.Thursday, October 08, 2015
Jatho A, Hartmann S, Kittana N, Mügge F, Wuertz CM, Tiburcy M, Zimmermann WH, Katschinski DM, Lutz S,
PloS one. 7-10-2015
RhoA positively and negatively influences myofibroblast characteristics by differential signaling cascades and depending on environmental conditions. These include gene expression, migration and proliferation. Reduction of RhoA leads to an increased viscoelasticity and a decrease in contractile force in engineered cardiac tissue.
Comparison between Folin-Ciocalteu and Prussian Blue Assays to Estimate The Total Phenolic Content of Juices and Teas Using 96-Well Microplates.Thursday, October 08, 2015
Margraf T, Karnopp AR, Rosso ND, Granato D,
Journal of food science. 8-Oct-2015
Folin-Ciocalteu colorimetric assay (FC) is the most widely used assay to estimate the total phenolic content in foods, beverages, herbs and other plant extracts, but many chemical compounds may act as interfering agents, producing inaccurate estimations of the real concentration of phenolic compounds in the matrix. Based on this limitation, the objective of this study was to compare, quantitatively, the Folin-Ciocalteu and Prussian Blue (PB) assays in estimating the total phenolic content in purple grape juices (n = 20; Vitis labrusca L.) and teas (n = 25) from different botanical origins using 96-well microplates. PB assay presented a low limit of detection (PB = 0.27 mg/L; FC = 0.25 mg/L) and quantification (PB = 0.92 mg/L; FC = 0.82 mg/L), showing its suitability in screening the total phenolic content in grape juices and teas. FC and PB assays presented a high association (P < 0.0001) for teas (r = 0.887) and grape juices (r = 0.923). The advantages of PB over FC assay are its simplicity, low time consumption (15 min reaction as compared to 60 min reaction for the FC assay), lower usage of reagents (solutions are prepared in a mM base), and higher selectivity. Additionally, PB assay was proven to be reproducible and repeatable and, therefore, may be used as an alternative to FC assay.
The Effects of Synthetic Estrogen Exposure on the Sexually Dimorphic Liver Transcriptome of the Sex-Role-Reversed Gulf Pipefish.Thursday, October 08, 2015
Rose E, Flanagan SP, Jones AG,
PloS one. 8-10-2015
Species exhibiting sex-role reversal provide an unusual perspective on the evolution of sex roles and sex differences. However, the proximate effects of sex-role reversal are largely unknown. Endocrine disruptors provide an experimental mechanism to address hormonal regulation of sexually dimorphic gene expression in sex-role-reversed taxa. Here, we investigate gene expression patterns in the liver of the sex-role-reversed Gulf pipefish, because the liver is known to be sexually dimorphic and estrogen-regulated in species with conventional sex roles. Using next-generation RNA-sequencing technology (RNA-seq), we detected sexually dimorphic hepatic gene expression patterns, with a total of 482 differentially expressed genes between the sexes in Gulf pipefish. Two-thirds of these genes were over-expressed in females, and the sex-specific transcriptomes of this sex-role-reversed pipefish's liver were superficially similar to those of fishes with conventional sex-roles. We exposed females, pregnant males, and non-pregnant males to 17α-ethinylestradiol (EE2) at ecologically relevant concentrations of 5ng/L and compared gene expression patterns in the livers of exposed fish to control fish. Several genes that were up-regulated in EE2-exposed males relative to control males were also found to be female-biased in control animals. These genes included several of the classic estrogen biomarkers, such as vitellogenin, choriogenin, and zona pellucida. Thus, estrogen exposure induced feminization of the male liver transcriptome in a sex-role-reversed pipefish. These results suggest that the ancestral state of estrogen-regulated female reproductive physiology has been retained in all sex-role-reversed vertebrates thus far studied, despite substantial evolution of the hormonal regulation of ornamentation and mating behavior in these interesting taxa.
Ultrasensitive visual detection of DNA with tunable dynamic range by using unmodified gold nanoparticles and target catalyzed hairpin assembly amplification.Thursday, October 08, 2015
Yun W, Jiang J, Cai D, Zhao P, Liao J, Sang G,
Biosensors & bioelectronics. 30-Sep-2015
A simple and novel strategy for enzyme-free ultrasensitive DNA detection platform has been present here based on gold nanoparticles (AuNPs) colorimetry and target catalyzed hairpin assembly amplification. Three hairpin auxiliary probes (H1, H2, and H3) are designed with signal-stranded DNA (ssDNA) sticky ends which could effectively stabilize AuNPs against salt-induced aggregation. However, a cascade of assembly steps with H1, H2, and H3 are activated in the presence of the target DNA, followed by a disassembly step in which H3 displaces the target DNA from the complex, freeing the target DNA to catalyze the self-assembly of additional branched junctions. The formed branched junction consisted with dsDNA is stiffer, and cannot prevent salt-induced AuNPs aggregation, corresponding to a red-to-blue color change. The result can be read out by naked eyes or UV-vis spectrometer. The detection limit of this method is 0.1pM by naked eyes, and this result is comparable or even better than enzyme or hybridization chain reaction (HCR) based amplification AuNPs colorimetric assays. Moreover, the dynamic range of sensor could be tuned by using different concentration of hairpins. Importantly, this strategy provides a versatile ultrasensitive detection platform for the DNA and related filed targets including metal ions, small molecules, proteins, cells et al. by combining with specific DNAzymes and aptamers.
Lipid composition of viral envelope of three strains of influenza virus - not all viruses are created equal.Thursday, October 08, 2015
Ivanova PT, Myers DS, Milne SB, McClaren JL, Thomas PG, Brown HA,
ACS infectious diseases. 11-Sep-2015
While differences in the rate of virus fusion and budding from the host cell membrane have been correlated with pathogenicity, no systematic study of the contribution of differences in viral envelope composition has previously been attempted. Using rigorous virus purification, marked differences between virions and host were observed. Over 125 phospholipid species have been quantitated for three strains of influenza (HKx31- H3N2, PR8- H1N1, and VN1203- H5N1) grown in eggs. The glycerophospholipid composition of purified virions differs from that of the host or that of typical mammalian cells. Phosphatidylcholine is the major component in most mammalian cell membranes, while in purified virions phosphatidylethanolamine dominates. Due to its effects on membrane curvature, it is likely that the variations in its content are important to viral processing during infection. This integrated method of virion isolation with systematic analysis of glycerophospholipids provides a tool for the assessment of species specific biomarkers of viral pathogenicity.
Euphol from Euphorbia tirucalli Negatively Modulates TGF-β Responsiveness via TGF-β Receptor Segregation inside Membrane Rafts.Thursday, October 08, 2015
Chen CL, Chen YP, Lin MW, Huang YB, Chang FR, Duh TH, Wu DC, Wu WC, Kao YC, Yang PH,
PloS one. 24-6-2015
Transforming growth factor-β (TGF-β) responsiveness in cultured cells can be modulated by TGF-β partitioning between lipid raft/caveolae- and clathrin-mediated endocytosis pathways. Lipid rafts are plasma membrane microdomains with an important role in cell survival signaling, and cholesterol is necessary for the lipid rafts' structure and function. Euphol is a euphane-type triterpene alcohol that is structurally similar to cholesterol and has a wide range of pharmacological properties, including anti-inflammatory and anti-cancer effects. In the present study, euphol suppressed TGF-β signaling by inducing TGF-β receptor movement into lipid-raft microdomains and degrading TGF-β receptors.
Ectopic Expression of the Coleus R2R3 MYB-Type Proanthocyanidin Regulator Gene SsMYB3 Alters the Flower Color in Transgenic Tobacco.Thursday, October 08, 2015
Zhu Q, Sui S, Lei X, Yang Z, Lu K, Liu G, Liu YG, Li M,
PloS one. 8-10-2015
Proanthocyanidins (PAs) play an important role in plant disease defense and have beneficial effects on human health. We isolated and characterized a novel R2R3 MYB-type PA-regulator SsMYB3 from a well-known ornamental plant, coleus (Solenostemon scutellarioides), to study the molecular regulation of PAs and to engineer PAs biosynthesis. The expression level of SsMYB3 was correlated with condensed tannins contents in various coleus tissues and was induced by wounding and light. A complementation test in the Arabidopsis tt2 mutant showed that SsMYB3 could restore the PA-deficient seed coat phenotype and activated expression of the PA-specific gene ANR and two related genes, DFR and ANS. In yeast two-hybrid assays, SsMYB3 interacted with the Arabidopsis AtTT8 and AtTTG1 to reform the ternary transcriptional complex, and also interacted with two tobacco bHLH proteins (NtAn1a and NtJAF13-1) and a WD40 protein, NtAn11-1. Ectopic overexpression of SsMYB3 in transgenic tobacco led to almost-white flowers by greatly reducing anthocyanin levels and enhancing accumulation of condensed tannins. This overexpression of SsMYB3 upregulated the key PA genes (NtLAR and NtANR) and late anthocyanin structural genes (NtDFR and NtANS), but downregulated the expression of the final anthocyanin gene NtUFGT. The formative SsMYB3-complex represses anthocyanin accumulation by directly suppressing the expression of the final anthocyanin structural gene NtUFGT, through competitive inhibition or destabilization of the endogenous NtAn2-complex formation. These results suggested that SsMYB3 may form a transcription activation complex to regulate PA biosynthesis in the Arabidopsis tt2 mutant and transgenic tobacco. Our findings suggest that SsMYB3 is involved in the regulation of PA biosynthesis in coleus and has the potential as a molecular tool for manipulating biosynthesis of PAs in fruits and other crops using metabolic engineering.
Homoharringtonine binds to and increases myosin-9 in myeloid leukemia.Thursday, October 08, 2015
Zhang T, Shen S, Zhu Z, Lu S, Yin X, Zheng J, Jin J,
British journal of pharmacology. 8-Oct-2015
These results indicate that myosin-9 is the target protein of HHT and plays an important role in the HHT-induced apoptosis of leukemia cells.
Use of Biomarkers in Irritable Bowel Syndrome: To Predict the Future, Look at the Past.Thursday, October 08, 2015
Sood R, Ford AC,
Clinical and translational gastroenterology. 8-10-2015
Identification of High-Risk Plaques by MRI and Fluorescence Imaging in a Rabbit Model of Atherothrombosis.Thursday, October 08, 2015
Hua N, Baik F, Pham T, Phinikaridou A, Giordano N, Friedman B, Whitney M, Nguyen QT, Tsien RY, Hamilton JA,
PloS one. 8-10-2015
Our targeted fluorescence ACPP probes distinguished disrupted plaques from stable plaques with high sensitivity and specificity. The combination of anatomic, MRI-derived predictors for disruption and ACPP uptake can further improve the power for identification of high-risk plaques and suggests future development of ACPPs with molecular MRI as a readout.
Persisting signs of disease activity at Magnetic Resonance Enterocolonography predict clinical relapse and disease progression in quiescent Crohn's disease.Thursday, October 08, 2015
Meunier P, Cousin F, Van Kemseke C, Reenaers C, Latour P, Belaiche J, Seidel L, Louis E,
Acta gastro-enterologica Belgica. 8-10-2015
Half of the patients with clinically quiescent Crohn's disease had persisting signs of disease activity at MREC. These signs predicted time-to-relapse.
On-chip enzymatic assay for chloramphenicol acetyltransferase using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.Thursday, October 08, 2015
Choi I, Kim DE, Ahn JH, Yeo WS,
Colloids and surfaces. B, Biointerfaces. 30-Sep-2015
Herein, we report a chloramphenicol (CAP) acetyltransferase (CAT) activity assay based on self-assembled monolayers on gold as an alternative to conventional CAT reporter gene assay systems, which sometimes require toxic materials and complicated steps that limit their use. A CAP derivative presented on a monolayer was converted to the acetylated CAP by CAT in the presence of acetyl-CoA. The conversion was directly monitored by observing the molecular weight changes in CAP using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. CAT activity was determined under various reaction conditions by changing reaction times, CAT and acetyl-CoA concentrations. As a practical application, we identified gene expression in bacteria that were transformed with pCAT plasmid DNA. Our strategy can provide a simple and rapid assay that eliminates some commonly used but potentially detrimental steps in enzymatic assays, such as radioactive labeling and complicated separation and purification of analytes prior to detection.
Latest developments in the treatment of hepatitis B.Thursday, October 08, 2015
Dandri M, Petersen J,
Minerva gastroenterologica e dietologica. 8-Oct-2015
Chronic hepatitis B Virus (HBV) infection continues to be a major health burden worldwide. Currently available antiviral treatment options for chronic hepatitis B include pegylated interferon alpha (PEG-IFN) or nucleos(t)ide analogues (NAs). The major advantages of NAs are good tolerance and potent antiviral activity associated with high rates of on-treatment response to therapy. The advantages of PEG-IFN include a finite course of treatment, the absence of drug resistance, and an opportunity to obtain a durable post-treatment response to therapy. The use of these two antiviral agents with different mechanisms of action in combination is theoretically an attractive approach for treatment. Although several studies have confirmed certain virological advantages of combination therapies, pivotal prospective studies demonstrating long-term clinical benefit to patients are still missing and monotherapy with PEG_IFN or NAs remains the therapy of choice. Furthermore, with the current treatment approaches, only a limited number of patients reach the aim HBsAg loss, which is closest to clinical cure. The limited efficacy of current approved therapeutic regimens demands the development of more efficient therapeutic approaches enabling not only suppression of viral replication, but resolution of HBV infection. The unique replication strategy employed by HBV enables its persistence within the infected hepatocytes. As a consequence, relapse of viral activity is commonly observed after cessation of treatment. Both the persistence of the HBV genome, which forms a stable minichromosome, the covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes, as well as the inability of the immune system to resolve chronic HBV infection are believed to be key mechanisms of HBV chronicity. The recent development and availability of innovative in vitro and in vivo systems and sensitive molecular techniques have opened new possibilities to study the complex network of interactions that HBV establishes with the host in the course of infection and to define new targets for antiviral strategies. Several new antiviral or immunomodulatory compounds have reached preclinical or clinical testing with the aim of a clinical cure of chronic HBV with the loss of HBsAg. This review summarizes the most recent therapeutic strategies designed to directly target the virus or to improve immune responses during chronic HBV infection.
Directly acting antivirals against hepatitis C virus: mechanisms of action and impact of resistant associated variants.Thursday, October 08, 2015
Premoli C, Aghemo A,
Minerva gastroenterologica e dietologica. 8-Oct-2015
HCV drug development has resulted in IFN-free regimens of direct-acting antivirals (DAAs). The new therapies are highly effective achieving 90-95% of SVR rates among all genotypes with minimal treatment-related side effects. They opened a new scenario in HCV treatment representing a treatment option for patients who were ineligible to IFN-based regimens as those with decompensated liver disease, autoimmune disorders and psychiatric disturbs. However, numerous research and clinical questions remain. In particular, drug resistance is an upcoming clinical issue in HCV treatment. The aim of this review is to provide an overview of the different DAAs approved or in clinical development and their mechanism of actions. For each class of agents the resistance profile will be examined according to the available in vitro and in vivo data discussing the clinical implications. Resistance-associated variants (RAVs) are driven by the selection of mutations at different virologic targets. The most clinically relevant NS3/4A protease substitutions are detected at positions V36, Q80, T54, R155 and A156. S282T is the most frequent NS5B polymerase amino acids substitutions. M28, Q30, L31 and Y39 mutations are involved in NS5A proteins associated resistance. The baseline RAVs seems not to be affect the SVR rates. Thus, their detection by sequencing analysis should not to be recommended. Conversely, RAVs testing after DAAs failure is of clinical practice concern in order to select the most appropriate re-treatment combination.
Milrinone dosing issues in critically ill children with kidney injury: A review.Thursday, October 08, 2015
Gist KM, Goldstein SL, Joy MS, Vinks AA,
Journal of cardiovascular pharmacology. 6-Oct-2015
Milrinone is an inotropic drug used in a variety of clinical settings in adults and children. The efficacy of milrinone in pediatric low cardiac output syndrome following cardiac surgery is reported. Its primary route of removal from the body is through the kidney as unchanged drug in the urine. Milrinone is not known to be efficiently removed by extracorporeal dialytic therapies, and thus has the potential to cause serious adverse effects and potentially worsen renal function in patients experiencing acute kidney injury.AKI is an important public health issue that is associated with increased morbidity, mortality and cost. It is a known risk factor for the development of chronic kidney disease. There are no specific therapies to mitigate AKI once it has developed, and interventions are focused on supportive care and dose adjustment of medications. Estimating glomerular filtration rate (GFR) based on height and serum creatinine is the most commonly used clinical method for assessing kidney function and modification of medication doses.The purpose of this review is to discuss our current understanding of milrinone pharmacokinetics and pharmacodynamics in children with AKI and to describe the potential use of urinary biomarkers to guide therapeutic decision making for milrinone dosing.
Stopped-Flow Enantioselective HPLC-CD Analysis and TD-DFT Stereochemical Characterization of Methyl Trans-3-(3,4-Dimethoxyphenyl)Glycidate.Thursday, October 08, 2015
Tedesco D, Fabini E, Barbakadze V, Merlani M, Zanasi R, Chankvetadze B, Bertucci C,
Chirality. 8-Oct-2015
Caffeic acid-derived polyethers are a class of natural products isolated from the root extracts of comfrey and bugloss, which are endowed with intriguing pharmacological properties as anticancer agents. The synthesis of new polyether derivatives is achieved through ring-opening polymerization of chiral 2,3-disubstituted oxiranes, whose absolute configurations define the overall stereochemistry of the produced polymer. The absolute stereochemistry of one of these building blocks, methyl trans-3-(3,4-dimethoxy-phenyl)glycidate (3), was therefore characterized by the combination of enantioselective high-performance liquid chromatography (HPLC), electronic circular dichroism (ECD) spectroscopy, and time-dependent density functional theory (TD-DFT) calculations. Initial efforts aiming at the isolation of enantiomers by means of a standard preparative HPLC protocol followed by offline ECD analysis failed due to unexpected degradation of the samples after collection. The stopped-flow HPLC-CD approach, by which the ECD spectra of enantiomers are measured online with the HPLC system, was applied to overcome this issue and allowed a fast, reliable, and chemical-saving analysis, while avoiding the risks of sample degradation during the collection and processing of enantiomeric fractions. Subsequent TD-DFT calculations identified ( as the first eluted enantiomeric fraction on the Lux Cellulose-2 column, therefore achieving a full stereochemical characterization of the chiral oxirane under investigation. Chirality 00:000-000, 2015. © 2015 Wiley Periodicals, Inc.
Interrupted Pummerer Reaction in Latent-Active Glycosylation: Glycosyl Donors with Recyclable and Regenerative Leaving Group.Thursday, October 08, 2015
Shu P, Xiao X, Zhao Y, Xu Y, Yao W, Tao J, Wang H, Yao G, Lu Z, Zeng J, Wan Q,
Angewandte Chemie (International ed. in English). 8-Oct-2015
Latent O-glycosides, 2-(2-propylthiol)benzyl (PTB) glycosides, were converted into the corresponding active glycosyl donors, 2-(2-propylsulfinyl)benzyl (PSB) glycosides, by a simple and efficient oxidation. Treatment of the PSB donor and various acceptors with triflic anhydride provided the desired glycosides in good to excellent yields. The leaving group, which was activated by an interrupted Pummerer reaction, can be recycled (PSB-OH) and regenerated as the precursor (PTB-OH). A natural hepatoprotective glycoside, leonoside F, was efficiently synthesized in a convergent [3+1] manner with this newly developed method. The present total synthesis also led to a structural revision of this phenylethanoid glycoside.
Potential Application of Biological Products for the Treatment of Ocular Surface Inflammation.Thursday, October 08, 2015
Sakimoto T,
Cornea. Nov-2015
Various biological products have been introduced for the treatment of autoimmune diseases. The injection of tocilizumab [anti-interleukin (IL)-6R antibody] and a tumor necrosis factor receptor fusion protein (TNFR-Fc) has been approved for the treatment of rheumatoid arthritis. We investigated the effect of the anti-IL-6R antibody and TNFR-Fc on corneal inflammation. Topical instillation of the anti-IL-6R antibody (MR16-1, 2 μg/μL; anti-IL-6R group) or TNFR1-Fc (100 μg/mL; TNFR1 group) was performed after corneal wounds were induced in BALB/c mice by alkali burns. The injured eye was analyzed on day 14 or 28 after injury, and topical instillation was performed until day 14 or day 28. Corneal stromal sections were made using a laser capture microdissection system, and total RNA from the specimens was subjected to quantitative polymerase chain reaction array analysis. Topical instillation of phosphate-buffered saline (PBS) served as a control. The vascularized area was significantly reduced in the anti-IL-6R (day 14) and TNFR1 groups (day 28) compared with that in the PBS group. In the anti-IL-6R group, the expression levels of matrix metalloproteinase-13, monocyte chemotactic protein-1, and C-C motif ligand-22 were downregulated compared with those in the PBS group. In the TNFR1 group, expression of mitogen-activated protein kinase 8 was downregulated. These results indicate the possible application of biological products for topical instillation for the treatment of corneal inflammation.
Transient Receptor Potential Channels and Corneal Stromal Inflammation.Thursday, October 08, 2015
Okada Y, Reinach PS, Shirai K, Kitano-Izutani A, Miyajima M, Yamanaka O, Sumioka T, Saika S,
Cornea. Nov-2015
Corneal transparency is dependent on the maintenance of the structural integrity and functional activity of its epithelial and endothelial limiting layers and the stroma. Different transient receptor potential (TRP) channel subtypes are expressed in cells and on corneal sensory nerve endings. They serve as sensors and transducers of environmental stimuli that can reduce tissue transparency. These nonselective cation channels are members of a superfamily sharing TRP box protein sequence homology having 6 membrane spanning domains with a pore between the fifth and sixth segments. TRP channels are composed of 4 monomeric subunits that oligomerize in homomeric or heteromeric configurations derived from different TRP subtypes belonging to the same or any of 6 different subfamilies. TRP subfamily members identified in the cornea include those belonging to the canonical, vanilloid, ankyrin, or melastatin subfamilies. In this review, we specifically focus on the functional roles of TRPV1 and TRPA1 expression in the cornea as their activation provides adaptive nociceptive and immune responses to noxious environmental stresses such as irritating ligands, temperature fluctuations, rises in ambient osmolarity, mechanical stretch, decline in pH, and tissue injury. Our previous studies have indicated that TRPV1 and TRPA1 subtypes are potential drug targets for improving corneal wound healing after alkali burns, because injury-induced fibrosis, neovascularization, and inflammation in either TRPV1 or TRPA1 gene-silenced mice were all significantly reduced.
Resveratrol ameliorates lipid accumulation in HepG2 cells, associated with down-regulation of lipin1 expression.Thursday, October 08, 2015
Tang LY, Chen Y, Rui BB, Hu CM,
Canadian journal of physiology and pharmacology. 6-Aug-2015
The pathogenesis of alcoholic fatty liver (AFL) disease is associated with the excessive accumulation of lipids in hepatocytes as well as oxidative stress. Resveratrol (RES), a dietary polyphenol found in red wine and grapes, has been shown to protect against AFL disease. However, the precise mechanisms that lead to this protective effect remain elusive. In this study, we used HepG2 cells to investigate the effects of RES on lipid metabolism and the mechanisms underlying these effects. HepG2 cells were cultured with oleic acid and alcohol for 48 h to induce excessive lipid accumulation. Oil red O staining showed that administration of oleic acid and alcohol induced more lipid accumulation than was observed in the control group, and that RES (15, 45, or 135 μmol/L) treatment reduced intracellular lipid droplets. RES treatment also significantly attenuated hepatic steatosis and lowered levels of intracellular triglycerides (TG). Western blot analysis showed that RES enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) and down-regulated the expression of sterol regulatory element-binding protein 1c (SREBP-1c) and lipin1. However, compound C, an AMPK inhibitor, reversed these effects of RES. In conclusion, RES reduced lipid accumulation and protected HepG2 cells. This effect may be associated with the down-regulation of SREBP-1c and lipin1 expression, increased levels of phosphorylated AMPK and ACC, and the activation of AMPK-lipin1 signaling.
A comparison of four different conformations adopted by human telomeric G-Quadruplex using Computer Simulations.Thursday, October 08, 2015
Ray A, Panigrahi S, Bhattacharyya D,
Biopolymers. 8-Oct-2015
The telomeric G-quadruplexes for their unique structural features are considered as potential anticancer drug targets. These, however, exhibit structural polymorphism as different topology types for the intra-molecular G-quadruplexes from human telomeric G-rich sequences have been reported based on NMR spectroscopy and X-ray crystallography. These techniques provide detailed atomic-level information about the molecule but relative conformational stability of the different topologies remains unsolved. Therefore, to understand the conformational preference, we have carried out quantum chemical calculations on G-quartets; used all-atom Molecular Dynamics (MD) simulations and Steered Molecular Dynamics (SMD) simulations to characterize the four human telomeric G-quadruplex topologies based on its G-tetrad core-types, viz., parallel, anti-parallel, mixed-(3 + 1)-form1 and mixed-(3 + 1)-form2. We have also studied a non-telomeric sequence along with these telomeric forms giving a comparison between the two G-rich forms. The structural properties such as base pairing, stacking geometry and backbone conformations have been analyzed. The quantum calculations indicate that presence of a sodium ion inside the G-tetrad plane or two potassium ions on both sides of the plane give it an overall planarity which is much needed for good stacking to form a helix. Molecular dynamics simulations indicate that capping of the G-tetrad core by the TTA loops keep the terminal guanine bases away from water. The SMD simulations along with equilibrium MD studies indicate that the parallel and non-telomeric forms are comparatively less stable. We could come to the conclusion that the anti-parallel form and also the mixed-(3 + 1)-form1 topology are most likely to represent the major conformation. This article is protected by copyright. All rights reserved.
Ecdysone-Related Biomarkers of Toxicity in the Model Organism Chironomus riparius: Stage and Sex-Dependent Variations in Gene Expression Profiles.Thursday, October 08, 2015
Planelló R, Herrero Ó, Gómez-Sande P, Ozáez I, Cobo F, Servia MJ,
PloS one. 8-10-2015
Despite being considered a model organism in toxicity studies, particularly in assessing the environmental impact of endocrine disrupting compounds (EDCs) and other chemicals, the molecular basis of development is largely unknown in Chironomus riparius. We have characterized the expression patterns of important genes involved in the ecdysone pathway from embryos to pupa, but specially during the different phases of C. riparius fourth larval instar, according to the development of genital and thoracic imaginal discs. Real-Time PCR was used to analyze: EcR and usp, two genes encoding the two dimerizing partners of the functional ecdysone receptor; E74, an early response gene induced by ecdysteroids; vg (vitellogenin), an effector gene; hsp70 and hsc70, two heat-shock genes involved in the correct folding of the ecdysone receptor; and rpL13, as a part of the ribosomal machinery. Our results show for the first time stage and sex-dependent variations in ecdysone-responsive genes, specially during the late larval stage of C. riparius. The induction in the expression of EcR and usp during the VII-VIII phase of the fourth instar is concomitant with a coordinated response in the activity of the other genes analyzed, suggesting the moment where larvae prepare for pupation. This work is particularly relevant given that most of the analyzed genes have been proposed previously in this species as sensitive biomarkers for the toxicological evaluation of aquatic ecosystems. Identifying the natural regulation of these molecular endpoints throughout the Chironomus development will contribute to a more in-depth and accurate evaluation of the disrupting effects of EDCs in ecotoxicological studies.
Optimization of on-resin palladium-catalyzed Sonogashira cross-coupling reaction for peptides and its use in a structure-activity relationship study of a class B GPCR ligand.Thursday, October 08, 2015
Doan ND, Poujol de Molliens M, Létourneau M, Fournier A, Chatenet D,
European journal of medicinal chemistry. 21-Sep-2015
Class B G protein-coupled receptors are activated by their cognate ligands following a two-step binding model involving a specific network of ligand-receptor intermolecular interactions. In particular, a N-capping structure present in the ligand would contribute significantly to position the N-terminal segment of the ligand once bound to its receptor. The aim of the current study was to implement the use of Pd-catalyzed Sonogashira coupling for the investigation of this structural motif. First, we have developed and evaluated various Sonogashira-based procedures for on-resin post-synthesis modification using a Leu-enkephalin derivative as a model peptide. Next, we have prepared a small library of PACAP-based analogs and evaluated the pharmacological profile of a few of them using a competitive binding assay, as well as functional and survival assays. Notably, our results suggest that the modification of the N-capping region could alter the binding specificity of PACAP without altering its biological activity, thereby opening the way for the design of more selective compounds. Finally, the possibility to achieve sequential multiple point substitutions via the Sonogashira cross-coupling method, during solid phase peptide synthesis, was also evaluated. Altogether, we demonstrated the versatility of such a procedure for the incorporation of various mono- and multiple alkyne-derived modifications during solid phase peptide synthesis and confirmed its usefulness for the structure-activity study of a class B GPCR ligand.
Urinary Biomarkers Improve the Diagnosis of Intrinsic Acute Kidney Injury in Coronary Care Units.Thursday, October 08, 2015
Chang CH, Yang CH, Yang HY, Chen TH, Lin CY, Chang SW, Chen YT, Hung CC, Fang JT, Yang CW, Chen YC,
Medicine. Oct-2015
Acute kidney injury (AKI) is associated with increased morbidity and mortality and is frequently encountered in coronary care units (CCUs). Its clinical presentation differs considerably from that of prerenal or intrinsic AKI. We used the biomarkers calprotectin and neutrophil gelatinase-associated lipocalin (NGAL) and compared their utility in predicting and differentiating intrinsic AKI.This was a prospective observational study conducted in a CCU of a tertiary care university hospital. Patients who exhibited any comorbidity and a kidney stressor were enrolled. Urinary samples of the enrolled patients collected between September 2012 and August 2013 were tested for calprotectin and NGAL. The definition of AKI was based on Kidney Disease Improving Global Outcomes classification. All prospective demographic, clinical, and laboratory data were evaluated as predictors of AKI.A total of 147 adult patients with a mean age of 67 years were investigated. AKI was diagnosed in 71 (50.3%) patients, whereas intrinsic AKI was diagnosed in 43 (60.5%) of them. Multivariate logistic regression analysis revealed urinary calprotectin and serum albumin as independent risk factors for intrinsic AKI. For predicting intrinsic AKI, both urinary NGAL and calprotectin displayed excellent areas under the receiver operating characteristic curve (AUROC) (0.918 and 0.946, respectively). A combination of these markers revealed an AUROC of 0.946.Our result revealed that calprotectin and NGAL had considerable discriminative powers for predicting intrinsic AKI in CCU patients. Accordingly, careful inspection for medication, choice of therapy, and early intervention in patients exhibiting increased biomarker levels might improve the outcomes of kidney injury.
Impact of Dialysate Calcium Concentration on Clinical Outcomes in Incident Hemodialysis Patients.Thursday, October 08, 2015
Kim HW, Kim SH, Kim YO, Jin DC, Song HC, Choi EJ, Kim YL, Kim YS, Kang SW, Kim NH, Yang CW, Kim YK,
Medicine. Oct-2015
The association between dialysate calcium (DCa) concentration and mortality in hemodialysis (HD) patients is controversial. In this study, we evaluated the impact of DCa concentration on mortality in incident HD patient.Incident HD patients were selected from the Clinical Research Center registry-a prospective cohort study on dialysis patients in Korea. Patients were categorized into 3 groups according to the prescribed DCa concentration at the time of enrollment. High DCa was defined as a concentration of 3.5 mEq/L, mid-DCa as 3.0 mEq/L, and low DCa as 2.5 to 2.6 mEq/L. The primary outcome was all-cause mortality and secondary outcomes were cardiovascular or infection-related hospitalization.A total of 1182 patients with incident HD were included. The number of patients in each group was 182 (15.4%) in high DCa group, 701 (59.3%) in the mid-DCa group, and 299 (25.3%) in the low DCa group. The median follow-up period was 16 months. The high DCa group had a significantly higher risk of all-cause mortality compared with the mid-DCa group (hazard ratio [HR] 2.23, 95% confidence interval [CI] 1.28-3.90, P = 0.005) and the low DCa group (HR 3.67, 95% CI 1.78-7.55, P < 0.001) after adjustment for clinical variables. The high DCa group was associated with higher risk of cardiovascular and infection-related hospitalization compared with the low DCa group (HR 3.25, 95% CI 1.53-6.89, P = 0.002; and HR 2.77, 95% CI 1.29-5.94, P = 0.009, respectively). Of these 1182 patients, 163 patients from each group were matched by propensity scores. In the propensity score matched analysis, the high DCa group had a significantly higher risk of all-cause mortality compared with the mid-DCa group (HR 2.52, 95% CI 1.04-6.07, P = 0.04) and the low DCa group (HR 4.25, 95% CI 1.64-11.03, P = 0.003) after adjustment for clinical variables.Our data showed that HD using a high DCa was a significant risk factor for all-cause mortality and cardiovascular or infection-related hospitalization in incident HD patients.
Variants in Vitamin D Binding Protein Gene Are Associated With Gestational Diabetes Mellitus.Thursday, October 08, 2015
Wang Y, Wang O, Li W, Ma L, Ping F, Chen L, Nie M,
Medicine. Oct-2015
To investigate whether single nucleotide polymorphisms (SNPs) within 4 representative genes (VDR, GC, CYP2R1, and CYP24A1) encoding the core proteins involved in vitamin D production, degradation, and ligand-dependent signaling pathway are associated with gestational diabetes mellitus (GDM) in a Chinese population.A total of 1494 pregnant Han Chinese women (692 women with GDM and 802 women with normal glucose served as controls) were recruited through a 2-step approach. Participants were further divided into 2 groups according to body mass index before gestation (pre-BMI) (25 kg/m). Nine SNPs (rs3733359, rs2282679, and rs16847024 in GC, rs2060793 and rs10741657 in CYP2R1, rs2248359 and rs6013897 in CYP24A1, rs11574143 and rs739837 in VDR) were genotyped using TaqMan allelic discrimination assays. The relationships between genotypes/alleles of a single locus as well as haplotypes of each gene and GDM were analyzed.We did not observe a significant difference in genotype frequency of each SNP between cases and controls. However, in the obese subgroup (pre-BMI ≥ 25 kg/m), the risk allele-A of rs3733359 showed an association with increased risk of GDM (OR = 1.739, 95% CI = 1.066-2.837, P = 0.027). The GG-haplotype frequency of rs3733359 and rs2282679 in GC was modestly lower in the GDM group (OR = 0.848, 95% CI = 0.719-0.999, P = 0.048). Rs2060793 and rs10741657 were associated with insulin area under the curve (P = 0.028, P = 0.042, respectively), while rs739837 and rs6013897 demonstrated a correlation with fasting glucose (P = 0.019, P = 0.049, respectively). Additionally, rs2248359 displayed an association with leukocyte counts (B = 0.063 P = 0.033) and rs16847024 was related to high-sensitivity C-reactive protein levels (B = 0.086, P = 0.005).Our results indicate an association between GC variants and GDM, as well as a relation between a subset of loci in CYP2R1, CYP24A1, and VDR and clinical parameters related to GDM. Our findings may provide information for identifying biomarkers for early risk prediction of GDM and the pathways involved in disease progression.
Chromatography/Mass Spectrometry-Based Biomarkers in the Field of Obstructive Sleep Apnea.Thursday, October 08, 2015
Xu H, Zheng X, Jia W, Yin S,
Medicine. Oct-2015
Biomarker assessment is based on quantifying several proteins and metabolites. Recent developments in proteomics and metabolomics have enabled detection of these small molecules in biological samples and exploration of the underlying disease mechanisms in obstructive sleep apnea (OSA). This systemic review was performed to identify biomarkers, which were only detected by chromatography and/or mass spectrometry (MS) and to discuss the role of these biomarkers in the field of OSA.We systemically reviewed relevant articles from PubMed and EMBASE referring to proteins and metabolite profiles of biological samples in patients with OSA. The analytical platforms in this review were focused on chromatography and/or MS.In total, 30 studies evaluating biomarkers in patients with OSA using chromatography and/or MS methods were included. Numerous proteins and metabolites, including lipid profiles, adrenergic/dopaminergic biomarkers and derivatives, amino acids, oxidative stress biomarkers, and other micromolecules were identified in patients with OSA.Applying chromatography and/or MS methods to detect biomarkers helps develop an understanding of OSA mechanisms. More proteomic and metabolomic studies are warranted to develop potential diagnostic and clinical monitoring methods for OSA.
Angiogenic and Inflammatory Vitreous Biomarkers Associated With Increasing Levels of Retinal Ischemia.Thursday, October 08, 2015
Kovacs K, Marra KV, Yu G, Wagley S, Ma J, Teague GC, Nandakumar N, Lashkari K, Arroyo JG,
Investigative ophthalmology & visual science. 1-Oct-2015
While the role of angioproliferative growth factors is well documented in ischemic retinopathy, our study delineates the importance of inflammatory and previously underreported angiogenic proteins. It also demonstrates a significant incremental increase in certain factors with increasing levels of ischemia. Both of these findings may guide the development of future therapies for ischemic retinopathies.
Ranibizumab and Aflibercept: Intraocular Pharmacokinetics and Their Effects on Aqueous VEGF Level in Vitrectomized and Nonvitrectomized Macaque Eyes.Thursday, October 08, 2015
Niwa Y, Kakinoki M, Sawada T, Wang X, Ohji M,
Investigative ophthalmology & visual science. 1-Oct-2015
Intravitreally injected ranibizumab and aflibercept have similar half-lives in aqueous humor and shorter half-lives in vitrectomized eyes. Compared to IVR, IVA suppresses VEGF level for a longer time period.
Inhibition of Noninfectious Uveitis Using Intravenous Administration of Collagen II-Specific Type 1 Regulatory T Cells.Thursday, October 08, 2015
Asnagli H, Jacquin M, Belmonte N, Gertner-Dardenne J, Hubert MF, Sales A, Fall PB, Ginet C, Marchetti I, Ménard F, Lara G, Bobak N, Foussat A,
Investigative ophthalmology & visual science. 1-Oct-2015
These results demonstrate the therapeutic potential of Col-Treg cells as a targeted approach for the treatment of NIU and the feasibility of translating this approach to the human clinical setting.
Synthesis and Biological Evaluation of Novel Epothilone B Side Chain Analogues.Thursday, October 08, 2015
Nicolaou KC, Rhoades D, Wang Y, Totokotsopoulos S, Bai R, Hamel E,
ChemMedChem. 8-Oct-2015
The design, synthesis, and biological evaluation of a series of epothilone analogues with novel side chains equipped with an amino group are described. Their design facilitates potential conjugation to selective drug delivery systems such as antibodies. Their synthesis proceeded efficiently via Stille coupling of a readily available vinyl iodide and heterocyclic stannanes. Cytotoxicity studies and tubulin binding assays revealed two of these analogues to be more potent than epothilones A-D and the anticancer agent ixabepilone, currently in clinical use.
A benchmark for evaluation of algorithms for identification of cellular correlates of clinical outcomes.Thursday, October 08, 2015
Aghaeepour N, Chattopadhyay P, Chikina M, Dhaene T, Van Gassen S, Kursa M, Lambrecht BN, Malek M, Qian Y, Qiu P, Saeys Y, Stanton R, Tong D, Vens C, Walkowiak S, Wang K, Finak G, Gottardo R, Mosmann T, Nolan GP, Scheuermann RH, Brinkman RR,
Cytometry. Part A : the journal of the International Society for Analytical Cytology. 8-Oct-2015
The Flow Cytometry: Critical Assessment of Population Identification Methods (FlowCAP) challenges were established to compare the performance of computational methods for identifying cell populations in multidimensional flow cytometry data. Here we report the results of FlowCAP-IV where algorithms from seven different research groups predicted the time to progression to AIDS among a cohort of 384 HIV+ subjects, using antigen-stimulated peripheral blood mononuclear cell (PBMC) samples analyzed with a 14-color staining panel. Two approaches (FlowReMi.1 and flowDensity-flowType-RchyOptimyx) provided statistically significant predictive value in the blinded test set. Manual validation of submitted results indicated that unbiased analysis of single cell phenotypes could reveal unexpected cell types that correlated with outcomes of interest in high dimensional flow cytometry datasets. © 2015 International Society for Advancement of Cytometry.
The Expression of Cohesin Subunit SA2 Predicts Breast Cancer Survival.Thursday, October 08, 2015
Repo H, Löyttyniemi E, Nykänen M, Lintunen M, Karra H, Pitkänen R, Söderström M, Kuopio T, Kronqvist P,
Applied immunohistochemistry & molecular morphology : AIMM / official publication of the Society for Applied Immunohistochemistry. 1-Oct-2015
Cohesin is one of the main regulators of sister chromatid separation during the metaphase/anaphase transition. It is a multiprotein complex consisting of 4 core subunits, one of those being the SA2 subunit. SA2 plays the final role in dismantling the cohesion complex from the sister chromatids and also functions in DNA double-strand break repair and gene regulation. There is increasing evidence regarding the involvement of both overexpression and underexpression of cohesin in cancer. Here, we present expression patterns of SA2 in different types of human breast tissue, and the prognostic analysis in the material from breast cancer patients with long-term follow-up. SA2 immunoexpression was evaluated in benign, precancerous, and malignant breast tissue, and was classified into low-intensity or high-intensity groups. The DNA content was determined by image cytometry on breast cancer cell imprints. Prognostic analyses were based on 445 breast cancer patients with upto 20 years' follow-up. SA2 immunoexpression was equally high in both benign and precancerous breast tissue. Instead, 72% of the invasive breast cancers showed deficient SA2 expression. These patients were also associated with an unfavorable outcome as indicated by a 1.6-fold risk of breast cancer death (P=0.0208). The majority (75%) of the patients with low SA2 expression were alive 6.0 years after the diagnosis, whereas the majority of the patients with high SA2 expression survived 17.6 years after the diagnosis. No statistically significant association could be detected between SA2 immunoexpression and DNA aneuploidy. Our results and previous literature indicate that decreased SA2 immunoexpression is associated with malignant breast disease and a particularly unfavorable course of disease.
The Potential Prognostic Value of Connexin 43 Expression in Head and Neck Squamous Cell Carcinomas.Thursday, October 08, 2015
Dános K, Brauswetter D, Birtalan E, Pató A, Bencsik G, Krenács T, Peták I, Tamás L,
Applied immunohistochemistry & molecular morphology : AIMM / official publication of the Society for Applied Immunohistochemistry. 1-Oct-2015
Gap juctions are transmembrane communication channels known to be involved in the control of cell proliferation by mediating the exchange of ions and small molecules between cells. Gap junctions are composed of connexon hemichannels made up of 6 connexin proteins, which abnormal expression and functions have been linked to tumor progression and poorer prognosis. Here, we studied the prognostic impact of the most prevalent connexin isotype, connexin 43 (Cx43) in head and neck squamous cell carcinomas (HNSCC). Tissue microarrays made from tumor samples of 90 HNSCC patients were immunostained for Cx43 and cell cycle regulation-related biomarkers including p53, Ki67, p16, aurora A, geminin, and p21 proteins. Scoring and histopathologic evaluation were performed in digital slides. A 4-tier scoring distinguishing the percentage of positively stained tumor cells was used including score 1: <5%, score 2: 6% to 20%, score 3: 21% to 60%, and score 4: >60%. For statistics, Kaplan-Meier curves with log-rank tests, Cox-regression, and Pearson χ/Fisher exact tests were used.A significant positive correlation was found between Cx43 expression and disease-specific survival of patients (P=0.004). The rate of p21 protein-positive tumor cells also proved to be a significant positive prognostic marker (P=0.014). Cx43 levels also showed a significant positive correlation with p53 expression (P=0.036). However, there was no statistical association between Cx43 levels and the rest of the markers tested neither with T, N, or M stage.In conclusion, our data suggest that reduced Cx43 expression and low p21 protein levels may have a significant negative impact on HNSCC prognosis.
Treatment with 5-Aza-2'-Deoxycytidine Induces Expression of NY-ESO-1 and Facilitates Cytotoxic T Lymphocyte-Mediated Tumor Cell Killing.Thursday, October 08, 2015
Klar AS, Gopinadh J, Kleber S, Wadle A, Renner C,
PloS one. 1-10-2015
These results indicate that NY-ESO-1 directed immunotherapy with specific CAR T cells might benefit from concomitant DAC treatment.
Immune checkpoint inhibitors with radiotherapy and locoregional treatment: synergism and potential clinical implications.Thursday, October 08, 2015
Esposito A, Criscitiello C, Curigliano G,
Current opinion in oncology. Nov-2015
Radiation therapy is confirmed to be a sensitizer of tumors to immune checkpoint inhibitors in clinical trials, and its application will be easy to implement and widespread. Conversely, many issues need to be addressed before radiotherapy can become such a valid immunogenic tool. An area of increasing importance will be the development of suitable biomarkers that will be able to reliably assess 'immunogenic tumor cell death', immune effector stimulation, and adaptive immunity. Such an immune profile of biomarkers will aid in searching for an optimal combination of radiotherapy and immunomodulation and allows patient selection and response prediction.
Design, Synthesis, and Photophysical Properties of Pyrroloquinoline-Based Compounds Showing Strong Blue Fluorescence as Potential Dyes for Biomedical Applications.Thursday, October 08, 2015
Carta D, Balasso A, Caliceti P, Ferlin MG,
ChemMedChem. 8-Oct-2015
A small library of 3-ethylpyrrolo[3,2-f]quinoline derivatives was synthesized to identify a novel class of dyes for use in biological studies. According to the spectroscopic analyses performed to evaluate the fluorimetric parameters of quantum yield and brightness, 7-methyl- and 6,7-dimethylpyrroloquinolin(9)one derivatives were found to be the best blue luminescent dyes for biological applications. To enhance the luminescence profiles and to obtain probes that could be conjugated to functional groups of supramolecular drug delivery systems, these compounds were further modified at position 3 to obtain 3-heptanoic acid and 3-aminohexylpyrroloquinolin(9)one methylated derivatives. The most brilliant 6,7-dimethyl-3-aminohexylpyrroloquinolinone hydrochloride was conjugated to pullulan, a biocompatible polysaccharide used to produce colloidal systems for drug delivery. Comparative studies showed that this compound can be properly exploited as a blue fluorescent label in biological investigations, namely cell trafficking and pharmacokinetics/biodistribution studies. These molecules possess higher fluorescence efficiency than commercial dyes in biological media, making them suitable alternatives to commercially available products in current use.
Circulating microRNA-200 Family as Diagnostic Marker in Hepatocellular Carcinoma.Thursday, October 08, 2015
Dhayat SA, Hüsing A, Senninger N, Schmidt HH, Haier J, Wolters H, Kabar I,
PloS one. 8-10-2015
Circulating microRNA-200 family members are significantly deregulated in patients with HCC and liver cirrhosis. Further studies are necessary to confirm the diagnostic value of the microRNA-200 family as accurate serum marker for cirrhosis-associated HCC.
Transcriptomic Signatures of Auger Electron Radioimmunotherapy Using Nuclear Targeting (111)In-Trastuzumab for Potential Combination Therapies.Thursday, October 08, 2015
Li HK, Morokoshi Y, Daino K, Furukawa T, Kamada T, Saga T, Hasegawa S,
Cancer biotherapy & radiopharmaceuticals. Oct-2015
(111)In-labeled trastuzumab modified with nuclear localizing signal (NLS) peptides ((111)In-trastuzumab-NLS) efficiently delivers an Auger electron (AE) emitter (111)In into the cell nucleus and is thus a promising radiopharmaceutical in AE radioimmunotherapy (AE-RIT) for targeted killing of HER2-positive cancer. However, further improvement of its therapeutic efficacy is required. In this study, the authors show a transcriptomic approach to identify potential targets for enhancing the cytotoxic effects of (111)In-trastuzumab-NLS. They generated two types of (111)In-trastuzumab-NLS harboring different numbers of NLS peptides, (111)In-trastuzumab-NLS-S and -L. These radioimmunoconjugates (230 and 460 kBq) showed a significant higher cytotoxicity to SKBR3 human breast cancer cells overexpressing HER2 compared to (111)In-trastuzumab. Microarray analysis revealed that NF-kB-related genes (38 genes) were significantly changed in transcription by (111)In trastuzumab-NLS-L (230 kBq) treatment. Quantitative reverse transcription polymerase chain reaction confirmed the microarray data by showing transcriptional alternation of selected NF-κB target genes in cells treated with (111)In-trastuzumab-NLS-L. Interestingly, bortezomib, a drug known as a NF-κB modulator, significantly enhanced the cytotoxicity of (111)In-trastuzumab-NLS-L in SKBR3 cells. Taken together, the transcriptome data suggest the possibility that the modulation of NF-kB signaling activity is a molecular signature of (111)In-trastuzumab-NLS and coadministration of bortezomib may be efficacious in enhancement of AE-RIT with (111)In-trastuzumab-NLS.
Longitudinal, 3D In Vivo Imaging of Collagen Remodeling in Murine Hypertrophic Scars using Polarization-sensitive Optical Frequency Domain Imaging.Thursday, October 08, 2015
Lo WC, Villiger M, Golberg A, Broelsch GF, Khan S, Lian CG, Austen WG, Yarmush M, Bouma BE,
The Journal of investigative dermatology. 8-Oct-2015
Hypertrophic scars (HTS), frequently seen after traumatic injuries and surgery, remain a major clinical challenge due to the limited success of existing therapies. A significant obstacle to understanding HTS etiology is the lack of tools to monitor scar remodeling longitudinally and non-invasively. We present an in vivo, label-free technique using polarization-sensitive optical frequency domain imaging (PS-OFDI) for the 3D, longitudinal assessment of collagen remodeling in murine HTS. In this study, HTS was induced with a mechanical tension device for 4 to 10 days on incisional wounds and imaged up to one month after device removal; an excisional HTS model was also imaged at 6 months after injury to investigate deeper and more mature scars. We showed that local retardation (LR) and degree of polarization (DOP) provide a robust signature for HTS. Compared to normal skin with heterogeneous LR and low DOP, HTS was characterized by an initially low LR, which increased as collagen fibers remodeled, and a persistently high DOP. This study demonstrates that PS-OFDI offers a powerful tool to gain significant biological insights into HTS remodeling by enabling longitudinal assessment of collagen in vivo, which is critical to elucidating HTS etiology and developing more effective HTS therapies.Journal of Investigative Dermatology accepted article preview online, 08 October 2015. doi:10.1038/jid.2015.399.
Mitochondrial DNA Copy Number in Egyptian Patients with Hepatitis C Virus-Related Hepatocellular Carcinoma.Thursday, October 08, 2015
Hashad DI, Elyamany AS, Salem PE,
Genetic testing and molecular biomarkers. 8-Oct-2015
mtDNA content analysis could serve as a noninvasive molecular biomarker that reflects tumor burden in HCV-HCC cases and could be used as a predictor of HCC risk in patients of HCV-cirrhosis. In addition, the nonsignificant difference of mtDNA level between HCV-cirrhosis patients and healthy controls could eliminate the gray zone created by the use of alpha-fetoprotein in some cirrhotic patients.
Biomarkers to predict opioid analgesia, a most difficult conundrum: Commentary on a paper by Gram et al.Thursday, October 08, 2015
Plaghki L,
European journal of pain (London, England). Nov-2015
Monodispersity of magnetic immuno-nanoprobes enhances the detection sensitivity of low abundance biomarkers in one drop of serum.Thursday, October 08, 2015
Capangpangan RY, Dela Rosa MA, Obena RP, Chou YJ, Tzou DL, Shih SJ, Chiang MH, Lin CC, Chen YJ,
The Analyst. 8-Oct-2015
To enhance the detection sensitivity of target clinical protein biomarkers, a simple and rapid nanoprobe-based immuno-affinity mass spectrometry assay employing biocompatible monodisperse magnetic nanoparticles (MNPs) is reported herein. The MNPs were synthesized via a streamlined protocol that includes (a) fabrication of core MNPs using the thermal decomposition method to minimize aggregation, (b) surface protection by gold coating (MNP@Au) and surfactant coating using MNP@IGEPAL to improve hydrophilicity, and lastly, (c) oriented functionalization of antibodies to maximize immuno-affinity. The enrichment performances of the monodisperse MNPs for the C-reactive protein (CRP) serum biomarker were then evaluated and compared with aggregated magnetic nanoparticles synthesized from the conventional co-precipitation method (MNPCP). The detection sensitivity for CRP at an extremely low amount of serum sample (1 μL) was enhanced ∼19- and ∼15-fold when monodisperse MNP@Au and MNP@IGEPAL, respectively, were used. Furthermore, the detection sensitivity of CRP by this approach (1 ng mL(-1), S/N = 3) provided a 1000-fold sensitivity enhancement to the clinical cut-off (1 μg mL(-1)) of CRP. We supposed that these observed improvements are due to the enhanced nanoparticle dispersibility and size uniformity which eliminated completely other non-specific binding of high-abundance serum proteins. Most interestingly, the enrichment efficiency correlates more closely with the MNP dispersibility than the ligand density. Our investigation revealed the critical role of MNP dispersibility, as well as provided mechanistic insight into its impact on immunoaffinity enrichment and detection of CRP in one drop of serum sample. This strategy offers an essential advantage over the other methods by providing a simple and facile biofunctionalization protocol while maintaining excellent solvent dispersibility of MNPs.
Sulfonamide derivative targeting carbonic anhydrase IX as a nuclear imaging probe for colorectal cancer detection in vivo.Thursday, October 08, 2015
Guan SS, Cheng CC, Ho AS, Wang CC, Luo TY, Liao TZ, Chang J, Wu CT, Liu SH,
Oncotarget. 5-Oct-2015
Hypoxic microenvironment is a common situation in solid tumors. Carbonic anhydrase IX (CA9) is one of the reliable cellular biomarkers of hypoxia. The role of CA9 in colorectal cancer (CRC) remains to be clarified. CA9 inhibitor such as sulfonamides is known to block CA9 activation and reduce tumor growth consequently. Here, we aimed to investigate the CA9 expression in serum and tumor from different stages of CRC patients and utilize sulfonamide derivative with indium-111 labeling as a probe for CRC nuclear imaging detection in vivo. The serum CA9 was correlated with the tumor CA9 levels in different stages of CRC patients. Hypoxia increased cell viability and CA9 expression in colorectal cancer HCT-15 cells. Sulfonamide derivative 5-(2-aminoethyl)thiophene-2-sulfonamide (ATS) could bind with CA9 in vitro under hypoxia. Moreover, tumor tissues in HCT-15-induced xenograft mice possessed higher hypoxic fluorescence signal as compared with other organs. We also found that the radioisotope signal of indium-111 labeled ATS, which was utilized for CRC detection in HCT-15-induced xenograft mice, was markedly enhanced in tumors as compared with non-ATS control. Taken together, these findings suggest that CA9 is a potential hypoxic CRC biomarker and measurement of serum CA9 can be as a potential tool for diagnosing CA9 expressions in CRC clinical practice. The radioisotope-labeled sulfonamide derivative (ATS) may be useful to apply in CRC patients for nuclear medicine imaging.
Expression profile of long non-coding RNAs in pancreatic cancer and their clinical significance as biomarkers.Thursday, October 08, 2015
Wang Y, Li Z, Zheng S, Zhou Y, Zhao L, Ye H, Zhao X, Gao W, Fu Z, Zhou Q, Liu Y, Chen R,
Oncotarget. 2-Oct-2015
Long non-coding RNAs (lncRNAs) have shown great potential as powerful and non-invasive tumor markers. However, little is known about their value as biomarkers in pancreatic cancer (PC). We applied an Arraystar Human LncRNA Microarray which targeting 7419 lncRNAs to determine the lncRNA expression profile in PC and to screen the potential biomarkers. The most increased lncRNAs in PC tissues were HOTTIP-005, XLOC_006390, and RP11-567G11.1. Increased HOTTIP-005 and RP11-567G11.1 expression were poor prognostic factors for patients with PC (n = 144, p < 0.0001). The expression patterns of HOTTIP splice variants in PC were also detected. HOTTIP-005 and HOTTIP-001 were the first and second most increased HOTTIP splice variants, respectively. Plasma HDRF and RDRF (HOTTIP-005 and RP11-567G11.1 derived RNA fragments in plasma/serum) were present in stable form. Their levels were significantly increased in the patients with PC as compared to the healthy controls (n = 127 and 122 respectively, p < 0.0001) and the high levels were derived from PC. HDRF and RDRF levels are promising indicators for distinguishing patients with PC from those without PC. This study identified HOTTIP-005 and RP11-567G11.1 and their plasma fragments with the potential to be used as prognostic and diagnostic biomarkers of PC. Further large-scale prospective studies are needed to confirm our findings.
The Association Between Periodontal Inflammation and Labor Triggers Elevated Cytokine Levels in Pre-Term Birth: A Cross-Sectional Study.Thursday, October 08, 2015
Perunovic ND, Rakic MM, Nikolic LI, Jankovic SM, Aleksic ZM, Plecas DV, Madianos PN, Cakic SS,
Journal of periodontology. 8-Oct-2015
PTB women demonstrated worse periodontal parameters and significantly increased GCF levels of IL-6 and PGE2 compared to FTB. Based on significant correlation between serum PGE2 and PD, CAL and GCF TNFα in PTB it seems that periodontitis might impact overall increase of labor triggers hence contribute to the pre-term labor onset.
Comparative Analysis of Calcium-Binding Myeloid-Related Protein-8/14 in Saliva and Serum of Patients With Periodontitis and Healthy Individuals.Thursday, October 08, 2015
Haririan H, Andrukhov O, Pablik E, Neuhofer M, Moritz A, Rausch-Fan X,
Journal of periodontology. 8-Oct-2015
MRP-8/14 in saliva might be a potential diagnostic parameter for periodontal disease.
Predicting functional regulatory SNPs in the human antimicrobial peptide genes DEFB1 and CAMP in tuberculosis and HIV/AIDS.Thursday, October 08, 2015
Flores Saiffe Farías A, Jaime Herrera López E, Moreno Vázquez CJ, Li W, Prado Montes de Oca E,
Computational biology and chemistry. 9-Sep-2015
Single nucleotide polymorphisms (SNPs) in transcription factor binding sites (TFBSs) within gene promoter region or enhancers can modify the transcription rate of genes related to complex diseases. These SNPs can be called regulatory SNPs (rSNPs). Data compiled from recent projects, such as the 1000 Genomes Project and ENCODE, has revealed essential information used to perform in silico prediction of the molecular and biological repercussions of SNPs within TFBS. However, most of these studies are very limited, as they only analyze SNPs in coding regions or when applied to promoters, and do not integrate essential biological data like TFBSs, expression profiles, pathway analysis, homotypic redundancy (number of TFBSs for the same TF in a region), chromatin accessibility and others, which could lead to a more accurate prediction. Our aim was to integrate different data in a biologically coherent method to analyze the proximal promoter regions of two antimicrobial peptide genes, DEFB1 and CAMP, that are associated with tuberculosis (TB) and HIV/AIDS. We predicted SNPs within the promoter regions that are more likely to interact with transcription factors (TFs). We also assessed the impact of homotypic redundancy using a novel approach called the homotypic redundancy weight factor (HWF). Our results identified 10 SNPs, which putatively modify the binding affinity of 24 TFs previously identified as related to TB and HIV/AIDS expression profiles (e.g. KLF5, CEBPA and NFKB1 for TB; FOXP2, BRCA1, CEBPB, CREB1, EBF1 and ZNF354C for HIV/AIDS; and RUNX2, HIF1A, JUN/AP-1, NR4A2, EGR1 for both diseases). Validating with the OregAnno database and cell-specific functional/non functional SNPs from additional 13 genes, our algorithm performed 53% sensitivity and 84.6% specificity to detect functional rSNPs using the DNAseI-HUP database. We are proposing our algorithm as a novel in silico method to detect true functional rSNPs in antimicrobial peptide genes. With further improvement, this novel method could be applied to other promoters in order to design probes and to discover new drug targets for complex diseases.
Deletion of G-protein coupled receptor 55 promotes obesity by reducing physical activity.Thursday, October 08, 2015
Meadows A, Lee JH, Wu CS, Wei Q, Pradhan G, Yafi M, Lu HC, Sun Y,
International journal of obesity (2005). 8-Oct-2015
Background/objectivesCannabinoid receptor 1 (CB1) is the best characterized cannabinoid receptor, and CB1 antagonists are used in clinical trials to treat obesity. Due to wide range of CB1 functions, the side effects of CB1 antagonists pose serious concerns. G protein-coupled receptor 55 (GPR55) is an atypical cannabinoid receptor, and its pharmacology and functions are distinct from CB1. GPR55 regulates neuropathic pain, gut, bone, immune functions, and motor coordination. GPR55 is expressed in various brain regions and peripheral tissues. However, the roles of GPR55 in energy- and glucose-homeostasis are unknown. Here we have investigated the roles of GPR55 in energy balance and insulin sensitivity using GPR55-null mice (GPR55(-/-)).MethodsBody composition of the mice was measured by EcoMRI. Food intake, feeding behavior, energy expenditure, and physical activity of GPR55(-/-) mice were determined by indirect calorimetry. Muscle function was assessed by forced treadmill running test. Insulin sensitivity was evaluated by glucose and insulin tolerance tests. Adipose inflammation was assessed by flow cytometry analysis of adipose tissue macrophages. The expression of inflammatory markers in adipose tissues and orexigenic/anorexigenic peptides in hypothalamus were also analyzed by real-time PCR.ResultsGPR55(-/-) mice had normal total energy intake and feeding pattern (i.e. no changes in meal size, meal number, or feeding frequency). Intriguingly, while adult GPR55(-/-) mice only showed a modest increase in overall body weight, they exhibited significantly increased fat-mass and insulin resistance. The spontaneous locomotor activity of GPR55(-/-) mice was dramatically decreased, while resting metabolic rate and non-shivering thermogenesis were unchanged. Moreover, GPR55(-/-) mice exhibited significantly decreased voluntary physical activity, showing reduced running distance on the running wheels, while muscle function appeared to be normal.ConclusionsGPR55 plays an important role in energy homeostasis. GPR55 ablation increases adiposity and insulin resistance by selectively decreasing physical activity, but not by altering feeding behavior as CB1.International Journal of Obesity accepted article preview online, 08 October 2015. doi:10.1038/ijo.2015.209.
Distribution of Leptospira interrogans by Multispacer Sequence Typing in Urban Norway Rats (Rattus norvegicus): A Survey in France in 2011-2013.Thursday, October 08, 2015
Ayral F, Zilber AL, Bicout DJ, Kodjo A, Artois M, Djelouadji Z,
PloS one. 08-10-2015
This study demonstrated that MST could be used for the purpose of field studies, either on culture isolates or on DNA extracted from kidneys and urine, to distinguish among L. interrogans isolates in rats. MST could thus be used to monitor their distributions in urban rats from the same city, thereby providing new knowledge that could be applied to explore the circulation of L. interrogans infection in rat colonies. Because the strains are related to those previously found in humans, this application of MST could aid in the source tracking of human leptospirosis, and the findings would be relevant for public health purposes according to the One Health principle.
Novel Cell Preservation Technique to Extend Bovine In Vitro White Blood Cell Viability.Thursday, October 08, 2015
Laurin EL, McKenna SL, Sanchez J, Bach H, Rodriguez-Lecompte JC, Chaffer M, Keefe GP,
PloS one. 8-10-2015
Although cell-mediated immunity based diagnostics can be integral assays for early detection of various diseases of dairy cows, processing of blood samples for these tests is time-sensitive, often within 24 hours of collection, to maintain white blood cell viability. Therefore, to improve utility and practicality of such assays, the objective of this study was to assess the use of a novel white blood cell preservation technology in whole bovine blood. Blood samples from ten healthy cows were each divided into an unpreserved control sample and a test sample preserved with commercially-available cell transport medium. Samples were maintained at room temperature and stimulated with the mitogens pokeweed and concanavalinA, as well as with interleukin-12 p40. Stimulation was completed on days 1, 5, and 8 post-sampling. Viability of white blood cells was assessed through interferon gamma production determined with a commercial enzyme linked immunosorbent assay. In addition, mononuclear cell viability was assessed with propidium iodide flow cytometry. Greater interferon gamma production was observed on days 5 and 8 post-collection in preserved samples, with both pokeweed and concanavalinA stimulating positive interferon gamma production on day 5 post-collection. A greater proportion of the amount of interferon gamma produced on day 1 continued to be produced on days 5 and 8 post-collection with concanavalinA stimulation (with or without interleukin 12) as compared to pokeweed stimulation. Additionally, viable mononuclear cells were still present at eight days post-collection, with a higher mean proportion detected at days 5 and 8 in all stimulated preserved samples. This practical and simple method to extend in vitro white blood cell viability could benefit the efficient utilization of cell-based blood tests in ruminants.
A systematic review of biomarkers in the diagnosis of infective endocarditis.Thursday, October 08, 2015
Snipsøyr MG, Ludvigsen M, Petersen E, Wiggers H, Honoré B,
International journal of cardiology. 21-Sep-2015
Timely diagnosis of bacterial infective endocarditis (IE) is crucial, as mortality remains high in this severe bacterial infection, currently without any distinct biological markers. Our goal was to evaluate potential diagnostic biomarkers by reviewing current literature. The MEDLINE, Embase and Scopus databases were searched for articles published from 1980 through June 2015 restricted to English, Norwegian, Danish and Swedish. Eighteen studies qualified, providing a review of the most promising candidates for future studies. Several studies are inconclusive, since they are characterized by using improper control groups. Patients with IE have bacteremia, and control groups should therefore be patients with bacteremia without IE. Based on current research, N-terminal-pro-B-type natriuretic peptide (NT-proBNP) alone or in combination with Cystatin C (Cys C), lipopolysaccharide-binding protein (LBP), troponins, aquaporin-9 (AQP9), S100 calcium binding protein A11 (S100A11), E-selectin (CD62E) and VCAM-1 (CD54) and interleukin-6 (IL-6) are potential biomarkers for future studies.
Fluorescent DNA-protected Silver Nanoclusters for Ligand-HIV RNA Interaction Assay.Thursday, October 08, 2015
Qi L, Huo Y, Wang H, Zhang J, Dang FQ, Zhang ZQ,
Analytical chemistry. 8-Oct-2015
Studying ligand-biomacromolecule interactions provides opportunities for creating new compounds that can efficiently regulate specific biological processes. Ribonucleic acid (RNA) molecules have become attractive drug targets since the discovery of their roles in modulating gene expression, while only a limited number of studies have investigated interactions between ligands and functional RNA molecules, especially those based on nanotechnology. DNA-protected silver nanoclusters (AgNCs) was used to investigate ligand-RNA interactions for the first time in this study. The anthracycline anticancer drug mitoxantrone (MTX) was found to quench the fluorescence of AgNCs. After adding human immunodeficiency virus trans-activation responsive region (TAR) RNA or Rev-response element (RRE) RNA to AgNCs-MTX mixtures, the fluorescence of the AgNCs recovered due to interactions between MTX with RNAs. The binding constants and number of binding sites of MTX to TAR and RRE RNA were determined through theoretical calculations. MTX-RNA interactions were further confirmed in fluorescence polarization and mass spectrometry experiments. The mechanism of MTX-based fluorescence quenching of the AgNCs was also explored. This study provides a new strategy for ligand-RNA binding interaction assay.
Editorial: Stem Cell Engineering.Thursday, October 08, 2015
Cabral JM, Palecek SP,
Biotechnology journal. Oct-2015
In recent years, the promise of stem cells as tools for basic research, in vitro diagnostics, and in vivo therapeutics is increasingly being realized. This Special issue of Biotechnology Journal explores recent advances in the emerging field of stem cell engineering, with a focus on applying engineering approaches to understanding stem cell biology and enabling translation of stem cells to commercial and clinical products.
[Peripheral Th17 cell frequencies predict postoperative complications in patients with hepatitis B virus-related liver cirrhosis following liver transplantation].Thursday, October 08, 2015
Wang Y, Li XX, Cao JL, Gao QJ, Dou J, Nan YM,
Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology. 20-Aug-2015
Th17/CD4+T cell level in peripheral blood might be a useful marker for risk assessment and monitoring of OLT postoperative complications, such as acute rejection and postoperative infection, in the early stage, and might help to improve patient prognosis by allowing for timely application of anti-rejection and antibacterial agents.
[Expression of NKG2D/MIC in natural killer cell subsets of patients with primary biliary cirrhosis].Thursday, October 08, 2015
Tang YM, Bao WM, Yang JH, Ding Q,
Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology. 20-Aug-2015
PBC patients have lower levels of NK cells in peripheral blood than their healthy counterparts. PBC patients also have higher levels of the CD56+ NK cell subset and cells with surface expression of the activated NKG2D receptor. It appears that PBC patients have a greater level of CD14+MICA+ peripheral blood mononuclear cells. NK cells may be affected by the PBC-related monocytes and participate in disease pathogenesis through immune regulation.
CD44-mediated activation of α5β1-integrin, cortactin and paxillin signaling underpins adhesion of basal-like breast cancer cells to endothelium and Fibronectin-enriched matrices.Thursday, October 08, 2015
McFarlane S, McFarlane C, Montgomery N, Hill A, Waugh DJ,
Oncotarget. 2-Oct-2015
CD44 expression is elevated in basal-like breast cancer (BLBC) tissue, and correlates with increased efficiency of distant metastasis in patients and experimental models. We sought to characterize mechanisms underpinning CD44-promoted adhesion of BLBC cells to vascular endothelial monolayers and extracellular matrix (ECM) substrates. Stimulation with hyaluronan (HA), the native ligand for CD44, increased expression and activation of β1-integrin receptors, and increased α5-integrin subunit expression. Adhesion assays confirmed that CD44-signalling potentiated BLBC cell adhesion to endothelium and Fibronectin in an α5B1-integrin-dependent mechanism. Co-immunoprecipitation experiments confirmed HA-promoted association of CD44 with talin and the β1-integrin chain in BLBC cells. Knockdown of talin inhibited CD44 complexing with β1-integrin and repressed HA-induced, CD44-mediated activation of β1-integrin receptors. Immunoblotting confirmed that HA induced rapid phosphorylation of cortactin and paxillin, through a CD44-dependent and β1-integrin-dependent mechanism. Knockdown of CD44, cortactin or paxillin independently attenuated the adhesion of BL-BCa cells to endothelial monolayers and Fibronectin. Accordingly, we conclude that CD44 induced, integrin-mediated signaling not only underpins efficient adhesion of BLBC cells to BMECs to facilitate extravasation but initiates their adhesion to Fibronectin, enabling penetrant cancer cells to adhere more efficiently to underlying Fibronectin-enriched matrix present within the metastatic niche.
Nanotherapeutics shielded with a pH responsive polymeric layer.Thursday, October 08, 2015
Kostka L, Šubr V, Laga R, Chytil P, Ulbrich K, Seymour LW, Etrych T,
Physiological research / Academia Scientiarum Bohemoslovaca. 8-Oct-2015
Efficient intravenous delivery is the greatest single hurdle, with most nanotherapeutics frequently found to be unstable in the harsh conditions of the bloodstream. In the case of nanotherapeutics for gene delivery, viral vectors are often avidly recognized by both the innate and the adaptive immune systems. So, most modern delivery systems have benefited from being coated with hydrophilic polymers. Self-assembling delivery systems can achieve both steric and lateral stabilization following surface coating, endowing them with much improved systemic circulation properties and better access to disseminated targets; similarly, gene delivery viral vectors can be 'stealthed' and their physical properties modulated by surface coating. Polymers that start degrading under acidic conditions are increasingly investigated as a pathway to trigger the release of drugs or genes once the carrier reaches a slightly acidic tumor environment or after the carrier has been taken up by cells, resulting in the localization of the polymer in acidic endosomes and lysosomes. Advances in the design of acid-degradable drug and gene delivery systems have been focused and discussed in this article with stress placed on HPMA-based copolymers. We designed a system that is able to "throw away" the polymer coat after successful transport of the vector into a target cell. Initial biological studies were performed and it was demonstrated that this principle is applicable for real adenoviral vectors. It was shown that the transfection ability of coated virus at pH 7.4 is 75 times lower then transfection at pH 5.4.
Activin a signaling regulates cell invasion and proliferation in esophageal adenocarcinoma.Thursday, October 08, 2015
Taylor C, Loomans HA, Le Bras GF, Koumangoye RB, Romero-Morales AI, Quast LL, Zaika AI, El-Rifai W, Andl T, Andl CD,
Oncotarget. 6-Oct-2015
TGFβ signaling has been implicated in the metaplasia from squamous epithelia to Barrett's esophagus and, ultimately, esophageal adenocarcinoma. The role of the family member Activin A in Barrett's tumorigenesis is less well established. As tumorigenesis is influenced by factors in the tumor microenvironment, such as fibroblasts and the extracellular matrix, we aimed to determine if epithelial cell-derived Activin affects initiation and progression differently than Activin signaling stimulation from a mimicked stromal source. Using Barrett's esophagus cells, CPB, and the esophageal adenocarcinoma cell lines OE33 and FLO-1, we showed that Activin reduces colony formation only in CPB cells. Epithelial cell overexpression of Activin increased cell migration and invasion in Boyden chamber assays in CPB and FLO-1 cells, which exhibited mesenchymal features such as the expression of the CD44 standard form, vimentin, and MT1-MMP. When grown in organotypic reconstructs, OE33 cells expressed E-cadherin and Keratin 8. As mesenchymal characteristics have been associated with the acquisition of stem cell-like features, we analyzed the expression and localization of SOX9, showing nuclear localization of SOX9 in esophageal CPB and FLO-1 cells.In conclusion, we show a role for autocrine Activin signaling in the regulation of colony formation, cell migration and invasion in Barrett's tumorigenesis.
miRNA profiling in gastrointestinal stromal tumors: implication as diagnostic and prognostic markers.Thursday, October 08, 2015
Nannini M, Ravegnini G, Angelini S, Astolfi A, Biasco G, Pantaleo MA,
Epigenomics. 8-Oct-2015
MicroRNAs are a class of short noncoding RNAs, that play a relevant role in multiple biological processes, such as differentiation, proliferation and apoptosis. Gastrointestinal stromal tumors (GIST) are considered as a paradigm of molecular biology in solid tumors worldwide, and after the discovery of specific alterations in the KIT and PDGFRA genes, they have emerged from anonymity to become a model for targeted therapy. Epigenetics have an emerging and relevant role in different steps of GIST biology such as tumorigenesis, disease progression, prognosis and drug resistance. The aim of the present review was to summarize the current evidence about the role of microRNAs in GIST, including their potential application as well as their limits.
Biomarkers of cellular apoptosis and necrosis in donor myocardium are not predictive of primary graft dysfunction.Thursday, October 08, 2015
Szarszoi O, Besik J, Smetana M, Maly J, Urban M, Maluskova J, Lodererova A, Hoskova L, Tucanova Z, Pirk J, Netuka I,
Physiological research / Academia Scientiarum Bohemoslovaca. 8-Oct-2015
Primary graft dysfunction (PGD) is a life-threatening complication among heart transplant recipients and a major cause of early mortality. Although the pathogenesis of PGD is still unclear, ischemia/reperfusion injury has been identified as a predominant factor. Both necrosis and apoptosis contribute to the loss of cardiomyocytes during ischemia/reperfusion injury, and this loss of cells can ultimately lead to PGD. The aim of our prospective study was to find out whether cell death, necrosis and apoptosis markers present in the donor myocardium can predict PGD. The prospective study involved 64 consecutive patients who underwent orthotopic heart transplantation at our institute between September 2010 and January 2013. High-sensitive cardiac troponin T (hs-cTnT) as a marker of minor myocardial necrosis was detected from arterial blood samples before the donor's pericardium was opened. Apoptosis (caspase-3, active + pro-caspase-3, bcl-2, TUNEL) was assessed from bioptic samples taken from the right ventricle prior graft harvesting. In our study, 14 % of transplant recipients developed PGD classified according to the standardized definition proposed by the ISHLT Working Group. We did not find differences between the groups in regard to hs-cTnT serum levels. The mean hs-cTnT value for the PGD group was 57.4+/-22.9 ng/l, compared to 68.4+/-10.8 ng/l in the group without PGD. The presence and severity of apoptosis in grafted hearts did not differ between grafts without PGD and hearts that subsequently developed PGD. In conclusion, our findings did not demonstrate any association between measured myocardial cell death, necrosis or apoptosis markers in donor myocardium and PGD in allograft recipients. More detailed investigations of cell death signaling pathways in transplanted hearts are required.
Enzymatic hydrolysis does not reduce the biological reactivity of soybean proteins for all allergic subjects.Thursday, October 08, 2015
Panda R, Tetteh AO, Pramod SN, Goodman RE,
Journal of agricultural and food chemistry. 8-Oct-2015
Many soybean protein products are processed by enzymatic hydrolysis to attain desirable functional properties or in some cases to reduce the allergenicity. However, few studies have investigated the effects of enzymatic hydrolysis on the allergenicity of soybean products. In this study the allergenicity of soybean protein isolates (SPI) hydrolyzed by Alcalase, trypsin, chymotrypsin, bromelain or papain was evaluated by IgE immunoblots using eight soybean allergic patient sera. The biological relevance of IgE binding was evaluated by a functional assay using a humanized rat basophilic leukemia (hRBL) cell line. Results indicated that hydrolysis of SPI by the enzymes does not make them less allergenic and hydrolysis by chymotrypsin or bromelain has the potential to increase the allergenicity of SPI. Two dimensional (2D) immunoblot and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of the chymotrypsin hydrolyzed samples indicated fragments of β-conglycinin protein are responsible for apparent higher allergenic potential of digested SPI.
Altered Innate Immune and Glial Cell Responses to Inflammatory Stimuli in Amyloid Precursor Protein Knockout Mice.Thursday, October 08, 2015
Carrano A, Das P,
PloS one. 8-10-2015
Amyloid precursor protein (APP) and its cleaved products have been reported to have important functions in CNS health, including in memory and synapse formation, cell survival and neuroprotection. Furthermore APP and its cleaved products have been shown to be transiently increased in response to various CNS stressors, suggesting a role in response to acute cellular injury. In an attempt to further understand the function of APP in response to CNS injury, we have used intracranial LPS injection as an inflammatory injury model in APP knock out mice (APPKO). Our data show that innate immune responses to LPS injection is significantly blunted in APPKO mice compared to APP sufficient wild type (BL6) mice. Morphologically, glial cells in APPKO mice appear less reactive, with shorter ramified processes and smaller cell bodies in response to LPS. Additionally, quantitative RT-PCR analysis for several glia markers and innate immune cytokine levels (e.g. TNFα, IL-6, IL-1β and IL-10) showed significantly reduced expression levels in LPS injected APPKO mice. In vitro cell culture assays confirmed this attenuated response to LPS stimulation by primary microglial cells isolated from APPKO mice. Our data suggests that APP full length protein and/or its cleaved products are necessary to mount a complete and effective innate immune cell response to inflammatory injury.
Calcium Ion Flow Permeates Cells through SOCs to Promote Cathode-Directed Galvanotaxis.Thursday, October 08, 2015
Guo L, Xu C, Li D, Zheng X, Tang J, Bu J, Sun H, Yang Z, Sun W, Yu X,
PloS one. 8-10-2015
Sensing and responding to endogenous electrical fields are important abilities for cells engaged in processes such as embryogenesis, regeneration and wound healing. Many types of cultured cells have been induced to migrate directionally within electrical fields in vitro using a process known as galvanotaxis. The underlying mechanism by which cells sense electrical fields is unknown. In this study, we assembled a polydimethylsiloxane (PDMS) galvanotaxis system and found that mouse fibroblasts and human prostate cancer PC3 cells migrated to the cathode. By comparing the effects of a pulsed direct current, a constant direct current and an anion-exchange membrane on the directed migration of mouse fibroblasts, we found that these cells responded to the ionic flow in the electrical fields. Taken together, the observed effects of the calcium content of the medium, the function of the store-operated calcium channels (SOCs) and the intracellular calcium content on galvanotaxis indicated that calcium ionic flow from the anode to the cathode within the culture medium permeated the cells through SOCs at the drift velocity, promoting migration toward the cathode. The RTK-PI3K pathway was involved in this process, but the ROCK and MAPK pathways were not. PC3 cells and mouse fibroblasts utilized the same mechanism of galvanotaxis. Together, these results indicated that the signaling pathway responsible for cathode-directed cellular galvanotaxis involved calcium ionic flow from the anode to the cathode within the culture medium, which permeated the cells through SOCs, causing cytoskeletal reorganization via PI3K signaling.
Functional Diversification of Motor Neuron-specific Isl1 Enhancers during Evolution.Thursday, October 08, 2015
Kim N, Park C, Jeong Y, Song MR,
PLoS genetics. Oct-2015
Functional diversification of motor neurons has occurred in order to selectively control the movements of different body parts including head, trunk and limbs. Here we report that transcription of Isl1, a major gene necessary for motor neuron identity, is controlled by two enhancers, CREST1 (E1) and CREST2 (E2) that allow selective gene expression of Isl1 in motor neurons. Introduction of GFP reporters into the chick neural tube revealed that E1 is active in hindbrain motor neurons and spinal cord motor neurons, whereas E2 is active in the lateral motor column (LMC) of the spinal cord, which controls the limb muscles. Genome-wide ChIP-Seq analysis combined with reporter assays showed that Phox2 and the Isl1-Lhx3 complex bind to E1 and drive hindbrain and spinal cord-specific expression of Isl1, respectively. Interestingly, Lhx3 alone was sufficient to activate E1, and this may contribute to the initiation of Isl1 expression when progenitors have just developed into motor neurons. E2 was induced by onecut 1 (OC-1) factor that permits Isl1 expression in LMCm neurons. Interestingly, the core region of E1 has been conserved in evolution, even in the lamprey, a jawless vertebrate with primitive motor neurons. All E1 sequences from lamprey to mouse responded equally well to Phox2a and the Isl1-Lhx3 complex. Conversely, E2, the enhancer for limb-innervating motor neurons, was only found in tetrapod animals. This suggests that evolutionarily-conserved enhancers permit the diversification of motor neurons.
Lewis Lung Cancer Cells Promote SIGNR1(CD209b)-Mediated Macrophages Polarization Induced by IL-4 to Facilitate Immune Evasion.Thursday, October 08, 2015
Yan X, Li W, Pan L, Fu E, Xie Y, Chen M, Mu D,
Journal of cellular biochemistry. 8-Oct-2015
Tumor-associated macrophages are a prominent component of lung cancer and contribute to tumor progression by facilitating the immune evasion of cancer cells. DC-SIGN (CD209) assists in the immune evasion of a broad spectrum of pathogens and neoplasms by inhibiting the maturation of DCs and subsequent cytokines production. However, the expression of DC-SIGN in macrophages and its role in mediating immune evasion in lung cancer and the underlying mechanism remain unclear. Our study aimed to identify the immunosuppressive role of SIGNR1 in murine macrophage differentiation and lung cancer progression. We found that SIGNR1-positive RAW264.7 macrophages were enriched in mixed cultures with Lewis lung cancer cells (LLC) (ratio of RAW 264.7 to LLC being 1:1) after stimulation with IL-4. Moreover, LLC-educated macrophages exhibited significantly higher levels of IL-10 but lower IL-12 in response to IL-4 treatment as determined by RT-PCR and ELISA. However, inhibition of SIGNR1 markedly hampered the production of IL-10, indicating that SIGNR1 was indispensable for IL-4 + LLC induced macrophage polarization towards the M2 subtype. Furthermore, polarized M2 cells immersed in a tumor microenvironment promoted the migration of LLCs, as measured by transwell assays, but migration was suppressed after blockade of SIGNR1 using CD209b antibody. In addition, IL-4 + LLC-educated macrophages reduced the proliferation of the activated T cells and reduced IFN-γ-mediated Th1 response in T cells, while SIGNR1 inhibition rescued Th1 cell functions. In conclusion, murine SIGNR1 expressed in LLC-educated macrophages appears to mediate IL-4-induced RAW264.7 macrophage polarization and thus facilitate lung cancer evasion. This article is protected by copyright. All rights reserved.
Evidence for Bergmann's Rule and Not Allopatric Subspeciation in the Threatened Kaka (Nestor meridionalis).Thursday, October 08, 2015
Dussex N, Sainsbury J, Moorhouse R, Jamieson IG, Robertson BC,
The Journal of heredity. 7-Oct-2015
Species of conservation concern characterized by small and declining populations greatly benefit from proactive management approaches such as population translocations. Because they often show intra-specific genetic and phenotypic variation, which can result from drift or differential selective pressures between habitats, understanding the distribution of such variation and its underlying processes is a prerequisite to develop effective management guidelines. Indeed, translocations among genetically differentiated populations potentially locally adapted are discouraged in order to avoid outbreeding depression, while translocations among populations characterized by high gene flow with no evidence for local adaptation are encouraged. Here, we first test whether 2 recognized subspecies, the North Island kaka (Nestor meridionalis septentrionalis) and South Island kaka (Nestor meridionalis meridionalis) of New Zealand fit a scenario of allopatric subspeciation following the separation of the North and South Islands at the end of the Pleistocene using 1 mtDNA (n = 96) and 9 microsatellite markers (n = 126). We then test whether morphological differences among the 2 subspecies support a pattern of local adaptation, comparing phenotypic divergence (P ST) and the level of divergence by drift alone (F ST) among populations. We find little population structure between islands, ruling out allopatric subspeciation in kaka. Further, P ST exceeds F ST, supporting an adaptive latitudinal size cline consistent with Bergmann's rule. These results therefore suggest that using neutral genetic diversity alone can be misleading when identifying management units and that the nature of phenotypic variation should be considered in translocations efforts. We finally discuss North and South Island management units but suggest that cross-island translocation be allowed.
Functional-genetic dissection of HDAC dependencies in mouse lymphoid and myeloid malignancies.Thursday, October 08, 2015
Matthews GM, Mehdipour P, Cluse LA, Falkenberg KJ, Wang E, Roth M, Santoro F, Vidacs E, Stanley K, House CM, Rusche JR, Vakoc CR, Zuber J, Minucci S, Johnstone RW,
Blood. 7-Oct-2015
Histone deacetylase inhibitors have demonstrated activity in hematological and solid malignancies. Vorinostat, romidepsin, belinostat and panobinostat are FDA-approved for hematological malignancies and inhibit class II and/or class I HDACs including HDAC1, 2, 3 and 6. We combined genetic and pharmacological approaches to investigate whether suppression of individual or multiple Hdacs phenocopied broad-acting HDACi in three genetically distinct leukemias and lymphomas. Individual Hdacs were depleted in murine AMLs (MLL-AF9;Nras(G12D); PML-RARα APL) and Eμ-Myc lymphoma in vitro and in vivo. Strikingly, Hdac3-depleted cells were selected against in competitive assays for all three tumor types. Decreased proliferation following Hdac3 knockdown was not prevented by BCL-2 over-expression, caspase inhibition or knockout of Cdkn1a in Eμ-Myc lymphoma and depletion of Hdac3 in vivo significantly reduced tumor burden. Interestingly, APL cells depleted of Hdac3 demonstrated a more differentiated phenotype. Consistent with these genetic studies, the HDAC3 inhibitor RGFP966 reduced proliferation of Eμ-Myc lymphoma and induced differentiation in APL. Genetic co-depletion of Hdac1 with Hdac2 was pro-apoptotic in Eμ-Myc lymphoma in vitro and in vivo and was phenocopied by the HDAC1/2-specific agent RGFP233. This study demonstrates the importance of HDAC3 for the proliferation of leukemia and lymphoma cells suggesting that HDAC3-selective inhibitors could prove useful for the treatment of hematological malignancies. Moreover, our results demonstrate that co-depletion of Hdac1 with Hdac2 mediates a robust pro-apoptotic response. Our integrated genetic and pharmacological approach provides important insights into the individual or combinations of HDACs that could be prioritized for targeting in a range of hematological malignancies.
Vitamin D status is inversely associated with anemia and serum erythropoietin during pregnancy.Thursday, October 08, 2015
Thomas CE, Guillet R, Queenan RA, Cooper EM, Kent TR, Pressman EK, Vermeylen FM, Roberson MS, O'Brien KO,
The American journal of clinical nutrition. 7-Oct-2015
In this group of pregnant adolescents, suboptimal vitamin D status was associated with increased risk of iron insufficiency and vice versa. These findings emphasize the need for screening for multiple nutrient deficiencies during pregnancy and greater attention to overlapping metabolic pathways when selecting prenatal supplementation regimens.
Carotenoids, retinol, tocopherols, and prostate cancer risk: pooled analysis of 15 studies.Thursday, October 08, 2015
Key TJ, Appleby PN, Travis RC, Albanes D, Alberg AJ, Barricarte A, Black A, Boeing H, Bueno-de-Mesquita HB, Chan JM, Chen C, Cook MB, Donovan JL, Galan P, Gilbert R, Giles GG, Giovannucci E, Goodman GE, Goodman PJ, Gunter MJ, Hamdy FC, Heliövaara M, Helzlsouer KJ, Henderson BE, Hercberg S, Hoffman-Bolton J, Hoover RN, Johansson M, Khaw KT, King IB, Knekt P, Kolonel LN, Le Marchand L, Männistö S, Martin RM, Meyer HE, Mondul AM, Moy KA, Neal DE, Neuhouser ML, Palli D, Platz EA, Pouchieu C, Rissanen H, Schenk JM, Severi G, Stampfer MJ, Tjønneland A, Touvier M, Trichopoulou A, Weinstein SJ, Ziegler RG, Zhou CK, Allen NE,
The American journal of clinical nutrition. 7-Oct-2015
Overall prostate cancer risk was positively associated with retinol and inversely associated with α-tocopherol, and risk of aggressive prostate cancer was inversely associated with lycopene and α-tocopherol. Whether these associations reflect causal relations is unclear.
Fitness Assays Reveal Incomplete Functional Redundancy of the HoxA1 and HoxB1 Paralogs of Mice.Thursday, October 08, 2015
Ruff JS, Saffarini RB, Ramoz LL, Morrison LC, Baker S, Laverty SM, Tvrdik P, Potts WK,
Genetics. Oct-2015
Gene targeting techniques have led to the phenotypic characterization of numerous genes; however, many genes show minimal to no phenotypic consequences when disrupted, despite many having highly conserved sequences. The standard explanation for these findings is functional redundancy. A competing hypothesis is that these genes have important ecological functions in natural environments that are not needed under laboratory settings. Here we discriminate between these hypotheses by competing mice (Mus musculus) whose Hoxb1 gene has been replaced by Hoxa1, its highly conserved paralog, against matched wild-type controls in seminatural enclosures. This Hoxb1(A1) swap was reported as a genetic manipulation resulting in no discernible embryonic or physiological phenotype under standard laboratory tests. We observed a transient decline in first litter size for Hoxb1(A1) homozygous mice in breeding cages, but their fitness was consistently and more dramatically reduced when competing against controls within seminatural populations. Specifically, males homozygous for the Hoxb1(A1) swap acquired 10.6% fewer territories and the frequency of the Hoxb1(A1) allele decreased from 0.500 in population founders to 0.419 in their offspring. The decrease in Hoxb1(A1) frequency corresponded with a deficiency of both Hoxb1(A1) homozygous and heterozygous offspring. These data suggest that Hoxb1 and Hoxa1 are more phenotypically divergent than previously reported and support that sub- and/or neofunctionalization has occurred in these paralogous genes leading to a divergence of gene function and incomplete redundancy. Furthermore, this study highlights the importance of obtaining fitness measures of mutants in ecologically relevant conditions to better understand gene function and evolution.
TCR sequencing facilitates diagnosis and identifies mature T cells as the cell of origin in CTCL.Thursday, October 08, 2015
Kirsch IR, Watanabe R, O'Malley JT, Williamson DW, Scott LL, Elco CP, Teague JE, Gehad A, Lowry EL, LeBoeuf NR, Krueger JG, Robins HS, Kupper TS, Clark RA,
Science translational medicine. 7-Oct-2015
Early diagnosis of cutaneous T cell lymphoma (CTCL) is difficult and takes on average 6 years after presentation, in part because the clinical appearance and histopathology of CTCL can resemble that of benign inflammatory skin diseases. Detection of a malignant T cell clone is critical in making the diagnosis of CTCL, but the T cell receptor γ (TCRγ) polymerase chain reaction (PCR) analysis in current clinical use detects clones in only a subset of patients. High-throughput TCR sequencing (HTS) detected T cell clones in 46 of 46 CTCL patients, was more sensitive and specific than TCRγ PCR, and successfully discriminated CTCL from benign inflammatory diseases. HTS also accurately assessed responses to therapy and facilitated diagnosis of disease recurrence. In patients with new skin lesions and no involvement of blood by flow cytometry, HTS demonstrated hematogenous spread of small numbers of malignant T cells. Analysis of CTCL TCRγ genes demonstrated that CTCL is a malignancy derived from mature T cells. There was a maximal T cell density in skin in benign inflammatory diseases that was exceeded in CTCL, suggesting that a niche of finite size may exist for benign T cells in skin. Last, immunostaining demonstrated that the malignant T cell clones in mycosis fungoides and leukemic CTCL localized to different anatomic compartments in the skin. In summary, HTS accurately diagnosed CTCL in all stages, discriminated CTCL from benign inflammatory skin diseases, and provided insights into the cell of origin and location of malignant CTCL cells in skin.
Detection of T790M, the acquired resistance EGFR mutation, by tumor biopsy versus noninvasive blood-based analyses.Thursday, October 08, 2015
Sundaresan TK, Sequist LV, Heymach JV, Riely GJ, Janne PA, Koch WH, Sullivan JP, Fox DB, Maher R, Muzikansky A, Webb A, Tran HT, Giri U, Fleisher M, Yu H, Wei W, Johnson BE, Barber TA, Walsh JR, Engelman JA, Stott SL, Kapur R, Maheswaran S, Toner M, Haber DA,
Clinical cancer research : an official journal of the American Association for Cancer Research. 7-Oct-2015
Discordant genotypes between tumor biopsy and blood-based analyses may result from technological differences, as well as sampling different tumor cell populations. The use of complementary approaches may provide the most complete assessment of each patient's cancer, which should be validated in predicting response to T790M-targeted inhibitors.
Effect of a Smac Mimetic (TL32711, Birinapant) on the Apoptotic Program and Apoptosis Biomarkers Examined with Validated Multiplex Immunoassays Fit for Clinical Use.Thursday, October 08, 2015
Srivastava AK, Jaganathan S, Stephen L, Hollingshead MG, Govindharajulu JP, Layhee A, Damour E, Donohue J, Esposito D, Mapes JP, Kinders R, Takebe N, Tomaszewski JE, Kummar S, Doroshow JH, Parchment RE,
Clinical cancer research : an official journal of the American Association for Cancer Research. 7-Oct-2015
The validated multiplex immunoassays developed for this study provided proof of mechanism data for TL32711 and are suitable for quantifying apoptotic biomarkers in clinical trials.
Condition-specific genetic interaction maps reveal crosstalk between the cAMP/PKA and the HOG MAPK pathways in the activation of the general stress response.Thursday, October 08, 2015
Gutin J, Sadeh A, Rahat A, Aharoni A, Friedman N,
Molecular systems biology. 2015
Cells must quickly respond and efficiently adapt to environmental changes. The yeast Saccharomyces cerevisiae has multiple pathways that respond to specific environmental insults, as well as a generic stress response program. The later is regulated by two transcription factors, Msn2 and Msn4, that integrate information from upstream pathways to produce fast, tunable, and robust response to different environmental changes. To understand this integration, we employed a systematic approach to genetically dissect the contribution of various cellular pathways to Msn2/4 regulation under a range of stress and growth conditions. We established a high-throughput liquid handling and automated flow cytometry system and measured GFP levels in 68 single-knockout and 1,566 double-knockout strains that carry an HSP12-GFP allele as a reporter for Msn2/4 activity. Based on the expression of this Msn2/4 reporter in five different conditions, we identified numerous genetic and epistatic interactions between different components in the network upstream to Msn2/4. Our analysis gains new insights into the functional specialization of the RAS paralogs in the repression of stress response and identifies a three-way crosstalk between the Mediator complex, the HOG MAPK pathway, and the cAMP/PKA pathway.
Arctigenin antagonizes mineralocorticoid receptor to inhibit the transcription of Na/K-ATPase.Thursday, October 08, 2015
Cheng Y, Zhou M, Wang Y,
Journal of receptor and signal transduction research. 8-Oct-2015
Our current findings demonstrate that Arctigenin is an antagonist of MR and effectively decreases the Na/K-ATPase 1 gene expression. Our work provides a hint for the drug discovery against cardiovascular disease.
A Novel Tandem Duplication Assay to Detect Minimal Residual Disease in FLT3/ITD AML.Thursday, October 08, 2015
Lin MT, Tseng LH, Dudley JC, Riel S, Tsai H, Zheng G, Pratz KW, Levis MJ, Gocke CD,
Molecular diagnosis & therapy. 7-Oct-2015
Detection of MRD by TD-PCR may guide patient selection for early clinical intervention. In contrast to clone-specific approaches, the TD-PCR assay can be more easily validated for MRD detection in clinical laboratories because it uses standardized primers and a universal positive control. In addition, our findings on multi-clonality and low-level ITDs suggest that further studies are warranted to elucidate their clinical/biological significance.
Development of single-chain variable fragments (scFv) against influenza virus targeting hemagglutinin subunit 2 (HA2).Thursday, October 08, 2015
Li TW, Cheng SF, Tseng YT, Yang YC, Liu WC, Wang SC, Chou MJ, Lin YJ, Wang Y, Hsiao PW, Wu SC, Chang DK,
Archives of virology. 8-Oct-2015
Influenza A viruses (IAV) are widespread in birds and domestic poultry, occasionally causing severe epidemics in humans and posing health threats. Hence, the need to develop a strategy for prophylaxis or therapy, such as a broadly neutralizing antibody against IAV, is urgent. In this study, single-chain variable fragment (scFv) phage display technology was used to select scFv fragments recognizing influenza envelope proteins. The Tomlinson I and J scFv phage display libraries were screened against the recombinant HA2 protein (rHA2) for three rounds. Only the third-round elution sample of the Tomlinson J library showed high binding affinity to rHA2, from which three clones (3JA18, 3JA62, and 3JA78) were chosen for preparative-scale production as soluble antibody by E. coli. The clone 3JA18 was selected for further tests due to its broad affinity for influenza H1N1, H3N2 and H5N1. Simulations of the scFv 3JA18-HA trimer complex revealed that the complementarity-determining region of the variable heavy chain (VH-CDR2) bound the stem region of HA. Neutralization assays using a peptide derived from VH-CDR2 also supported the simulation model. Both the selected antibody and its derived peptide were shown to suppress infection with H5N1 and H1N1 viruses, but not H3N2 viruses. The results also suggested that the scFvs selected from rHA2 could have neutralizing activity by interfering with the function of the HA stem region during virus entry into target cells.
Effects of NMDA receptor antagonists and antipsychotics on high frequency oscillations recorded in the nucleus accumbens of freely moving mice.Thursday, October 08, 2015
Hunt MJ, Olszewski M, Piasecka J, Whittington MA, Kasicki S,
Psychopharmacology. 8-Oct-2015
NMDA receptor antagonists and antipsychotics produce broadly similar fundamental effects on HFO, as reported previously for rats, but we did observe several notable differences. In mice, HFO at baseline were weak or not detectable unlike rats. Post-injection of NMDA receptor antagonists HFO was also weaker but significantly faster. Additionally, we found that atypical antipsychotic drugs may reduce the frequency of HFO by interacting with NMDA and/or 5-HT1A receptors.
The mitochondrial fission receptor Mff selectively recruits oligomerized Drp1.Thursday, October 08, 2015
Liu R, Chan DC,
Molecular biology of the cell. 7-Oct-2015
Dynamin-related protein 1 (Drp1) is the GTP-hydrolyzing mechanoenzyme that catalyzes mitochondrial fission in the cell. Residing in the cytosol as dimers and tetramers, Drp1 is recruited by receptors on the mitochondrial outer membrane, where it further assembles into a helical ring that drives division via GTP-dependent constriction. The Drp1 receptor Mff is a major regulator of mitochondrial fission, and its overexpression results in increased fission. In contrast, the alternative Drp1 receptors MiD51 and MiD49 appear to recruit inactive forms of Drp1, because their overexpression inhibits fission. Using genetic and biochemical assays, we studied the interaction of Drp1 with Mff. We show the insert B region of Drp1 inhibits Mff-Drp1 interactions, such that recombinant Drp1 mutants lacking insert B form a stable complex with Mff. Mff cannot bind to assembly-deficient mutants of Drp1, suggesting that Mff selectively interacts with higher order complexes of Drp1. In contrast, the alternative Drp1 receptors MiD51 and MiD49 can recruit Drp1 dimers. Therefore, Drp1 recruitment by Mff versus MiD51 and MiD49 may result in different outcomes because they recruit different subpopulations of Drp1 from the cytosol.
Source: NCBI - Disclaimer and Copyright notice

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,600+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos