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Cocaine self-administration in the mouse: A low-cost, chronic catheter preparation
Full text linkIntravenous drug self-administration is the most valid animal model of human addiction because it allows volitional titration of the drug in the blood based on an individual’s motivational state together with the pharmacokinetic properties of the drug. Here we describe a reliable low-cost mouse self-administration catheter assembly and protocol that that can be used to assess a variety of drugs of abuse with a variety of protocols. We describe a method for intravenous catheter fabrication that allows for efficient and long-lasting intravenous drug delivery. The intravenous catheters remained intact and patent for several weeks allowing us to establish stable maintenance of cocaine acquisition. This was followed by a dose response study in the same mice. For collaborators interested in premade catheters for research please make a request at www.neuro-cloud.net/nature-precedings/pomerenze
Cancer Clinical Trials Optimization and Pharmacogenomics
Full text linkA critical overview of recent clinical trials in cancer is presented focused on signaling pathways blockers or inhibitors with a view to developing successful clinical trials employing personalized cancer therapies. Rational, pharmacogenomic strategies in cancer trials should be adopted that include specific molecular targeting based on adequate data for, and detailed modeling of, cancer cell genomes, modifications of cancer signaling pathways and epigenetic mechanisms. Novel translational oncogenomics research is rapidly expanding through the application of highly sensitive and specific advanced technology, research findings and computational tools and complex models to both pharmaceutical and clinical problems. Multiple sample analyses from several recent clinical studies have shown that gene expression data for cancer cells can be employed to distinguish between tumor types as well as to predict outcomes. Potentially important applications of such results are individualized human cancer therapies or, in general,'personalized medicine' that will have to be validated through optimally designed clinical trials in cancer. A Human Cancer Genomes and Epigenetics Project is proposed that can provide the essential data required for the optimal design of clinical trials with the goal of achieving significant improvements of the survival rates of cancer patients participating in clinical trials for advanced cancer stages. The results of such a six-year Human Cancer Genomes and Epigenetics Project should also greatly aid with the accelerated, rational development of effective anti-cancer medicines and the chemoprevention of cancers
Bevacizumab-induced tumor calcifications can be elicited in glioblastoma microspheroid culture and represent massive calcium accumulation death (MCAD) of tumor endothelial cells
Full text linkBähr and colleagues reported that 22 of 36 glioblastoma patients treated with bevacizumab showed tumor calcifications on 8 week post therapy follow up with MRI. Early tumor calcification strongly predicted for response, time to progression, and overall survival. The authors didn’t understand the mechanism, but speculated that it was vascular in nature. At the 13th International Anti-Angiogenic Symposium (2011), we presented our discovery of the phenomenon of massive calcium accumulation death, wherein MCAD occurred in endothelial cells (tumor, circulating, and HUVEC), in response to VEGF depletion by bevacizumab and other putative anti-angiogenic agents, but not in response to non-specific cytotoxins. In subsequent work, we have documented marked MCAD to occur in primary microcluster cultures from 6 fresh human glioblastoma biopsies, following 96 hours of VEGF depletion in vitro by bevacizumab. The presence and degree of MCAD is strikingly dependent on the type of serum in the culture medium (RPMI-1640 + 25% serum) -- typically most striking in (very low VEGF) fetal calf serum, but inhibited (often) or enhanced (rarely) by 25% human serum from different patients or normal donors containing variable quantities of VEGF. There was not a linear relationship between VEGF concentration and MCAD inhibition (or enhancement), suggesting that other pro-angiogenic (or anti-angiogenic) serum factors may play a role. In epithelial metastatic tumors, circulating peripheral blood endothelial cells may be easily tested, using our methods, and the serum inhibition (or, rarely, enhancement) is faithfully reproduced on circulating endothelial cells, in comparison with the tumor cluster-associated endothelial cells. We propose MCAD as the mechanism of glioblastoma calcification following bevacizumab and further propose that testing tumor microclusters and/or circulating endothelial cells, in the presence of autologous serum, could be a useful predictive biomarker and research tool
A unified mechanistic model of niche, neutrality and violation of the competitive exclusion principle
Full text linkThe origin of species richness is one of the most widely discussed questions in ecology. The absence of unified mechanistic model of competition makes difficult our deep understanding of this subject. Here we show such a two-species competition model that unifies (i) a mechanistic niche model, (ii) a mechanistic neutral (null) model and (iii) a mechanistic violation of the competitive exclusion principle. Our model is an individual-based cellular automaton. We demonstrate how two trophically identical and aggressively propagating species can stably coexist in one stable homogeneous habitat without any trade-offs in spite of their 10% difference in fitness. Competitive exclusion occurs if the fitness difference is significant (approximately more than 30%). If the species have one and the same fitness they stably coexist and have similar numbers. We conclude that this model shows diffusion-like and half-soliton-like mechanisms of interactions of colliding population waves. The revealed mechanisms eliminate the existing contradictions between ideas of niche, neutrality and cases of violation of the competitive exclusion principle
Co-expression Toggling of MicroRNAs in Alzheimer’s Brain
No full textWe present the findings on how microRNA expression profiles changes in Alzheimer's brain
Finding Bicliques in Digraphs: Application into Viral-host Protein Interactome
Full text linkWe provide the first formalization true to the best of our knowledge to the problem of finding bicliques in a directed graph. The problem is addressed employing a two-stage approach based on an existing biclustering algorithm. This novel problem is useful in several biological applications of which we focus only on analyzing the viral-host protein interaction graphs. Strong and significant bicliques of HIV-1 and human proteins are derived using the proposed methodology, which provides insights into some novel regulatory functionalities in case of the acute immunodeficiency syndrome in human
Reduced GABA-B/GIRK-mediated regulation of the VTA following a single exposure to cocaine
Full text linkIn this paper, Arora and colleagues expand on their previous work on GIRK channels in the ventral tegmental area (VTA) presenting evidence that a single exposure to cocaine reduces inhibitory GABAergic transmission to dopamine (DA) neurons in the ventral tegmental area. Mice receiving i.p. injections of cocaine saw a short lived (1-5 days) decrease in GABAb mediated G-protein coupled inwardly-rectifying potassium (GIRK) currents in DA neurons in the VTA. This decrease parallels an NMDA-mediated increase in the frequency of glutamatergic neurotransmission. Chronic cocaine injections had no additional effects beyond those seen with single injections. Though they found no change in mRNA levels for GABAb receptors, GIRK channels, or RGS-2 (a G-protein regulator), immunoelectron microscopy indicated a decrease in levels of GIRK channels in the plasma membrane of the dendrites of VTA DA neurons. The cocaine-mediated decrease in GIRK currents was abolished in the presence of D2/3R antagonist sulpiride, but not in the presence of D1/5 antagonist SCH23390, indicating a link between D2/3 receptor activation and GIRK activity. Interestingly, the addition of quinpirole, a D2/3 agonist, elicited similar GIRK currents, though they were smaller than those mediated by GABAb receptors. Similarly, acute injections of cocaine significantly diminished quinpirole-evoked currents
Ligand induced cleavage and nuclear localization of the rice XA21 immune receptor
Full text linkThe rice XA21 receptor confers immunity to the Gram-negative bacterial pathogen, _Xanthomonas oryzae_ pv. _oryzae_ (_Xoo_) upon recognition of the conserved microbial signature AxY^S^22. Here, we demonstrate that the intracellular kinase domain of XA21 translocates to the nucleus upon AxY^S^22-mediated perception and that this translocation event is required for XA21-mediated immunity
SED-ML: Nested Simulation Proposal
No full textThis document describes a second version of the proposal for nested simulation experiments for SED-ML (http://sed-ml.org). The proposal has been updated to include the feedback received in the meantime and has been enhanced by examples. A full implementation is available with libSedML (http://libsedml.sf.net) and the SED-ML Web Tools (http://sysbioapps.dyndns.org/SED-ML_Web_Tools/
Mobile Image Ratiometry: A New Method for Instantaneous Analysis of Rapid Test Strips
Full text linkHere we describe Mobile Image Ratiometry (MIR), a new method for the automated quantification of standardized rapid immunoassay strips using consumer-based mobile smartphone and tablet cameras. To demonstrate MIR we developed a standardized method using rapid immunotest strips directed against cocaine (COC) and its major metabolite, benzoylecgonine (BE). We performed image analysis of three brands of commercially available dye-conjugated anti-COC/BE antibody test strips in response to three different series of cocaine concentrations ranging from 0.1 to 300 ng/ml and BE concentrations ranging from 0.003 to 0.1 ng/ml. These data were then used to create standard curves to allow quantification of COC/BE in biological samples. MIR quantification of COC and BE proved to be a sensitive, economical, and faster alternative to more costly methods, such as gas chromatography-mass spectrometry, tandem mass spectrometry, or high pressure liquid chromatography. MIR is a valuable tool that provides instant data acquisition, tracking and analysis for the emerging field of mobile platform informatics (MPI)