196,017 research outputs found
Biocompatible palladium catalysts for biological applications
No full textTransition metals have been used to mediate bioorthogonal reactions within a biological
environment. In particular, applications of biocompatible palladium catalysis currently range
from biomolecules modification to the in cellulo synthesis or activation of drugs. Here, the
scope of palladium-mediated chemistry in living systems has been further extended with the
development of a new homogenous palladium catalyst. This water-soluble, biocompatible,
and traceable catalysts is based on a palladium-carbene complex coupled to a fluorescent
labelled homing peptide for targeted delivery inside cells. This “SMART” catalyst is
designed to activate both caged fluorophores and drugs through the cleavage of protecting
groups or cross-coupling reactions. A second strategy for targeted delivery of a
biocompatible palladium catalysis involves metal nanoparticles loaded onto a heterogeneous
solid support. This “modular” catalyst can be implanted in vivo at the desired site of action,
e.g. a tumour, and locally activate biomolecules.
These two catalytic systems will allow us to selectively activate pro-drugs in vivo, with
spatial control, thus minimising the side effects of the treatment on the whole body
Author response
No full textRas-ERK signalling in the brain plays a central role in drug addiction. However, to date, no clinically relevant inhibitor of this cascade has been tested in experimental models of addiction, a necessary step toward clinical trials. We designed two new cell-penetrating peptides - RB1 and RB3 - that penetrate the brain and, in the micromolar range, inhibit phosphorylation of ERK, histone H3 and S6 ribosomal protein in striatal slices. Furthermore, a screening of small therapeutics currently in clinical trials for cancer therapy revealed PD325901 as a brain-penetrating drug that blocks ERK signalling in the nanomolar range. All three compounds have an inhibitory effect on cocaine-induced ERK activation and reward in mice. In particular, PD325901 persistently blocks cocaine-induced place preference and accelerates extinction following cocaine self- administration. Thus, clinically relevant, systemically administered drugs that attenuate Ras-ERK signalling in the brain may be valuable tools for the treatment of cocaine addiction
Identification of novel RasGRF1 interacting partners by large-scale proteomic analysis
No full textThe brain-specific Ras guanine nucleotide exchange factor RasGRF1 is a protein harbouring a complex array of structural motifs. It contains a pleckstrin homology (PH1) domain, a coiled coil region (CC) and an ilimaquinone (IQ) one in addition to the catalytic Ras and Rac exchange factor domains. In this study, we used the recombinant N-terminal PH1, CC and IQ region (PHCCIQ) fused to the chitin-binding domain to isolate interacting proteins from mouse brain extracts. The use of an advanced software tool, the Pep-Miner, allowed clustering similar spectra from multiple mass spectrometry analysis, simplifying and improving the analysis of the complex peptide mixture. The most representative classes of RasGRF1-interacting proteins were ribosomal and other RNA-binding proteins, cytoskeletal proteins and proteins involved in vesicular trafficking. We confirmed the interaction of some of the identified proteins using different experimental approaches. We also demonstrated an RNA-dependent association of the PHCCIQ moiety of RasGRF1 with ribosomal protein S6 and Ras-GTPase-activating protein SH3-domain binding protein 2. In addition, we found that purified total RNA binds to the PHCCIQ fusion protein and the recombinant protein associates with poly(A)-sepharose. These data indicate that RasGRF1 can interact with different protein categories and exhibits a potential RNA-binding property
Pharmacological modulation of neuronal activity for the treatment of Rett syndrome
No full textRett syndrome (RTT) is a neurodevelopmental disorder, representing the most common genetic cause of severe intellectual disability in females. More than 95% of classical RTT cases are caused by mutations in the X-linked MECP2 gene, and in line with its role as a master regulator of gene expression, null neurons display widespread transcriptional changes, reduced activity, and defective morphology. These elements are linked in a feed-forward cycle where neuronal activity drives transcriptional and morphological changes that increase network maturity. Neuronal activity plays a key role during brain development, thus any variation from physiological ranges leads to severe consequences. We tested the possible causative link between immaturity and reduced neuronal activity by pharmacologically stimulating in vitro and in vivo Mecp2 null neurons within different time windows of differentiation.
Methods: To enhance activity and rescue maturation in vitro, we used Ampakine CX546, a positive AMPA receptor modulator. The efficacy of an early treatment with CX546 in vivo was tested by evaluating the general well-being of mice, and by performing motor and cognitive behavioral tests. Moreover, we tested the value of a prolonged treatment in which animals were injected mice every other week.
Results: By treating cortical neurons with CX546 we ameliorated null neurons transcription and activity, highlighting the contribution of defective mechanisms of development to typical RTT phenotypes.
Although the early time window of treatment in vivo suggested a prolonged benefic effect on knock-out mice, it was devoid of translational value. We thus tested later timepoints and different Ampakines.
Conclusions: Our results support the value of an early therapeutic approach acting on neuronal activity as a strategy for RTT therapy. More studies are needed to pinpoint the correct time window and to identify the molecular pathways involved in any observed benefits
Dr. Duane M. Jackson, Morehouse College, July 2011
No full textThis video is a conversation with Dr. Duane M. Jackson. Dr. Jackson talks about his paper, "Recall and the Serial Position Effect: The Role of Primacy and Recency on Accounting Students' Performance." Jackie Daniel, AUC Woodruff Library, is the interviewer
Pharmacological modulation of neuronal activity to treat Rett syndrome
No full textRett syndrome (RTT) is a neurodevelopmental disorder, representing the most common genetic cause of severe intellectual disability in females. RTT is caused by mutations in the X-linked MECP2 gene. Given its role as master regulator of gene expression, transcriptional maturation is affected in null neurons, as well as the ability to respond to external stimuli. Neuronal activity plays a key role during brain development, thus we tested the possible causative link between immaturity and reduced activity by pharmacologically stimulating in vitro and in vivo Mecp2 null neurons within different time windows of differentiation.
To enhance activity, we used a positive AMPA receptor modulator, Ampakine CX546. By treating neurons we ameliorated their transcription and activity, highlighting the contribution of defective mechanisms of development to RTT phenotypes. In vivo the efficacy was tested by evaluating the well-being of mice and by performing motor and cognitive behavioral tests. Although the early time window suggested a prolonged benefic effect on knock-out mice, it was devoid of translational value. Therefore, to validate the possibility that ampakine might represent a safe and efficient approach for the treatment of RTT, we tested different time windows with different ampakines. Obtained results will be presented and future perspective discussed
Pharmacological modulation of neuronal activity for the treatment of Rett syndrome
No full textMutations in the MECP2 gene cause Rett syndrome (RTT), a severe neurodevelopmental disorder that typically affects females. Early developmental defects have been reported, but their contribution to the pathogenesis is still not understood. In line with the role of Mecp2 as a master regulator of gene expression, transcriptional maturation is affected in null samples both in vivo and in vitro, as well as the ability of null neurons to respond to external stimuli. We tested the possible causative link between immaturity and reduced neuronal activity by pharmacologically stimulating null neurons within early time windows of differentiation. By treating NPCs derived neurons with Ampakine CX546, a positive modulator of AMPA receptor, we ameliorated null neurons transcription, morphology, and activity, highlighting the contribution of defective mechanisms of development to typical RTT phenotypes. Preliminary results suggested a positive result of an early treatment also in vivo. Although the selected time window of treatment suggested a prolonged benefic effect on Mecp2 null mice, it was devoid of translational value. We thus decided to test in vivo later time points. To identify the best therapeutic window for intervention, we selected two pre-symptomatic (P3-P9 and P15-21) time points, an early symptomatic (P28-34) and a late symptomatic (P55-61) phase. First results were collected administrating two different ampakines at P28-P34. The efficacy of the treatment was tested by evaluating the lifespan, the phenotypic score commonly used for RTT mice, and performing some behavioral tests at different time points
"Reflections on the subject of Emigration from Europe with a view to Settlement in the United States" By M. Carey.
No full text"Reflections on the subject of Emigration from Europe with a view to Settlement in the United States: containing bried sketches of the moral and political character of those states.
By M. Carey, member of the American philosophical, and of the American Antiquarian Society, and author of The Olive Branch, Cindiciae Hibernicae, essays on banking, on political economy, and on internal improvement.
To which are now added the English editor's comments on the subject; together with Important Advice to Emigrants, and Cautions Against Impositions Practiced in the Outports
Dispelling the Myths Behind First-author Citation Counts
No full textWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Pharmacological modulation of neuronal activity for the treatment of Rett syndrome
No full textRett syndrome (RTT) is a neurodevelopmental disorder, representing the most common genetic cause of severe intellectual disability in females. RTT is caused by mutations in the X-linked MECP2 gene. Given its role as a master regulator of gene expression, transcriptional maturation is affected in null neurons, as well as the ability to respond to external stimuli. Neuronal activity plays a key role during brain development, thus any variation from physiological ranges lead to severe consequences. We tested the possible causative link between immaturity and reduced neuronal activity by pharmacologically stimulating in vitro and in vivo Mecp2 null neurons within different time windows of differentiation.
Methods: To enhance activity and rescue maturation in vitro, we used Ampakine CX546, a positive AMPA receptor modulator. The efficacy of an early treatment with CX546 in vivo was tested by evaluating the general well-being of mice, and by performing motor and cognitive behavioral tests.
Results: By treating cortical neurons with CX546 we ameliorated null neurons transcription and activity, highlighting the contribution of defective mechanisms of development to typical RTT phenotypes.
Although the early time window of treatment in vivo suggested a prolonged benefic effect on knock-out mice, it was devoid of translational value. We thus tested later timepoints and different Ampakines.
Conclusions: Our results support the value of an early therapeutic approach acting on neuronal activity as a strategy for RTT therapy. More studies are needed to pinpoint the correct time window and to identify the molecular pathways involved in any observed benefits
- …
