Nanoneuromedicines for degenerative, inflammatory, and infectious nervous system diseases

Interest in nanoneuromedicine has grown rapidly due to the immediate need for improved biomarkers and therapies for psychiatric, developmental, traumatic, inflammatory, infectious and degenerative nervous system disorders. These, in whole or in part, are a significant societal burden due to growth in numbers of affected people and in disease severity. Lost productivity of the patient and his or her caregiver, and the emotional and financial burden cannot be overstated. The need for improved health care, treatment and diagnostics is immediate. A means to such an end is nanotechnology. Indeed, recent developments of health-care enabling nanotechnologies and nanomedicines range from biomarker discovery including neuroimaging to therapeutic applications for degenerative, inflammatory and infectious disorders of the nervous system. This review focuses on the current and future potential of the field to positively affect clinical outcomes. From the Clinical Editor Many nervous system disorders remain unresolved clinical problems. In many cases, drug agents simply cannot cross the blood-brain barrier (BBB) into the nervous system. The advent of nanomedicines can enhance the delivery of biologically active molecules for targeted therapy and imaging. This review focused on the use of nanotechnology for degenerative, inflammatory, and infectious diseases in the nervous system

Estimation Of Travel Time Distribution And Detection Of Incidents Based On Automatic Vehicle Classificatin

We study the problem of travel time estimation along a section of a freeway based on data derived from vehicle detectors at multiple locations. We pose the problem as one of pattern recognition. We derive algorithms that aim to recognize patterns which persist between the error-prone upstream detector samples and the error-prone downstream detector samples. We describe how these can allow us to estimate the distribution of the travel time between these detector locations. The most promising algorithm derived in this research is a dynamic programming based algorithm based on sequence matching techniques that would process the data as it arrives and could therefore provide continuously updated travel time estimates in real time. Keywords: Travel time estimation, pattern matching, sequence matching, dynamic programming

Estimation Of Travel Time Distribution And Detection Of Incidents Based On Automatic Vehicle Classificatin

We study the problem of travel time estimation along a section of a freeway based on data derived from vehicle detectors at multiple locations. We pose the problem as one of pattern recognition. We derive algorithms that aim to recognize patterns which persist between the error-prone upstream detector samples and the error-prone downstream detector samples. We describe how these can allow us to estimate the distribution of the travel time between these detector locations. The most promising algorithm derived in this research is a dynamic programming based algorithm based on sequence matching techniques that would process the data as it arrives and could therefore provide continuously updated travel time estimates in real time. Keywords: Travel time estimation, pattern matching, sequence matching, dynamic programming.Travel time (Traffic engineering)--Mathematical models, Pattern recognition systems, Automatic vehicle classification, Automatic incident detection

Nanoneuromedicines for degenerative, inflammatory, and infectious nervous system diseases

Interest in nanoneuromedicine has grown rapidly due to the immediate need for improved biomarkers and therapies for psychiatric, developmental, traumatic, inflammatory, infectious and degenerative nervous system disorders. These, in whole or in part, are a significant societal burden due to growth in numbers of affected people and in disease severity. Lost productivity of the patient and his or her caregiver, and the emotional and financial burden cannot be overstated. The need for improved health care, treatment and diagnostics is immediate. A means to such an end is nanotechnology. Indeed, recent developments of health-care enabling nanotechnologies and nanomedicines range from biomarker discovery including neuroimaging to therapeutic applications for degenerative, inflammatory and infectious disorders of the nervous system. This review focuses on the current and future potential of the field to positively affect clinical outcomes. From the Clinical Editor Many nervous system disorders remain unresolved clinical problems. In many cases, drug agents simply cannot cross the blood-brain barrier (BBB) into the nervous system. The advent of nanomedicines can enhance the delivery of biologically active molecules for targeted therapy and imaging. This review focused on the use of nanotechnology for degenerative, inflammatory, and infectious diseases in the nervous system.This article is published as Gendelman, Howard E., Vellareddy Anantharam, Tatiana Bronich, Shivani Ghaisas, Huajun Jin, Anumantha G. Kanthasamy, Xinming Liu et al. "Nanoneuromedicines for degenerative, inflammatory, and infectious nervous system diseases." Nanomedicine: Nanotechnology, Biology and Medicine 11, no. 3 (2015): 751-767. 10.1016/j.nano.2014.12.014. Posted with permission.</p

Suicidal Autointegration of <i>Sleeping Beauty</i> and <i>piggyBac</i> Transposons in Eukaryotic Cells

<div><p>Transposons are discrete segments of DNA that have the distinctive ability to move and replicate within genomes across the tree of life. ‘Cut and paste’ DNA transposition involves excision from a donor locus and reintegration into a new locus in the genome. We studied molecular events following the excision steps of two eukaryotic DNA transposons, <i>Sleeping Beauty</i> (<i>SB</i>) and <i>piggyBac (PB)</i> that are widely used for genome manipulation in vertebrate species. <i>SB</i> originates from fish and <i>PB</i> from insects; thus, by introducing these transposons to human cells we aimed to monitor the process of establishing a transposon-host relationship in a naïve cellular environment. Similarly to retroviruses, neither <i>SB</i> nor <i>PB</i> is capable of self-avoidance because a significant portion of the excised transposons integrated back into its own genome in a suicidal process called autointegration. Barrier-to-autointegration factor (BANF1), a cellular co-factor of certain retroviruses, inhibited transposon autointegration, and was detected in higher-order protein complexes containing the <i>SB</i> transposase. Increasing size sensitized transposition for autointegration, consistent with elevated vulnerability of larger transposons. Both <i>SB</i> and <i>PB</i> were affected similarly by the size of the transposon in three different assays: excision, autointegration and productive transposition. Prior to reintegration, <i>SB</i> is completely separated from the donor molecule and followed an unbiased autointegration pattern, not associated with local hopping. Self-disruptive autointegration occurred at similar frequency for both transposons, while aberrant, pseudo-transposition events were more frequently observed for <i>PB</i>.</p></div

The cellular factor of BANF1 interferes with autointegration.

<p>A. Relative autointegration frequencies of <i>SB</i> (<i>SB7K</i>, left panel) and PB (<i>PB7K</i>, right panel) in HeLa cells, where BANF1 was either knocked-down or overexpressed. Knocking down of BANF1 stimulated, whereas overexpressing of BANF1 inhibited autointegration of both <i>SB</i> and <i>PB</i> transposons (n = 3). The statistical significance of differences is shown by asterisk above the bars *P<0.05. B. A SILAC pull-down experiment using anti-HA resin to investigate interaction partners of HMGXB4 in the presence/absence of <i>SB10</i> transposase in transiently transfected HEK293T cells. Schematic representation of the SILAC/pull-down experimental approach in which stable isotope labeled amino acids [Light (L) or Medium heavy (M)] are added in the form of medium supplement to culture HEK293T cells. Detection of interaction partners is performed by mass spectrometry. Scatter plot displays the normalized log2 SILAC ratio M/L values (X-axis) versus log2 intensity (Y-axis) of proteins detected in the interactome around HMGXB4⁻ in presence of the SB transposase. Each dot represents an individual protein, while their position indicates their abundance in the complex pulled down by the bait of HMGXB4. Proteins with a positive log2 SILAC M/L ratio, including BANF1 and <i>SB</i> are enriched in the protein complex around HMGXB4. C. Co-immunoprecipitation assay to investigate the interaction partners of HMGXB4, a physical interaction partner of the <i>Sleeping Beauty</i> transposase, SB10 <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004103#pgen.1004103-Walisko2" target="_blank">[13]</a>. <i>SB10</i> and HA-tagged HMGXB4 were transiently transfected into HEK293T cells (see Methods). In comparison to negative control, BANF1 and <i>SB</i> are enriched in the pull-down by HMGXB4-HA.</p

Comparing autointegration profile to the predicted, close-to-random target site distribution of <i>SB</i> transposition.

<p>A. Distribution of 53 <i>de novo</i> autointegration events (triangles) detected by the assay shown in (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004103#pgen-1004103-g001" target="_blank">Figure 1B</a>). Autointegration products were isolated from individual bacterial clones, sequenced and mapped to the <i>SBrescue</i> construct. The thin arrow indicates the location of the sequencing primer on the left IR. B. Comparison of the predicted and experimental insertion events. The <i>SBrescue</i> construct is shown in a linear mode. The <i>SB Vstep</i> scores and experimental insertion events were shown below. Un, undetectable.</p