Measuring the Effect of Job Creation Tax Credits

Measuring the Effect of Job Creation Tax Credits. A presentation by Laura Wheeler (FRC Senior Research Associate) at the annual […

Elucidating the consequence and cause of microRNA dysregulation in amyotrophic lateral sclerosis (ALS)

Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neurodegenerative disorder with an average life expectancy of 2-5 years post-diagnosis. Common pathological features associated with ALS are the formation of cytoplasmic inclusions of intermediate filaments and RNA-binding proteins within motor neurons. The formation of intermediate filament cytoplasmic inclusions is believed to be driven by a loss of stochiometric expression between five neuronal intermediate filament proteins—NFL, NFM, NFH, INA and PRPH—where there is a selective suppression of the steady-state levels of NEFL, INA and PRPH mRNA. Further, three RNA-binding proteins—TDP-43, FUS and RGNEF—have been shown to co-aggregate with each other in ALS motor neurons indicating a possible common mechanism that leads to their dysregulation. In the last decade, microRNAs (miRNAs)—small RNA molecules generally responsible for post-transcriptional regulation of gene expression—were observed to be massively dysregulated in the spinal cord tissue of ALS patients, providing a possible explanation for the changes observed in intermediate filament steady-state mRNA levels and RNA-binding protein dysregulation in ALS. Further, TDP-43 and FUS regulate miRNA biogenesis, indicating there may be a regulatory network between RNA-binding proteins and miRNAs that is disrupted in ALS. I hypothesize that a regulatory network between specific RNA-binding proteins and miRNAs is disrupted in ALS leading to changes in miRNA processing which contributes to intermediate filament and RNA-binding protein pathology. In this dissertation, I have examined: 1) whether ALS-linked miRNA(s) contribute to the selective suppression of NEFL, PRPH, and INA; 2) whether ALS-linked miRNAs regulate the expression of NEFM and NEFH; 3) whether ALS-linked miRNAs regulate the expression of RNA-binding proteins whose metabolism is dysregulated in ALS (TDP-43, FUS, and RGNEF); and, 4) whether TDP-43 and FUS are in a regulatory network with ALS-linked miRNAs. Overall, 12 ALS-linked miRNAs were identified to regulate either intermediate filament or RNA-binding protein expression, and further, a novel negative feedback loop between TDP-43 and two miRNAs (miR-27b-3p and miR-181c-5p) was identified. This dissertation highlights that changes to miRNA levels, as seen in ALS, would contribute to overall ALS pathology, making them viable avenues for potential therapeutics

Measuring the Effect of Job Creation Tax Credits

Measuring the Effect of Job Creation Tax Credits. A presentation by Laura Wheeler (FRC Senior Research Associate) at the annual […

Constraint preserving boundary conditions for the Ideal Newtonian MHD equations

We study and develop constraint preserving boundary conditions for the Newtonian magnetohydrodynamic equations and analyze the behavior of the numerical solution upon considering different possible options.Comment: uses elsart styl

MotomiRs: miRNAs in Motor Neuron Function and Disease

MiRNAs are key regulators of the mammalian transcriptome that have been increasingly linked to degenerative diseases of the motor neurons. Although many of the miRNAs currently incriminated as participants in the pathogenesis of these diseases are also important to the normal development and function of motor neurons, at present there is no knowledge of the complete miRNA profile of motor neurons. In this review, we examine the current understanding with respect to miRNAs that are specifically required for motor neuron development, function and viability, and provide evidence that these should be considered as a functional network of miRNAs which we have collectively termed MotomiRs. We will also summarize those MotomiRs currently known to be associated with both amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), and discuss their potential use as biomarkers

The 13th Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the SDSS-IV Survey Mapping Nearby Galaxies at Apache Point Observatory

The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) began observations in July 2014. It pursues three core programs: APOGEE-2,MaNGA, and eBOSS. In addition, eBOSS contains two major subprograms: TDSS and SPIDERS. This paper describes the first data release from SDSS-IV, Data Release 13 (DR13), which contains new data, reanalysis of existing data sets and, like all SDSS data releases, is inclusive of previously released data. DR13 makes publicly available 1390 spatially resolved integral field unit observations of nearby galaxies from MaNGA,the first data released from this survey. It includes new observations from eBOSS, completing SEQUELS. In addition to targeting galaxies and quasars, SEQUELS also targeted variability-selected objects from TDSS and X-ray selected objects from SPIDERS. DR13 includes new reductions ofthe SDSS-III BOSS data, improving the spectrophotometric calibration and redshift classification. DR13 releases new reductions of the APOGEE-1data from SDSS-III, with abundances of elements not previously included and improved stellar parameters for dwarf stars and cooler stars. For the SDSS imaging data, DR13 provides new, more robust and precise photometric calibrations. Several value-added catalogs are being released in tandem with DR13, in particular target catalogs relevant for eBOSS, TDSS, and SPIDERS, and an updated red-clump catalog for APOGEE.This paper describes the location and format of the data now publicly available, as well as providing references to the important technical papers that describe the targeting, observing, and data reduction. The SDSS website, http://www.sdss.org, provides links to the data, tutorials and examples of data access, and extensive documentation of the reduction and analysis procedures. DR13 is the first of a scheduled set that will contain new data and analyses from the planned ~6-year operations of SDSS-IV.PostprintPeer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Dysregulation of human NEFM and NEFH mRNA stability by ALS-linked miRNAs

Abstract Neurofilaments (NFs) are the most abundant cytoskeletal component of vertebrate myelinated axons. NFs function by determining axonal caliber, promoting axonal growth and forming a 3-dimensional lattice that supports the organization of cytoplasmic organelles. The stoichiometry of NF protein subunits (NFL, NFM and NFH) has to be tightly controlled to avoid the formation of NF neuronal cytoplasmic inclusions (NCIs), axonal degeneration and neuronal death, all pathological hallmarks of amyotrophic lateral sclerosis (ALS). The post-transcriptional control of NF transcripts is critical for regulating normal levels of NF proteins. Previously, we showed that miRNAs that are dysregulated in ALS spinal cord regulate the levels of NEFL mRNA. In order to complete the understanding of altered NF expression in ALS, in this study we have investigated the regulation of NEFM and NEFH mRNA levels by miRNAs. We observed that a small group of ALS-linked miRNAs that are expressed in human spinal motor neurons directly regulate NEFM and NEFH transcript levels in a manner that is associated with an increase in NFM and NFH protein levels in ALS spinal cord homogenates. In concert with previous observations demonstrating the suppression of NEFL mRNA steady state levels in ALS, these observations provide support for the hypothesis that the dysregulation of miRNAs in spinal motor neurons in ALS fundamentally alters the stoichiometry of NF expression, leading to the formation of pathological NCIs

Novel miR-b2122 regulates several ALS-related RNA-binding proteins

Abstract Common pathological features of amyotrophic lateral sclerosis (ALS) include cytoplasmic aggregation of several RNA-binding proteins. Out of these RNA-binding proteins, TDP-43, FUS/TLS and RGNEF have been shown to co-aggregate with one another within motor neurons of sporadic ALS (sALS) patients, suggesting that there may be a common regulatory network disrupted. MiRNAs have been a recent focus in ALS research as they have been identified to be globally down-regulated in the spinal cord of ALS patients. The objective of this study was to identify if there are miRNA(s) dysregulated in sALS that are responsible for regulating the TDP-43, FUS/TLS and RGNEF network. In this study, we identify miR-194 and miR-b2122 to be significantly down-regulated in sALS patients, and were predicted to regulate TARDBP, FUS/TLS and RGNEF expression. Reporter gene assays and RT-qPCR revealed that miR-b2122 down-regulates the reporter gene through direct interactions with either the TARDBP, FUS/TLS, or RGNEF 3’UTR, while miR-194 down-regulates firefly expression when it contained either the TARDBP or FUS/TLS 3’UTR. Further, we showed that miR-b2122 regulates endogenous expression of all three of these genes in a neuronal-derived cell line. Also, an ALS-associated mutation in the FUS/TLS 3’UTR ablates the ability of miR-b2122 to regulate reporter gene linked to FUS/TLS 3’UTR, and sALS samples which showed a down-regulation in miR-b2122 also showed an increase in FUS/TLS protein expression. Overall, we have identified a novel miRNA that is down-regulated in sALS that appears to be a central regulator of disease-related RNA-binding proteins, and thus its dysregulation likely contributes to TDP-43, FUS/TLS and RGNEF pathogenesis in sALS