740 research outputs found
Concise Review: Stem Cell Therapies for Amyotrophic Lateral Sclerosis: Recent Advances and Prospects for the Future
Amyotrophic lateral sclerosis (ALS) is a lethal disease involving the loss of motor neurons. Although the mechanisms responsible for motor neuron degeneration in ALS remain elusive, the development of stem cellâbased therapies for the treatment of ALS has gained widespread support. Here, we review the types of stem cells being considered for therapeutic applications in ALS, and emphasize recent preclinical advances that provide supportive rationale for clinical translation. We also discuss early trials from around the world translating cellular therapies to ALS patients, and offer important considerations for future clinical trial design. Although clinical translation is still in its infancy, and additional insight into the mechanisms underlying therapeutic efficacy and the establishment of longâterm safety are required, these studies represent an important first step toward the development of effective cellular therapies for the treatment of ALS. S tem C ells 2014;32:1099â1109Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106861/1/stem1628.pd
RNA polymerase V-dependent small RNAs in Arabidopsis originate from small, intergenic loci including most SINE repeats.
In plants, heterochromatin is maintained by a small RNA-based gene silencing mechanism known as RNA-directed DNA methylation (RdDM). RdDM requires the non-redundant functions of two plant-specific DNA-dependent RNA polymerases (RNAP), RNAP IV and RNAP V. RNAP IV plays a major role in siRNA biogenesis, while RNAP V may recruit DNA methylation machinery to target endogenous loci for silencing. Although small RNA-generating regions that are dependent on both RNAP IV and RNAP V have been identified previously, the genomic loci targeted by RNAP V for siRNA accumulation and silencing have not been described extensively. To characterize the RNAP V-dependent, heterochromatic siRNA-generating regions in the Arabidopsis genome, we deeply sequenced the small RNA populations of wild-type and RNAP V null mutant (nrpe1) plants. Our results showed that RNAP V-dependent siRNA-generating loci are associated predominately with short repetitive sequences in intergenic regions. Suppression of small RNA production from short repetitive sequences was also prominent in RdDM mutants including dms4, drd1, dms3 and rdm1, reflecting the known association of these RdDM effectors with RNAP V. The genomic regions targeted by RNAP V were small, with an estimated average length of 238 bp. Our results suggest that RNAP V affects siRNA production from genomic loci with features dissimilar to known RNAP IV-dependent loci. RNAP V, along with RNAP IV and DRM1/2, may target and silence a set of small, intergenic transposable elements located in dispersed genomic regions for silencing. Silencing at these loci may be actively reinforced by RdDM
Stem cell technology for neurodegenerative diseases
Over the past 20 years, stem cell technologies have become an increasingly attractive option to investigate and treat neurodegenerative diseases. In the current review, we discuss the process of extending basic stem cell research into translational therapies for patients suffering from neurodegenerative diseases. We begin with a discussion of the burden of these diseases on society, emphasizing the need for increased attention toward advancing stem cell therapies. We then explain the various types of stem cells utilized in neurodegenerative disease research, and outline important issues to consider in the transition of stem cell therapy from bench to bedside. Finally, we detail the current progress regarding the applications of stem cell therapies to specific neurodegenerative diseases, focusing on Parkinson disease, Huntington disease, Alzheimer disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. With a greater understanding of the capacity of stem cell technologies, there is growing public hope that stem cell therapies will continue to progress into realistic and efficacious treatments for neurodegenerative diseases. Ann Neurol 2011;70: 353â361.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86937/1/22487_ftp.pd
Chromophore-labelled, luminescent platinum complexes: syntheses, structures, and spectroscopic properties
Ligands based upon 4-carboxamide-2-phenylquinoline derivatives have been synthesised with solubilising octyl hydrocarbon chains and tethered aromatic chromophores to give naphthyl (HL2), anthracenyl (HL3) and pyrenyl (HL4) ligand variants, together with a non-chromophoric analogue (HL1) for comparison. 1H NMR spectroscopic studies of the ligands showed that two non-interchangeable isomers exist for HL2 and HL4 while only one isomer exists for HL1 and HL3. Supporting DFT calculations on HL4 suggest that the two isomers may be closely isoenergetic with a relatively high barrier to exchange of ca. 100 kJ molâ1. These new ligands were cyclometalated with Pt(II) to give complexes [Pt(L1â4)(acac)] (acac = acetylacetonate). The spectroscopically characterised complexes were studied using multinuclear NMR spectroscopy including 195Pt{1H} NMR studies which revealed ÎŽPt ca. â2785 ppm for [Pt(L1â4)(acac)]. X-ray crystallographic studies were undertaken on [Pt(L3)(acac)] and [Pt(L4)(acac)], each showing the weakly distorted square planar geometry at Pt(II); the structure of [Pt(L3)(acac)] showed evidence for intermolecular PtâPt interactions. The UV-vis. absorption studies show that the spectral profiles for [Pt(L2â4)(acac)] are a composite of the organic chromophore centred bands and a broad 1MLCT (5d â Ï*) band (ca. 440 nm) associated with the complex. Luminescence studies showed that complexes [Pt(L2â4)(acac)] are dual emissive with fluorescence characteristic of the tethered fluorophore and long-lived phosphorescence attributed to 3MLCT emission. In the case of the pyrenyl derivative, [Pt(L4)(acac)], the close energetic matching of the 3MLCT and 3LCpyr excited states led to an elongation of the 3MLCT emission lifetime (Ï = 42 ÎŒs) under degassed solvent conditions, suggestive of energy transfer processes between the two states
Plants regenerated from tissue culture contain stable epigenome changes in rice.
Most transgenic crops are produced through tissue culture. The impact of utilizing such methods on the plant epigenome is poorly understood. Here we generated whole-genome, single-nucleotide resolution maps of DNA methylation in several regenerated rice lines. We found that all tested regenerated plants had significant losses of methylation compared to non-regenerated plants. Loss of methylation was largely stable across generations, and certain sites in the genome were particularly susceptible to loss of methylation. Loss of methylation at promoters was associated with deregulated expression of protein-coding genes. Analyses of callus and untransformed plants regenerated from callus indicated that loss of methylation is stochastically induced at the tissue culture step. These changes in methylation may explain a component of somaclonal variation, a phenomenon in which plants derived from tissue culture manifest phenotypic variability. DOI:http://dx.doi.org/10.7554/eLife.00354.001
Near-IR luminescent neodymium complexes: spectroscopic probes for hydroamination catalysis
Neodymium complexes bearing the sensitising bis(oxazolinylphenyl)amine (BOPA) ligands have been prepared, and analysed spectroscopically under both catalytic and pseudo-catalytic conditions with respect to the intramolecular hydroamination of an aminoalkene, providing a direct means of monitoring binding events and relative space around the metal centre
Autocrine Production of IGFâI Increases Stem CellâMediated Neuroprotection
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder resulting in motor neuron (MN) loss. There are currently no effective therapies; however, cellular therapies using neural progenitor cells protect MNs and attenuate disease progression in G93AâSOD1 ALS rats. Recently, we completed a phase I clinical trial examining intraspinal human spinal stem cell (HSSC) transplantation in ALS patients which demonstrated our approach was safe and feasible, supporting the phase II trial currently in progress. In parallel, efforts focused on understanding the mechanisms underlying the preclinical benefit of HSSCs in vitro and in animal models of ALS led us to investigate how insulinâlike growth factorâI (IGFâI) production contributes to cellular therapy neuroprotection. IGFâI is a potent growth factor with proven efficacy in preclinical ALS studies, and we contend that autocrine IGFâI production may enhance the salutary effects of HSSCs. By comparing the biological properties of HSSCs to HSSCs expressing sixfold higher levels of IGFâI, we demonstrate that IGFâI production augments the production of glialâderived neurotrophic factor and accelerates neurite outgrowth without adversely affecting HSSC proliferation or terminal differentiation. Furthermore, we demonstrate that increased IGFâI induces more potent MN protection from excitotoxicity via both indirect and direct mechanisms, as demonstrated using hanging inserts with primary MNs or by culturing with organotypic spinal cord slices, respectively. These findings support our theory that combining autocrine growth factor production with HSSC transplantation may offer a novel means to achieve additive neuroprotection in ALS. Stem Cells 2015;33:1480â1489Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111155/1/stem1933.pd
Near-IR luminescent lanthanide complexes with 1,8-diaminoanthraquinone-based chromophoric ligands
Three new chromophoric anthraquinone-based multidentate ligands have been synthesised in a step-wise manner from 1,8-dichloroanthraquinone. The ligands each comprise two dipicolyl amine units and react with trivalent lanthanide ions to form monometallic complexes of the form [Ln(L)](OTf)3 as indicated by MS studies and elemental analyses. Supporting DFT studies show that the monometallic species are highly favoured (>1000 kJ molâ1) over the formation of a 2 : 2 dimetallic congener. Both ligands and complexes absorb light efficiently (Δ ⌠104 Mâ1 cmâ1) in the visible part of the spectrum, with λabs ca. 535â550 nm through an intramolecular charge transfer (ICT) transition localised on the substituted anthraquinone unit. In all cases the complexes show a fluorescence band at ca. 675 nm due to the ICT emitting state. The corresponding Nd(III), Yb(III) and Er(III) complexes also reveal sensitised near-IR emission characteristic of each ion following excitation of the ICT visible absorption band at 535 nm
TH17 cells require ongoing classic IL-6 receptor signaling to retain transcriptional and functional identity
Acting in concert with TGF-b, IL-6 signaling induces Th17 cell development by programming Th17-related genes via STAT3. A role for IL-6 signaling beyond the inductive phase of Th17 cell development has not been defined, as IL-23 signaling downstream of Th17 cell induction also activates STAT3 and is thought responsible for Th17 cell maintenance. Here, we find that IL-6 signaling is required for both induction and maintenance of Th17 cells; IL-6Raâdeficient Th17 cells rapidly lost their Th17 phenotype and did not cause disease in two models of colitis. Cotransfer of WT Th17 cells with IL-6Raâdeficient Th17 cells induced colitis but was unable to rescue phenotype loss of the latter. High IL-6 in the colon promoted classic, or cis, rather than trans receptor signaling that was required for maintenance of Th17 cells. Thus, ongoing classic IL6 signaling underpins the Th17 program and is required for Th17 cell maintenance and function
Human Cortical Neural Stem Cells Expressing InsulinâLike Growth FactorâI: A Novel Cellular Therapy for Alzheimerâs Disease
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135291/1/sct3201653379.pd
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