67 research outputs found

    PKCθ Is Required For Alloreactivity And GVHD But Not For Immune Responses Toward Leukemia And Infection In Mice

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    Loss of function mutations in HARS cause a spectrum of inherited peripheral neuropathies.

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    Inherited peripheral neuropathies are a genetically heterogeneous group of disorders characterized by distal muscle weakness and sensory loss. Mutations in genes encoding aminoacyl-tRNA synthetases have been implicated in peripheral neuropathies, suggesting that these tRNA charging enzymes are uniquely important for the peripheral nerve. Recently, a mutation in histidyl-tRNA synthetase (HARS) was identified in a single patient with a late-onset, sensory-predominant peripheral neuropathy; however, the genetic evidence was lacking, making the significance of the finding unclear. Here, we present clinical, genetic, and functional data that implicate HARS mutations in inherited peripheral neuropathies. The associated phenotypic spectrum is broad and encompasses axonal and demyelinating motor and sensory neuropathies, including four young patients presenting with pure motor axonal neuropathy. Genome-wide linkage studies in combination with whole-exome and conventional sequencing revealed four distinct and previously unreported heterozygous HARS mutations segregating with autosomal dominant peripheral neuropathy in four unrelated families (p.Thr132Ile, p.Pro134His, p.Asp175Glu and p.Asp364Tyr). All mutations cause a loss of function in yeast complementation assays, and p.Asp364Tyr is dominantly neurotoxic in a Caenorhabditis elegans model. This study demonstrates the role of HARS mutations in peripheral neuropathy and expands the genetic and clinical spectrum of aminoacyl-tRNA synthetase-related human disease

    Stimuli responsive polymeric nanoparticles in regulated drug delivery for cancer

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    Stimuli-responsive drug delivery system is a concept in which a drug is delivered at a suitable rate in response to stimuli. States of diseases may cause an alteration in some parameters of the body (e.g. in tumors) and the onset and offset of the drug delivery can be done by using this as a stimuli or a "trigger". Stimuli-responsive ("intellectual" or "sharp") resources and molecules show abrupt property changes in response to miniature changes in external stimuli such as pH, temperature etc. For regulated drug delivery, environmental stimuli such as pH and temperature, which undertake phase transition in polymer system, have been investigated. Thermally-responsive polymers can be tuned to a preferred temperature variety by copolymerization with a hydrophilic co-monomer or a hydrophobic co-monomer. Hydrophilic co-monomers increase the LCST while hydrophobic co-monomers decrease the LCST. The stimuli responsive polymer for regulated drug delivery can contain a polymer and copolymers having equilibrium of hydrophilic and hydrophobic groups. A number of these polymers have been investigated extensively and some success in drug delivery with them has been achieved, such as polymers and copolymers of N-isopropylacrylamide, PLGA, and PLA, HEMA etc. Thus this review is designed for stimuli pH and temperature responsive polymeric nanoparticles, which would be helpful to treat various cronic diseases such as cancer and others, for scientists in the field of the regulated drug delivery system
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