42 research outputs found
Mutations in mitochondrial enzyme GPT2 cause metabolic dysfunction and neurological disease with developmental and progressive features
Mutations that cause neurological phenotypes are highly informative with regard to mechanisms governing human brain function and disease. We report autosomal recessive mutations in the enzyme glutamate pyruvate transaminase 2 (GPT2) in large kindreds initially ascertained for intellectual and developmental disability (IDD). GPT2 [also known as alanine transaminase 2 (ALT2)] is one of two related transaminases that catalyze the reversible addition of an amino group from glutamate to pyruvate, yielding alanine and α-ketoglutarate. In addition to IDD, all affected individuals show postnatal microcephaly and âŒ80% of those followed over time show progressive motor symptoms, a spastic paraplegia. Homozygous nonsense p.Arg404* and missense p.Pro272Leu mutations are shown biochemically to be loss of function. The GPT2 gene demonstrates increasing expression in brain in the early postnatal period, and GPT2 protein localizes to mitochondria. Akin to the human phenotype, Gpt2-null mice exhibit reduced brain growth. Through metabolomics and direct isotope tracing experiments, we find a number of metabolic abnormalities associated with loss of Gpt2. These include defects in amino acid metabolism such as low alanine levels and elevated essential amino acids. Also, we find defects in anaplerosis, the metabolic process involved in replenishing TCA cycle intermediates. Finally, mutant brains demonstrate misregulated metabolites in pathways implicated in neuroprotective mechanisms previously associated with neurodegenerative disorders. Overall, our data reveal an important role for the GPT2 enzyme in mitochondrial metabolism with relevance to developmental as well as potentially to neurodegenerative mechanisms.National Institute of Neurological Diseases and Stroke (U.S.) (R01NS035129)United States. National Institutes of Health (R21TW008223)National Cancer Institute (U.S.) (R01CA157996
Concise review:workshop review: understanding and assessing the risks of stem cell-based therapies
The field of stem cell therapeutics is moving ever closer to widespread application in the clinic. However, despite the undoubted potential held by these therapies, the balance between risk and benefit remains difficult to predict. As in any new field, a lack of previous application in man and gaps in the underlying science mean that regulators and investigators continue to look for a balance between minimizing potential risk and ensuring therapies are not needlessly kept from patients. Here, we attempt to identify the important safety issues, assessing the current advances in scientific knowledge and how they may translate to clinical therapeutic strategies in the identification and management of these risks. We also investigate the tools and techniques currently available to researchers during preclinical and clinical development of stem cell products, their utility and limitations, and how these tools may be strategically used in the development of these therapies. We conclude that ensuring safety through cutting-edge science and robust assays, coupled with regular and open discussions between regulators and academic/industrial investigators, is likely to prove the most fruitful route to ensuring the safest possible development of new product
Corrigendum to âMolecular and macro-scale analysis of enzyme-crosslinked silk hydrogels for rational biomaterial designâ [Acta Biomater. 63 (2017) 76â84]
The Emergence of Rule-Based Security Forces: Lessons from Early Modern State-Building Applied to the Afghan Local Police
Laser-based three-dimensional multiscale micropatterning of biocompatible hydrogels for customized tissue engineering scaffolds
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Molecular disparity in human leukocyte antigens is associated with outcomes in haploidentical stem cell transplantation
Haploidentical donors are increasingly used for patients requiring hematopoietic stem cell transplantation (HSCT). Although several factors have been associated with transplant outcomes, the impact of HLA disparity in haploidentical HSCT (haplo-HSCT) remains unclear. We investigated the impact of HLA disparity quantified by mismatched eplets (ME) load of each HLA locus on the clinical outcome of 278 consecutive haploidentical transplants. Here, we demonstrated that the degree of HLA molecular mismatches, at individual HLA loci, may be relevant to clinical outcome in the haplo-HSCT. A significantly better overall survival was associated with higher ME load from HLA-A (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.95-0.99; P = .003) and class I loci (HR, 0.99; 95% CI, 0.97-0.99; P = .045) in the host-versus-graft direction. The apparent survival advantage of HLA-A ME was primarily attributed to reduced risk in relapse associated with an increase in HLA-A ME load (subdistribution HR, 0.95; 95% CI, 0.92-0.98; P = .004). Furthermore, we have identified an association between the risk of grade 3-4 acute graft-versus-host disease (GVHD) and a higher ME load at HLA-B and class I loci in graft-versus-host (GVH) direction. Additionally, GVH nonpermissive HLA-DPB1 mismatch defined by T-cell epitope grouping was significantly associated with relapse protection (subdistribution HR, 0.19; 95% CI, 0.06-0.59; P = .004) without a concurrent increase in GVHD. These findings indicate that alloreactivity generated by HLA disparity at certain HLA loci is associated with transplant outcomes, and ME analysis of individual HLA loci might assist donor selection and risk stratification in haplo-HSCT
Transparent, Nanostructured Silk Fibroin Hydrogels with Tunable Mechanical Properties
Silk fibroin from the <i>Bombyx
mori</i> caterpillar
has been processed into many material forms, with potential applications
in areas ranging from optoelectronics to tissue engineering. As a
hydrogel, silk fibroin has been engineered as a substrate for the
regeneration of soft tissues where hydration and mechanical compatibility
are necessary. Current fabrication of silk fibroin hydrogels produces
microstructured materials that lack transparency and limits the ability
to fully exploit the hydrogel form. Transparency is the main characteristic
of some human tissues (e.g., cornea) where silk fibroin in the film
format has shown potential as scaffolding material, however, lacking
the necessary hydration and successful attachment of cells without
biochemical functionalization. Additionally, detection using light
is an important method to translate information for instruction, sensing,
and visualization of biological entities and light sensitive molecules.
Here, we introduce a method for the fabrication of transparent silk
hydrogels by driving the formation of nanostructures in the silk fibroin
material. These nanostructures are formed by exposing silk solution
(concentration below 15 mg/mL) to organic solvents that induce the
amorphous to crystalline transition of the protein and indeed the
solâgel transition of the material. We have also explored a
process to modulate the mechanical properties of silk fibroin hydrogel
within the physiological range by controlling the amount of metal
ions present in the protein structure. Nanostructured silk fibroin
hydrogels are biocompatible and allow for attachment and proliferation
of human dermal fibroblasts without any biochemical functionalization.
In addition, seeding of human cornea epithelial cells (HCECs) on the
hydrogel surface results in the formation of an epithelium, which
does not alter the gelsâ transparency and shows biological
properties that challenge the performances of HCECs seeded in collagen
hydrogels, the current standard material for the engineering of corneal
tissue