University of Massachusetts Medical School

About: University of Massachusetts Medical School is a education organization based out in Worcester, Massachusetts, United States. It is known for research contribution in the topics: Population & Health care. The organization has 16161 authors who have published 31822 publications receiving 1909739 citations. The organization is also known as: UMass Medical School.

Clinical gene therapy using recombinant adeno-associated virus vectors

Abstract: Recombinant adeno-associated virus (rAAV) vectors possess a number of properties that may make them suitable for clinical gene therapy, including being based upon a virus for which there is no known pathology and a natural propensity to persist in human cells. Wild-type adeno-associated viruses (AAVs) are now known to be very diverse and ubiquitous in humans and nonhuman primates, which adds to the degree of confidence one may place in the natural history of AAV, namely that it has never been associated with any human tumors or other acute pathology, other than sporadic reports of having been isolated from spontaneously aborted fetuses. On the basis of this understanding of AAV biology and a wide range of preclinical studies in mice, rabbits, dogs and nonhuman primates, a growing number of clinical trials have been undertaken with this class of vectors. Altogether, over 40 clinical trials have now been approved. Although all previous trials were undertaken using AAV serotype 2 vectors, at least two current trials utilize AAV2 vector genomes cross-packaged or pseudotyped into AAV1 capsids, which appear to mediate more efficient gene delivery to muscle. The explosion of capsid isolates available for use as vectors to over 120 has now provided the potential to broaden the application of AAV-based gene therapy to other cell types.

Inflammasomes: too big to miss

Abstract: Inflammation is the coordinated immune response to harmful stimuli that appear during infections or after tissue damage. Cells of the innate immune system are the central players in mediating inflammatory tissue responses. These cells are equipped with an array of signaling receptors that detect foreign molecular substances or altered endogenous molecules that appear under situations of stress. This review provides an overview of recent progress in elucidating the molecular mechanisms that lead to inflammatory reactions. We discuss the current knowledge of the mechanisms leading to the activation of cytoplasmic, multimolecular protein complexes, termed "inflammasomes," which regulate the activity of caspase-1 and the maturation and release of IL-1beta.

26S proteasomes and immunoproteasomes produce mainly N‐extended versions of an antigenic peptide

Abstract: Protein degradation by proteasomes is the source of most antigenic peptides presented on MHC class I molecules. To determine whether proteasomes generate these peptides directly or longer precursors, we developed new methods to measure the efficiency with which 26S and 20S particles, during degradation of a protein, generate the presented epitope or potential precursors. Breakdown of ovalbumin by the 26S and 20S proteasomes yielded the immunodominant peptide SIINFEKL, but produced primarily variants containing 1–7 additional N‐terminal residues. Only 6–8% of the times that ovalbumin molecules were digested was a SIINFEKL or an N‐extended version produced. Surprisingly, immunoproteasomes which contain the interferon‐γ‐induced β‐subunits and are more efficient in antigen presentation, produced no more SIINFEKL than proteasomes. However, the immunoproteasomes released 2–4 times more of certain N‐extended versions. These observations show that the changes in cleavage specificity of immunoproteasomes influence not only the C‐terminus, but also the N‐terminus of potential antigenic peptides, and suggest that most MHC‐presented peptides result from N‐terminal trimming of larger proteasome products by aminopeptidases (e.g. the interferon‐γ‐induced enzyme leucine aminopeptidase).

Amyloid β induces neuronal cell death through ROS-mediated ASK1 activation

Abstract: Amyloid β (Aβ) is a main component of senile plaques in Alzheimer's disease and induces neuronal cell death. Reactive oxygen species (ROS), nitric oxide and endoplasmic reticulum (ER) stress have been implicated in Aβ-induced neurotoxicity. We have reported that apoptosis signal-regulating kinase 1 (ASK1) is required for ROS- and ER stress-induced JNK activation and apoptosis. Here we show the involvement of ASK1 in Aβ-induced neuronal cell death. Aβ activated ASK1 mainly through production of ROS but not through ER stress in cultured neuronal cells. Importantly, ASK1−/− neurons were defective in Aβ-induced JNK activation and cell death. These results indicate that ROS-mediated ASK1 activation is a key mechanism for Aβ-induced neurotoxicity, which plays a central role in Alzheimer's disease.