Assessing Descriptive Substance in Free-Text Collection-Level Metadata

Collection-level metadata has the potential to provide important information about the features and purpose of individual collections. This paper reports on a content analysis of collection records in an aggregation of cultural heritage collections. The findings show that the free-text Description field often provides more accurate and complete representation of subjects and object types than the specified fields. Properties such as importance, uniqueness, comprehensiveness, provenance, and creator are articulated, as well as other vital contextual information about the intentions of a collector and the value of a collection, as a whole, for scholarly users. The results demonstrate that the semantically rich free-text Description field is essential to understanding the context of collections in large aggregations and can serve as a source of data for enhancing and customizing controlled vocabulariesIMLS NLG Research and Demonstration grant LG-06-07-0020-07published or submitted for publicationis peer reviewe

MHC Class I Antigen Presentation of DRiP-Derived Peptides from a Model Antigen Is Not Dependent on the AAA ATPase p97

CD8⁺ T cells are responsible for killing cells of the body that have become infected or oncogenically transformed. In order to do so, effector CD8⁺ T cells must recognize their cognate antigenic peptide bound to a MHC class I molecule that has been directly presented by the target cell. Due to the rapid nature of antigen presentation, it is believed that antigenic peptides are derived from a subset of newly synthesized proteins which are degraded almost immediately following synthesis and termed Defective Ribosomal Products or DRiPs. We have recently reported on a bioassay which can distinguish antigen presentation of DRiP substrates from other forms of rapidly degraded proteins and found that poly-ubiquitin chain disassembly may be necessary for efficient DRiP presentation. The AAA ATPase p97 protein is necessary for efficient crosspresentation of antigens on MHC class I molecules and plays an important role in extracting mis-folded proteins from the endoplasmic reticulum. Here, we find that genetic ablation or chemical inhibition of p97 does not diminish DRiP antigen presentation to any great extent nor does it alter the levels of MHC class I molecules on the cell surface, despite our observations that p97 inhibition increased the levels of poly-ubiquitinated proteins in the cell. These data demonstrate that inhibiting poly-ubiquitin chain disassembly alone is insufficient to abolish DRiP presentation

Influence of wild-type MLL on glucocorticoid sensitivity and response to DNA-damage in pediatric acute lymphoblastic leukemia

<p>Abstract</p> <p>Background</p> <p>Rearrangement of the mixed-lineage leukemia gene (<it>MLL</it>) is found in 80% of infant acute lymphoblastic leukemia (ALL) and is associated with poor prognosis and resistance to glucocorticoids (GCs). We have recently observed that GC resistance in T-ALL cell lines is associated with a proliferative metabolism and reduced expression of <it>MLL</it>. In this study we have further explored the relationship between <it>MLL </it>status and GC sensitivity.</p> <p>Results</p> <p>Negative correlation of <it>MLL </it>expression with GC resistance in 15 T-ALL cell lines was confirmed by quantitative RT-PCR. The absence of <it>MLL</it>-rearrangements suggested that this relationship represented expression of wild-type <it>MLL</it>. Analysis of <it>MLL </it>expression patterns revealed a negative relationship with cellular metabolism, proliferation and anti-apoptotic transcriptional networks. <it>In silico </it>analysis of published data demonstrated that reduced levels of <it>MLL </it>mRNA are associated with relapse and prednisolone resistance in T-ALL patients and adverse clinical outcome in children with <it>MLL</it>-rearranged ALL. RNAi knockdown of <it>MLL </it>expression in T-ALL cell lines significantly increased resistance to dexamethasone and gamma irradiation indicating an important role for wild-type <it>MLL </it>in the control of cellular apoptosis.</p> <p>Conclusions</p> <p>The data suggests that reduced expression of wild-type <it>MLL </it>can contribute to GC resistance in ALL patients both with and without <it>MLL</it>-translocations.</p

Mycobacterium avium subsp hominissuis effector MAVA5_06970 promotes rapid apoptosis in secondary-infected macrophages during cell-to-cell spread

Mycobacterium avium subsp, hominissuis is an opportunistic intracellular pathogen associated with disease in patients either immunosuppression or chronic lung pathology. Once in the host, M. avium preferentially infects and replicates within the phagocytic cells. The host driven macrophage apoptosis appears to be an essential aspect of innate immunity during bacterial infection; however, the existing evidence suggests that M. avium has evolved adaptive approaches to trigger the phagocyte apoptosis, exit apoptotic cells or via ingestion of infected apoptotic bodies subsequently infect neighboring macrophages. By evaluating 4,000 transposon mutants of M. avium in THP-1 cells, we identified clones that can trigger a new form of early host cell apoptosis, which is only observed upon entry into the "secondary-infected" macrophages. Inactivation of MAVA5_06970 gene lead to significant attenuation in intracellular growth within macrophages and mice, and impaired M. avium to induce rapid apoptosis in the "secondary-infected" cells as measured by Annexin V-FITC detection assay. Complementation of MAVA5_06970 gene corrected the attenuation as well as apoptotic phenotypes. The MAVA5_06970 gene encodes for a secreted protein. Using the pull-down assay and then confirmed with the yeast two-hybrid screen, we found that MAVA5_06970 effector interacts with the Secreted Phosphoprotein 1, the cytokine also known as Osteopontin. This interaction enhances the THP-1 cell apoptosis and, consequently, restricts the production of interleukin-12 that likely may limit the activation of the type I immunity pathway in vivo. This work identified a key virulence effector of M. avium that contributes to the cell-to-cell spread of the pathogen

DNM1 encephalopathy: A new disease of vesicle fission.

ObjectiveTo evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.MethodsWe reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.ResultsWe identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.ConclusionsThe phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention

Enhanced Direct Major Histocompatibility Complex Class I Self-Antigen Presentation Induced by Chlamydia Infection

The direct major histocompatibility complex (MHC) class I antigen presentation pathway ensures intracellular peptides are displayed at the cellular surface for recognition of infected or transformed cells by CD8⁺ cytotoxic T lymphocytes. Chlamydia spp. are obligate intracellular bacteria and, as such, should be targeted by CD8⁺ T cells. It is likely that Chlamydia spp. have evolved mechanisms to avoid the CD8⁺ killer T cell responses by interfering with MHC class I antigen presentation. Using a model system of self-peptide presentation which allows for posttranslational control of the model protein's stability, we tested the ability of various Chlamydia species to alter direct MHC class I antigen presentation. Infection of the JY lymphoblastoid cell line limited the accumulation of a model host protein and increased presentation of the model-protein-derived peptides. Enhanced self-peptide presentation was detected only when presentation was restricted to defective ribosomal products, or DRiPs, and total MHC class I levels remained unaltered. Skewed antigen presentation was dependent on a bacterial synthesized component, as evidenced by reversal of the observed phenotype upon preventing bacterial transcription, translation, and the inhibition of bacterial lipooligosaccharide synthesis. These data suggest that Chlamydia spp. have evolved to alter the host antigen presentation machinery to favor presentation of defective and rapidly degraded forms of self-antigen, possibly as a mechanism to diminish the presentation of peptides derived from bacterial proteins

The flower garden banks Siderastrea siderea coral as a candidate global boundary stratotype section and point for the Anthropocene series

The proposed Anthropocene Global Boundary Stratotype Section and Point (GSSP) candidate site of West Flower Garden Bank (27.8762°N, 93.8147°W) is an open ocean location in the Gulf of Mexico with a submerged coral reef and few direct human impacts. Corals contain highly accurate and precise (<±1 year) internal chronologies, similar to tree rings, and their exoskeletons are formed of aragonite and can be preserved in the rock record. Here we present results from a large Siderastrea siderea coral (core 05WFGB3; 1755–2005 CE) sampled with annual and monthly resolutions that show clear markers of global and regional human impacts. Atmospheric nuclear bomb testing by-products (14C, 239+240Pu) have clear increases in this coral starting in 1957 for 14C and the first increase in 1956 for 239+240Pu (potential bases for the Anthropocene GSSP). Coral δ13C declined especially after 1956 consistent with the Suess Effect resulting from the burning of fossil fuels. Coral skeletal δ15N starts to increase in 1963 corresponding with the increase in agricultural fertilizers. Coral Hg concentrations (1933–1980) loosely track fluctuations in industrial pollution and coral Ba/Ca increases from 1965–1983 when offshore oil operations expand after 1947. Coral temperature proxies contain the 20th-century global warming trend whereas coral growth declines during this interval

ROS-Induced Nanotherapeutic Approach for Ovarian Cancer Treatment Based on the Combinatorial Effect of Photodynamic Therapy and DJ-1 Gene Suppression

This study represents a novel approach for intraoperative ovarian cancer treatment based on the combinatorial effect of a targeted photodynamic therapy (PDT) associated with suppression of the DJ-1 protein, one of the key players in the ROS defense of cancer cells. To assess the potential of the developed therapy, dendrimer-based nanoplatforms for cancer-targeted delivery of near-infrared photosensitizer, phthalocyanine, and DJ-1 siRNA have been constructed. In vitro studies revealed that therapeutic efficacy of the combinatorial approach was enhanced when compared to PDT alone and this enhancement was more pronounced in ovarian carcinoma cells, which are characterized by higher basal levels of DJ-1 protein. Moreover, the ovarian cancer tumors exposed to a single dose of combinatorial therapy were completely eradicated from the mice and the treated animals showed no evidence of cancer recurrence. Thus, the developed therapeutic approach can be potentially employed intraoperatively to eradicate unresactable cancer cells.Keywords: DJ-1, ovarian cancer, ROS, photodynamic therapy, siRNA therapyKeywords: DJ-1, ovarian cancer, ROS, photodynamic therapy, siRNA therap