Biomedical subjects

E W Wang

Publications and source records attributed to E W Wang.

10 recordsLinked to original sources

PubMed2002

Proteasome inhibitors: complex tools for a complex enzyme.

As the dominant protease dedicated to protein turnover, the proteasome shapes the cellular protein repertoire. Our knowledge of proteasome regulation and activity has improved considerably over the past decade. Novel inhibitors, in particular, have helped to advance our understanding of proteasome biology. They range from small peptide-based structures that can be modified to vary target specificity, to large macromolecular inhibitors that include proteins. While these reagents have played an important role in establishing our current knowledge of the proteasome's catalytic mechanism, many questions remain. Rapid advances in the synthesis and identification of new classes of proteasome inhibitors over the last 10 years serve as a positive indicator that many of these questions will soon be resolved. The future lies in designing compounds that can function as drugs to target processes involved in disease progression. It may only be a short while before the products of such research have safe application in a practical setting. Structural and combinatorial chemistry approaches are powerful techniques that will bring us closer to these goals.

Acetylcysteine↗

PubMed2001

Antigen presentation subverted: Structure of the human cytomegalovirus protein US2 bound to the class I molecule HLA-A2.

Many persistent viruses have evolved the ability to subvert MHC class I antigen presentation. Indeed, human cytomegalovirus (HCMV) encodes at least four proteins that down-regulate cell-surface expression of class I. The HCMV unique short (US)2 glycoprotein binds newly synthesized class I molecules within the endoplasmic reticulum (ER) and subsequently targets them for proteasomal degradation. We report the crystal structure of US2 bound to the HLA-A2/Tax peptide complex. US2 associates with HLA-A2 at the junction of the peptide-binding region and the alpha3 domain, a novel binding surface on class I that allows US2 to bind independently of peptide sequence. Mutation of class I heavy chains confirms the importance of this binding site in vivo. Available data on class I-ER chaperone interactions indicate that chaperones would not impede US2 binding. Unexpectedly, the US2 ER-luminal domain forms an Ig-like fold. A US2 structure-based sequence alignment reveals that seven HCMV proteins, at least three of which function in immune evasion, share the same fold as US2. The structure allows design of further experiments to determine how US2 targets class I molecules for degradation.

Amino Acid Sequence↗

PubMed2001

Virus subversion of immunity: a structural perspective.

Over the past year, we have witnessed the discovery of further virus immuno-evasins--proteins that alter the host immune response. Although many of these factors have been described over the past decade, the structural basis underlying their biology has lagged behind. Structural data have now been obtained for several such proteins. Major advances of the past year include the structures of a viral chemokine-binding protein, of an intact viral regulator of complement activation and of an immuno-evasin with its cellular target.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

The prevalence of mental illness in prison.

Over the last decade state prisons have experienced unprecedented growth and many demographic changes. At the same time, courts are requiring states to provide mental health screening and treatment to prisoners. Findings from recent studies indicate that the prevalence of mental illness is higher in prisons than in the community, and comorbidity is common. Our ability to generalize from these studies is limited, however, because of major shifts in the demographic mix in prisons during the past decade. New studies on the prevalence of mental illness in prisons, which consider these recent changes would help planners allocate funds and staff to more effectively meet the needs of these individuals.

Cross-Sectional Studies↗

PubMed2001

Human cytomegalovirus US2 endoplasmic reticulum-lumenal domain dictates association with major histocompatibility complex class I in a locus-specific manner.

The human cytomegalovirus-encoded US2 glycoprotein targets endoplasmic reticulum-resident major histocompatibility complex (MHC) class I heavy chains for rapid degradation by the proteasome. We demonstrate that the endoplasmic reticulum-lumenal domain of US2 allows tight interaction with class I molecules encoded by the HLA-A locus. Recombinant soluble US2 binds properly folded, peptide-containing recombinant HLA-A2 molecules in a peptide sequence-independent manner, consistent with US2's ability to broadly downregulate class I molecules. The physicochemical properties of the US2/MHC class I complex suggest a 1:1 stoichiometry. These results demonstrate that US2 does not require additional cellular proteins to specifically interact with soluble class I molecules. Binding of US2 does not significantly alter the conformation of class I molecules, as a soluble T-cell receptor can simultaneously recognize class I molecules associated with US2. The lumenal domain of US2 can differentiate between the products of distinct class I loci, as US2 binds several HLA-A locus products while being unable to bind recombinant HLA-B7, HLA-B27, HLA-Cw4, or HLA-E. We did not observe interaction between soluble US2 and either recombinant HLA-DR1 or recombinant HLA-DM. The substrate specificity of US2 may help explain the presence in human cytomegalovirus of multiple strategies for downregulation of MHC class I molecules.

Cytomegalovirus↗

PubMed2000

Integration of the ubiquitin-proteasome pathway with a cytosolic oligopeptidase activity.

Cytosolic proteolysis is carried out predominantly by the proteasome. We show that a large oligopeptidase, tripeptidylpeptidase II (TPPII), can compensate for compromised proteasome activity. Overexpression of TPPII is sufficient to prevent accumulation of polyubiquitinated proteins and allows survival of EL-4 cells at otherwise lethal concentrations of the covalent proteasome inhibitor NLVS (NIP-leu-leu-leu-vinylsulfone). Elevated TPPII activity also partially restores peptide loading of MHC molecules. Purified proteasomes from adapted cells lack the chymotryptic-like activity, but still degrade longer peptide substrates via residual activity of their Z subunits. However, growth of adapted cells depends on induction of other proteolytic activities. Therefore, cytosolic oligopeptidases such as TPPII normalize rates of intracellular protein breakdown required for normal cellular function and viability.

Amino Acid Sequence↗

PubMed1999

Empirically identifying factors related to violence risk in corrections.

The authors used structural modeling to predict institutional aggression among male mentally ill offenders using the predictors of anger, antisocial personality style, current violent offense, ethnicity, and impulsivity. Measures included the Barratt Impulsiveness Scale, the Buss-Perry Aggression Questionnaire, the Personality Assessment Inventory, age, ethnicity, current violent offense, victim injury from current offense, and institutional incidents of physical and verbal aggression. The model fit the data, and accounted for 94% and 87% of the variance of physical and verbal aggression, respectively. Results indicated anger, antisocial personality style, and impulsivity are stronger predictors of institutional aggression than are ethnicity and current violent offense; anger was the best predictor. Results suggest dynamic variables such as anger can be targeted for clinical intervention to reduce institutional violence.

Adult↗

PubMed1998

The PAI and feigning: A cautionary note on its use in forensic-correctional settings.

Indicators of feigned PAI profiles were derived from comparisons of simulators instructed to feign and genuine patient groups. Concerns are raised regarding whether these indicators are applicable to forensic and correctional populations and can be cross-validated with a known-groups comparison. Compiling data on 57 malingerers and 58 genuine patients from two forensic and correctional sites, three primary indicators of feigning, Negative Impression (NIM) scale, Malingering Index, and the Rogers Discriminant Function (RDF) were investigated. Results suggested that the RDF was not applicable to forensic referrals. However, NIM 77T appeared to be a useful screen for forensic samples. In addition, convergent evidence of feigning was found across designs (simulation and known-groups) and samples (non-forensic and forensic) for extreme elevations on NIM (>/=110T) and Malingering Index (>/=5).

Adult↗

PubMed1997

A pilot study of the Personality Assessment Inventory (PAI) in corrections: assessment of malingering, suicide risk, and aggression in male inmates.

Provision of mental health services to correctional populations places considerable demands on clinical staff to provide efficient and effective means to screen patients for severe mental disorders and other emergent conditions that necessitate immediate interventions. Among the highly problematic behaviors found in correctional settings are forms of acting out (e.g., suicide and aggression towards others) and response style (e.g., motivations to malinger). The current study examined the usefulness of the Personality Assessment Inventory (PAI) in assessing problematic behaviors in a corrections-based psychiatric hospital. As evidence of criterion related validity, selected PAI scales were compared to (a) evidence of malingering on the Structured Interview of Reported Symptoms (SIRS), (b) suicidal threats and gestures, and (c) ratings of aggression on the Overt Aggression Scale (OAS). In general, results supported the use of the PAI for the assessment of these problematic behaviors.

Adult↗

PubMed1988

An adenovirus mRNA which encodes a 14,700-Mr protein that maps to the last open reading frame of region E3 is expressed during infection.

The E3 regions of adenovirus types 2 and 5, respectively, are known to synthesize proteins of 19,000 Mr (19K) and 11.6K, but information regarding the identity and characterization of other potential E3 proteins encoded by the six remaining open reading frames (ORFs) is lacking. In this study, we show that the last ORF of region E3, which encodes a 14.7K protein, is expressed in adenovirus-infected cells. This information was largely derived from analysis of an E3 deletion mutant (H2dl801) in which an extensive deletion (1,939 base pairs) was found to eliminate all ORFs except for two proteins of 12.5K and 14.7K. The 14.7K protein was translated from RNA isolated from H2dl801-infected cells that had been hybridization selected to E3 DNA; hybridization-selected RNA from wild-type adenovirus type 5-infected cells translated both the 19K and the 14.7K proteins. Moreover, an antiserum directed against a bacterial 14.7K fusion protein (A. E. Tollefson and W. S. M. Wold, J. Virol. 62:33-39, 1988) immunoprecipitated the 14.7K translation product synthesized by wild-type and mutant H2dl801 adenovirus mRNAs.

Adenoviruses, Human↗