Allosteric Tuning of Caspase-7: Establishing the Nexus of Structure and Catalytic Power.

Invited for the cover of this issue is the group of Michael Ashley Spies at the University of Iowa. The image depicts how mapping allosteric structure-activity relationships reveals the nexus between the active site and the remote allosteric pocket. Read the full text of the article at 10.

Therapeutic disruption of RAD52-ssDNA complexation via novel drug-like inhibitors.

RAD52 protein is a coveted target for anticancer drug discovery. Similar to poly-ADP-ribose polymerase (PARP) inhibitors, pharmacological inhibition of RAD52 is synthetically lethal with defects in genome caretakers BRCA1 and BRCA2 (∼25% of breast and ovarian cancers). Emerging structure activity relationships for RAD52 are complex, making it challenging to transform previously identified disruptors of the RAD52-ssDNA interaction into drug-like leads using traditional medicinal chemistry approaches.

Allosteric Tuning of Caspase-7: Establishing the Nexus of Structure and Catalytic Power.

Caspase-7 (C7), a cysteine protease involved in apoptosis, is a valuable drug target for its role in human diseases (e. g., Parkinson's, Alzheimer's, sepsis).

The impact of a multimodal professional network on developing social capital and research capacity of faculty at historically black colleges and universities.

This qualitative case study examined how a multimodal professional network environment (STEM for all Video Showcase) affected five STEM educational researchers' capacity to engage in grant funded research at U.S. Historically Black Colleges and Universities (HBCUs).

Decrypting a cryptic allosteric pocket in H. pylori glutamate racemase.

One of our greatest challenges in drug design is targeting cryptic allosteric pockets in enzyme targets. Drug leads that do bind to these cryptic pockets are often discovered during HTS campaigns, and the mechanisms of action are rarely understood. Nevertheless, it is often the case that the allosteric pocket provides the best option for drug development against a given target.

Decrypting a Cryptic Allosteric Pocket in Glutamate Racemase.

One of our greatest challenges in drug design is targeting cryptic allosteric pockets in enzyme targets. Drug leads that do bind to these cryptic pockets are often discovered during HTS campaigns, and the mechanisms of action are rarely understood. Nevertheless, it is often the case that the allosteric pocket provides the best option for drug development against a given target.

Optimization of Ligands Using Focused DNA-Encoded Libraries To Develop a Selective, Cell-Permeable CBX8 Chromodomain Inhibitor.

Polycomb repressive complex 1 (PRC1) is critical for mediating gene expression during development. Five chromobox (CBX) homolog proteins, CBX2, CBX4, CBX6, CBX7, and CBX8, are incorporated into PRC1 complexes, where they mediate targeting to trimethylated lysine 27 of histone H3 (H3K27me3) the N-terminal chromodomain (ChD). Individual CBX paralogs have been implicated as drug targets in cancer; however, high similarities in sequence and structure among the CBX ChDs provide a major obstacle in developing selective CBX ChD inhibitors.

Efficacy and Safety of Epratuzumab in Moderately to Severely Active Systemic Lupus Erythematosus: Results From Two Phase III Randomized, Double-Blind, Placebo-Controlled Trials.

Objective: Epratuzumab, a monoclonal antibody that targets CD22, modulates B cell signaling without substantial reductions in the number of B cells. The aim of this study was to report the results of 2 phase III multicenter randomized, double-blind, placebo-controlled trials, the EMBODY 1 and EMBODY 2 trials, assessing the efficacy and safety of epratuzumab in patients with moderately to severely active systemic lupus erythematosus (SLE).

Methods: Patients met ≥4 of the American College of Rheumatology revised classification criteria for SLE, were positive for antinuclear antibodies and/or anti-double-stranded DNA antibodies, had an SLE Disease Activity Index 2000 (SLEDAI-2K) score of ≥6 (increased disease activity), had British Isles Lupus Assessment Group 2004 index (BILAG-2004) scores of grade A (severe disease activity) in ≥1 body system or grade B (moderate disease activity) in ≥2 body systems (in the mucocutaneous, musculoskeletal, or cardiorespiratory domains), and were receiving standard therapy, including mandatory treatment with corticosteroids (5-60 mg/day).

Goal attributions and instrumental helping at 14 and 24 months of age.

Infants reason about goals and helping as early as 3 months of age, but toddlers fail to help others appropriately until well into the second year. Five experiments explored the reasons for this discrepancy. First, we verified that 14-month-old toddlers encode the goal of an actor's reaching action, in a situation in which a social agent selectively reaches for one of two objects.

Randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of etanercept in patients with moderately active rheumatoid arthritis despite DMARD therapy.

This study evaluated the efficacy and safety of adding etanercept to disease-modifying antirheumatic drugs (DMARDs) in patients with moderately active rheumatoid arthritis (RA). This randomized, double-blind, placebo-controlled study (ClinicalTrials.gov #NCT01313208) enrolled RA patients with Disease Activity Score using 28 joints with C-reactive protein (DAS28-CRP) >3.

Epratuzumab for patients with moderate to severe flaring SLE: health-related quality of life outcomes and corticosteroid use in the randomized controlled ALLEVIATE trials and extension study SL0006.

Objective: To evaluate health-related quality of life (HRQOL) and corticosteroid use in patients with moderate to severely active SLE enrolled in two international, multicentre, randomized controlled trials of epratuzumab (ALLEVIATE-1 and -2) and a long-term extension study (SL0006).

Methods: Ninety ALLEVIATE patients (43% BILAG A, mean BILAG score 13.2) were randomized to receive 360 mg/m(2) (n = 42) or 720 mg/m(2) (n = 11) epratuzumab or placebo (n = 37), plus standard of care, in 12-week cycles.

Efficacy and safety of epratuzumab in patients with moderate/severe flaring systemic lupus erythematosus: results from two randomized, double-blind, placebo-controlled, multicentre studies (ALLEVIATE) and follow-up.

Objective: To evaluate epratuzumab treatment in patients with moderately-to-severely active SLE in two international, randomized, controlled trials (ALLEVIATE-1 and -2) and an open-label extension study (SL0006).

Methods: Ninety ALLEVIATE patients (43% BILAG A, median BILAG score 12.0) received standard of care plus 10 total doses of placebo (n = 37) or 360 mg/m(2) (n = 42) or 720 mg/m(2) (n = 11) epratuzumab, administered across 12-week cycles for up to 48 weeks, with BILAG assessments every 4 weeks.

Rheumatoid arthritis disease measurement: a new old idea.

In many medical treatment areas, the use of treatment targets has led to improved outcomes, including a reduction in end-organ damage. In rheumatology, appropriate targets appear elusive, although preventing joint damage, minimizing disability and improving mortality are end results on which most clinicians would agree. Sophisticated measures of disease activity, particularly in early disease, have only recently been objectively evaluated.

The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: Phase 2 methodological report.

Objective: The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set.

Methods: Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2.

2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.

Objective: The 1987 American College of Rheumatology (ACR; formerly, the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticized for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA.

Methods: A joint working group from the ACR and the European League Against Rheumatism developed, in 3 phases, a new approach to classifying RA.

2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.

Objective: The 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticised for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA.

Methods: A joint working group from the ACR and the European League Against Rheumatism developed, in three phases, a new approach to classifying RA.

Safety, tolerability, and clinical outcomes after intraarticular injection of a recombinant adeno-associated vector containing a tumor necrosis factor antagonist gene: results of a phase 1/2 Study.

Objective: To assess safety and clinical outcomes in patients with inflammatory arthritis after intraarticular (IA) injection of rAAV2-TNFR:Fc, a recombinant adeno-associated viral vector containing the human tumor necrosis factor (TNF) receptor-immunoglobulin (IgG1) Fc fusion (TNFR:Fc) gene.

Methods: In this phase 1/2 randomized study, adults with persistent moderate or severe inflammation in a target joint, being treated with or without systemic anti-TNF therapy, received a single IA injection of either rAAV2-TNFR:Fc (1 x 10(11), 1 x 10(12), or 1 x 10(13) DNase-resistant particles/ml joint volume) or placebo, followed by open-label rAAV2-TNFR:Fc 12-30 weeks later, depending on when the target joint met predetermined criteria for reinjection.

Results: 127 subjects received the first injection of blinded study drug; 95 subjects received open-label rAAV2-TNFR:Fc.

Lipodystrophy and metabolic abnormalities in a case of adult dermatomyositis.

Lipodystrophy and metabolic abnormalities, primarily hypertriglyceridemia and insulin resistance, have been reported in juvenile dermatomyositis. We report a 55-year-old woman with adult dermatomyositis who developed lipodystrophy of the thighs, hypertriglyceridemia, and insulin resistance. Our case illustrates that lipodystrophy may occur in adult and juvenile dermatomyositis.

A retrospective analysis of low-field strength magnetic resonance imaging and the management of patients with rheumatoid arthritis.

Objective: To assess how in-office magnetic resonance imaging (MRI) scans of the hand/wrist or feet are utilized in a rheumatology practice to make clinical evaluations regarding therapeutic options for rheumatoid arthritis (RA) patients.

Methods: In a large clinical practice, a retrospective review was conducted on the first 300 RA patients who had office-based MRI scans at baseline. Information was collected on demographics, baseline therapy, and whether any change in therapy occurred at the time of the MRI scans.

The benefit/risk profile of TNF-blocking agents: findings of a consensus panel.

Objective: To review the benefits and risks associated with the use of the tumor necrosis factor (TNF)-blockers in various indications (eg, rheumatoid arthritis [RA], Crohn's disease [CD], psoriasis).

Methods: The members of the consensus panel were selected based on their expertise. Centocor, Inc provided an educational grant to the Center for Health Care Education to facilitate the consensus panel.

Effects of prasterone on disease activity and symptoms in women with active systemic lupus erythematosus.

Objective: To determine whether prasterone administration results in improvement or stabilization of systemic lupus erythematosus (SLE) disease activity and its symptoms.

Methods: Women with active SLE were treated with prasterone 200 mg/day plus standard SLE treatments or with placebo plus standard SLE treatments for up to 12 months in this randomized, double-blind investigation conducted at 27 centers. Standard SLE treatments included prednisone (/=6 weeks prior to enrollment and remain unchanged during protocol treatment.

Genetic interactions with CLF1 identify additional pre-mRNA splicing factors and a link between activators of yeast vesicular transport and splicing.

Clf1 is a conserved spliceosome assembly factor composed predominately of TPR repeats. Here we show that the TPR elements are not functionally equivalent, with the amino terminus of Clf1 being especially sensitive to change. Deletion and add-back experiments reveal that the splicing defect associated with TPR removal results from the loss of TPR-specific sequence information.

The Clf1p splicing factor promotes spliceosome assembly through N-terminal tetratricopeptide repeat contacts.

Spliceosome assembly follows a well conserved pathway of subunit addition that includes both small nuclear ribonucleoprotein (snRNP) particles and non-snRNP splicing factors. Clf1p is an unusual splicing factor composed almost entirely of direct repeats of the tetratricopeptide repeat (TPR) protein-binding motif. Here we show that the Clf1p protein resides in at least two multisubunit protein complexes, a small nuclear RNA-free structure similar to what was reported as the Prp19p complex (nineteen complex; NTC) and an RNP structure that contains the U2, U5, and U6 small nuclear RNAs.