The Center for Computational Biology: resources, achievements, and challenges

The Center for Computational Biology (CCB) is a multidisciplinary program where biomedical scientists, engineers, and clinicians work jointly to combine modern mathematical and computational techniques, to perform phenotypic and genotypic studies of biological structure, function, and physiology in health and disease. CCB has developed a computational framework built around the Manifold Atlas, an integrated biomedical computing environment that enables statistical inference on biological manifolds. These manifolds model biological structures, features, shapes, and flows, and support sophisticated morphometric and statistical analyses. The Manifold Atlas includes tools, workflows, and services for multimodal population-based modeling and analysis of biological manifolds. The broad spectrum of biomedical topics explored by CCB investigators include the study of normal and pathological brain development, maturation and aging, discovery of associations between neuroimaging and genetic biomarkers, and the modeling, analysis, and visualization of biological shape, form, and size. CCB supports a wide range of short-term and long-term collaborations with outside investigators, which drive the center's computational developments and focus the validation and dissemination of CCB resources to new areas and scientific domains.     

Predictors of rhythm outcomes after cardiac resynchronization therapy in atrial fibrillation patients: When should we use an atrial lead?

BackgroundCardiac resynchronization therapy (CRT) is widely used in atrial fibrillation (AF) patients and could impact rhythm stability.HypothesisWe aimed to identify predictors of sinus rhythm (SR) stability or AF progression in a real‐word cohort of CRT‐AF patients.MethodsFrom 330 consecutive implantable cardioverter‐defibrillator implantations due to ischemic or dilated cardiomyopathy, 65 (20%) patients with AF history (paroxysmal, n = 32) underwent a CRT implantation with an atrial electrode and were regularly followed every 4–6 months. Rhythm restoration was attempted for most AF patients based on symptoms, biventricular pacing (BP), and lack of thrombi.ResultsAfter 33 months, 18 (28%) patients progressed to permanent mode switch (MS≥99%) and 20 (31%) patients had stable SR (MS < 1%). Logistic regression showed that history of persistent AF (OR: 8.01, 95%CI: 2.0–31.7, p = .003) is associated with higher risk of permanent MS. In persistent AF patients, a bigger left atrium (OR: 1.2 per mm, 95%CI: 1.03–1.4, p = .025) and older age (OR: 1.15 per life‐year, 95%CI: 1.01–1.3, p = .032) were predictors of future permanent MS. Paroxysmal AF at implantation (OR: 5.96, 95%CI: 1.6–21.9, p = .007) and increased BP (OR: 1.4 per 1%, 95%CI: 1.05–1.89, p = .02) were associated with stable SR. In persistent AF patients, stable SR correlated with higher BP (98 ± 2 vs. 92 ± 8%, p < .001).ConclusionIn patients with AF undergoing CRT implantation, persistent AF, LA dilatation and advanced age relate to future permanent MS (AF), whereas high BP promotes SR stability. These findings could facilitate the management of CRT‐AF patients and guide therapy in order to maximize its effect on rhythm.     

Human Rh D monoclonal antibodies (BRAD-3 and BRAD-5) cause accelerated clearance of Rh D+ red blood cells and suppression of Rh D immunization in Rh D- volunteers

The use of prophylactic anti-D to prevent Rh D immunization in Rh D- women and subsequent hemolytic disease in Rh D+ infants is widespread, but has led to shortages of the anti-D Ig. With the aim of substituting monoclonal anti-D for Rh D prophylaxis, we have compared the abilities of monoclonal and polyclonal anti-D to clear Rh D+ red blood cells (RBCs) infused into Rh D- male volunteers and to suppress Rh D immunization. Two human monoclonal antibodies (MoAbs), BRAD-3 (IgG3) and BRAD-5 (IgG1), produced from stable Epstein-Barr virus-transformed B-lymphoblastoid cell lines, were selected because of their proven in vitro activity in promoting RBC lysis in antibody-dependent cell- mediated cytotoxicity assays. RBC clearance was assessed by intravenous injection of 3 mL of 51chromium-labeled D+ RBCs into 27 volunteers 48 hours after intramuscular injection of monoclonal or polyclonal anti-D. Further 3-mL injections of unlabeled D+ cells were administered at 6 and 9 months to induce immunization. Blood samples were taken throughout the 12-month period of study for the serologic detection of anti-D. The mean half-life (t50%) of RBCs in 7 recipients of 300 micrograms BRAD-5 (5.9 hours) was similar to that in 8 recipients of 500 IU polyclonal anti-D (5.0 hours), whereas D+ cells were cleared more slowly in some of the 8 subjects injected with 300 micrograms BRAD- 3 (mean t50% 12.7 hours) and in 1 individual administered 100 micrograms BRAD-3 (t50% 41.0 hours). The rate of RBC clearance in both groups administered 300 micrograms monoclonal anti-D correlated with the amount of antibody bound per cell, determined by flow cytometry. There was no evidence of primary immunization having occurred in any subject after 6 months of follow-up. Five of 24 subjects produced anti- D after one or two further injections of RBCs, confirming that they were responders who had been protected by the monoclonal or polyclonal anti-D administered initially. Four of these responders were recipients of monoclonal anti-D (3 BRAD-3, 1 BRAD-5). One individual who received BRAD-5 produced accelerated clearance of D+ RBCs at the third unprotected RBC challenge but did not seroconvert. This study shows that the human MoAbs BRAD-3 and BRAD-5 can prevent Rh D immunization, and indicates that they may be suitable replacements for the polyclonal anti-D presently used in prophylaxis of Rh D hemolytic disease of the newborn.(ABSTRACT TRUNCATED AT 400 WORDS)     

The L4F3 antigen is expressed by unipotent and multipotent colony- forming cells but not by their precursors

Antibody L4F3 is a murine monoclonal antibody that recognizes an antigen expressed on in vitro colony-forming cells, including virtually all CFU-GM, CFU-Meg, BFU-E, and CFU-Mix. In the present study we examined whether cells that do not express the L4F3 antigen include precursors of hematopoietic colony-forming cells. Colony-forming cells were depleted from marrow by treatment with L4F3 and complement. The remaining cells generated CFU-GM, BFU-E, and CFU-Mix when cultured in the presence of irradiated adherent cell layers from long-term marrow cultures. Marrow cells not expressing the L4F3 antigen, which were separated by cell-sorting techniques, were depleted of colony-forming cells but nevertheless generated CFU-GM when cultured over irradiated adherent cell layers. These data suggest that there are marrow precursors that do not express the L4F3 antigen and that give rise to colony-forming cells of multiple types. Negative selection techniques should allow the enrichment of these precursors of colony-forming cells, thereby enabling direct studies of these immature stem cells.