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Computational prediction of human metabolic pathways from the complete human genome
(BioMed Central, 2005) Romero, Pedro; Wagg, Jonathan; Green, Michelle L.; Kaiser, Dale; Krummenacker, Markus; Karp, Peter D.; Center for Computational Biology and Bioinformatics, School of Medicine
Background: We present a computational pathway analysis of the human genome that assigns enzymes encoded therein to predicted metabolic pathways. Pathway assignments place genes in their larger biological context, and are a necessary first step toward quantitative modeling of metabolism.
Results: Our analysis assigns 2,709 human enzymes to 896 bioreactions; 622 of the enzymes are assigned roles in 135 predicted metabolic pathways. The predicted pathways closely match the known nutritional requirements of humans. This analysis identifies probable omissions in the human genome annotation in the form of 203 pathway holes (missing enzymes within the predicted pathways). We have identified putative genes to fill 25 of these holes. The predicted human metabolic map is described by a Pathway/Genome Database called HumanCyc, which is available at http://HumanCyc.org/. We describe the generation of HumanCyc, and present an analysis of the human metabolic map. For example, we compare the predicted human metabolic pathway complement to the pathways of Escherichia coli and Arabidopsis thaliana and identify 35 pathways that are shared among all three organisms.
Conclusions: Our analysis elucidates a significant portion of the human metabolic map, and also indicates probable unidentified genes in the genome. HumanCyc provides a genome-based view of human nutrition that associates the essential dietary requirements of humans with a set of metabolic pathways whose existence is supported by the human genome. The database places many human genes in a pathway context, thereby facilitating analysis of gene expression, proteomics, and metabolomics datasets through a publicly available online tool called the Omics Viewer.
Mispolarization of Desmosomal Proteins and Altered Cell Adhesion in Autosomal Dominant Polycystic Kidney Disease
(American Physiological Society, 2005) Silberberg, Melina; Charron, Audra J.; Bacallao, Robert; Wandinger-Ness, Angela; Medicine, School of Medicine
Polycystin-1, the product of the major gene mutated in autosomal dominant polycystic kidney disease (ADPKD), has been shown to associate with multiple epithelial cell junctions. Our hypothesis is that polycystin-1 is an important protein for the initial establishment of cell-cell junctions and maturation of the cell and that polycystin-1 localization is dependent on the degree of cell polarization. Using laser-scanning confocal microscopy and two models of cell polarization, polycystin-1 and desmosomes were found to colocalize during the initial establishment of cell-cell contact when junctions were forming. However, colocalization was lost in confluent monolayers. Parallel morphological and biochemical evaluations revealed a profound mispolarization of desmosomal components to both the apical and basolateral domains in primary ADPKD cells and tissue. Studies of the intermediate filament network associated with desmosomes showed that there is a decrease in cytokeratin levels and an abnormal expression of the mesenchymal protein vimentin in the disease. Moreover, we show for the first time that the structural alterations seen in adherens and desmosomal junctions have a functional impact, leaving the ADPKD cells with weakened cell-cell adhesion. In conclusion, in this paper we show that polycystin-1 transiently colocalizes with desmosomes and that desmosomal proteins are mislocalized as a consequence of polycystin-1 mutation.
Altered Twist1 and Hand2 dimerization is associated with Saethre-Chotzen syndrome and limb abnormalities
(Springer Nature, 2005) Firulli, Beth A.; Krawchuk, Dayana; Centonze, Victoria E.; Virshup, David M.; Conway, Simon J.; Cserjesi, Peter; Laufer, Ed; Firulli, Anthony B.; Pediatrics, School of Medicine
Autosomal dominant mutations in the gene encoding the basic helix-loop-helix transcription factor Twist1 are associated with limb and craniofacial defects in humans with Saethre-Chotzen syndrome. The molecular mechanism underlying these phenotypes is poorly understood. We show that ectopic expression of the related basic helix-loop-helix factor Hand2 phenocopies Twist1 loss of function in the limb and that the two factors have a gene dosage-dependent antagonistic interaction. Dimerization partner choice by Twist1 and Hand2 can be modulated by protein kinase A- and protein phosphatase 2A-regulated phosphorylation of conserved helix I residues. Notably, multiple Twist1 mutations associated with Saethre-Chotzen syndrome alter protein kinase A-mediated phosphorylation of Twist1, suggesting that misregulation of Twist1 dimerization through either stoichiometric or post-translational mechanisms underlies phenotypes of individuals with Saethre-Chotzen syndrome.
Association between adherence measurements of metoprolol and health care utilization in older patients with heart failure
(Wiley, 2005) Tu, Wanzhu; Morris, Andrew B.; Li, Jingjin; Wu, Jingwei; Young, James; Murray, Michael D.; Medicine, School of Medicine
Objective: Data from electronic dosing monitors and published pharmacokinetic parameters were used to derive medication adherence measures for immediate-release metoprolol and examine their association with health care utilization of outpatients aged 50 years or older with heart failure.
Methods: We used a 1-compartment model and published population pharmacokinetic parameters to estimate mean plasma metoprolol concentrations for patients treated for 6 to 12 months. In the absence of directly measured plasma concentrations, we calculated the intended mean plasma concentration (Cp'(ave)) under the assumption of perfect adherence to the prescribed dose and frequency of administration. Projected mean plasma concentrations (Cp(ave)) were estimated by use of data from recorded dosing times. In addition to taking adherence (percentage of dose taken) and scheduling adherence (percentage of doses taken on schedule), we calculated the deviation from the intended exposure (DeltaCp(ave) = Cp'(ave) - Cp(ave)) and the proportion of intended exposure achieved by the patient (Cp(ave) /Cp'(ave)). We assessed the association between the adherence measures and the numbers of emergency department visits and hospital admissions experienced by the patients.
Results: Patients (N = 80) were aged 62 +/- 8 years. Mean DeltaCp(ave) and Cp(ave)/Cp'(ave) were 7.9 ng/mL (SD, 10.7) and 0.6 (SD, 0.3), respectively. Log-linear models adjusted for patient functional status indicated that greater deviation from the intended metoprolol exposure (DeltaCp(ave)) was associated with increased numbers of emergency department visits ( P < .0001) and hospital admissions (P < .0001). A higher proportion of intended exposure (Cp(ave) /Cp'(ave)) corresponded to a reduced number of emergency department visits (P = .0204) and hospital admissions (P = .0093). Taking adherence was univariately associated with both emergency department visits and hospital visits (P < .0001 and P = .0010, respectively). Scheduling adherence was associated with the number of emergency department visits (P = .0181) but not with the number of hospital admissions (P = .1602). Model selection procedures consistently chose the proposed measures over taking adherence and scheduling adherence.
Conclusion: Deviation from the intended exposure and proportion of intended exposure achieved by the patient are valid adherence measures for immediate-release metoprolol and are associated with health care utilization. The potential utility of these measures for other beta-adrenergic antagonists and perhaps other cardiovascular drugs should be investigated.
Connecting Families to Futures: Reflections on a Bilingual, Community-Based Career Pathways Innovations
(2026-04-24) Jamison , Andrew; Mares, Cesar; Rodriguez, Hugo; Beatty, Molly; Tews, Matthew; Soto, Katelynn; Cruz Portillo, Margot
Parental engagement is a critical determinant of children’s educational and career trajectories, yet families with limited exposure to higher education—particularly Spanish-speaking families—often face linguistic, structural, and informational barriers to early college and career exploration. These challenges are especially salient in communities where Hispanic and foreign-born populations are growing but remain a minority. This project aimed to adapt the traditional career fair model into a bilingual, community-based intervention designed to promote early college and career exploration through intentional, family-centered engagement of caregivers and children in elementary and middle school.
A one-day bilingual career pathways and community resource fair was developed in collaboration with local educational institutions, community organizations, and bilingual professionals. Career presenters facilitated hands-on, profession-specific activities for children while sharing personal educational and career journeys, including nontraditional and first-generation pathways. Community partners provided information on educational and social resources to support caregivers in guiding children’s educational planning. Programming was delivered in English and Spanish, and families were encouraged to self-navigate the event to promote autonomy and caregiver–child engagement.
An IRB-exempt, anonymous pre- and post-event survey was planned to assess caregiver perceptions of education, career pathways, and access to community resources. Due to limited attendance, no survey responses were collected, restricting formal evaluation. However, implementation yielded important insights regarding event timing, dissemination strategies, trust-building, and evaluation feasibility.
Despite low attendance, informal feedback reinforced the value of family-centered, bilingual engagement. This innovation underscores the importance of sustained, relationship-centered approaches and iterative refinement when implementing community-based educational initiatives that engage caregivers alongside children.