Search tips
Search criteria

Results 1-9 (9)

Clipboard (0)

Select a Filter Below

Year of Publication
Document Types
1.  Discovering co-occurring patterns and their biological significance in protein families 
BMC Bioinformatics  2014;15(Suppl 12):S2.
The large influx of biological sequences poses the importance of identifying and correlating conserved regions in homologous sequences to acquire valuable biological knowledge. These conserved regions contain statistically significant residue associations as sequence patterns. Thus, patterns from two conserved regions co-occurring frequently on the same sequences are inferred to have joint functionality. A method for finding conserved regions in protein families with frequent co-occurrence patterns is proposed. The biological significance of the discovered clusters of conserved regions with co-occurrences patterns can be validated by their three-dimensional closeness of amino acids and the biological functionality found in those regions as supported by published work.
Using existing algorithms, we discovered statistically significant amino acid associations as sequence patterns. We then aligned and clustered them into Aligned Pattern Clusters (APCs) corresponding to conserved regions with amino acid conservation and variation. When one APC frequently co-occured with another APC, the two APCs have high co-occurrence. We then clustered APCs with high co-occurrence into what we refer to as Co-occurrence APC Clusters (Co-occurrence Clusters).
Our results show that for Co-occurrence Clusters, the three-dimensional distance between their amino acids is closer than average amino acid distances. For the Co-occurrence Clusters of the ubiquitin and the cytochrome c families, we observed biological significance among the residing amino acids of the APCs within the same cluster. In ubiquitin, the residues are responsible for ubiquitination as well as conventional and unconventional ubiquitin-bindings. In cytochrome c, amino acids in the first co-occurrence cluster contribute to binding of other proteins in the electron transport chain, and amino acids in the second co-occurrence cluster contribute to the stability of the axial heme ligand.
Thus, our co-occurrence clustering algorithm can efficiently find and rank conserved regions that contain patterns that frequently co-occurring on the same proteins. Co-occurring patterns are biologically significant due to their three-dimensional closeness and other evidences reported in literature. These results play an important role in drug discovery as biologists can quickly identify the target for drugs to conduct detailed preclinical studies.
PMCID: PMC4243116  PMID: 25474736
Spectral Clustering; Align Pattern Clustering; Jaccard Index; Ubiquitin; Cytochrome C; Protein Function Prediction; Sequence Patterns
2.  A Conserved Endoplasmic Reticulum Membrane Protein Complex (EMC) Facilitates Phospholipid Transfer from the ER to Mitochondria 
PLoS Biology  2014;12(10):e1001969.
Tethering of the endoplasmic reticulum to mitochondria by a conserved endoplasmic reticulum complex is needed for the transfer of phospholipids between these organelles.
Mitochondrial membrane biogenesis and lipid metabolism require phospholipid transfer from the endoplasmic reticulum (ER) to mitochondria. Transfer is thought to occur at regions of close contact of these organelles and to be nonvesicular, but the mechanism is not known. Here we used a novel genetic screen in S. cerevisiae to identify mutants with defects in lipid exchange between the ER and mitochondria. We show that a strain missing multiple components of the conserved ER membrane protein complex (EMC) has decreased phosphatidylserine (PS) transfer from the ER to mitochondria. Mitochondria from this strain have significantly reduced levels of PS and its derivative phosphatidylethanolamine (PE). Cells lacking EMC proteins and the ER–mitochondria tethering complex called ERMES (the ER–mitochondria encounter structure) are inviable, suggesting that the EMC also functions as a tether. These defects are corrected by expression of an engineered ER–mitochondrial tethering protein that artificially tethers the ER to mitochondria. EMC mutants have a significant reduction in the amount of ER tethered to mitochondria even though ERMES remained intact in these mutants, suggesting that the EMC performs an additional tethering function to ERMES. We find that all Emc proteins interact with the mitochondrial translocase of the outer membrane (TOM) complex protein Tom5 and this interaction is important for PS transfer and cell growth, suggesting that the EMC forms a tether by associating with the TOM complex. Together, our findings support that the EMC tethers ER to mitochondria, which is required for phospholipid synthesis and cell growth.
Author Summary
Mitochondrial membrane biogenesis and lipid metabolism depend on the transfer of phospholipid from the endoplasmic reticulum to mitochondria. This transfer is thought to occur at regions where these organelles are in close contact, and, although the process is thought not to involve vesicles, the mechanism is not known. In this study, we found a complex of proteins in the endoplasmic reticulum that is required for the transfer of one phospholipid—phosphatidylserine—from the endoplasmic reticulum to mitochondria. Cells lacking this protein complex have nonfunctional mitochondria with an abnormal lipid composition. We show that the complex is required to maintain close contacts between the endoplasmic reticulum and mitochondria; the complex probably directly interacts with at least one protein on the surface of mitochondria. In addition, cells lacking this complex and a second previously identified tethering complex are not viable. Thus, our findings suggest that tethering of the endoplasmic reticulum and mitochondria is essential for cell growth, likely because it is necessary for lipid exchange between these organelles.
PMCID: PMC4196738  PMID: 25313861
3.  Atypical Mycobacterial Exit-Site Infection and Peritonitis in Peritoneal Dialysis Patients on Prophylactic Exit-Site Gentamicin Cream 
We report 9 cases of exit-site infection and continuous ambulatory peritoneal dialysis peritonitis associated with atypical mycobacteria. All patients had been using topical gentamicin cream as prophylaxis for exit-site infection before the onset of these infections. Gentamicin cream is postulated to be a potential risk factor for atypical mycobacterial infection because of selective pressure on other micro-organisms. The microbiology of atypical mycobacteria and the treatment for atypical mycobacterial infections are discussed.
PMCID: PMC3649895  PMID: 23032088
Atypical mycobacterial infection; exit site; peritonitis
4.  Polymorphism at the TNF superfamily gene TNFSF4 confers susceptibility to systemic lupus erythematosus 
Nature genetics  2007;40(1):83-89.
Systemic lupus erythematosus (SLE) is a multisystem complex autoimmune disease of uncertain etiology (OMIM 152700). Over recent years a genetic component to SLE susceptibility has been established1–3. Recent successes with association studies in SLE have identified genes including IRF5 (refs. 4,5) and FCGR3B6. Two tumor necrosis factor (TNF) superfamily members located within intervals showing genetic linkage with SLE are TNFSF4 (also known as OX40L; 1q25), which is expressed on activated antigen-presenting cells (APCs)7,8 and vascular endothelial cells9, and also its unique receptor, TNFRSF4 (also known as OX40; 1p36), which is primarily expressed on activated CD4+ T cells10. TNFSF4 produces a potent co-stimulatory signal for activated CD4+ T cells after engagement of TNFRSF4 (ref. 11). Using both a family-based and a case-control study design, we show that the upstream region of TNFSF4 contains a single risk haplotype for SLE, which is correlated with increased expression of both cell-surface TNFSF4 and the TNFSF4 transcript. We hypothesize that increased expression of TNFSF4 predisposes to SLE either by quantitatively augmenting T cell–APC interaction or by influencing the functional consequences of T cell activation via TNFRSF4.
PMCID: PMC3705866  PMID: 18059267
5.  Natural history of multiple meningiomas 
Asymptomatic solitary meningiomas are typically managed with clinical and radiographic follow-up. Multiple meningiomas represents a clinical entity distinct from solitary meningiomas and can be sporadic, radiation-induced, associated with neurofibromatosis, or exhibit other familial inheritance. The growth rate for multiple meningiomas is not known and therefore management of these complicated patients can be difficult.
A retrospective chart review was performed on 12 patients with a total of 55 meningiomas. Patients with neurofibromatosis were not included. Serial enhanced magnetic resonance imaging was used to determine tumor growth rates. Treatment history was also reviewed and included for analysis.
Analysis of all 55 tumors demonstrated an average rate of growth of 0.46 cm3/year (range: −0.57-2.94 cm3/year). In the 23 tumors that received no treatment, the average rate of growth was 0.34 cm3/year (range: −0.03-1.8 cm3/year). Ten of the 23 tumors that received no treatment had no history of cranial irradiation. This group demonstrated a growth rate of 0.44 cm3/year (range: −0.01-1.8 cm3/year). Linear regression analysis did not yield any significant relationship between tumor burden and rates of growth.
Tumor growth rates in patients with multiple meningiomas did not appear to be higher than reported rates for incidentally found solitary meningiomas. As such, asymptomatic multiple meningioma patients should be managed with clinical and radiographic follow-up.
PMCID: PMC3683641  PMID: 23776757
Meningioma; multiple meningioma; natural history
6.  IRF5 haplotypes demonstrate diverse serological associations which predict serum interferon alpha activity and explain the majority of the genetic association with systemic lupus erythematosus 
Annals of the Rheumatic Diseases  2011;71(3):463-468.
High serum interferon α (IFNα) activity is a heritable risk factor for systemic lupus erythematosus (SLE). Auto-antibodies found in SLE form immune complexes which can stimulate IFNα production by activating endosomal Toll-like receptors and interferon regulatory factors (IRFs), including IRF5. Genetic variation in IRF5 is associated with SLE susceptibility; however, it is unclear how IRF5 functional genetic elements contribute to human disease.
1034 patients with SLE and 989 controls of European ancestry, 555 patients with SLE and 679 controls of African–American ancestry, and 73 patients with SLE of South African ancestry were genotyped at IRF5 polymorphisms, which define major haplotypes. Serum IFNα activity was measured using a functional assay.
In European ancestry subjects, anti-double-stranded DNA (dsDNA) and anti-Ro antibodies were each associated with different haplotypes characterised by a different combination of functional genetic elements (OR > 2.56, p >003C; 1.9×10−14 for both). These IRF5 haplotype-auto-antibody associations strongly predicted higher serum IFNα in patients with SLE and explained > 70% of the genetic risk of SLE due to IRF5. In African–American patients with SLE a similar relationship between serology and IFNα was observed, although the previously described European ancestry-risk haplotype was present at admixture proportions in African–American subjects and absent in African patients with SLE.
The authors define a novel risk haplotype of IRF5 that is associated with anti-dsDNA antibodies and show that risk of SLE due to IRF5 genotype is largely dependent upon particular auto-antibodies. This suggests that auto-antibodies are directly pathogenic in human SLE, resulting in increased IFNα in cooperation with particular combinations of IRF5 functional genetic elements.
SLE is a systemic autoimmune disorder affecting multiple organ systems including the skin, musculoskeletal, renal and haematopoietic systems. Humoral autoimmunity is a hallmark of SLE, and patients frequently have circulating auto-antibodies directed against dsDNA, as well as RNA binding proteins (RBP). Anti-RBP autoantibodies include antibodies which recognize Ro, La, Smith (anti-Sm), and ribonucleoprotein (anti-nRNP), collectively referred to as anti-retinol-binding protein). Anti-retinol-binding protein and anti-dsDNA auto-antibodies are rare in the healthy population.1 These auto-antibodies can be present in sera for years preceding the onset of clinical SLE illness2 and are likely pathogenic in SLE.34
PMCID: PMC3307526  PMID: 22088620
7.  Transtibial ACL reconstruction technique fails to position drill tunnels anatomically in vivo 3D CT study 
The purpose of this study was to visualize and quantify the positions of femoral and tibial tunnels in patients who underwent traditional transtibial single-bundle ACL reconstruction, as performed by multiple surgeons, utilizing 3D CT models, and to compare these positions to our previously reported anatomical tunnel positions.
Fifty-eight knee computed tomography (CT) scans were performed on patients who underwent primary or revision transtibial single-bundle ACL reconstruction, and three-dimensional reconstructions of the CT scans were aligned within an anatomical coordinate system. The position of femoral tunnel aperture centers was measured with (1) the quadrant method and (2) in the anatomic posterior-to-anterior and proximal-to-distal directions. The position of tibia tunnel aperture centers were measured similarly, in the anterior-to-posterior and medial-to-lateral dimensions on the tibial plateau. Comparisons were made to previously established anatomical tunnel positions, and data were presented as “mean value ± standard deviation (range).”
The location of tibial tunnels was at 48.0 ± 5.4% (35.6–59.5%) of the anterior-to-posterior plateau depth and at 47.9 ± 2.9% (42.2–57.4%) of the medial-to-lateral plateau width. The location of femoral tunnels was at 55.8 ± 8.0% (41.5–79.5%) in the anatomic posterior-to-anterior direction and at 41.2 ± 10.4% (15.1–67.4%) in the proximal-to-distal directions. Utilizing a quadrant method, femoral tunnels were positioned at 37.4 ± 5.1% (24.9–50.6%) from the proximal condylar surface, parallel to Blumensaat line, and at 11.0 ± 7.3% (−6.0–28.7%) from the notch roof, perpendicular to Blumensaat line. In summary, tibial tunnels were positioned medial to the anatomic PL position (p < 0.001), and femoral tunnels were positioned anterior to both AM and PL anatomic tunnel locations (p < 0.001 and p < 0.001).
ACL reconstruction via traditional transtibial technique fails to accurately position femoral and tibial tunnels within the native ACL insertion site. To achieve anatomical graft placement, other surgical techniques should be considered.
Level of evidence
Electronic supplementary material
The online version of this article (doi:10.1007/s00167-011-1851-z) contains supplementary material, which is available to authorized users.
PMCID: PMC3477486  PMID: 22210518
ACL; Anatomy; Transtibial; Anterior cruciate ligament; 3D CT
8.  Meniscus tear developed by pulling of the anomalous insertion of medial meniscus on anterior cruciate ligament 
There is no report regarding a medial meniscus tear arising from an anomalous insertion of medial meniscus on the ACL, which seemed to be developed by the same mechanism as ACL tear. A case of a combined medial meniscus tear with ACL tear in the presence of an anomalous insertion of the medial meniscus on the ACL is reported.
PMCID: PMC3176407  PMID: 21468619
Anomalous insertion of medial meniscus; Anterior cruciate ligament; Meniscus tear; Knee; Arthroscopy
9.  Genetic Variants Near TNFAIP3 on 6q23 are Associated with Systemic Lupus Erythematosus (SLE) 
Nature genetics  2008;40(9):1059-1061.
SLE is an autoimmune disease influenced by genetic and environmental components. We performed a genome-wide association scan (GWAS) and observed novel association evidence with a variant inTNFAIP3(rs5029939, P = 2.89×10−12, OR = 2.29). We also found evidence of two independent signals of association to SLE risk, including one described in Rheumatoid Arthritis. These results establish that genetic variation inTNFAIP3contributes to differential risk for SLE and RA.
PMCID: PMC2772171  PMID: 19165918

Results 1-9 (9)