Biomedical subjects

Christopher Lee

Publications and source records attributed to Christopher Lee.

40 records · Page 3Linked to original sources

PubMed2002

Multiple sequence alignment using partial order graphs.

MOTIVATION: Progressive Multiple Sequence Alignment (MSA) methods depend on reducing an MSA to a linear profile for each alignment step. However, this leads to loss of information needed for accurate alignment, and gap scoring artifacts. RESULTS: We present a graph representation of an MSA that can itself be aligned directly by pairwise dynamic programming, eliminating the need to reduce the MSA to a profile. This enables our algorithm (Partial Order Alignment (POA)) to guarantee that the optimal alignment of each new sequence versus each sequence in the MSA will be considered. Moreover, this algorithm introduces a new edit operator, homologous recombination, important for multidomain sequences. The algorithm has improved speed (linear time complexity) over existing MSA algorithms, enabling construction of massive and complex alignments (e.g. an alignment of 5000 sequences in 4 h on a Pentium II). We demonstrate the utility of this algorithm on a family of multidomain SH2 proteins, and on EST assemblies containing alternative splicing and polymorphism. AVAILABILITY: The partial order alignment program POA is available at http://www.bioinformatics.ucla.edu/poa.

Algorithms↗

PubMedDate not supplied

Assessing the impact of alternative splicing on domain interactions in the human proteome.

We have constructed a database of alternatively spliced protein forms (ASP), consisting of 13,384 protein isoform sequences of 4422 human genes (www.bioinformatics.ucla.edu/ASP). We identified fifty protein domain types that were selectively removed by alternative splicing at much higher frequencies than average (p-value < 0.01). These include many well-known protein-interaction domains (e.g., KRAB; ankyrin repeats; Kelch) including some that have been previously shown to be regulated functionally by alternative splicing (e.g., collagen domain). We present a number of novel examples (Kruppel transcription factors; Pbx2; Enc1) from the ASP database, illustrating how this pattern of alternative splicing changes the structure of a biological pathway, by redirecting protein interaction networks at key switch points. Our bioinformatics analysis indicates that a major impact of alternative splicing is removal of protein-protein interaction domains that mediate key linkages in protein interaction networks. ASP expands the available dataset of human alternatively spliced protein forms from 1989 human genes (SwissProt release 42) to 5413 (nonredundant set, ASP + SwissProt), a nearly 3-fold increase. ASP will enhance the existing pool of protein sequences that are searched by mass spectroscopy software during the identification of peptide fragments.

Alternative Splicing↗

PubMedDate not supplied

Use of a SCID mouse model to select for a more aggressive strain of prostate cancer.

BACKGROUND: Prostate cancer is the most common non-cutaneous malignancy to affect men and has a propensity for metastasizing to bone. To better mimic the biology of metastatic prostate cancer, we have developed a model that utilizes both human prostate cancer and human bone in the SCID mouse. MATERIALS AND METHODS: Injection of a xenograft of human prostate cancer, LAPC-4, near a human bone core that was previously implanted within the hindlimb of a SCID mouse allowed for the selection of a more aggressive subset of cells, known as LAPC-4(2) (read as "LAPC-4 squared"). RESULTS: As compared to LAPC-4 cells, these "bone-selected" LAPC-4(2) cells form tumors more rapidly, develop PSA-positive serum at an earlier time-point as well as with higher levels, develop androgen independence, and metastasize to human bone after orthotopic injection. CONCLUSION: The selection of a more aggressive subset of prostate cancer cells that have developed androgen independence and the propensity to metastasize is of paramount importance as these are the cellular characteristics that are clinically linked to morbidity. Analysis of these "bone-selected" cells may lead to a better understanding of the molecular basis behind the conversion of low-grade prostate carcinoma to its more deadly, metastatic form.

Adult↗

PubMedDate not supplied

AIDS-related opportunistic infections in Hospital Kuala Lumpur.

We retrospectively reviewed 419 HIV/AIDS patients in Hospital Kuala Lumpur from 1994 to 2001. In the male group, the age range was 20-74, with a mean age 37 years, while in the female group it was 17-63, with a mean age of 33 years. With regard to age group, it was found that the preponderant age group was 25-34 years. The majority of male subjects were Chinese (52.5%), single (56.3%), and unemployed (55.1%), whereas the females were Malay (42.3%), married (79.5%), and non-laborer (64.1%). Also, both groups resided in Kuala Lumpur and had heterosexual contact as the leading cause of HIV transmission. More than half of the patients had CD4 cell counts of <200 cells/cumm. We found that the acquisition of HIV infection via intravenous drug use (IDU) was directly related to the incidence of tuberculosis infection (P < 0.05). Further analysis showed HIV-related tuberculosis with IDU was also dependently correlated with occupational status (unemployed) (P < 0.05). The four main AIDS-defining diseases include tuberculosis (48%), Pneumocystis carinii pneumonia (13%), toxoplasmic encephalitis (11%), and cryptococcal meningitis (7%); in addition, 53% of these patients were found to have CD4 cell counts of less than 200 cells/cumm at the time of diagnosis.

AIDS-Related Opportunistic Infections↗