Interaction specificity of clustered protocadherins inferred from sequence covariation and structural analysis.

Clustered protocadherins, a large family of paralogous proteins that play important roles in neuronal development, provide an important case study of interaction specificity in a large eukaryotic protein family. A mammalian genome has more than 50 clustered protocadherin isoforms, which have remarkable homophilic specificity for interactions between cellular surfaces. A large antiparallel dimer interface formed by the first 4 extracellular cadherin (EC) domains controls this interaction. To understand how specificity is achieved between the numerous paralogs, we used a combination of structural and computational approaches. Molecular dynamics simulations revealed that individual EC interactions are weak and undergo binding and unbinding events, but together they form a stable complex through polyvalency. Strongly evolutionarily coupled residue pairs interacted more frequently in our simulations, suggesting that sequence coevolution can inform the frequency of interaction and biochemical nature of a residue interaction. With these simulations and sequence coevolution, we generated a statistical model of interaction energy for the clustered protocadherin family that measures the contributions of all amino acid pairs at the interface. Our interaction energy model assesses specificity for all possible pairs of isoforms, recapitulating known pairings and predicting the effects of experimental changes in isoform specificity that are consistent with literature results. Our results show that sequence coevolution can be used to understand specificity determinants in a protein family and prioritize interface amino acid substitutions to reprogram specific protein-protein interactions.

Do nutraceutics play a role in the prevention and treatment of colorectal cancer?

Colorectal cancer is the third most common cancer worldwide with a 5-year survival of 50%. Current chemotherapeutic regimens used for advanced colorectal cancer provide an average survival of approximately 20 months. Non-toxic agents such as nutraceutics and supplements have been shown to aid in the prevention and adjuvant treatment of colorectal cancer. This article will discuss the epidemiology, progression, prevention, treatment, and recurrence of colorectal cancer and the role of nutraceutics and supplements in the treatment process.

Unique case of presumed lisinopril-induced hepatotoxicity.

PURPOSE: A case of presumed lisinopril-induced hepatotoxicity is reported. SUMMARY: A 30-year-old woman had complained of fatigue and yellow eyes for two days. Her medical history included hypertension and nephrotic syndrome. Her medications included furosemide 20 mg daily (for almost 6.5 years) and lisinopril 10 mg daily (for eight months). She had been treated with quinapril, enalapril, and lisinopril in the past by different primary care physicians without any adverse effects. She did not abuse alcohol and denied any liver-related problems in the past. Her physical examination revealed icterus and right-upper-quadrant abdominal tenderness. Initial laboratory tests revealed elevated liver enzyme values. Ultrasonography and computed tomography (CT) scans of the patient's abdomen suggested hepatocellular disease with mild hepatomegaly and a normal biliary tract. Due to worsening bilirubin and liver enzyme values, lisinopril was stopped. In the absence of a probable cause of the patient's hepatotoxicity, a CT-guided liver biopsy was performed. Histological examination of the liver tissue showed moderate chronic inflammatory cell infiltrates in the portal area, predominantly composed of lymphocytes with mild-to-moderate interface hepatitis. No centrolobular necrosis or steatosis was seen. After lisinopril was discontinued, there was a rapid improvement in the patient's clinical and biochemical pictures. On her follow-up clinic visit approximately two months later, all of her liver enzyme values had normalized. CONCLUSION: A woman who had received quinapril, enalapril, and lisinopril in the past without apparent adverse effects developed hepatocellular disease that became evident eight months after lisinopril therapy was reinstituted. The presumed hepatotoxicity resolved after discontinuation of lisinopril.