Deducing topology of protein-protein interaction networks from experimentally measured sub-networks.

BackgroundProtein-protein interaction networks are commonly sampled using yeast two hybrid approaches. However, whether topological information reaped from these experimentally-measured sub-networks can be extrapolated to complete protein-protein interaction networks is unclear.ResultsBy analyzing various experimental protein-protein interaction datasets, we found that they are not random samples of the parent networks. Based on the experimental bait-prey behaviors, our computer simulations show that these non-random sampling features may affect the topological information. We tested the hypothesis that a core sub-network exists within the experimentally sampled network that better maintains the topological characteristics of the parent protein-protein interaction network. We developed a method to filter the experimentally sampled network to result in a core sub-network that more accurately reflects the topology of the parent network. These findings have fundamental implications for large-scale protein interaction studies and for our understanding of the behavior of cellular networks.ConclusionThe topological information from experimental measured networks network as is may not be the correct source for topological information about the parent protein-protein interaction network. We define a core sub-network that more accurately reflects the topology of the parent network

Rb and p130 control cell cycle gene silencing to maintain the postmitotic phenotype in cardiac myocytes

Both Rb and p130 are required for the recruitment of heterochromatin proteins that mediate silencing of proliferation genes in adult cardiac myocytes

Divergent Mitochondrial Biogenesis Responses in Human Cardiomyopathy

Background—Mitochondria are key players in the development and progression of heart failure (HF). Mitochondrial (mt) dysfunction leads to diminished energy production and increased cell death contributing to the progression of left ventricular failure. The fundamental mechanisms that underlie mt dysfunction in HF have not been fully elucidated. Methods and Results—To characterize mt morphology, biogenesis, and genomic integrity in human HF, we investigated left ventricular tissue from nonfailing hearts and end-stage ischemic (ICM) or dilated (DCM) cardiomyopathic hearts. Although mt dysfunction was present in both types of cardiomyopathy, mt were smaller and increased in number in DCM compared with ICM or nonfailing hearts. mt volume density and mtDNA copy number was increased by ≈2-fold (P<0.001) in DCM hearts in comparison with ICM hearts. These changes were accompanied by an increase in the expression of mtDNA-encoded genes in DCM versus no change in ICM. mtDNA repair and antioxidant genes were reduced in failing hearts, suggestive of a defective repair and protection system, which may account for the 4.1-fold increase in mtDNA deletion mutations in DCM (P<0.05 versus nonfailing hearts, P<0.05 versus ICM). Conclusions—In DCM, mt dysfunction is associated with mtDNA damage and deletions, which could be a consequence of mutating stress coupled with a peroxisome proliferator-activated receptor γ coactivator 1α–dependent stimulus for mt biogenesis. However, this maladaptive compensatory response contributes to additional oxidative damage. Thus, our findings support further investigations into novel mechanisms and therapeutic strategies for mt dysfunction in DCM

Albumin levels predict survival in patients with systolic heart failure.

BackgroundHypoalbuminemia is associated with poor prognosis in patients with certain chronic diseases, such as end-stage renal disease and cancer. Although low serum albumin is common in patients with heart failure (HF), the relationship between albumin and HF prognosis has not been well characterized. This study investigated the effect of serum albumin level on survival in patients with advanced HF.MethodsWe analyzed 1726 systolic HF patients (age 52 +/- 13 years, ejection fraction [EF] 23% +/- 7%) followed at a university HF center. Albumin level was determined at initial referral. Patients were divided by into groups based on presence of hypoalbuminemia (&lt; or = 3.4 g/dL). Mean albumin was 3.8 +/- 0.6 g/dL, and 25% of patients had hypoalbuminemia.ResultsPatients with and without low albumin levels were similar in age, HF etiology, and EF. Hypoalbuminemia was associated with higher New York Heart Association (NYHA) class, higher serum urea nitrogen, creatinine level, C-reactive protein, and B-type natriuretic peptide but lower levels of sodium, hemoglobin, and cholesterol. In patients with BMI &lt; 25 kg/m(2), 27% had albumin &lt; or = 3.4 g/dL, compared to 22% of those with BMI &gt; or = 25 kg/m(2) (P &lt; .01). One-year survival was 66% in patients with and 83% in those without hypoalbuminemia (P &lt; .0001). Risk-adjusted hazard ratios for 1- and 5-year mortality were 2.2 (1.4-3.3) and 2.2 (1.4-3.2), respectively.ConclusionsHypoalbuminemia is common in HF and is independently associated with increased risk of death in HF. Further investigation of pathophysiologic mechanisms underlying hypoalbuminemia in HF is warranted

The role of E2F-1 and downstream target genes in mediating ischemia/reperfusion injury in vivo.

E2Fs are a family of transcription factors that regulate proliferation, differentiation and apoptosis in many cell types. E2F-1 is the prototypical E2F and the family member that has most often been implicated in also mediating apoptosis. To better understand the role of E2F-1 in mediating cardiomyocyte injury we initially analyzed E2F family member expression after ischemia/reperfusion (I/R) in vivo or simulated ischemia in vitro. I/R injury in vivo caused a 3.4-fold increase specifically in E2F-1 protein levels. Expression of other E2F family members did not change. To establish the role of E2F-1 in I/R we examined the response of germline deleted E2F-1 mice to I/R injury. Infarct size as a percentage of the area at risk was decreased 39.8% in E2F-1(-/-) mice compared to E2F-1(+/+) controls. Interestingly, expression of classic, E2F-1 apoptotic target genes was not altered in E2F-1 null cardiomyocytes after I/R. However, upregulation of the primary member of the Forkhead family of transcription factors, FoxO-1a, was attenuated. Consistent, with a role for FoxO-1a as an important target of E2F-1 in I/R, a number of proapoptotic FoxO-1a target genes were also altered. These results suggest that E2F-1 and FoxO-1a belong to a complex transcriptional network that may modulate myocardial cell death during I/R injury

Albumin levels predict survival in patients with systolic heart failure.

BackgroundHypoalbuminemia is associated with poor prognosis in patients with certain chronic diseases, such as end-stage renal disease and cancer. Although low serum albumin is common in patients with heart failure (HF), the relationship between albumin and HF prognosis has not been well characterized. This study investigated the effect of serum albumin level on survival in patients with advanced HF.MethodsWe analyzed 1726 systolic HF patients (age 52 +/- 13 years, ejection fraction [EF] 23% +/- 7%) followed at a university HF center. Albumin level was determined at initial referral. Patients were divided by into groups based on presence of hypoalbuminemia (&lt; or = 3.4 g/dL). Mean albumin was 3.8 +/- 0.6 g/dL, and 25% of patients had hypoalbuminemia.ResultsPatients with and without low albumin levels were similar in age, HF etiology, and EF. Hypoalbuminemia was associated with higher New York Heart Association (NYHA) class, higher serum urea nitrogen, creatinine level, C-reactive protein, and B-type natriuretic peptide but lower levels of sodium, hemoglobin, and cholesterol. In patients with BMI &lt; 25 kg/m(2), 27% had albumin &lt; or = 3.4 g/dL, compared to 22% of those with BMI &gt; or = 25 kg/m(2) (P &lt; .01). One-year survival was 66% in patients with and 83% in those without hypoalbuminemia (P &lt; .0001). Risk-adjusted hazard ratios for 1- and 5-year mortality were 2.2 (1.4-3.3) and 2.2 (1.4-3.2), respectively.ConclusionsHypoalbuminemia is common in HF and is independently associated with increased risk of death in HF. Further investigation of pathophysiologic mechanisms underlying hypoalbuminemia in HF is warranted