Description: Article Protein aggregates are associated with a wide variety of diseases. Here, in order to address how protein aggregation affects cellular homoeostasis, the authors describe a method to rapidly create protein aggregates in living cells and organisms with precise spatial and temporal control. Nature Communications doi: 10.1038/ncomms11689 Authors: Yusuke Miyazaki, Kota Mizumoto, Gautam Dey, Takamasa Kudo, John Perrino, Ling-chun Chen, Tobias Meyer, Thomas J. Wandless

Description: Background: Multiple solutes are retained in uremia, but it is currently unclear which solutes are toxic. Small studies suggest that protein-bound solutes, such as p-cresol sulfate and indoxyl sulfate and intracellular solutes, such as methylamine (MMA) and dimethylamine (DMA), may be toxic. Our objective was to test whether elevated levels of these solutes were associated with mortality. Methods: We conducted a prospective cohort study in 521 U.S. incident hemodialysis patients to evaluate associations between these solutes and all-cause and cardiovascular mortality. P-cresol sulfate, indoxyl sulfate, MMA and DMA levels were measured from frozen plasma samples obtained 2 to 6 months after initiation of dialysis. Mortality data was available through 2004 using the National Death Index. Results: Elevated (greater than the population median) p-cresol sulfate, MMA or DMA levels were not associated with all-cause or cardiovascular mortality. Elevated indoxyl sulfate levels were associated with all-cause mortality but not cardiovascular mortality (hazard ratio 1.30 (95% confidence interval 1.01, 1.69) p-value 0.043). Conclusions: In this cohort of 521 incident hemodialysis patients, only elevated indoxyl sulfate levels were associated with all-cause mortality. Further research is needed to identify causes of the toxicity of uremia to provide better care for patients with kidney disease.

Description: Background: Accurate estimation of parameters of biochemical models is required to characterize the dynamics of molecular processes. This problem is intimately linked to identifying the most informative experiments for accomplishing such tasks. While significant progress has been made, effective experimental strategies for parameter identification and for distinguishing among alternative network topologies remain unclear. We approached these questions in an unbiased manner using a unique community-based approach in the context of the DREAM initiative (Dialogue for Reverse Engineering Assessment of Methods). We created an in silico test framework under which participants could probe a network with hidden parameters by requesting a range of experimental assays; results of these experiments were simulated according to a model of network dynamics only partially revealed to participants. Results: We proposed two challenges; in the first, participants were given the topology and underlying biochemical structure of a 9-gene regulatory network and were asked to determine its parameter values. In the second challenge, participants were given an incomplete topology with 11 genes and asked to find three missing links in the model. In both challenges, a budget was provided to buy experimental data generated in silico with the model and mimicking the features of different common experimental techniques, such as microarrays and fluorescence microscopy. Data could be bought at any stage, allowing participants to implement an iterative loop of experiments and computation. Conclusions: A total of 19 teams participated in this competition. The results suggest that the combination of state-of-the-art parameter estimation and a varied set of experimental methods using a few datasets, mostly fluorescence imaging data, can accurately determine parameters of biochemical models of gene regulation. However, the task is considerably more difficult if the gene network topology is not completely defined, as in challenge 2. Importantly, we found that aggregating independent parameter predictions and network topology across submissions creates a solution that can be better than the one from the best-performing submission.

Description: Consistent epidemiological data demonstrate that patients with heart failure with preserved ejection fraction (HFpEF) are more likely to be women than men. Exploring mechanisms behind this sex difference in heart failure epidemiology may enrich the understanding of underlying HFpEF pathophysiology and phenotypes, with the ultimate goal of identifying therapeutic approaches for the broader HFpEF population. In this review we evaluate the influence of sex on the key domains of cardiac structure and function, the systemic and pulmonary circulation, as well as extracardiac factors and comorbidities that may explain the predisposition of women to HFpEF. We highlight the potential role of factors exclusive to or more prevalent in women such as pregnancy, preeclampsia, and iron deficiency. Finally, we discuss existing controversies and gaps in knowledge, as well as the clinical importance of known sex differences in the context of the potential need for sex-specific diagnostic criteria, improved risk stratification models, and targeted therapies.