Follistatin binds and neutralizes members of the TGFbeta superfamily including activin, myostatin, and growth and differentiation factor 11 (GDF11). Crystal structure analysis of the follistatin-activin complex revealed extensive contacts between follistatin domain (FSD)-2 and activin that was critical for the high-affinity interaction. However, it remained unknown whether follistatin residues involved with myostatin and GDF11 binding were distinct from those involved with activin binding. If so, this would allow development of myostatin antagonists that would not inhibit activin actions, a desirable feature for development of myostatin antagonists for treatment of muscle-wasting disorders. We tested this hypothesis with our panel of point and domain swapping follistatin mutants using competitive binding analyses and in vitro bioassays. Our results demonstrate that activin binding and neutralization are mediated primarily by FSD2, whereas myostatin binding is more dependent on FSD1, such that deletion of FSD2 or adding an extra FSD1 in place of FSD2 creates myostatin antagonists with vastly reduced activin antagonism. However, these mutants also bind GDF11, indicating that further analysis is required for creation of myostatin antagonists that will not affect GDF11 activity that could potentially elicit GDF11-induced side effects in vivo.

The driving mechanism for the wintertime (December–March) Aleutian Low–Icelandic Low (AL‐IL) seesaw is investigated with National Centers for Environmental Prediction/National Center for Atmospheric Research reanalysis data for 1948–2009. It is shown that the AL and the IL are dynamically linked through the eastern Pacific wave train (EPW) and that both the EPWs and the stratospheric polar vortex are found to work cooperatively to produce a significant AL‐IL seesaw. In general, it is found that wave reflection by the polar vortex is crucial for the formation of the AL‐IL seesaw. However, when the EPWs are extremely strong, the AL‐IL seesaw appears to be caused primarily by horizontal wave propagation. It is further shown that the Pacific center of the traditional Arctic Oscillation pattern is present when the AL‐IL seesaw is active, but it disappears when the AL‐IL seesaw is absent.

Comparing outcomes related to dialysis modality is complicated by selection bias introduced by patients and physicians. To address the impact of selection bias, this study compared mortality by initial dialysis modality among patients who had ESRD and were placed on the transplant waiting list. This study was a historical prospective cohort of 12,568 patients in the United States who initiated dialysis between May 1, 1995, and October 31, 1998, and were placed on the transplant waiting list before dialysis initiation. Two-year mortality was compared using Kaplan-Meier curves and Cox proportional hazards models that analyzed patients primarily using an intention-to-treat approach and separately censored patients on a modality switch. At 2 yr, the unadjusted mortality rate was 6.6% among peritoneal dialysis (PD) patients compared with 6.9% among hemodialysis (HD) patients (hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.82 to 1.23). After controlling for differences in baseline characteristics, comorbidities, and laboratory variables, the selection of PD versus HD remained associated with a similar 2-yr mortality risk (HR 1.03; 95% CI 0.83 to 1.28). In separate models, 2-yr mortality associated with PD versus HD was significant among patients with body mass index (BMI) >26 kg/m 2 (HR 1.37; 95% CI 1.01 to 1.83) but not among patients with BMI <26 kg/m 2 (HR 0.81; 95% CI 0.61 to 1.07). Results were similar after censoring on a modality switch. In conclusion, although choice of initial dialysis modality seems to be associated with equivalent outcomes among patients who have ESRD and are placed on the transplant waiting list, patients with BMI >26 kg/m 2 have increased 2-yr mortality associated with the selection of PD versus HD. Because the interpretation of observational data is highly affected by residual confounding and selection bias, further efforts should focus on the formation and testing of hypotheses to improve dialysis delivery.