Dynamic design: manipulation of millisecond timescale motions on the energy landscape of cyclophilin A

Proteins need to interconvert between many conformations in order to function, many of which are formed transiently, and sparsely populated. Particularly when the lifetimes of these states approach the millisecond timescale, identifying the relevant structures and the mechanism by which they interconvert remains a tremendous challenge. Here we introduce a novel combination of accelerated MD (aMD) simulations and Markov state modelling (MSM) to explore these ‘excited’ conformational states. Applying this to the highly dynamic protein CypA, a protein involved in immune response and associated with HIV infection, we identify five principally populated conformational states and the atomistic mechanism by which they interconvert. A rational design strategy predicted that the mutant D66A should stabilise the minor conformations and substantially alter the dynamics, whereas the similar mutant H70A should leave the landscape broadly unchanged. These predictions are confirmed using CPMG and R1ρ solution state NMR measurements. By efficiently exploring functionally relevant, but sparsely populated conformations with millisecond lifetimes in silico, our aMD/MSM method has tremendous promise for the design of dynamic protein free energy landscapes for both protein engineering and drug discovery

Physically-based Assessment of Hurricane Surge Threat under Climate Change

Storm surges are responsible for much of the damage and loss of life associated with landfalling hurricanes. Understanding how global warming will affect hurricane surges thus holds great interest. As general circulation models (GCMs) cannot simulate hurricane surges directly, we couple a GCM-driven hurricane model with hydrodynamic models to simulate large numbers of synthetic surge events under projected climates and assess surge threat, as an example, for New York City (NYC). Struck by many intense hurricanes in recorded history and prehistory, NYC is highly vulnerable to storm surges. We show that the change of storm climatology will probably increase the surge risk for NYC; results based on two GCMs show the distribution of surge levels shifting to higher values by a magnitude comparable to the projected sea-level rise (SLR). The combined effects of storm climatology change and a 1 m SLR may cause the present NYC 100-yr surge flooding to occur every 3–20 yr and the present 500-yr flooding to occur every 25–240 yr by the end of the century.United States. National Oceanic and Atmospheric Administration (Postdoctoral Fellowship Program)National Science Foundation (U.S.

Localized-Statistical Quantification of Human Serum Proteome Associated with Type 2 Diabetes

BACKGROUND: Recent advances in proteomics have shed light to discover serum proteins or peptides as biomarkers for tracking the progression of diabetes as well as understanding molecular mechanisms of the disease. RESULTS: In this work, human serum of non-diabetic and diabetic cohorts was analyzed by proteomic approach. To analyze total 1377 high-confident serum-proteins, we developed a computing strategy called localized statistics of protein abundance distribution (LSPAD) to calculate a significant bias of a particular protein-abundance between these two cohorts. As a result, 68 proteins were found significantly over-represented in the diabetic serum (p<0.01). In addition, a pathway-associated analysis was developed to obtain the overall pathway bias associated with type 2 diabetes, from which the significant over-representation of complement system associated with type 2 diabetes was uncovered. Moreover, an up-stream activator of complement pathway, ficolin-3, was observed over-represented in the serum of type 2 diabetic patients, which was further validated with statistic significance (p = 0.012) with more clinical samples. CONCLUSIONS: The developed LSPAD approach is well fit for analyzing proteomic data derived from biological complex systems such as plasma proteome. With LSPAD, we disclosed the comprehensive distribution of the proteins associated with diabetes in different abundance levels and the involvement of ficolin-related complement activation in diabetes

Search for B → μ μ And B0 → μ+ μ- Decays

A search for the rare decays B → μ μ and B → μ μ is performed in pp collisions at ps = 7TeV, with a data sample corresponding to an integrated luminosity of 5 fb collected by the CMS experiment at the LHC. In both decays, the number of events observed after all selection requirements is consistent with the expectation from background plus standard model signal predictions. The resulting upper limits on the branching fractions are B(B → μ μ-) < 7:7 × 10 and B(B → μ μ ) < 1:8 × 10 at 95% confidence level

Vertical trapezius musculocutaneous flap: A retrospective study

From 1986 to 2001, 17 patients ( aged 26 - 77 years) were treated using the vertical trapezius musculocutaneous flap. A two-stage procedure was used in 7 and a single-stage island flap in 10. The donor site was closed directly in all patients. Mean length of hospital stay was 16 days ( range 12 - 25). There was no operative mortality. Complications were one partial flap necrosis and two seromas of the donor site, complicated by infection. With a minimum follow-up of more than two years, our study confirms the usefulness of the vertical trapezius musculocutaneous flap in head and neck reconstructive surgery. It is a reliable, thin flap of uniform thickness, which carries hairless skin. The length and thickness of its pedicle allows excellent mobility. The main disadvantage of the flap is the complete sacrifice of the muscle necessary for total mobilisation of the flap, and the intraoperative repositioning of the patient