Mean square of the dipole moment of a macromolecule as a function of the ordering of its monomeric units

The most important information for the practical use of flexible-chain polymers is the change in structure in the presence of external influences. A conformational model for calculating the mean square of the dipole moment of a macromolecule is constructed in this work, provided that there is no correlation between the conformations of monomer units in a heterogeneous temperature field.

Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells

Regulatory T cells (Tregs) are the key cells regulating peripheral autoreactive T lymphocytes. Tregs exert their function by suppressing effector T cells. Tregs have been shown to play essential roles in the control of a variety of physiological and pathological immune responses. However, Tregs are unstable and can lose the expression of FOXP3 and suppressive functions as a consequence of outer stimuli. Available literature suggests that secreted proteins regulate Treg functional states, such as differentiation, proliferation and suppressive function. Identification of secreted proteins that affect Treg cell function are highly interesting for both therapeutic and diagnostic purposes in either hyperactive or immunosuppressed populations. Here, we report a phenotypic screening of a human secretome library in human Treg cells utilising a high throughput flow cytometry technology. Screening a library of 575 secreted proteins allowed us to identify proteins stabilising or destabilising the Treg phenotype as suggested by changes in expression of Treg marker proteins FOXP3 and/or CTLA4. Four proteins including GDF-7, IL-10, PAP and IFNα-7 were identified as positive regulators that increased FOXP3 and/or CTLA4 expression. PAP is a phosphatase. A catalytic-dead version of the protein did not induce an increase in FOXP3 expression. Ten interferon proteins were identified as negative regulators that reduced the expression of both CTLA4 and FOXP3, without affecting cell viability. A transcriptomics analysis supported the differential effect on Tregs of IFNα-7 versus other IFNα proteins, indicating differences in JAK/STAT signaling. A conformational model experiment confirmed a tenfold reduction in IFNAR-mediated ISG transcription for IFNα-7 compared to IFNα-10. This further strengthened the theory of a shift in downstream messaging upon external stimulation. As a summary, we have identified four positive regulators of FOXP3 and/or CTLA4 expression. Further exploration of these Treg modulators and their method of action has the potential to aid the discovery of novel therapies for both autoimmune and infectious diseases as well as for cancer.

Calcium Sparks in Cardiac Cells in Silico

We simulate elementary calcium release events (sparks) in a single calcium release unit in ventricular myocyte. Previously developed and tested electron-conformational model of the stochastic dynamics of RyR-channels is integrated to the calcium dynamics model in the cardiac cell. This approach allows to observe RyRs opening/closing in details on the macromolecular level during the calcium dynamics course. We simulate calcium diffusion in the dyadic space and “domino-like” RyR’s activation during the so-called “calcium induced-calcium release process”. Ca2+ sparks initiation, spread and termination are investigated in the computer experiments. Sparks’ initiation and termination rate dependence on the Ca2+ diffusion velocity is observed. We show that sarcoplasmic reticulum lumen local depletion and RyR’s stochastic attrition could be the reasons of Ca2+ spark termination.

A Conformational Model for MTPA Esters of Chiral N-(2-Hydroxyalkyl)acrylamides

The absolute stereochemistry of novel chiral N-(2-hydroxylalkyl)acrylamides prepared by a lipase-catalyzed resolution was successfully determined by 1H NMR of their MTPA esters. The method was validated for this particular case by computational experiments.

Joining the interface: a site for Nmd3 association on 60S ribosome subunits

The adaptor protein Nmd3 is required for Crm1-dependent export of large ribosomal subunits from the nucleus. In this issue, Sengupta et al. (2010. J. Cell Biol. doi:10.1083/jcb.201001124) identify a binding site for yeast Nmd3 on 60S ribosomal subunits using cryoelectron microscopy and suggest a conformational model for its release in the cytoplasm. The study provides the first detailed structural description of a ribosome biogenesis factor in complex with the large subunit.