Comparing the Effects of Rocaglates on Energy Metabolism and Immune Modulation on Cells of the Human Immune System.

A promising new approach to broad spectrum antiviral drugs is the inhibition of the eukaryotic translation initiation factor 4A (elF4A), a DEAD-box RNA helicase that effectively reduces the replication of several pathogenic virus types. Beside the antipathogenic effect, modulation of a host enzyme activity could also have an impact on the immune system. Therefore, we performed a comprehensive study on the influence of elF4A inhibition with natural and synthetic rocaglates on various immune cells. The effect of the rocaglates zotatifin, silvestrol and CR-31-B (-), as well as the nonactive enantiomer CR-31-B (+), on the expression of surface markers, release of cytokines, proliferation, inflammatory mediators and metabolic activity in primary human monocyte-derived macrophages (MdMs), monocyte-derived dendritic cells (MdDCs), T cells and B cells was assessed. The inhibition of elF4A reduced the inflammatory potential and energy metabolism of M1 MdMs, whereas in M2 MdMs, drug-specific and less target-specific effects were observed. Rocaglate treatment also reduced the inflammatory potential of activated MdDCs by altering cytokine release. In T cells, the inhibition of elF4A impaired their activation by reducing the proliferation rate, expression of CD25 and cytokine release. The inhibition of elF4A further reduced B-cell proliferation, plasma cell formation and the release of immune globulins. In conclusion, the inhibition of the elF4A RNA helicase with rocaglates suppressed the function of M1 MdMs, MdDCs, T cells and B cells. This suggests that rocaglates, while inhibiting viral replication, may also suppress bystander tissue injury by the host immune system. Thus, dosing of rocaglates would need to be adjusted to prevent excessive immune suppression without reducing their antiviral activity.

Interactions between a dsDNA Oligonucleotide and Imidazolium Chloride Ionic Liquids: Effect of Alkyl Chain Length, Part I.

Ionic liquids (ILs) have become nearly ubiquitous solvents and their interactions with biomolecules has been a focus of study. Here, we used the fluorescence emission of DAPI, a groove binding fluorophore, coupled with molecular dynamics (MD) simulations to report on interactions between imidazolium chloride ([Imn,1]+) ionic liquids and a synthetic DNA oligonucleotide composed entirely of T/A bases (7(TA)) to elucidate the effects ILs on a model DNA duplex. Spectral shifts on the order of 500-1000 cm-1, spectral broadening (~1000 cm-1), and excitation and emission intensity ratio changes combine to give evidence of an increased DAPI environment heterogeneity on added IL. Fluorescence lifetimes for DAPI/IL solutions yielded two time constants 0.15 ns (~80% to 60% contribution) and 2.36-2.71 ns for IL up to 250 mM. With DNA, three time constants were required that varied with added IL (0.33-0.15 ns (1-58% contribution), ~1.7-1.0 ns (~5% contribution), and 3.8-3.6 ns (94-39% contribution)). MD radial distribution functions revealed that π-π stacking interactions between the imidazolium ring were dominant at lower IL concentration and that electrostatic and hydrophobic interactions become more prominent as IL concentration increased. Alkyl chain alignment with DNA and IL-IL interactions also varied with IL. Collectively, our data showed that, at low IL concentration, IL was primarily bound to the DNA minor groove and with increased IL concentration the phosphate regions and major groove binding sites were also important contributors to the complete set of IL-DNA duplex interactions.

Sublabral foramen and buford complex: inferior extent of the unattached or absent labrum in 50 patients.

PURPOSE: To determine the inferiormost extent of the anterosuperior labral variants on conventional transverse MR images. MATERIALS AND METHODS: We reviewed transverse MR images in 50 consecutive patients with a sublabral foramen or Buford complex at arthroscopy. Images were randomly mixed with those of 58 patients with either a normal labrum (n = 20) or an anterior labral tear (n = 38) at arthroscopy. MR imaging was fat suppressed fast spin echo intermediate or T2 weighted (repetition time msec/effective echo time msec, 1,800-3,000/30-102). Two radiologists evaluated by means of consensus the anterior labrum while blinded to patient history and arthroscopic results. Transverse images obtained through the glenoid fossa were totalled to determine the midpoint. Sensitivity, specificity, and accuracy of MR for depicting a sublabral foramen or Buford complex were calculated along with 95% CIs, by using surgical findings as the reference standard. RESULTS: The sensitivity of MR for diagnosing a sublabral foramen or Buford complex was 0.94 (47 of 50 patients, 95% CI: 0.87, 1.00), specificity was 0.80 (16 of 20 patients, 95% CI: 0.62, 0.97), and accuracy was 0.90 (63 of 70 patients, 95% CI: 0.82, 0.97). The anterior labrum was abnormal on the first transverse section inferior to the midpoint in nine (18%) patients. The labrum was also abnormal on the second section below the midpoint in three (6%) patients. Because of the anterior tilt of the scapula, the midpoint was near the anterior glenoid notch at about the position between 2- and 3-o'clock. CONCLUSION: The labrum may be unattached or absent on the first two transverse images obtained below the midpoint.