Probing the MgATP-bound conformation of the nitrogenase Fe protein by solution small-angle X-ray scattering

The MgATP-bound conformation of the Fe protein of nitrogenase from Azotobacter vinelandii has been examined in solution by small-angle X-ray scattering (SAXS) and compared to existing crystallographically characterized Fe protein conformations. The results of the analysis of the crystal structure of an Fe protein variant with a Switch II single-amino acid deletion recently suggested that the MgATP-bound state of the Fe protein may exist in a conformation that involves a large-scale reorientation of the dimer subunits, resulting in an overall elongated structure relative to the more compact structure of the MgADP-bound state. It was hypothesized that the Fe protein variant may be a conformational mimic of the MgATP-bound state of the native Fe protein largely on the basis of the observation that the spectroscopic properties of the [4Fe-4S] cluster of the variant mimicked in part the spectroscopic signatures of the native nitrogenase Fe protein in the MgATP-bound state. In this work, SAXS studies reveal that the large-scale conformational differences between the native Fe protein and the variant observed by X-ray crystallography are also observed in solution. In addition, comparison of the SAXS curves of the Fe protein nucleotide-bound states to the nucleotide-free states indicates that the conformation of the MgATP-bound state in solution does not resemble the structure of the variant as initially proposed, but rather, at the resolution of this experiment, it resembles the structure of the nucleotide-free state. These results provide insights into the Fe protein conformations that define the role of MgATP in nitrogenase catalysis.     

From Bench to Bedside: Attempt to Evaluate Repositioning of Drugs in the Treatment of Metastatic Small Cell Lung Cancer (SCLC)

Backgrounds

Based on in vitro data and results of a recent drug repositioning study, some medications approved by the FDA for the treatment of various non-malignant disorders were demonstrated to have anti-SCLC activity in preclinical models. The aim of our study is to confirm whether use of these medications is associated with survival benefit.

Methods

Consecutive patients with pathologically confirmed, stage 4 SCLC were analyzed in this retrospective study. Patients that were prescribed statins, aspirin, clomipramine (tricyclic antidepressant; TCA), selective serotonin reuptake inhibitors (SSRIs), doxazosin or prazosin (α1-adrenergic receptor antagonists; ADRA1) were identified.

Results

There were a total of 876 patients. Aspirin, statins, SSRIs, ADRA1, and TCA were administered in 138, 72, 20, 28, and 5 cases, respectively. A statistically significant increase in median OS was observed only in statin-treated patients when compared to those not receiving any of the aforementioned medications (OS, 8.4 vs. 6.1 months, respectively; p = 0.002). The administration of SSRIs, aspirin, and ADRA1 did not result in a statistically significant OS benefit (median OS, 8.5, 6.8, and 6.0 months, respectively). The multivariate Cox model showed that, besides age and ECOG PS, radiotherapy was an independent survival predictor (Hazard Ratio, 2.151; 95% confidence interval, 1.828–2.525; p <0.001).

Conclusions

Results of drug repositioning studies using only preclinical data or small numbers of patients should be treated with caution before application in the clinic. Our data demonstrated that radiotherapy appears to be an independent survival predictor in stage 4 SCLC, therefore confirming the results of other prospective and retrospective studies.     

Trichophyton rubrum (Castellani) var. flava,var. nova a yellow pigment forming Trichophyton rubrum

Summary and Conclusions A hitherto unknown variant ofT. rubrum var.flava is described which besides its yellow pigment has the following characteristics different fromT. rubrum (Castellani). A much slower growth and a smaller diameter of the giant culture and an appreciable difference in the light absorption curve of the extracted pigment.     

Immunological studies of the anticryptococcal factor of normal human serum

Preliminary studies have shown a very high inhibitory activity in the alpha₂ and gamma zone of human serum towards the growth of Cryptococcus neoformans. These findings are now corroborated by single radial immunodiffusion tests, which showed the some loss of IgA and IgM globulins and of the other three globulin fractions (ceruloplasmin, alpha₂ macroglobulin and alpha₂ HS glycoprotein) which migrate in the alpha₂ zone. The data was obtained by single radial immunodiffusion tests. The losses were not statistically significant however. No change in the immunoglobulin content of the sera kept for 6 days in contact with a heat-killed suspension of C. neoformans was noted. These findings suggest, that the inhibitory activity of the normal human serum on the in-vitro growth of C. neoformans is due to the above mentioned globulin fractions and not to a single specific factor.