High-Density Glass Scintillators for Proton Radiography-Relative Luminosity, Proton Response, and Spatial Resolution.

Proton radiography is a promising development in proton therapy, and researchers are currently exploring optimal detector materials to construct proton radiography detector arrays. High-density glass scintillators may improve integrating-mode proton radiography detectors by increasing spatial resolution and decreasing detector thickness. We evaluated several new scintillators, activated with europium or terbium, with proton response measurements and Monte Carlo simulations, characterizing relative luminosity, ionization quenching, and proton radiograph spatial resolution. We applied a correction based on Birks's analytical model for ionization quenching. The data demonstrate increased relative luminosity with increased activation element concentration, and higher relative luminosity for samples activated with europium. An increased glass density enables more compact detector geometries and higher spatial resolution. These findings suggest that a tungsten and gadolinium oxide-based glass activated with 4% europium is an ideal scintillator for testing in a full-size proton radiography detector.

Thiol-disulphide balance in infertility secondary to varicocele.

Oxidative stress plays an important role in the development of infertility secondary to varicocele. We aimed to investigate the dynamic thiol-disulphide homeostasis as an oxidative stress marker in the spermatic vein of infertility secondary to varicocele. Sixty-one patients with varicocele were included in the study. Blood was drawn from the median cubital vein and the testicular venous return side before the spermatic vein was separated during surgery. Total thiol, native thiol, disulphide, ischaemia modified albumin (IMA) and albumin values were measured from both the dilated spermatic vein and the median cubital vein. The disulphide/native thiol, disulphide/total thiol and native thiol/total thiol ratios were determined. The mean age of the patients was 27.0 ± 6.68 (15-50) years. While the albumin, native thiol and total thiol values and the native thiol/total thiol ratio were significantly lower (p = 0.004, p < 0.001, p < 0.001, p < 0.001 respectively), the IMA value and the disulphide/native thiol and disulphide/total thiol ratios were significantly higher (p < 0.001, p < 0.001, p < 0.001 respectively) in the samples taken from spermatic venous blood. Thiol-disulphide balance had deteriorated towards disulphide formation in the spermatic vein compared with the peripheral vein. Abnormal thiol-disulphide balance may be an independent risk factor for infertility secondary to varicocele.

Characterizing the binding interactions between P-glycoprotein and eight known cardiovascular transport substrates.

The multidrug efflux pump P-glycoprotein (Pgp) is upregulated in cardiomyocytes following chronic ischemia from infarction and hypoxia caused by sleep apnea. This report summarizes the molecular dynamic studies performed on eight cardiovascular drugs to determine their corresponding binding sites on mouse Pgp. Selected Pgp transport ligands include: Amiodarone, Bepridil, Diltiazem, Dipyridamole, Nicardipine, Nifedipine, Propranolol, and Quinidine. Extensive molecular dynamic equilibration simulations were performed to determine drug docking interactions. Distinct binding sites were not observed, but rather a binding belt was seen with multiple residues playing a role in each studied drug's stable docking. Three key drug-protein interactions were identified: hydrogen bonding, hydrophobic packing, and the formation of a "cage" of aromatic residues around the drug. After drug stabilization, water molecules were observed to leak into the binding belt and condense around the drug. Water influx into the binding domain of Pgp may play a role in catalytic transition and drug expulsion. The cytoplasmic recruitment theory was also tested, and the drugs were observed to interact with conserved loops of residues with a strong affinity. A free energy change of astronomical value is required to recruit the drug from the cytoplasm to the binding belt within the transmembrane domain of Pgp.

Periplasmic vestibule plays an important role for solute recruitment, selectivity, and gating in the Rh/Amt/MEP superfamily.

AmtB, a member of the Rh/Amt/MEP superfamily, is responsible for ammonia transport in Escherichia coli. The ammonia pathway in AmtB consists of a narrow hydrophobic lumen in between hydrophilic periplasmic and cytoplasmic vestibules. A series of molecular dynamics simulations (greater than 0.4 µs in total) were performed to determine the mechanism of solute recruitments and selectivity by the periplasmic vestibule. The results show that the periplasmic vestibule plays a crucial role in solute selectivity, and its solute preferences follow the order of NH4(+) > NH3 > CO2. Based on our results, NH4(+) recruitment is initiated by its interaction with either E70 or E225, highly conserved residues located at the entrance of the vestibule. Subsequently, the backbone carbonyl groups at the periplasmic vestibule direct NH4(+) to the conserved aromatic cage at the bottom of the vestibule (known as the Am1 site). The umbrella sampling simulations suggest that the conserved residue D160 is not directly involved in the ammonia conduction; rather its main function is to keep the structure of periplasmic vestibule intact. The MD simulations also revealed that two partially stacked phenyl rings of F107 and F215, separating the periplasmic vestibule from the hydrophobic lumen, flip open and closed simultaneously with a frequency of approximately 10(8) flipping events per second. These results show how the periplasmic vestibule selectively recruits NH4(+) to the Am1 site, and also that the synchronized flipping of two phenyl rings potentially facilitates the solute transition from the periplasmic vestibule to the hydrophobic lumen in the Rh/Amt/MEP superfamily.