Background

Schistosomiasis is a serious global health problem that afflicts more than 230 million people in 77 countries. Long-term mass treatments with the only available drug, praziquantel, have caused growing concerns about drug resistance. PSD-95/Dlg/ZO-1 (PDZ) domain-containing proteins are recognized as potential targets for the next generation of drug development. However, the PDZ domain-containing protein family in parasites has largely been unexplored.

Methods

We present the molecular characteristics of a PDZ domain-containing protein, GIPC3, from Schistosoma japonicum (SjGIPC3) according to bioinformatics analysis and experimental approaches. The ligand binding specificity of the PDZ domain of SjGIPC3 was confirmed by screening an arbitrary peptide library in yeast two-hybrid (Y2H) assays. The native ligand candidates were predicted by Tailfit software based on the C-terminal binding specificity, and further validated by Y2H assays.

Results

SjGIPC3 is a single PDZ domain-containing protein comprised of 328 amino acid residues. Structural prediction revealed that a conserved PDZ domain was presented in the middle region of the protein. Phylogenetic analysis revealed that SjGIPC3 and other trematode orthologues clustered into a well-defined cluster but were distinguishable from those of other phyla. Transcriptional analysis by quantitative RT-PCR revealed that the SjGIPC3 gene was relatively highly expressed in the stages within the host, especially in male adult worms. By using Y2H assays to screen an arbitrary peptide library, we confirmed the C-terminal binding specificity of the SjGIPC3-PDZ domain, which could be deduced as a consensus sequence, -[SDEC]-[STIL]-[HSNQDE]-[VIL]*. Furthermore, six proteins were predicted to be native ligand candidates of SjGIPC3 based on the C-terminal binding properties and other biological information; four of these were confirmed to be potential ligands using the Y2H system.

Conclusions

In this study, we first characterized a PDZ domain-containing protein GIPC3 in S. japonicum. The SjGIPC3-PDZ domain is able to bind both type I and II ligand C-terminal motifs. The identification of native ligand will help reveal the potential biological function of SjGIPC3. These data will facilitate the identification of novel drug targets against S. japonicum infections.

Low-toxicity magnetic nanocarriers (MNCs) composed of a shell of poly [aniline-co-N-(1-one-butyric acid) aniline] over a Fe3O4 magnetic nanoparticle core were developed to carry recombinant tissue plasminogen activator (rtPA) in MNC-rtPA for targeted thrombolysis. With an average diameter of 14.8 nm, the MNCs exerted superparamagnetic properties. Up to 276 μg of active rtPA was immobilized per mg of MNCs, and the stability of the immobilized rtPA was greatly improved during storage at 4°C and 25°C. In vitro thrombolysis testing with a tubing system demonstrated that magnet-guided MNC-rtPA showed significantly improved thrombolysis compared with free rtPA and reduced the clot lysis time from 39.2 ± 3.2 minutes to 10.8 ± 4.2 minutes. In addition, magnet-guided MNC-rtPA at 20% of the regular rtPA dose restored blood flow within 15–25 minutes of treatment in a rat embolism model without triggering hematological toxicity. In conclusion, this improved system is based on magnetic targeting accelerated thrombolysis and is potentially amenable to therapeutic applications in thromboembolic diseases.

Young children with fragile X syndrome (FXS) often experience anxiety, irritability, and hyperactivity related to sensory hyperarousal. However, there are no medication recommendations with documented efficacy for children under 5 years old of age with FXS. We examined data through a chart review for 45 children with FXS, 12–50 months old, using the Mullen Scales of Early Learning (MSEL) for baseline and longitudinal assessments. All children had clinical level of anxiety, language delays based on MSEL scores, and similar early learning composite (ELC) scores at their first visit to our clinic. Incidence of autism spectrum disorder (ASD) was similar in both groups. There were 11 children who were treated with sertraline, and these patients were retrospectively compared to 34 children who were not treated with sertraline by chart review. The baseline assessments were done at ages ranging from 18 to 44 months (mean 26.9, SD 7.99) and from 12 to 50 months (mean 29.94, SD 8.64) for treated and not treated groups, respectively. Mean rate of improvement in both expressive and receptive language development was significantly higher in the group who was treated with sertraline (P < 0.0001 and P = 0.0071, resp.). This data supports the need for a controlled trial of sertraline treatment in young children with FXS.

Malignant glioma is a common and severe primary brain tumor with a high recurrence rate and an extremely high mortality rate within 2 years of diagnosis, even when surgical, radiological, and chemotherapeutic interventions are applied. Intravenously administered drugs have limited use because of their adverse systemic effects and poor blood–brain barrier penetration. Here, we combine 2 methods to increase drug delivery to brain tumors. Focused ultrasound transiently permeabilizes the blood–brain barrier, increasing passive diffusion. Subsequent application of an external magnetic field then actively enhances localization of a chemotherapeutic agent immobilized on a novel magnetic nanoparticle. Combining these techniques significantly improved the delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea to rodent gliomas. Furthermore, the physicochemical properties of the nanoparticles allowed their delivery to be monitored by magnetic resonance imaging (MRI). The resulting suppression of tumor progression without damaging the normal regions of the brain was verified by MRI and histological examination. This noninvasive, reversible technique promises to provide a more effective and tolerable means of tumor treatment, with lower therapeutic doses and concurrent clinical monitoring.

1,2,3,4,6-Penta-O-galloyl-β-d-glucopyranose (PGG) is an active ingredient in plants that are commonly used in Chinese medicine to treat inflammation. We demonstrate here that PGG, at 6.25 μM, does not inhibit the growth of Staphylococcus aureus, and yet it prevents biofilm formation on polystyrene and polycarbonate surfaces. At the same concentration, PGG is not toxic to human epithelial and fibroblast cells. PGG has an IB50 value, i.e., the PGG concentration that inhibits 50% biofilm formation, of 3.6 μM. The value is substantially lower than that of N-acetylcysteine, iodoacetamide, and N-phenyl maleimide, which are known to inhibit biofilm formation by S. aureus. Biochemical and scanning electron microscopy results also reveal that PGG inhibits initial attachment of the bacteria to solid surface and the synthesis of polysaccharide intercellular adhesin, explaining how PGG inhibits biofilm formation. The results of this study demonstrate that coating PGG on polystyrene and silicon rubber surfaces with polyaniline prevents biofilm formation, indicating that PGG is highly promising for clinical use in preventing biofilm formation by S. aureus.

The asymmetric unit of the title compound, C14H10O4, contains one half mol­ecule, the complete mol­ecule being generated by a twofold axis. The two benzene rings form a dihedral angle of 43.11 (5)°. Inter­molecular O—H⋯O hydrogen bonds link the mol­ecules into one-dimensional zigzag chains. These chains are further connected into two-dimensional supra­molecular layers by weak π–π stacking inter­actions between neighbouring benzene rings, with centroid–centroid distances of 3.7648 (8) Å.

A series of dopant-type polyaniline-polyacrylic acid composite (PAn-PAA) films with porous structures were prepared and developed for an enzyme-free hydrogen peroxide (H2O2) sensor. The composite films were highly electroactive in a neutral environment as compared to polyaniline (PAn). In addition, the carboxyl group of the PAA was found to react with H2O2 to form peroxy acid groups, and the peroxy acid could further oxidize the imine structure of PAn to form N-oxides. The N-oxides reverted to their original form via electrochemical reduction and increased the reduction current. Based on this result, PAn-PAA was used to modify a gold electrode (PAn-PAA/Au) as a working electrode for the non-enzymatic detection of H2O2. The characteristics of the proposed sensors could be tuned by the PAA/PAn molar ratio. Blending PAA with PAn enhanced the surface area, electrocatalytic activity, and conductivity of these sensors. Under optimal conditions, the linear concentration range of the H2O2 sensor was 0.04 to 12 mM with a sensitivity of 417.5 μA/mM-cm2. This enzyme-free H2O2 sensor also exhibited a rapid response time, excellent stability, and high selectivity.

The title compound, [Zn(C6H4N5)2(H2O)4]·4H2O, was synthesized by the hydro­thermal reaction of Zn(CH3COO)2·2H2O with 3-(2H-tetra­zol-5-yl)pyridine. The ZnII ion is located on an inversion center and is coordinated by two pyridine N atoms from two 5-(3-pyrid­yl)tetra­zolide ligands and four coordinated water mol­ecules in a slightly distorted octa­hedral geometry. The dihedral angle between the pyridine and tetra­zole rings is 9.920 (7)°. In the crystal, mol­ecules are linked into a three-dimensional network by inter­molecular O—H⋯O and O—H⋯N hydrogen bonds involving the tetra­zole group N atoms, the aqua ligands and solvent water mol­ecules.

This study characterizes 1,984 methicillin-resistant Staphylococcus aureus (MRSA) isolates collected in 2005 and 2006 from normally sterile sites in patients with invasive MRSA infection. These isolates represent a convenience sample of all invasive MRSA cases reported as part of the Active Bacterial Core surveillance system in eight states in the United States. The majority of isolates were from blood (83.8%), joints (4.1%), and bone (4.2%). Isolates were characterized by pulsed-field gel electrophoresis (PFGE); SCCmec typing; susceptibility to 15 antimicrobial agents; and PCR analysis of staphylococcal enterotoxin A (SEA) to SEH, toxic shock syndrome toxin 1, and Panton-Valentine leukocidin. Thirteen established PFGE types were recognized among these isolates, although USA100 and USA300 predominated, accounting for 53.2% and 31.4% of the isolates, respectively. As expected, isolates from hospital onset cases were predominantly USA100, whereas those from community-associated cases were predominantly USA300. USA100 isolates were diverse (Simpson's discriminatory index [DI] = 0.924); generally positive only for enterotoxin D (74.5%); and resistant to clindamycin (98.6%), erythromycin (99.0%), and levofloxacin (99.6%), in addition to β-lactam agents. USA300 isolates were less diverse (DI = 0.566), positive for Panton-Valentine leukocidin (96.3%), and resistant to erythromycin (94.1%) and, less commonly, levofloxacin (54.6%), in addition to β-lactam agents. This collection provides a reference collection of MRSA isolates associated with invasive disease, collected in 2005 and 2006 in the United States, for future comparison and ongoing studies.