Dual pH/ROS‐Responsive Nanoplatform with Deep Tumor Penetration and Self‐Amplified Drug Release for Enhancing Tumor Chemotherapeutic Efficacy

Poor deep tumor penetration and incomplete intracellular drug release remain challenges for antitumor nanomedicine application in clinical settings. Herein, a nanomedicine (RLPA‐NPs) is developed that can achieve prolonged blood circulation, deep tumor penetration, active‐targeting of cancer cells, endosome/lysosome escape, and intracellular selectivity self‐amplified drug release for effective drug delivery. The RLPA‐NPs are constructed by encapsulation of a pH‐sensitive polymer octadecylamine‐poly(aspartate‐1‐(3‐aminopropyl) imidazole) (OA‐P(Asp‐API)) and a ROS‐generation agent, β‐Lapachone (Lap), in micelles assembled by the tumor‐penetration peptide internalizing RGD (iRGD)‐modified ROS‐responsive paclitaxel (PTX)‐prodrug. iRGD could promote RLPA‐NPs penetration into deep tumor tissue, and specific targeting to cancer cells. After internalization by cancer cells through receptor‐mediated endocytosis, OA‐P(Asp‐API) can rapidly protonate in the endosome's acidic environment, resulting in RLPA‐NPs escape from the endosome through the “proton sponge effect”. At the same time, the RLPA‐NPs micelle disassembles, releasing Lap and PTX‐prodrug. Subsequently, the released Lap could generate ROS, consequently amplifying and accelerating PTX release to kill tumor cells. The in vitro and in vivo studies demonstrated that RLPA‐NPs can significantly improve the therapeutic effect compared to control groups. Therefore, RLPA‐NPs are a promising nanoplatform for overcoming multiple physiological and pathological barriers to enhance drug delivery.     

Efficient site specific removal of a C-terminal FLAG fusion from a Fab' using copper(II) ion catalysed protein cleavage

The peptide sequence ^NDKTH^C was investigated as a site for efficient,specific cleavage of a fusion protein by cupric ions using ahumanised 1 Fab' as a model protein. The native upper hinge^NDKTH^C sequence was mutated to create a site resistant to cleavageby cupric ions and a ^NDKTH^C sequence introduced between thehinge and a C-terminal FLAG peptide. Incubation of Fab' withCu²⁺ at 62°C at alkaline pHs resulted in removal of theFLAG peptide with efficiencies of up to 86%. Cleavage conditionsdid not detrimentally affect the Fab' protein. Use of the ^NDKTH^Csequence along with cupric ions may provide a cost-effectivemethod for large scale proteolytic cleavage of fusion proteins.     

Beneficial Use of Springer Pit Lake at Mount Polley Mine

While pit lakes can pose potential risks to the environment and liabilities to mining companies, they may also present opportunities for sustainable end uses, if managed appropriately. The Springer Pit Lake and Mount Polley Mine provided an opportunity to store mine waste such as tailings and mill process water while the mine repaired its tailings storage facility after a breach in its perimeter embankment, which released tailings to the downstream environment in 2014. 1 year after the breach, a water treatment plant was installed so that the pit lake could be drawn down. Frequent monitoring of water quality in the pit, combined with a calibrated and verified water quality model, shows that water quality is improving. Based on the observations that tailings, suspended solids, and associated constituents are being removed efficiently by the pit, the treatment plant was reconfigured to a “passive” mode, which did not entail the use of reagents or mechanical energy—only in-line instrumentation.     

Longitudinal associations between sibling relationship quality, parental differential treatment, and children's adjustment.

This study examined associations between changes in sibling relationships and changes in parental differential treatment and corresponding changes in children's adjustment. One hundred thirty-three families were assessed at 3 time points. Parents rated children's externalizing problems, and children reported on sibling relationship quality, parental differential treatment, and depressive symptoms. On average, older siblings were 10, 12, and 16 years old, and younger siblings were 8, 10, and 14 years old at Waves 1, 2, and 3, respectively. Results from hierarchical linear modeling indicated that as sibling relationships improved over time, children's depressive symptoms decreased over time. In addition, as children were less favored over their siblings over time, children's externalizing problems increased over time. Findings highlight the developmental interplay between the sibling context and children's adjustment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Shear‐Thinning Supramolecular Hydrogels with Secondary Autonomous Covalent Crosslinking to Modulate Viscoelastic Properties In Vivo

Clinical percutaneous delivery of synthetically engineered hydrogels remains limited due to challenges posed by crosslinking kinetics—too fast leads to delivery failure, too slow limits material retention. To overcome this challenge, supramolecular assembly is exploited to localize hydrogels at the injection site and introduce subsequent covalent crosslinking to control final material properties. Supramolecular gels are designed through the separate pendant modifications of hyaluronic acid (HA) by the guest–host pair cyclodextrin and adamantane, enabling shear‐thinning injection and high target site retention (>98%). Secondary covalent crosslinking occurs via addition of thiols and Michael‐acceptors (i.e., methacrylates, acrylates, vinyl sulfones) on HA and increases hydrogel moduli (E = 25.0 ± 4.5 kPa) and stability (>3.5 fold in vivo at 28 d). Application of the dual‐crosslinking hydrogel to a myocardial infarct model shows improved outcomes relative to untreated and supramolecular hydrogel alone controls, demonstrating its potential in a range of applications where the precise delivery of hydrogels with tunable properties is desired.     

Laplacian and orthogonal wavelet pyramid decompositions incoarse-to-fine registration

The authors develop orthogonal wavelet pyramid methods for registration and matching. The registration algorithm described compensates for the representation's lack of translation invariance. It shows better performance when tested with Laplacian pyramids. For matching applications, they derive filters that directly generate coarse representations of candidates for comparison to library prototypes     

Comparison of a microtitration plate ELISA with a standard cultural procedure for the detection of Salmonella spp. in chicken.

A rapid antibody-capture enzyme-linked immunosorbent assay (ELISA) detecting a wide range of Salmonella serotypes and employing only one culture stage was used to analyze the giblets and body cavity rinsings from frozen chickens. The results from the ELISA were compared with those obtained using a standard cultural procedure in current use in two laboratories, Norwich (N) and Ipswich (I), of the Public Health Laboratory Service (PHLS) in the UK. ELISAs were carried out on the same samples at each of two PHLS laboratories and at the Institute of Food Research with good agreement (94% and 90%). When compared with the cultural method there was 80% and 70% agreement with the ELISA with the PHLS(N) and PHLS(I) samples. The ELISA appeared to have a false-positive rate of 17% (samples from PHLS(N)) but on reculture of the "negative" samples this rate fell to 7%. The false-negative rate for the ELISA was 26% (samples from PHLS(N)) which appeared to be due to insufficient growth of the Salmonella spp. in the single cultural step employed in the ELISA rather than lack of recognition by the antibodies. The problem of false negatives with the cultural method is also discussed. These results are comparable to previously published studies relating immunoassays and the conventional procedure for Salmonella detection when analyzing similar samples. Suggestions are made as to how further increases in ELISA efficiency might be brought about.     

Low dose heparin lock (1000 U/mL) maintains tunnelled hemodialysis catheter patency when compared with high dose heparin (5000 U/mL): A randomised controlled trial

Introduction Heparin is commonly used after hemodialysis treatments as a locking solution to prevent catheter thrombosis. The comparative efficacy and safety of different heparin concentrations to maintain catheter patency has been previously reported in retrospective studies. We conducted a prospective, randomised, controlled study of 1000 U/mL heparin (low dose) versus 5000 U/mL heparin (high dose) locking solution to maintain patency of tunnelled catheters. Methods One hundred patients receiving chronic, unit‐based hemodialysis with newly placed tunnelled hemodialysis catheters (less than 1 week) were randomly assigned to either a low dose (n = 48) or high dose heparin (n=52). The primary intention‐to‐treat analysis examined time to malfunction in both groups over a 90 day period. A secondary analysis compared baseline patient characteristics in relation to catheter malfunction. Findings Overall rate of catheter patency loss was 32% of catheters by 90 days. There was no significant difference in time to malfunction of catheters locked with low dose or high dose heparin (P = 0.5770). Time to catheter malfunction was not associated with diabetic, hypertensive or smoking status. There was no difference in mean delivered blood flow rate, venous and arterial pressure, and dialysis adequacy between low dose and high dose groups. No patient suffered a hemorrhagic complication requiring hospitalisation during the study period. Discussion Low dose heparin is adequate to maintain tunnelled hemodialysis catheter patency when compared with high dose heparin. The study also suggests that there is no relationship between catheter malfunction and diabetic, hypertensive or smoking status.     

Orbitofrontal cortex and basolateral amygdala lesions result in suboptimal and dissociable reward choices on cue-guided effort in rats.

The orbitofrontal cortex (OFC) and basolateral nucleus of the amygdala (BLA) are important neural regions in responding adaptively to changes in the incentive value of reward. Recent evidence suggests these structures may be differentially engaged in effort and cue-guided choice behavior. In 2 T-maze experiments, we examined the effects of bilateral lesions of either BLA or OFC on (1) effortful choices in which rats could climb a barrier for a high reward or select a low reward with no effort and (2) effortful choices when a visual cue signaled changes in reward magnitude. In both experiments, BLA rats displayed transient work aversion, choosing the effortless low reward option. OFC rats were work averse only in the no cue conditions, displaying a pattern of attenuated recovery from the cue conditions signaling reward unavailability in the effortful arm. Control measures rule out an inability to discriminate the cue in either lesion group. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Psychotherapist mindfulness and the psychotherapy process.

[Correction Notice: An erratum for this article was reported in Vol 47(2) of Psychotherapy: Theory, Research & Practice (see record 2010-13424-005). the order of authorship and the affiliations of the authors was incorrectly printed. The correct order and affiliations are as follows: Noah Bruce, Shauna L. Shapiro, Michael J. Constantino, and Rachel Manber; Kaiser Permanente, Santa Clara University, University of Massachusetts, Stanford University] A psychotherapist’s ability to relate to his or her patients is essential for decreasing patient suffering and promoting patient growth. However, the psychotherapy field has identified few effective means for training psychotherapists in this ability. In this conceptual article, we propose that mindfulness practice may be a means for training psychotherapists to better relate to their patients. We posit that mindfulness is a means of self-attunement that increases one’s ability to attune to others (in this case, patients) and that this interpersonal attunement ultimately helps patients achieve greater self-attunement that, in turn, fosters decreased symptom severity, greater well-being, and better interpersonal relationships. (PsycINFO Database Record (c) 2010 APA, all rights reserved)