Design of novel biologically active polymers to enhance drug delivery across epithelial barriers.

Numerous linear, water-soluble polymers (particularly polyanions) are biologically active and can induce cytokines such as tumour necrosis factor-alpha (TNF-a), interferon-gamma (IFN-y) and interleukin-2 (IL-2) from cells depending on their molecular weight (MW), and composition. The proinflammatory cytokines TNF-a and IFN-y are able to permeabilise epithelial barriers by affecting the protein composition of the tight junctions (TJ) (Walsh et al, 2000). The aim of this work was to identify polymers that would promote enhanced drug delivery due to their inherent ability to stimulate TNF-a, IFN-y and IL-2 release, and therefore transiently permeabilise epithelial barriers. Several linear polyanions already used as excipients, including alginate, hyaluronic acid (HA), and polyacrylic acids (PAcA; MW 30,000, 100,000, or 450,000 Da), were chosen as the first polymer library to investigate. Branched polymers including polyamidoamine (PAMAM) generation 3.5 dendrimers and the polycation polyethylenimine, PEI (MW 750,000 Da), were also studied. Polyanions showed little cytotoxicity towards B16F10 cells and ECV304 cells at 72 h except PAcA of MW 100,000 Da in both cell lines, and 450,000 Da in B16F10. PEI was cytotoxic at low concentrations. Decreasing the incubation time to 1 h reduced polymer cytotoxicity (IC50 > 1 mg/mL) with the exception of PEI. Highest amounts of TNF-a, IL-2 and IFN-γ release from B16F10 and RAW 246.7 cells were seen with PEI (1 mg/mL). HA and HA sodium salt induced TNF-y release from DU937 cells in concentration-dependant manner. In transport studies, FITC-dextran transfer was greatest in the Ap-Bas direction, and in the absence of Peyer's patches. Cytokines had no significant effect on FITC-dextran transport, at either physiological or ng/mL concentrations. Polymers appeared to inhibit FITC-dextran transport in all directions and tissue types, though apically applied PAcA (MW 30,000 Da) and HA (1 mg/mL), showed some increase. This data was not significant. Lastly, PAcA (MW 30,000 Da) and PAMAM generation 3.5 dendrimers were labelled with OG cadaverine (OGcad) to monitor their transport across rat intestinal tissue (with or without Peyer's patches) also using the vertical diffusion system. The uptake of the polymers into Caco-2BBe cells (chosen as an enterocyte model) was investigated using flow cytometry. Fluorescently-labelled PAcA- (MW = 30,000 Da) and PAMAM-OG conjugates showed a greater rate of transport in the Bas-Ap direction. The conjugates did not appear to be taken up by Caco-2BBc cells. Although the scientific literature had suggested that certain polymers promote cytokine release, and that specific cytokines increase gastrointestinal permeability, it proved difficult here to validate the hypothesis that polymers might be designed to enhance transport in a reproducible and safe manner

Measurements of the Young’s modulus of hydroxide catalysis bonds, and the effect on thermal noise in ground-based gravitational wave detectors

With the outstanding results from the detection and observation of gravitational waves from coalescing black holes and neutron star inspirals, it is essential that pathways to further improve the sensitivities of the LIGO and VIRGO detectors are explored. There are a number of factors that potentially limit the sensitivities of the detectors. One such factor is thermal noise, a component of which results from the mechanical loss in the bond material between the silica fibre suspensions and the test mass mirrors. To calculate its magnitude, the Young’s modulus of the bond material has to be known with reasonable accuracy. In this paper we present a new combination of ultrasonic technology and Bayesian analysis to measure the Young’s modulus of hydroxide catalysis bonds between fused silica substrates. Using this novel technique, we measure the bond Young’s modulus to be 18.5 ± 2.0 2.3     GPa . We show that by applying this value to thermal noise models of bonded test masses with suitable attachment geometries, a reduction in suspension thermal noise consistent with an overall design sensitivity improvement allows a factor of 5 increase in event rate to be achieved

Let low-risk moms eat during labor?

Review of: Ciardulli A, Saccone G, Anastasio H, et al. Less-restrictive food intake during labor in low-risk singleton pregnancies: a systematic review and meta-analysis. Obstet Gynecol. 2017;129:473-480.Let low-risk moms eat during labor? Allowing low-risk pregnant women to eat less restrictive diets during labor may not only make them happier, but may shorten labor, too. Practice changer: Allowing low-risk patients planning for a vaginal delivery less restrictive diets during labor does not seem to increase the risk of aspiration or other harms and may shorten labor. Stength of recommendation: A: Based on a meta-analysis of 10 randomized controlled trials (RCTs) in tertiary hospitals.Karen Phelps, MD; Justin Deavers, MD; Dean A. Seehusen, MD, MPH; James J. Stevermer, MD, MSPH ; Eisenhower Army Medical Center, Fort Gordon, Ga (Drs. Phelps, Deavers, and Seehusen); Department of Family and Community Medicine, University of Missouri-Columbia (Dr. Stevermer)

Assessing Technological Literacy of Middle School Students

Project Lead the Way (PLTW) is a rigorous and relevant pre-engineering curriculum implemented in middle schools and high schools throughout the United States. PLTW has a hands-on approach using activities and project-based learning. The College of Engineering at Wichita State University has partnered with three local school districts to implement the PLTW program to increase interest in Science, Technology, Engineering and Mathematics (STEM). This study begins to assess the impact of the PLTW program on student perceptions and attitudes toward engineering and technology as part of an ongoing three-year assessment. A pre- and post-assessment were administered to middle school students (N=1063 and N=800, respectively) at the beginning and end of the 2010-2011 academic school year. The assessment consisted of 67-questions addressing students’ attitudes toward engineering and technology. This assessment was a combination of subscales from the Pupils’ Attitude Toward Technology (PATT-USA) and the Middle School Attitudes to Engineering, Science & Mathematics survey. Dependent variables of interest included attitude differences between PLTW students and nonPLTW students, gender differences, and differences attributed to length of involvement in the PLTW program. Results indicated PLTW students have a greater interest in technology, however there were notable gender differences and differences attributed to length of involvement in the program. Males had a greater interest in technology and longer involvement (0-3 years) in the program resulting in more positive attitudes. Females tended to have more negative opinions about technology at both pre- and post-assessment

Strength of hydroxide catalysis bonds between sapphire, silicon, and fused silica as a function of time

Hydroxide catalysis bonds have formed an integral part of ground-based gravitational wave (GW) observatories since the 1990s. By allowing the creation of quasimonolithic fused silica mirror suspensions in detectors such as GEO600 and Advanced LIGO, their use was crucial to the first ever direct detection of gravitational waves. Following these successes, this bonding technique has been included in advanced next generation cryogenic detector designs. Currently, they are used to create quasimonolithic crystalline sapphire suspensions in the KAGRA detector. They are also planned for use in silicon suspensions of future detectors such as the Einstein Telescope. In this paper we report how the strength of hydroxide catalysis bonds evolves over time, and compare the curing rates of bonds as they form between fused silica substrates to those between sapphire to sapphire and silicon to silicon substrates. For bonds between all three types of substrate material we show that newly formed bonds exhibit slightly higher breaking stresses than bonds cured for longer periods of time. We find that the strength stabilizes at ≥ 15     MPa for bonds cured for up to 30 weeks (7 months). This finding is important to future cryogenic GW detector design as it is crucial to ensure the long term integrity of the suspension interfaces. Monitoring the strength of bonds that have been allowed to cure for shorter lengths of time can also shed light on the chemistry of bond formation

MKS1 regulates ciliary INPP5E levels in Joubert syndrome

Background Joubert syndrome (JS) is a recessive ciliopathy characterised by a distinctive brain malformation \u27the molar tooth sign\u27. Mutations in \u3e 27 genes cause JS, and mutations in 12 of these genes also cause Meckel-Gruber syndrome (MKS). The goals of this work are to describe the clinical features of MKS1- related JS and determine whether disease causing MKS1 mutations affect cellular phenotypes such as cilium number, length and protein content as potential mechanisms underlying JS. Methods We measured cilium number, length and protein content (ARL13B and INPP5E) by immunofluorescence in fibroblasts from individuals with MKS1-related JS and in a three-dimensional (3D) spheroid rescue assay to test the effects of diseaserelated MKS1 mutations. Results We report MKS1 mutations (eight of them previously unreported) in nine individuals with JS. A minority of the individuals with MKS1-related JS have MKS features. In contrast to the truncating mutations associated with MKS, all of the individuals with MKS1- related JS carry \u3e1 non-truncating mutation. Fibroblasts from individuals with MKS1-related JS make normal or fewer cilia than control fibroblasts, their cilia are more variable in length than controls, and show decreased ciliary ARL13B and INPP5E. Additionally, MKS1 mutant alleles have similar effects in 3D spheroids. Conclusions MKS1 functions in the transition zone at the base of the cilium to regulate ciliary INPP5E content, through an ARL13B-dependent mechanism. Mutations in INPP5E also cause JS, so our findings in patient fibroblasts support the notion that loss of INPP5E function, due to either mutation or mislocalisation, is a key mechanism underlying JS, downstream of MKS1 and ARL13B

Professional Standards for School-Based Behavior Analysts

The Professional Standards for School-Based Behavior Analysts are intended to serve as an enhanced foundational layer for behavior analysts working specifically in the context of public school settings. These Professional Standards were developed by a team of behavior analysts with experience working in public schools and feedback was obtained from additional behavior analysts and other education professionals. There are five identified Professional Standard areas including: 1) Ethical & Professional Practice; 2) Collaboration; 3) Systems Capacity Building; 4) Instruction; and 5) Leadership & Policy

A ten-year follow-up of a study of memory for the attack of September 11, 2001: Flashbulb memories and memories for flashbulb events.

Within a week of the attack of September 11, 2001, a consortium of researchers from across the United States distributed a survey asking about the circumstances in which respondents learned of the attack (their flashbulb memories) and the facts about the attack itself (their event memories). Follow-up surveys were distributed 11, 25, and 119 months after the attack. The study, therefore, examines retention of flashbulb memories and event memories at a substantially longer retention interval than any previous study using a test-retest methodology, allowing for the study of such memories over the long term. There was rapid forgetting of both flashbulb and event memories within the first year, but the forgetting curves leveled off after that, not significantly changing even after a 10-year delay. Despite the initial rapid forgetting, confidence remained high throughout the 10-year period. Five putative factors affecting flashbulb memory consistency and event memory accuracy were examined: (a) attention to media, (b) the amount of discussion, (c) residency, (d) personal loss and/or inconvenience, and (e) emotional intensity. After 10 years, none of these factors predicted flashbulb memory consistency; media attention and ensuing conversation predicted event memory accuracy. Inconsistent flashbulb memories were more likely to be repeated rather than corrected over the 10-year period; inaccurate event memories, however, were more likely to be corrected. The findings suggest that even traumatic memories and those implicated in a community's collective identity may be inconsistent over time and these inconsistencies can persist without the corrective force of external influences.This is the author accepted manuscript. The final version is available from the American Psychological Association via http://dx.doi.org/10.1037/xge000005

Long-Term Memory for the Terrorist Attack of September 11: Flashbulb Memories, Event Memories, and the Factors That Influence Their Retention

More than 3,000 individuals from 7 U.S. cities reported on their memories of learning of the terrorist attacks of September 11, as well as details about the attack, 1 week, 11 months, and/or 35 months after the assault. Some studies of flashbulb memories examining long-term retention show slowing in the rate of forgetting after a year, whereas others demonstrate accelerated forgetting. This article indicates that (a) the rate of forgetting for flashbulb memories and event memory (memory for details about the event itself) slows after a year, (b) the strong emotional reactions elicited by flashbulb events are remembered poorly, worse than nonemotional features such as where and from whom one learned of the attack, and (c) the content of flashbulb and event memories stabilizes after a year. The results are discussed in terms of community memory practices.James S. McDonnell FoundationNational Institutes of Health (U.S.) (grant R01- MH0066972