Self-assembly of hydrophilic homopolymers: a matter of RAFT end groups

Unusual self-assembly behavior is observed for a range of hydrophilic homopolymers. This self-assembly behavior is contrary to the expected behavior of such hydrophilic polymers and instead mimics more commonly reported amphiphilic block copolymers. It is proposed that the unique combination of hydrophobic end groups at both the α and ω chain end accounts for this unusual self-assembly behavior. Complex internal polymer micelles are spontaneously formed when hydrophilic homopolymer polyelectrolytes and neutral polymers (with a weight fraction of the hydrophobic end groups <10 wt%) are directly dissolved in water. The homopolymers, poly[2-(diethylamino)ethyl methacrylate], poly(N-isopropylacrylamide), and poly(ethoxyethylacrylate) are synthesized by reversible addition-fragmentation chain-transfer (RAFT) polymerization using S'-1-dodecyl-(S')-(α,α'-dimethyl-α″-acetic acid) trithiocarbonate (DDMAT) and its derivatives as chain transfer agents (CTAs). A range of polyelectrolyte homopolymers with different terminal groups are designed and synthesized, which under acidic aqueous solution direct the self-assembly to form well-defined nanostructures. This assembly behavior was also observed for neutral polymers, and it was determined that the structure of the hydrophobic end groups (and thus choice of RAFT CTA) are very important in facilitating this unusual self-assembly behavior of hydrophilic homopolymers. It is proposed that the functionality of commonly used CTAs such as DDMAT, can affect the solution association of the resultant homopolymers and can in fact afford ABA' type polymers, which can undergo self-assembly to form higher-order nanostructures.     

Statistical analysis of nanoparticle dosing in a dynamic cellular system

The delivery of nanoparticles into cells is important in therapeutic applications and in nanotoxicology. Nanoparticles are generally targeted to receptors on the surfaces of cells and internalized into endosomes by endocytosis, but the kinetics of the process and the way in which cell division redistributes the particles remain unclear. Here we show that the chance of success or failure of nanoparticle uptake and inheritance is random. Statistical analysis of nanoparticle-loaded endosomes indicates that particle capture is described by an over-dispersed Poisson probability distribution that is consistent with heterogeneous adsorption and internalization. Partitioning of nanoparticles in cell division is random and asymmetric, following a binomial distribution with mean probability of 0.52-0.72. These results show that cellular targeting of nanoparticles is inherently imprecise due to the randomness of nature at the molecular scale, and the statistical framework offers a way to predict nanoparticle dosage for therapy and for the study of nanotoxins.     

A comparison of adult and adolescent rat behavior in operant learning, extinction, and behavioral inhibition paradigms.

Poor self-control, lack of inhibition, and impulsivity contribute to the propensity of adolescents to engage in risky or dangerous behaviors. Brain regions (e.g., prefrontal cortex) involved in impulse-control, reward-processing, and decision-making continue to develop during adolescence, raising the possibility that an immature brain contributes to dangerous behavior during adolescence. However, very few validated animal behavioral models are available for behavioral neuroscientists to explore the relationship between brain development and behavior. To that end, a valid model must be conducted in the relatively brief window of adolescence and not use manipulations that potentially compromise development. The present experiments used three operant arrangements to assess whether adolescent rats differ from adults in measures of learning, behavioral inhibition, and impulsivity, within the aforementioned time frame without substantial food restriction. In Experiment 1, separate squads of rats were trained to lever-press and then transitioned to two types of extinction. Relative to their baselines, adolescent rats responded more during extinction than adults, suggesting that they were less sensitive to the abolishment of the reinforcement contingency. Experiment 2 demonstrated similar age-related differences during exposure to a differential reinforcement of low rates schedule, a test of behavioral inhibition. Lastly, in Experiment 3, adolescent's responding decreased more slowly than adults during exposure to a resetting delay of reinforcement schedule, suggesting impaired self-control. Results from these experiments suggest that adolescents exhibit impaired learning, behavioral inhibition and self-control, and in concert with recent reports, provide researchers with three behavioral models to more fully explore neurobiology of risk-taking behavior in adolescence. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Distinguishing general and specific personality disorder features and implications for substance dependence comorbidity.

Clinical and population-based samples show high comorbidity between Substance Use Disorders (SUDs) and Axis II Personality Disorders (PDs). However, Axis II disorders are frequently comorbid with each other, and existing research has generally failed to distinguish the extent to which SUD/PD comorbidity is general or specific with respect to both specific types of PDs and specific types of SUDs. We sought to determine whether ostensibly specific comorbid substance dependence-Axis II diagnoses (e.g., alcohol use dependence and borderline personality disorder) are reflective of more pervasive or general personality pathology or whether the comorbidity is specific to individual PDs. Face-to-face interview data from Wave 1 and Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions were analyzed. Participants included 34,653 adults living in households in the United States. We used hierarchical factor models to statistically partition general and specific personality disorder dimensions while simultaneously testing for specific PD-substance dependence relations. Results indicated that substance dependence-Axis II comorbidity is characterized by general (pervasive) pathology and by Cluster B PD pathology over and above the relationship to the general PD factor. Further, these relations between PD factors and substance dependence diagnoses appeared to largely account for the comorbidity among substance dependence diagnoses in the younger but not older participants. Our findings suggest that a failure to consider the general PD factor, which we interpret as reflecting interpersonal dysfunction, can lead to potential mischaracterizations of the nature of certain PD and SUD comorbidities. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Book reviews

This article describes the planning activity in Portugal in the middle of the twentieth century, notably the work of two exceptional planners, Etienne de Groër and Antão Almeida Garrett. The article moves from a first overview on the national context, to a focus on the two largest cities of Portugal, Lisbon, and Oporto. It was there that these two planners developed their most successful planning proposals. The planning activity of de Groër and Garrett is presented, first taken in isolation and then on a comparative basis. Issues addressed include the urban structure and the organization of the city, the street layout, and the system of zoning. It is argued that de Groër municipal plan for Lisbon and Garrett municipal plan for Oporto were able to leave a profound and lasting impact on these cities, being the most influential planning documents of the twentieth century in Lisbon and in Oporto.     

Mechanistic and statistical models of total Vibrio abundance in the Neuse River Estuary

Bacteria in the genus Vibrio are ubiquitous to estuarine waters worldwide and are often the dominant genus recovered from these environments. This genus contains several potentially pathogenic species, including Vibrio vulnificus, Vibrio cholerae, Vibrio parahaemolyticus, and Vibrio alginolyticus. These bacteria have short generation times, as low as 20–30 min, and can thus respond rapidly to changing environmental conditions. A five-parameter mechanistic model was generated based on environmental processes including hydrodynamics, growth, and death rates of Vibrio bacteria to predict total Vibrio abundance in the Neuse River Estuary of eastern North Carolina. Additionally an improved statistical model was developed using the easily monitored parameters of temperature and salinity. This updated model includes data that covers more than eight years of constant bacterial monitoring, and incorporates extreme weather events such as droughts, storms, and floods. These models can be used to identify days in which bacterial abundance might coincide with increased health risks.     

Nuclear Export Inhibitor KPT-8602 Synergizes with PARP Inhibitors in Escalating Apoptosis in Castration Resistant Cancer Cells

Aberrant nuclear protein transport, often observed in cancer, causes mislocalization-dependent inactivation of critical cellular proteins. Earlier we showed that overexpression of exportin 1 is linked to higher grade and Gleason score in metastatic castration resistant prostate cancer (mCRPC). We also showed that a selective inhibitor of nuclear export (SINE) selinexor and second generation eltanexor (KPT-8602) could suppress mCRPC growth, reduce androgen receptor (AR), and re-sensitize to androgen deprivation therapy. Here we evaluated the combination of KPT-8602 with PARP inhibitors (PARPi) olaparib, veliparib and rucaparib in 22rv1 mCRPC cells. KPT-8602 synergized with PARPi (CI < 1) at pharmacologically relevant concentrations. KPT-8602-PARPi showed superior induction of apoptosis compared to single agent treatment and caused up-regulation of pro-apoptotic genes BAX, TP53 and CASPASE 9. Mechanistically, KPT-8602-PARPi suppressed AR, ARv7, PSA and AR targets FOXA1 and UBE2C. Western blot analysis revealed significant down-regulation of AR, ARv7, UBE2C, SAM68, FOXA1 and upregulation of cleaved PARP and cleaved CASPASE 3. KPT-8602 with or without olaparib was shown to reduce homologous recombination-regulated DNA damage response targets including BRCA1, BRCA2, CHEK1, EXO1, BLM, RAD51, LIG1, XRCC3 and RMI2. Taken together, this study revealed the therapeutic potential of a novel combination of KPT-8602 and PARP inhibitors for the treatment of mCRPC.     

Impact of a participatory agroecological development project on household wealth and food security in Malawi

This paper presents the impacts of a participatory agroecological development project on food security and wealth levels. The Malawi Farmer to Farmer Agroecology project (MAFFA) encourages farmer experimentation, community involvement and farmer-to-farmer teaching on agroecology, nutrition and gender equity. Recent international assessments of agriculture have highlighted the urgent need for changes in farming practices in Sub-Saharan Africa, due to land degradation, high levels of food insecurity and anticipated climate change impacts. Agroecological approaches have shown great potential to address these multiple needs. Using a longitudinal panel survey data and propensity score matching to account for selection bias in project participation, we analyzed the impact of the project on household income and food security in Malawi in 2012 (Wave 1 = 1200 households) and in 2014 (Wave 2 = 1000 households). We used the Household Food Insecurity Access Scale (HFIAS) for impact evaluation. Estimates of average treatment-effects using difference in difference methods showed that participating in MAFFA has led to a significant increase in household wealth (β = 3.54, p = 0.01) and a large reduction in food insecurity (β = ?3.21, p = 0.01) compared to non-participants, after 2 years, even after accounting for covariates and selection bias. These results indicate that agroecological methods combined with farmer led knowledge exchanges can be welfare enhancing, both in terms of food security and in terms of income for family farm households. Agroecological approaches should be promoted through upscaling of farmer-to-farmer knowledge exchanges, community involvement and attention to nutrition and social equity to enhance farmer learning and household welfare benefits.     

Approach to highly efficient dechlorination of PCDDs, PCDFs, and coplanar PCBs using metallic calcium in ethanol under atmospheric pressure at room temperature

Detoxification of highly toxic polychlorinated aromatic compounds such as polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs), and dioxin-like compounds such as coplanar polychlorinated biphenyls (co-PCBs) under mild conditions (atmospheric pressure and room temperature) was achieved by a simple stirring operation for 24 h using metallic calcium in ethanol, without any tedious decomposition procedures and harsh conditions such as high temperature and/or high pressure. Metallic calcium can be kept stable under atmospheric conditions for a long period as compared to metallic sodium since the surface is coated with CaCO3, which is formed in the contact with air. Moreover, ethanol, which is one of the safest solvents for humans, acts not only as a solvent but also as an accelerator due to its ablility to remove the carbonated coating. This decomposition method for PCDDs, PCDFs, and co-PCBs therefore is one of the most economical and environmentally friendly detoxification methods with respect to the input energy and safety of reagents used. Concentration for each isomer of PCDDs, PCDFs, and co-PCBs was reduced in 98.32-100% conversions by treatment in ethanol at room temperature. The toxicity equivalency quantity (TEQ), which was measured by the HRGC-HRMS analysis, for the total residues of isomers was reduced from 22,000 to 210 pg TEQ/mL of hexane (conversion: 99.05%) at room temperature. By refluxing over 24 h, the conversion increased up to 99.45%.