Sustainable process design by the process to planet framework

Sustainable process design (SPD) problems combine a process design problem with life cycle assessment (LCA) to optimize process economics and life cycle environmental impacts. While SPD makes use of recent advances in process systems engineering and optimization, its use of LCA has stagnated. Currently, only process LCA is utilized in SPD, resulting in designs based on incomplete and potentially inaccurate life cycle information. To address these shortcomings, the multiscale process to planet (P2P) modeling framework is applied to formulate and solve the SPD problem. The P2P framework offers a more comprehensive analysis boundary than conventional SPD and greater modeling detail than advanced LCA methodologies. Benefits of applying this framework to SPD are demonstrated with an ethanol process design case study. Results show that current methods shift emissions outside the analysis boundary, while applying the P2P modeling framework results in environmentally superior process designs. Future extensions of the P2P framework are discussed. © 2015 American Institute of Chemical Engineers AIChE J, 61: 3320–3331, 2015     

Distributed dynamic load balancing with applications in radio access networks

Managing and balancing load in distributed systems remains a challenging problem in resource management, especially in networked systems where scalability concerns favour distributed and dynamic approaches. Distributed methods can also integrate well with centralised control paradigms if they provide high‐level usage statistics and control interfaces for supporting and deploying centralised policy decisions. We present a general method to compute target values for an arbitrary metric on the local system state and show that autonomous rebalancing actions based on the target values can be used to reliably and robustly improve the balance for metrics based on probabilistic risk estimates. To balance the trade‐off between balancing efficiency and cost, we introduce 2 methods of deriving rebalancing actuations from the computed targets that depend on parameters that directly affects the trade‐off. This enables policy level control of the distributed mechanism based on collected metric statistics from network elements. Evaluation results based on cellular radio access network simulations indicate that load balancing based on probabilistic overload risk metrics provides more robust balancing solutions with fewer handovers compared to a baseline setting based on average load.     

Rationally Designed Polypharmacology: α-Helix Mimetics as Dual Inhibitors of the Oncoproteins Mcl-1 and HDM2

Protein–protein interactions (PPIs), many of which are dominated by α-helical recognition domains, play key roles in many essential cellular processes, and the dysregulation of these interactions can cause detrimental effects. For instance, aberrant PPIs involving the Bcl-2 protein family can lead to several diseases including cancer, neurodegenerative diseases, and diabetes. Interactions between Bcl-2 pro-life proteins, such as Mcl-1, and pro-death proteins, such as Bim, regulate the intrinsic pathway of apoptosis. p53, a tumor-suppressor protein, also has a pivotal role in apoptosis and is negatively regulated by its E3 ubiquitin ligase HDM2. Both Mcl-1 and HDM2 are upregulated in numerous cancers, and, interestingly, there is crosstalk between both protein pathways. Recently, synergy has been observed between Mcl-1 and HDM2 inhibitors. Towards the development of new anticancer drugs, we herein describe a polypharmacology approach for the dual inhibition of Mcl-1 and HDM2 by employing three densely functionalized isoxazoles, pyrazoles, and thiazoles as mimetics of key α-helical domains of their partner proteins.     

EGFR-Binding Peptides: From Computational Design towards Tumor-Targeting of Adeno-Associated Virus Capsids

The epidermal growth factor receptor (EGFR) plays a central role in the progression of many solid tumors. We used this validated target to analyze the de novo design of EGFR-binding peptides and their application for the delivery of complex payloads via rational design of a viral vector. Peptides were computationally designed to interact with the EGFR dimerization interface. Two new peptides and a reference (EDA peptide) were chemically synthesized, and their binding ability characterized. Presentation of these peptides in each of the 60 capsid proteins of recombinant adeno-associated viruses (rAAV) via a genetic based loop insertion enabled targeting of EGFR overexpressing tumor cell lines. Furthermore, tissue distribution and tumor xenograft specificity were analyzed with systemic injection in chicken egg chorioallantoic membrane (CAM) assays. Complex correlations between the targeting of the synthetic peptides and the viral vectors to cells and in ovo were observed. Overall, these data demonstrate the potential of computational design in combination with rational capsid modification for viral vector targeting opening new avenues for viral vector delivery and specifically suicide gene therapy.     

Pseudouridine synthase 7 impacts Candida albicans rRNA processing and morphological plasticity

RNA can be modified in over 100 distinct ways, and these modifications are critical for function. Pseudouridine synthases catalyse pseudouridylation, one of the most prevalent RNA modifications. Pseudouridine synthase 7 modifies a variety of substrates in Saccharomyces cerevisiae including tRNA, rRNA, snRNA, and mRNA, but the substrates for other budding yeast Pus7 homologues are not known. We used CRISPR-mediated genome editing to disrupt Candida albicans PUS7 and find absence leads to defects in rRNA processing and a decrease in cell surface hydrophobicity. Furthermore, C. albicans Pus7 absence causes temperature sensitivity, defects in filamentation, altered sensitivity to antifungal drugs, and decreased virulence in a wax moth model. In addition, we find C. albicans Pus7 modifies tRNA residues, but does not modify a number of other S. cerevisiae Pus7 substrates. Our data suggests C. albicans Pus7 is important for fungal vigour and may play distinct biological roles than those ascribed to S. cerevisiae Pus7.     

Aptamer-based electrochemical detection of picomolar platelet-derived growth factor directly in blood serum

We report an electrochemical, aptamer-based (E-AB) sensor for the detection of platelet-derived growth factor (PDGF) directly in blood serum. The E-AB approach employs alternating current voltammetry to monitor target-induced folding in a methylene blue-modified, PDGF-binding aptamer. The sensor is sensitive, highly selective, and essentially reagentless: we readily detect the BB variant of PDGF at 1 nM directly in undiluted, unmodified blood serum and at 50 pM (1.25 ng/mL) in serum-diluted 2-fold with aqueous buffer. The sensitivity and selectivity achieved by this sensor match or significantly exceed those of the best analogous optical approaches. For example, the detection limit attained in 50% serum is achieved against a >25 million-fold excess of contaminating blood proteins and represents a 4 order of magnitude improvement over the most sensitive optical PDGF aptasensor reported to date. Moreover, the E-AB sensor combines these promising attributes in a platform that is reusable, label-free, and electronic. Given these advantages, E-AB sensors appear well suited for implementation in portable microdevices directed at the direct detection of proteins and small molecules in complex, largely unprocessed clinical samples.     

Dopamine D? receptor stimulation of the nucleus accumbens or the medial preoptic area promotes the onset of maternal behavior in pregnancy-terminated rats.

There is good evidence that interference with the mesolimbic dopamine (DA) system results in impaired maternal responding in postpartum female rats. However, whether activation of the mesolimbic DA system is capable of promoting maternal behavior has not been investigated. This study examined whether increasing DA activity in various brain regions of pregnancy-terminated, naive female rats would stimulate the onset of maternal behavior. Experiments 1 and 2 examined the effects of microinjection of various doses (0, 0.2, or 0.5 μg/0.5 μl/side) of a D? DA receptor agonist, SKF 38393, or a D? DA receptor agonist, quinpirole, into the nucleus accumbens (NA) on latency to show full maternal behavior, and Experiment 3 determined the effects of SKF 38393 injection into a control site. Finally, because the medial preoptic area (MPOA) is also important for maternal behavior, receives DA input, and expresses DA receptors, the authors examined whether microinjection of SKF 38393 into MPOA was capable of stimulating the onset of maternal behavior. Results indicated that microinjection of SKF 38393 into either the NA or the MPOA facilitates maternal responding in pregnancy-terminated rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of the syllable in the processing of spoken English: Evidence from a nonword comparison task.

Previous research using monitoring tasks suggests that syllables do not play a role in the initial processing of speech by English listeners. The role of syllables in a different task, 1 involving the speeded comparison of 2 nonwords, was investigated. In 2 experiments, responses to nonword pairs that shared a complete syllable were significantly faster than responses to pairs that shared part of a syllable when the shared unit was at the beginning or in the middle of the nonwords. Results were mixed when the shared unit was at the end of the nonwords, possibly reflecting a confounding effect of rhyme. Findings suggest that syllabified representations of the nonwords may be used in a comparison task, even in English. Results are interpreted relative to different demands of the nonword comparison and monitoring tasks. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Measuring Developmental Changes in Alcohol Expectancies.

The goal of this study was to measure shifts in alcohol expectancies from childhood into adolescence while controlling for changes in the psychometric properties of the instrument. One thousand nine hundred ninety-three 4th-grade and 1,632 9th-grade students from South Dakota rated the likelihood that 23 outcomes would result from alcohol use. These expectancies were modeled using a 2-factor confirmatory factor analysis. After differences in the psychometric properties of the instrument were controlled, the cohorts were distinguished by a large difference in Alcohol Positivity, with older participants viewing alcohol's effects more positively. Additionally, older participants displayed greater Alcohol Potency, believing that alcohol has a larger impact on all outcomes. There were also significant differences in the interpretation of the alcohol expectancies items across cohorts. (PsycINFO Database Record (c) 2010 APA, all rights reserved)