Fixture-scheduling for the Australian Football League using a Multi-objective Evolutionary Algorithm

AFL football is a team sport that entertains millions and contributes a huge amount of money to the Australian economy. Scheduling games in the AFL is difficult, as a number of different, often conflicting, factors must be considered. In this paper, we propose the use of a multi-objective evolutionary algorithm for determining such a schedule. We detail the technical details needed to apply a multi-objective evolutionary algorithm to this problem and report on experiments that show the effectiveness of this approach. Comparison with actual schedules used in the AFL demonstrates that this approach could make a useful contribution

Meeting Report: Alternatives for Developmental Neurotoxicity Testing

Developmental neurotoxicity testing (DNT) is perceived by many stakeholders to be an area in critical need of alternatives to current animal testing protocols and guidelines. To address this need, the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), the U.S. Environmental Protection Agency, and the National Toxicology Program are collaborating in a program called TestSmart DNT, the goals of which are to: (a) develop alternative methodologies for identifying and prioritizing chemicals and exposures that may cause developmental neurotoxicity in humans; (b) develop the policies for incorporating DNT alternatives into regulatory decision making; and (c) identify opportunities for reducing, refining, or replacing the use of animals in DNT. The first TestSmart DNT workshop was an open registration meeting held 13–15 March 2006 in Reston, Virginia. The primary objective was to bring together stakeholders (test developers, test users, regulators, and advocates for children’s health, animal welfare, and environmental health) and individuals representing diverse disciplines (developmental neurobiology, toxicology, policy, and regulatory science) from around the world to share information and concerns relating to the science and policy of DNT. Individual presentations are available at the CAAT TestSmart website. This report provides a synthesis of workgroup discussions and recommendations for future directions and priorities, which include initiating a systematic evaluation of alternative models and technologies, developing a framework for the creation of an open database to catalog DNT data, and devising a strategy for harmonizing the validation process across international jurisdictional borders

Implications Of The Caacb Virus Contamination In Biomanufacturing Project For Cell Therapy Manufacturers

Adventitious agent contamination of cell culture-based biomanufacturing operations for the production of protein and monoclonal antibody biotherapeutics are infrequent, but when they do occur, they are very costly, impact manufacturing operations, and can potentially impact patient safety and product supply. In response to this need, the MIT Consortium on Adventitious Agent Contamination in Biomanufacturing (CAACB) began the confidential collection and analysis of industry-wide viral contamination data with an emphasis on “lessons learned”. This presentation will cover the learnings from this study, including identified industry risks and best practices to mitigate those risks. Some of the key findings which have significant implications to the emerging cell therapy industry are: 1) Raw materials, including non-animal-based raw materials, may be a potential source of viral contamination and stringent raw material testing and vendor selection and auditing programs are critical. 2) Traditional viral tests, including in vitro testing and PCR, have contributed to false-positive events, which may take extended times to resolve prior to release of raw materials, process intermediates, or final product. 3) The time frames needed for viral testing in general, and for investigation of positive viral tests, can range from weeks to months, and are not compatible with the requirements for near real-time release testing for some cell therapy products. 4) Viral testing programs, and potential investigations of positive results, are quite expensive, and application to the autologous cell therapy space will be challenging

Phase diffusion and charging effects in Josephson junctions

The supercurrent of a Josephson junction is reduced by phase diffusion. For ultrasmall capacitance junctions the current may be further decreased by Coulomb blockade effects. We calculate the Cooper pair current by means of time-dependent perturbation theory to all orders in the Josephson coupling energy and obtain the current-voltage characteristic in closed form in a range of parameters of experimental interest. The results comprehend phase diffusion of the coherent Josephson current in the classical regime as well as the supercurrent peak due to incoherent Cooper pair tunneling in the strong Coulomb blockade regime.Comment: 4 pages, 3 figures, RevTe

Optical Detection of Degraded Therapeutic Proteins

The quality of therapeutic proteins such as hormones, subunit and conjugate vaccines, and antibodies is critical to the safety and efficacy of modern medicine. Identifying malformed proteins at the point-of-care can prevent adverse immune reactions in patients; this is of special concern when there is an insecure supply chain resulting in the delivery of degraded, or even counterfeit, drug product. Identification of degraded protein, for example human growth hormone, is demonstrated by applying automated anomaly detection algorithms. Detection of the degraded protein differs from previous applications of machine-learning and classification to spectral analysis: only example spectra of genuine, high-quality drug products are used to construct the classifier. The algorithm is tested on Raman spectra acquired on protein dilutions typical of formulated drug product and at sample volumes of 25 μL, below the typical overfill (waste) volumes present in vials of injectable drug product. The algorithm is demonstrated to c orrectly classify anomalous recombinant human growth hormone (rhGH) with 92% sensitivity and 98% specificity even when the algorithm has only previously encountered high-quality drug product.United States. Defense Advanced Research Projects Agency (Contract N66001-13-C-4025

BVR-A deficiency leads to autophagy impairment through the dysregulation of AMPK/mTOR axis in the brain—Implications for neurodegeneration

Biliverdin reductase-A (BVR-A) impairment is associated with increased accumulation of oxidatively-damaged proteins along with the impairment of autophagy in the brain during neurodegenerative disorders. Reduced autophagy inhibits the clearance of misfolded proteins, which then form neurotoxic aggregates promoting neuronal death. The aim of our study was to clarify the role for BVR-A in the regulation of the mTOR/autophagy axis by evaluating age-associated changes (2, 6 and 11 months) in cerebral cortex samples collected from BVR-A knock-out (BVR-A−/−) and wild-type (WT) mice. Our results show that BVR-A deficiency leads to the accumulation of oxidatively-damaged proteins along with mTOR hyper-activation in the cortex. This process starts in juvenile mice and persists with aging. mTOR hyper-activation is associated with the impairment of autophagy as highlighted by reduced levels of Beclin-1, LC3β, LC3II/I ratio, Atg5–Atg12 complex and Atg7 in the cortex of BVR-A−/− mice. Furthermore, we have identified the dysregulation of AMP-activated protein kinase (AMPK) as a critical event driving mTOR hyper-activation in the absence of BVR-A. Overall, our results suggest that BVR-A is a new player in the regulation of autophagy, which may be targeted to arrive at novel therapeutics for diseases involving impaired autophagy

The mechanism of aquaporin inhibition by gold compounds elucidated by biophysical and computational methods

The inhibition of water and glycerol permeation via human aquaglyceroporin-3 (AQP3) by gold(III) complexes has been studied by stopped-flow spectroscopy and, for the first time, its mechanism has been described using molecular dynamics (MD), combined with density functional theory (DFT) and electrochemical studies. The obtained MD results showed that the most effective gold-based inhibitor, anchored to Cys40 in AQP3, is able to induce shrinkage of pores preventing glycerol and water permeation. Moreover, the good correlation between the affinity of the Au(III) complex to Cys binding and AQP3 inhibition effects was highlighted, while no influence of the different oxidative character of the complexes could be observed

Selective functionalization of carbon nanotubes

The present invention is directed toward methods of selectively functionalizing carbon nanotubes of a specific type or range of types, based on their electronic properties, using diazonium chemistry. The present invention is also directed toward methods of separating carbon nanotubes into populations of specific types or range(s) of types via selective functionalization and electrophoresis, and also to the novel compositions generated by such separations

What to Do When Accumulated Exposure Affects Health but Only Its Duration Was Measured? A Case of Linear Regression

Background: We considered a problem of inference in epidemiology when cumulative exposure is the true dose metric for disease, but investigators are only able to measure its duration on each subject. Methods: We undertook theoretical analysis of the problem in the context of a continuous response caused by cumulative exposure, when duration and intensity of exposure follow log-normal distributions, such that analysis by linear regression is natural. We present a Bayesian method to adjust duration-only analysis to incorporate partial knowledge about the relationship between duration and intensity of exposure and illustrate this method in the context of association of smoking and lung function. Results: We derive equations that (a) describe under what circumstances bias arises when duration of exposure is used as a proxy of cumulative exposure, (b) quantify the degree of such bias and loss of precision, and (c) describe how knowledge about relationship of duration and intensity of exposure can be used to recover an estimate of the effect of cumulative exposure when only duration was observed on every subject. Conclusions: Under our assumptions, when duration and intensity of exposure are either independent or positively correlated, we can be more confident in qualitatively interpreting the direction of effects that arise from use of duration of exposure per se. We can use external information on the relationship between duration and intensity of exposure (namely: correlation and variance of intensity), even if intensity of exposure is not available at the individual level, to make reliable inferences about the magnitude of effect of cumulative exposure on the outcome