Target Identification Strategies for MMV Malaria Box Inhibitors of Toxoplasma gondii Growth

Small molecule screening is commonly used to discover lead compounds for drug development, but it can also be a powerful way to identify chemical probes for studying biological mechanisms. Our lab uses small molecules to study the mechanisms by which the protozoan parasite Toxoplasma gondii infects and replicates within its hosts. In this work, we employed a fluorescence-based assay to screen the Medicines for Malaria Venture (MMV) Open Access Malaria box for compounds that affect T. gondii growth. The box contains 400 previously identified small-molecule inhibitors of the related parasite, Plasmodium falciparum. We identified 79 hits, including a 2,4-diaminoquinazoline (MMV006169; IC50=1.15µM) that strongly inhibits T. gondii intracellular replication and invasion with no evidence of toxicity to mammalian cells. Extensive structure-activity relationship analyses with T. gondii identified a number of analogs with changed potency and altered effects on replication and invasion. These structure-activity analyses provided the information necessary to synthesize a bivalent chemical inducer of dimerization (CID) containing MMV006169 for use in yeast three-hybrid experiments. Yeast growth competition assays showed that this CID is capable of entering the yeast nucleus, as required for yeast three-hybrid screening. Yeast three-hybrid was used in a targeted format to test the hypothesis that MMV006169 works by inhibiting parasite CDC48, an ATPase involved in trafficking and the degradation of misfolded proteins. Large-scale cDNA library screening by yeast three-hybrid suggests that the compound may instead be working through inhibition of a host cell target. This work has provided insight into how MMV006169 affects the parasite\u27s lytic cycle and generated a testable hypothesis for the biologically relevant target of the compound

A Distributed Optimal Control Approach for Multi-agent Trajectory Optimization

<p>This dissertation presents a novel distributed optimal control (DOC) problem formulation that is applicable to multiscale dynamical systems comprised of numerous interacting systems, or agents, that together give rise to coherent macroscopic behaviors, or coarse dynamics, that can be modeled by partial differential equations (PDEs) on larger spatial and time scales. The DOC methodology seeks to obtain optimal agent state and control trajectories by representing the system's performance as an integral cost function of the macroscopic state, which is optimized subject to the agents' dynamics. The macroscopic state is identified as a time-varying probability density function to which the states of the individual agents can be mapped via a restriction operator. Optimality conditions for the DOC problem are derived analytically, and the optimal trajectories of the macroscopic state and control are computed using direct and indirect optimization algorithms. Feedback microscopic control laws are then derived from the optimal macroscopic description using a potential function approach.</p><p>The DOC approach is demonstrated numerically through benchmark multi-agent trajectory optimization problems, where large systems of agents were given the objectives of traveling to goal state distributions, avoiding obstacles, maintaining formations, and minimizing energy consumption through control. Comparisons are provided between the direct and indirect optimization techniques, as well as existing methods from the literature, and a computational complexity analysis is presented. The methodology is also applied to a track coverage optimization problem for the control of distributed networks of mobile omnidirectional sensors, where the sensors move to maximize the probability of track detection of a known distribution of mobile targets traversing a region of interest (ROI). Through extensive simulations, DOC is shown to outperform several existing sensor deployment and control strategies. Furthermore, the computation required by the DOC algorithm is proven to be far reduced compared to that of classical, direct optimal control algorithms.</p>Dissertatio

5-fluorouracil induced cardiotoxicity: Review of the literature

5-fluorouracil (5-FU) is a key chemotherapeutic agent in the treatment of many gastrointestinal tract adenocarcinomas. Despite its proven therapeutic efficacy, 5-FU also possesses several undesired cardiac toxicities, including coronary vasospasm, coronary thrombosis, cardiomyopathy, and sudden cardiac death. This review addresses the incidence, mechanisms of action, clinical presentation, risk stratification, and management of 5-FU associated cardiotoxicity; it also highlights the importance of careful pre-administration cardiac risk stratification and close monitoring during and after drug administration. (Cardiol J 2012; 19, 5: 453-458

Influenza vaccine supply, 2005–2006: did we come up short?

<p>Abstract</p> <p>Background</p> <p>Although total influenza vaccine doses available in the 2005/2006 influenza season were over 80 million, CDC received many reports of delayed and diminished vaccine shipments in October to November of 2005. To better understand the supply problems, CDC and partners surveyed several health care professional groups.</p> <p>Methods</p> <p>Surveys were sent to representative samples of influenza vaccine providers including pediatricians, internists, federally qualified health centers, visiting nurse organizations, and all 64 state and other health departments receiving federal immunization funds directly. In November and December, 2005, providers were asked questions about their experience in ordering influenza vaccine, sources where orders were placed, proportion of orders received, and referral of patients to other vaccination sites.</p> <p>Results</p> <p>The number of providers surveyed (median: 154; range: 64 – 308) and response rates (median: 62%; range: 51% – 77%) varied among groups. Less than half of the providers in most groups placed a single order that was accepted (median: 31%; range: 8% – 53%), and most placed multiple orders. Only 57% of federally qualified health centers and 60% of internists reported they received at least 40% of their orders by the middle of December; the other provider groups received a greater proportion of their orders. Most internists (80%) and federally qualified health centers (54%) reported that they had referred priority group patients to other locations to receive the influenza vaccine due to inadequate supplies. Vaccine providers who ordered only from Chiron received a lower proportion of their orders than providers that ordered from another source or ordered from multiple sources.</p> <p>Conclusion</p> <p>Most of the providers surveyed received only part of their orders by the middle of December. Disruptions in receipt of influenza vaccine during the fall of 2005 were due primarily to shortfalls in vaccine from Chiron and also due to delays and partial shipments from other distributors.</p

Sleep Power Topography in Children with Attention Deficit Hyperactivity Disorder (ADHD).

OBJECTIVE Recent years saw an increasing interest towards sleep microstructure abnormalities in attention-deficit/hyperactivity disorder (ADHD). However, the existing literature on sleep electroencephalographic (EEG) power in ADHD is still controversial, often based on single electrode recordings, and mainly focused on slow wave activity (SWA) during NREM sleep. This study aimed to systematically investigate sleep power topography in all traditional frequency bands, in all sleep stages and across sleep cycles using high-density EEG (HD-EEG). METHOD Thirty drug-naïve children with ADHD (10.5 ± 2.1 years, 21 male) and 23 typically developing (TD) control participants (mean age: 10.2 ± 1.6 years, 13 male) were included in the current analysis. Signal power topography was computed in classical frequency bands during sleep, contrasted between groups and sleep cycles, and correlated with measures of ADHD severity, cognitive functioning and estimated total sleep time. RESULTS Compared to TD subjects, patients with ADHD consistently displayed a widespread increase in low-frequency activity (between 3 and 10 Hz) during NREM sleep, but not during REM sleep and wake before sleep onset. Such a difference involved a wide centro-posterior cluster of channels in the upper SWA range, in Theta, and low-Alpha. Between-group difference was maximal in sleep stage N3 in the first sleep cycle, and positively correlated with average total sleep time. CONCLUSIONS These results support the concept that children with ADHD, compared to TD peers, have a higher sleep pressure and altered sleep homeostasis, which possibly interfere with (and delay) cortical maturation

Mass Vaccine Administration under Supply Uncertainty

The insurgence of COVID-19 requires fast mass vaccination, hampered by scarce availability and uncertain supply of vaccine doses and a tight schedule for boosters. In this paper, we analyze planning strategies for the vaccination campaign to vaccinate as many people as possible while meeting the booster schedule. We compare a conservative strategy and q-days-ahead strategies against the clairvoyant strategy. The conservative strategy achieves the best trade-off between utilization and compliance with the booster schedule. Q-days-ahead strategies with q < 7 provide a larger utilization but run out of stock in over 30% of days

Machine Learning Solutions for Top-Down Cracking Design of Airport Rigid Pavement

692M15-20-T-00033The Federal Aviation Administration (FAA) rigid pavement design process is based on bottom-up cracking failure resulting from tensile stress at the bottom of a flat slab under aircraft loads. The FAA has a long-term goal to add top-down cracking failure mode to the FAA Rigid and Flexible Iterative Elastic Layered Design (FAARFIELD) program. The existing design procedure is not suitable to support design for the top-down cracking failure mode. Critical stresses for rigid pavement design can be calculated by Finite Element Analysis \u2013 FAA (FEAFAA), the FAA three-dimensional finite element (3D-FE) program. However, direct use of 3D-FE methods in design software is typically far more time-consuming than is acceptable for design procedures

Synthesis of a Novel Type of 2,3'-BIMs via Platinum-Catalysed Reaction of Indolylallenes with Indoles

Optimisation, scope and mechanism of the platinum-catalysed addition of indoles to indolylallenes is reported here to give 2,3'-BIMs with a novel core structure very relevant for pharmaceutical industry. The reaction is modulated by the electronic properties of the substituents on both indoles, with the 2,3'-BIMs favoured when electron donating groups are present. Although simple at first, a complex mechanism has been uncovered that explains the different behaviour of these systems with platinum when compared with other metals (e.g. gold). Detailed labelling studies have shown Pt-catalysed 6-endo-trig cyclisation of the indollylallene as the first step of the reaction and the involvement of two cyclic vinyl-platinum intermediates in equilibrium through a platinum carbene, as the key intermediates of the catalytic cycle towards the second nucleophilic attack and formation of the BIMs