Discovering novel neuroactive drugs through high-throughput behavior-based chemical screening in the zebrafish

Most neuroactive drugs were discovered through unexpected behavioral observations. Systematic behavioral screening is inefficient in most model organisms. But, automated technologies are enabling a new phase of discovery-based research in central nervous system (CNS) pharmacology. Researchers are using large-scale behavior-based chemical screens in zebrafish to discover compounds with new structures, targets, and functions. These compounds are powerful tools for understanding CNS signaling pathways. Substantial differences between human and zebrafish biology will make it difficult to translate these discoveries to clinical medicine. However, given the molecular genetic similarities between humans and zebrafish, it is likely that some of these compounds will have translational utility. We predict that the greatest new successes in CNS drug discovery will leverage many model systems, including in vitro assays, cells, rodents, and zebrafish

Selective Environmentally Benign Synthesis of Isotope Labeled Compounds: Introduction of Deuterium into Compounds of Medicinal Relevance

Deuterium (2H) is a less abundant isotope of hydrogen that possesses an additional neutron resulting in significant differences in the properties of a 1H-containing-molecule compared to its 2H homologues. Deuterium labeled organic compounds are valuable in medicinal chemistry as they offer widespread applications. For instance, in imaging deuteratium labeling can serve as biological tracers, thus, deuterated drugs can provide better understanding of the metabolic pathways; they can also help localize the metabolites of the drug and assess their toxicity. While metabolic enzymes easily transform drug molecules to metabolites that the body can excrete, the introduction of deuterium to drugs appears to strengthen the resistance of drugs toward metabolism. In fact, the carbon-deuterium bond is known to be six to ten times stronger than its C-1H counterpart. The higher the stability, the longer the drug remains intact, which allows lower dosage, potentially causing fewer side effects. Due to the carbon-deuterium bond strength, deuterated drugs can also prevent the formation of toxic metabolites observed with its hydrogen-containing homologue. There are several known methods for the introduction of deuterium to organic compounds; most methods, however, do not conform to the recent expectations and standards of sustainable synthesis. Therefore, a green synthesis of deuterated organic compounds would be an important advance in producing these compounds in an environmentally sustainable way. Thus, we have turned our attention to the Al-H2O system that is commonly applied for hydrogenation reactions. Replacing the H2O with its deuterated version D2O in the system constitutes an easy, economic and safe source of deuterium. The application of either the commercially available Ni-Al alloy or Al in combination with Pd, a common hydrogenation catalyst, for the H-D exchange of compounds with reactive C-H bonds was performed, while yielding no harmful byproducts. The low reactivity of the aluminum metal was significantly enhanced by the application of ultrasonic irradiation prior to the reaction. The H-D exchange reaction was carried out under microwave irradiation and achieved good yields in no more than 1h. The success of the method was demonstrated by applying a broad variety of compounds from essential amino acids to actual drug compounds

Establishment of Native Aquatic Vegetation in Conjunction with an Integrated Invasive Aquatic Vegetation Management Program

Invasive aquatic vegetation is problematic in many Texas lakes and reservoirs and requires management for control. Most often an integrated pest management program incorporating biological, mechanical or chemical means is implemented. Establishment of non-native plants can also be deterred by utilizing an ecological method of planting native vegetation into the empty niches of a disturbed ecosystems that do not have a propagule bank. However, native vegetation establishment can be delayed by herbivory resulting in the need for protection of plants. Lake Raven was chosen as the study site because an integrated pest management approach using chemical, mechanical and biological means has been implemented to control invasive aquatic plants. The most recent herbicide treatments were fluridone on June 6, 2014 and glyphosate in May and August 2014. Native plant restoration was conducted in July 2014 in niches opened from the management of invasive aquatic vegetation. Six deep water and six shallow water species of native aquatic plants were planted in protective exclosures along the shoreline. Plants were given one month to establish before half the treatment exclosures were opened to potential herbivory. Analysis of covariance was used to determine if herbicide and herbivory limited native plant survival. The herbicide application had a significant effect on deep water plants, but did not have a significant effect on shallow water plants. There was not a significant effect associated with herbivory for any of the plant species, which is likely due to remaining invasive aquatic vegetation. Future research is needed to develop an integrated pest management program that incorporates ecological method without limitations from herbicide application

Retrodirective phase-lock loop controlled phased array antenna for a solar power satellite system

This thesis proposes a novel technique using a phase-lock loop (PLL) style phase control loop to achieve retrodirective phased array antenna steering. This novel approach introduces the concept of phase scaling and frequency translation. It releases the retrodirective transmit-receive frequency ratio from integer constraints and avoids steering approximation errors. The concept was developed to achieve automatic and precise beam steering for the solar power satellite (SPS). The testing was performed using a transceiver converting a pair of received 2.9 GHz signals down to 10 MHz, and up converting two 10 MHz signals to 5.8 GHz. Phase scaling and conjugation was performed at the 10 MHz IF using linear XOR phase detectors and a PLL loop to synthesize a 10 MHz signal with conjugate phase. A phase control loop design is presented using PLL design theory achieving a full 2π steering range. The concept of retrodirective beam steering is also presented in detail. Operational theory and techniques of the proposed method are presented. The prototype circuit is built and the fabrication details are presented. Measured performance is presented along with measurement techniques. Pilot phase detectors and PCL achieve good linearity as required. The achieved performance is benchmarked with standards derived from likely performance requirements of the SPS and beam steering of small versus large arrays are considered

Corporate cash hoarding and corporate governance mechanisms : evidence from Borsa Istanbul

This study aims to examine the impact of corporate governance mechanisms on the cash hoarding decision. The study focuses on BIST100 non-financial firms listed on Borsa Istanbul over the period from 2010 to 2014. The study finds that firms with larger size of board of directors are more likely to hoard cash than firms with smaller board size. However, it finds firms with larger size of audit committee are more likely to hold less cash than firms with smaller audit committee size. Besides, it finds that firms with larger percent of independent directors are more likely to hoard more cash than firms with smaller percent of independent directors. It, also, finds that when the CEO of a firm is also the chairman, the firm tends to hoard more cash. Further, the study finds that firms audited by non-big auditor are more likely to hold more cash than firms audited by big auditor. The results suggest that firms with good corporate governance mechanisms (except for percent of independent directors) are less likely to hoard cash

Theoretical and Experimental Analysis of the Antioxidant and Anti-amyloid Features of Synthetic Resveratrol Mimics

Diaryl hydrazones, possessing similar structure to the popular red wine antioxidant resveratrol, have been previously identified as multitarget compounds interfering with several processes associated with the pathogenesis of Alzheimer’s disease (AD). These compounds exhibited particularly strong inhibition of the amyloid beta (A) peptide self-assembly, including blocking the formation of fibrils and oligomers, species that are widely accepted to be neurotoxic. The molecules were also powerful free radical scavengers and thus have a potential to defend against oxidative stress. In order to learn more about the mode of action of the compounds, theoretical and experimental studies have been carried out. First, the structural, energetic and electronic features of the core structure have been elucidated by density funtional theory (DFT) calculations. The DFT results identified the most likely form of the compounds, which was applied to a broad range of calculations using substituted derivates. Based on the structural information several characteristics such as logP, H-binding energy, HOMO-LUMO energies and band gap and electron densities were calculated. The compounds were subjected to three different antioxidant assays (DPPH, ABTS and ORAC). The % radical scavenging has been analyzed as a function of the above determined structural parameters in order to identify the role of the energetic and electronic features in the antioxidant activity. The analysis of the same parameters as potential markers to the anti-amyloid activity has also been carried out. Isotope labeling via H-D exchange and in situ hydrazone-radicals as well as hydrazone-A complex formation, applying 1H-NMR and HRMS, have also been used to experimentally observe the potential role of various tautomeric forms and the partially delocalized electron structure of the hydrazones

Zebrafish behavioural profiling identifies GABA and serotonin receptor ligands related to sedation and paradoxical excitation.

Anesthetics are generally associated with sedation, but some anesthetics can also increase brain and motor activity-a phenomenon known as paradoxical excitation. Previous studies have identified GABAA receptors as the primary targets of most anesthetic drugs, but how these compounds produce paradoxical excitation is poorly understood. To identify and understand such compounds, we applied a behavior-based drug profiling approach. Here, we show that a subset of central nervous system depressants cause paradoxical excitation in zebrafish. Using this behavior as a readout, we screened thousands of compounds and identified dozens of hits that caused paradoxical excitation. Many hit compounds modulated human GABAA receptors, while others appeared to modulate different neuronal targets, including the human serotonin-6 receptor. Ligands at these receptors generally decreased neuronal activity, but paradoxically increased activity in the caudal hindbrain. Together, these studies identify ligands, targets, and neurons affecting sedation and paradoxical excitation in vivo in zebrafish

LakeBench: Benchmarks for Data Discovery over Data Lakes

Within enterprises, there is a growing need to intelligently navigate data lakes, specifically focusing on data discovery. Of particular importance to enterprises is the ability to find related tables in data repositories. These tables can be unionable, joinable, or subsets of each other. There is a dearth of benchmarks for these tasks in the public domain, with related work targeting private datasets. In LakeBench, we develop multiple benchmarks for these tasks by using the tables that are drawn from a diverse set of data sources such as government data from CKAN, Socrata, and the European Central Bank. We compare the performance of 4 publicly available tabular foundational models on these tasks. None of the existing models had been trained on the data discovery tasks that we developed for this benchmark; not surprisingly, their performance shows significant room for improvement. The results suggest that the establishment of such benchmarks may be useful to the community to build tabular models usable for data discovery in data lakes

Zebrafish Behavioral Profiling Links Drugs to Biological Targets and Rest/Wake Regulation

A major obstacle for the discovery of psychoactive drugs is the inability to predict how small molecules will alter complex behaviors. We report the development and application of a high-throughput, quantitative screen for drugs that alter the behavior of larval zebrafish. We found that the multidimensional nature of observed phenotypes enabled the hierarchical clustering of molecules according to shared behaviors. Behavioral profiling revealed conserved functions of psychotropic molecules and predicted the mechanisms of action of poorly characterized compounds. In addition, behavioral profiling implicated new factors such as ether-a-go-go–related gene (ERG) potassium channels and immunomodulators in the control of rest and locomotor activity. These results demonstrate the power of high-throughput behavioral profiling in zebrafish to discover and characterize psychotropic drugs and to dissect the pharmacology of complex behaviors

Neurodegeneration and Epilepsy in a Zebrafish Model of CLN3 Disease (Batten Disease)

The neuronal ceroid lipofuscinoses are a group of lysosomal storage disorders that comprise the most common, genetically heterogeneous, fatal neurodegenerative disorders of children. They are characterised by childhood onset, visual failure, epileptic seizures, psychomotor retardation and dementia. CLN3 disease, also known as Batten disease, is caused by autosomal recessive mutations in the CLN3 gene, 80–85% of which are a ~1 kb deletion. Currently no treatments exist, and after much suffering, the disease inevitably results in premature death. The aim of this study was to generate a zebrafish model of CLN3 disease using antisense morpholino injection, and characterise the pathological and functional consequences of Cln3 deficiency, thereby providing a tool for future drug discovery. The model was shown to faithfully recapitulate the pathological signs of CLN3 disease, including reduced survival, neuronal loss, retinopathy, axonopathy, loss of motor function, lysosomal storage of subunit c of mitochondrial ATP synthase, and epileptic seizures, albeit with an earlier onset and faster progression than the human disease. Our study provides proof of principle that the advantages of the zebrafish over other model systems can be utilised to further our understanding of the pathogenesis of CLN3 disease and accelerate drug discovery