While both social information processing and cortisol secretion in childhood aggression have generated a great deal of interest and research in the past few decades, these social-cognitive and physiological components of aggressive behavior have not been examined in the context of an integrative model. This lack of an integrative framework may underlie some of the inconsistencies that have plagued the literature in this area to date, especially with respect to hypothalamic-pituitary-adrenal (HPA) axis functioning in aggressive children. This investigation tested a mediational model of the relationship between social-information processing, cortisol secretion, and reactive and proactive aggression. Specifically, it was hypothesized that social-information processing variables would mediate the proposed relationship between reactive and proactive aggression and cortisol secretion. One hundred and twenty-six children between the ages of 13 and 18 were administered the Child Behavior Rating Form (CBR), the Home Interview with Child (HIC), the Response Decision and Social Goals Instrument (RDSGI), the Antisocial Processes Screening Device (APSD), the Buss-Durkee Hostility Inventory (BDHI), the Children's Depression Inventory (CDI), and the Revised Children's Manifest Anxiety Scale (RCMAS). Each child also contributed two samples of saliva for cortisol assay, and each child's teacher completed a teacher-version of the APSD and the CBR. Regression analyses revealed no significant associations between proactive or reactive aggression and cortisol secretion, or between any of the social-information processing variables and cortisol secretion. Predicted associations between proactive and reactive aggression and social-information processing variables were found. Overall, therefore, the mediational model was not supported. However, cortisol secretion was found to be associated with both anxiety and depression, and exploratory analyses revealed significant associations between cortisol secretion and Psychopathy as measured by the APSD. Taken together, the findings suggest that while the specific relationship proposed here among social-cognitive, psychophysiological, and behavioral variables was not found, an integrative model examining each of these components may be useful in further investigations of the complex phenomenon of childhood aggression. / Ph. D.

Hydrogen sulfide (H2S) has been recognized as a biological signaling molecule for over twenty years now. Since these important findings emerged, many collaborative projects among chemists, biologists, and clinicians have demonstrated the physiological roles and potential therapeutic benefits of exogenous H2S delivery. As our understanding of the active roles H2S plays in biological systems has increased, so has the desire to investigate other related sulfur species (i.e. persulfides, R–SSH) for their physiological interactions with H2S and potential therapeutic efficacy. This recent interest in persulfides has stimulated a flurry of research in the field and created a new set of scientific problems to solve and opportunities to improve our understanding of persulfides in a biological context. With this surge of interest in persulfides, chemists set out to synthesize and characterize a variety of stimuli-responsive compounds that release persulfides under specific, biologically relevant conditions. In order to better understand persulfide reactivity and biological activity, and provide several prodrug platforms that respond to a variety of stimuli, this dissertation describes four persulfide-releasing prodrug systems, a pyrene-based fluorescent probe that measures H2S release in the presence of thiols, and efforts toward a peptide-based system for the release of H2S from a peptide thioacid (C(O)SH). The first four systems described utilize the well-known 1,6-benzyl elimination reaction (sometimes called self-immolation) to trigger release of a persulfide from a small molecule, polymeric, or peptide-based prodrug platform. Importantly, the first self-immolative small molecule persulfide prodrug (termed BDP-NAC) was designed to respond to reactive oxygen species (ROS). Specifically, BDP-NAC utilized a para-positioned boronic acid pinacol ester functionality to selectively react with H2O2, yielding N-acetylcysteine persulfide (NAC-SSH) and p-hydroxybenzyl alcohol as a byproduct. BDP-NAC showed trigger specificity towards H2O2, as determined by the use of a structurally analogous fluorescent probe (termed BDP-fluor). The prodrug also exhibited antioxidant properties in vitro, and served as the first example in the literature of a self-immolative persulfide donor. The second group of donors, self-immolative small molecule and peptide-based persulfide prodrugs (termed SOPD-Pep and SOPD-NAC), were designed to be responsive to superoxide (O2∙–), the primary precursor to all other ROS. In this work, the advantages of attaching small molecule persulfide donors to peptides were explored. In vitro experiments showed that SOPD-Pep mitigated toxicity induced by phorbol 12-myristate 13-acetate (PMA) more effectively than its small molecule counterpart SOPD-NAC and several common H2S donors. It is proposed that peptide scaffolds offer increased cellular uptake due to their nanoscale size, allowing for better antioxidant activity, as confirmed by fluorescence microscopy. The third section of this dissertation compares an esterase-responsive small molecule to an analogous polymeric persulfide releasing prodrug (termed EDP-NAC and polyEDP-NAC) and their abilities to decrease oxidative stress in response to immediate (H2O2) and sustained (5-fluorouracil, 5-FU) forms of ROS. Persulfide release half-lives were characterized using 1H NMR spectroscopy and showed over one order of magnitude difference between EDP-NAC and polyEDP-NAC. In vitro evaluation of the donors showed polyEDP-NAC was better suited to combat sustained production of ROS induced by 5-FU, whereas EDP-NAC was better suited to combat immediately available ROS from H2O2. These discrepancies in antioxidant activity between the two donors were deemed to be a result of their different persulfide release half-lives, indicating that scientists must take these factors into consideration when designing R–SSH prodrugs for specific disease indications. The fourth donor, NDP-NAC, responded to the bacteria-specific enzyme nitroreductase to release its persulfide payload. NDP-NAC elicited gastroprotective effects in mice that were not observed in animals treated with control compounds incapable of persulfide release or in animals treated with Na2S. NDP-NAC induced these effects by the upregulation of beneficial small and medium chain fatty acids and through increasing growth of Turicibacter sanguinis, a beneficial gut bacterium. It also decreased the populations of Synergistales bacteria, opportunistic pathogens implicated in gastrointestinal infections. Lastly, two appendices are provided in this dissertation that briefly describe the synthesis of a pyrene-based H2S sensor and efforts toward a readily accessible peptide-based thioacids as H2S donors. / Doctor of Philosophy / Hydrogen sulfide (H2S), produced naturally in hydrothermal vents and as a byproduct of industrial processes, has historically been known for its potent smell and toxicity. However, the recent discovery of H2S as a naturally-produced signaling molecule (termed gasotransmitter) in mammals has changed the way scientists view this malodorous gas. Our understanding of the biological roles and production of H2S is still growing, and recent research has suggested various links between changes in H2S concentrations in the body and a variety of disease states, including Alzheimer's, cardiovascular disease, and inflammation. Because of this link between various diseases and alterations in natural H2S production, collaborative efforts among chemists, biologists, and pharmacologists have demonstrated the usefulness of therapeutics that contain H2S-donating moieties, in an effort to alleviate these disease conditions. Persulfides (R-SSH), biological signaling molecules related to H2S, have emerged as critical species in sulfur signaling because of the similar observed antioxidative effects compared to H2S. This dissertation focuses on the synthesis and characterization of several compounds that release persulfides in response to specific stimuli (called persulfide donors). The first donor system described here releases persulfides in response to hydrogen peroxide (H2O2), a major cellular oxidant, and reduces oxidative stress in response to H2O2. The second donor system responds to superoxide (O2∙–), a precursor oxidant to H2O2 in cells, to release persulfides. Specifically, two variants of these donors, a small molecule and a peptide-based donor, exhibited antioxidant activity in response to O2∙–, but to varying degrees based on differences in cellular uptake of small molecules and self-assembled peptide nanostructures. The third donor system compares persulfide release from a small molecule and polymeric scaffold, both of which release persulfides in response to esterase enzymes. A large persulfide release half-life range was observed between the two donor systems, and antioxidant activity in response to H2O2 also varied based on the source and timescale of oxidant (H2O2 versus 5-fluorouracil). The fourth section of this dissertation focuses on a persulfide donor that responds to the bacterial enzyme nitroreductase. This donor increased levels of beneficial bacteria and short and medium chain fatty acids in murine models, while simultaneously decreasing levels of a niche subset of harmful bacteria. Taken together, these persulfide donor systems exhibit the strong reducing ability of persulfides in a biological context, showcasing the potential for therapeutic efficacy and avenues for more advanced donors to be synthesized in the future.

Bud dormancy is an essential characteristic of deciduous woody perennials, including apple, to cope with the low temperatures during winter. The release from dormancy and subsequent budburst in apple can only occur after fulfillment of chilling and heat requirements. In the Mid-Atlantic region, dormancy release and bud break of apple often coincide with late-spring freezes that cause severe damages to flowers, and small fruitlets. Therefore, the present study aimed to better understand mechanisms underlying bud dormancy in apple, with an ultimate goal of exploring chemical and/or genetic approaches for bloom-time modulation to avoid spring frost. Using two apple cultivars, 'Cripps Pink' and 'Honeycrisp,' representing early- and late-blooming cultivars, respectively, the present study specifically investigated the accumulation kinetics of plant hormones, carbohydrates, and reactive oxygen species (ROS) throughout the dormancy-regrowth cycle. Our results indicated that both cultivars required 1000 chilling hours for endodormancy release, but 'Honeycrisp' required 1000 growing degree hours (GDHs) more than 'Cripps Pink' for ecodormancy release and budburst. Among plant hormones, abscisic acid (ABA) showed remarkably elevated levels in the dormant buds of both cultivars during endodormancy, but its levels were significantly higher in 'Honeycrisp'. The decline of the ABA level at bud burst was combined with increased levels of cytokinin (CK). The ABA accumulation pattern during dormancy paralleled with an upregulation and downregulation of ABA biosynthetic and catabolic genes, respectively. On the other hand, the levels of hydrogen peroxide (H2O2) and superoxide (O2.-) were significantly higher in 'Cripps Pink' than 'Honeycrisp', particularly by the time of endodormancy and ecodormancy release, respectively. Our findings also showed a gradual decline in starch levels with the dormancy progression and increased levels of total soluble sugars (TSS) that were generally higher in the early-blooming cultivars. Transcriptomic profiling and module-trait relationship identified two modules that contrast between two cultivars mainly during eco-dormancy. Gene ontology (GO) analysis indicated that these DEGs were mostly involved in pathways related to hormones and signaling and co-expressed with H2O2 whereas, during ecodormancy pathways related to glutathione metabolism, auxin biosynthesis, carbohydrate metabolism and reproductive development were co-expressed with O2.-. Together, our results suggest that the contrasting bloom dates between 'Cripps Pink' and 'Honeycrisp' can be explained, at least partially, by the differential accumulation levels of ABA, ROS, antioxidants, and their associated genes in the buds of these cultivars throughout the dormancy cycle. / Doctor of Philosophy / Spring frosts represent a significant threat to apple production in many fruit-producing states of the United States including Virginia. The risk of frost damage is rising due to global climate change, and there is a high demand for effective measures to reduce frost damage. Exogenous applications of plant growth regulators (PGRs) to delay bloom has been suggested as an effective frost avoidance strategy, but with limited success. Therefore, the present study aimed to investigate molecular and biochemical pathways regulating bud dormancy and bloom time in apple, which can ultimate lead to novel approaches for bloom delay and frost mitigation. To this end, the accumulation patterns of major plant hormones (e.g. abscisic acid, ABA, cytokinin, CK and jasmonic acid, JA), reactive oxygen species (ROS) and carbohydrates (e.g. starch, sucrose, glucose and fructose) were thoroughly monitored throughout the dormancy-regrowth cycle in two apple cultivars, 'Cripps Pink' and 'Honeycrisp,' representing early- and late-blooming cultivars, respectively. Both these cultivars had similar chilling requirements (1000 chilling hours) but differed in their heat requirements; with 'Honeycrisp' requiring 1000 growing degree hours more than 'Cripps Pink'. Among plant hormones, ABA increased with the progression of dormancy and decreased with dormancy release in both cultivars. However, ABA levels were significantly higher in 'Honeycrisp' compared to 'Cripps Pink'. On the contrary, during dormancy release, the growth-promoting hormone, CK, increased earlier in 'Cripps Pink'. The levels of ROS, e.g., hydrogen peroxide (H2O2), and superoxide (O2.-), were also higher in 'Cripps Pink' than 'Honeycrisp', particularly by the time of endodormancy and ecodormancy release, respectively. Our data showed that starch levels generally declined during dormancy, whereas soluble sugars increased. However, there was no significant alternations in the carbohydrate accumulation profiles between the two cultivars that could account for the differences in their bloom dates. These results were verified further at the transcriptomic level. Using the RNA-sequencing technology, identified two modules that contrast between two cultivars mainly during eco-dormancy. Gene ontology (GO) analysis indicated that these genes were mostly involved in pathways related to hormones and signaling and co-expressed with H2O2 whereas during ecodormancy pathways related to glutathione metabolism, auxin biosynthesis, carbohydrate metabolism and reproductive development were co-expressed with O2.-. Overall, our results suggest that ABA, cytokinin, H2O2, and O2.- may, at least partially, explain the differences in the bloom time between the two apple cultivars. Further analysis of these molecules and their associated genes in other apple cultivars with contrasting bloom dates is necessary for better understanding of bloom time regulation in apple and developing strategies against frost damage.

Deficits in skeletal muscle mitochondrial metabolism are associated with a wide variety of chronic skeletal muscle and metabolic-related diseases, including diabetes and sarcopenia. Even in patients with advanced skeletal muscle-related diseases, exercise is a well-established method to improve skeletal muscle mitochondrial metabolism, culminating in enhanced whole-body metabolism and decreased disease severity. In response to exercise, there is an increase in reactive oxygen species (ROS) production. Historically, ROS were solely considered to drive disease development. However, ROS are also required for physiological adaptation and many questions still remain regarding their downstream pathways. One significant producer of skeletal muscle ROS with exercise is Nadph oxidase 4 (Nox4). Nox4 is unique compared to other Nox members as it predominantly produces hydrogen peroxide (H2O2), an effective signaling molecule. Here we demonstrate an essential role for Nox4 in mediating the beneficial effects of exercise. This work will contribute to our understanding of physiological ROS and their downstream targets by identifying a novel role for Nox4 in exercise adaptation. Further defining the molecular events that promote exercise adaptation will be essential for formulating new treatment strategies for patients with chronic metabolic diseases. / Doctor of Philosophy / Exercise is a widely effective tool for both preventing and reversing disease. Even patients with advanced skeletal muscle and metabolic-related diseases can benefit from continual and repeated exercise training. While decades of work have supported the effectiveness of exercise as a therapeutic intervention, the mechanistic understanding of what occurs at the cellular level remains incomplete. Here, we elucidate a novel pathway mediating important metabolic adaptations to exercise. In response to exercise stress, reactive oxygen species (ROS) are produced in skeletal muscle. ROS facilitate metabolic adaptations to meet the body's need for increased energy. One significant source of ROS comes from Nadph oxidase 4 (Nox4) which plays an essential role in metabolic regulation. The skeletal muscle metabolic response to stress is largely dependent on adaptations that include changes in gene expression, substrate oxidation, and mitochondrial metabolic adaptations. These mitochondrial adaptations include mitochondrial recycling after exercise in skeletal muscle (referred to as mitophagy). We have shown that Nox4 increases the expression of a subset of metabolic genes, is required for substrate oxidation after exercise, and is important for exercise-induced mitophagy.

Indiscriminate use of pesticides appears to alter immune response in non-target organisms such as humans and other animals. Thus, immune modulation is considered as one of the potential risks and consequences following exposure to these chemicals. Because of the widespread usage, exposure to mixtures of pesticides during the lifetime of individuals is unavoidable and can result in potentiation of the toxic effects. Because immune cells are more susceptible to toxic insults at a lower dose than most other cell types, the effects of pesticides and their mixtures on murine splenocytes were evaluated. C57BL/6 male mouse splenocytes, in vitro, were exposed to permethrin and endosulfan, individually and in-combination (25-200 µM). The immunotoxic potential of these pesticides was monitored using a flow cytometric technique in combination with 7-Amino Actinomycin D (7-AAD) staining. Endosulfan exposures (25-150 µM) resulted in time- and dose-dependent increase in apoptotic and necrotic cell death in murine splenocytes, in vitro. Permethrin exposure (50-200 µM) resulted in neither a time-dependent/dose-dependent loss of splenocyte viability nor induction of apoptosis in splenocytes. With mixtures of permethrin and endosulfan, depressed viability and enhanced early apoptosis and late apoptosis/necrosis were observed. Exposure to mixtures of 50 µM endosulfan with 50 or 100 µM permethrin increased late apoptosis/necrosis compared to exposure to either chemical alone. DNA fragmentation, a hall mark of apoptosis was observed by DNA ladder technique, confirming the occurrence of apoptosis. Morphological observation using cytospun slides was also carried out to further confirm the presence of apoptosis and necrosis. These findings suggest that the immunotoxicity of endosulfan both individually and in mixtures with permethrin is associated with the occurrence of apoptotic and necrotic processes. Further, the ability of these pesticides to alter the oxidative status of the cells, via reactive oxygen species (ROS) generation and modulation of intracellular antioxidant enzymes levels, was investigated. We monitored the generation of ROS such as hydrogen peroxide (H₂O₂) with 2´, 7´- dichlorofluorescin diacetate (DCFH-DA) assay and superoxide anion (O₂⁻) with hydroethidine (HE) assay in combination with flow cytometry. Spectrophotometric techniques were used to measure antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GR) and glutathione peroxidase (GPX). Results of the analyses revealed that individual pesticides increased the production of H₂O₂ in a time and dose-dependent manner. Both time and dose-dependent increases in O₂⁻ production were caused by permethrin; whereas endosulfan exposure resulted in only a dose-dependent increase. However, exposure to mixtures of these pesticides had little or no effect on the generation of H₂O₂ and O₂⁻ radicals as compared to individual pesticides. The levels of SOD and GPX in pesticide-treated splenocytes were found to be not different from solvent control. An increase in GR and CAT levels in cells was noticed with permethrin (100 µM) exposure. These findings suggest that permethrin and endosulfan have the ability to affect the cellular oxidative status and can cause toxicity in immune cells, in vitro. / Master of Science

No / In this work, energy consumption in a middle vessel batch reactive distillation (MVBRD) column is considered for the production of lactic acid via hydrolysis of methyl lactate. A dynamic optimization problem incorporating a process model is formulated to minimize the batch time which consequently minimizes the total energy consumption. The problem is subject to constraints on the amount and purity of lactic acid. The optimisation variables are reflux ratio and/or reboil ratio which are treated as piecewise constant. The earlier work of the authors on energy consumption in conventional batch reactive distillation column (CBRD) for the same reaction system is used for comparative analysis with the energy consumption in MVBRD. As an example, for a given separation task, the optimization results show that MVBRD is capable of saving over 23 % energy compared to energy consumption in CBRD column for the same task.

Reactive material liners paired with high explosives can significantly increase blast effects. This research aims to study the properties that primarily control the interaction between reactive materials (RM) and high explosives (HE). This will facilitate blast performance optimization for the RM and HE combinations. A laser spectroscopic sensor will be utilized to measure the performance of these RM and HE combinations. Laser absorption spectroscopy (LAS) is a technique that measures the chemical concentration of a medium through the intensity change of the laser beam. The laser diagnostic instrument is composed of two tunable diode lasers, one centered at 2.48 μm and the other at 2.55 μm. The sensor is designed to measure H2O species concentration in the blast wave using the beer-lambert law. It will also measure the temperature of the blast with a high temperature sensitivity in the 1000 K to 2600 K range. The temperature and concentration data will be used to assess the combustion performance of the blast. The data was collected at a 200 MHz sampling frequency through a fiber-coupled optical probe designed to shield the sensitive optical equipment. The resulting blast temperature and molar concentration of H2O will be used to determine the optimal RM liner and HE pairings in the MMRT chamber. This research will enable the AFRL to expand their understanding of the RM and HE pairings.

Water availability is presently under risk owing to the increased discharge of pollutants from both industrial and residential properties. A distinct category of pollutants known as "emerging contaminants" (ECs), whose hazards were either unknown before they were noticed, e.g., antibiotics, dyes, PFAS, etc. Most of the ECs are unregulated and pose a threat to aquatic and human life at even low doses. Our water treatment facilities are not designed to efficiently eliminate these toxic substances. Therefore, we need an economical tertiary treatment approach. Adsorptionis a sustainable, cost effective and simple technique, making it a viable technique for pollutants elimination on a worldwide scale. The removal of these ECs has been made possible by several commercially available adsorbents, however most of them are expensive. Adsorbents fabrication using, agricultural wastes is an effective waste management technique that helps reduce greenhouse gas emissions via carbon sequestration. The adsorption capability of adsorbents can be enhanced by further modification of its properties. This research study focuses on conversion of biomass into environmentally friendly adsorbents including biochar and nanocellulose aerogel. In the first study, a natural mineral dolomite (CaMg(CO3)2) modified biochar was fabricated from rice husk and used to remove anionic reactive dyes, Remazol Brilliant Blue (RBB) and Reactive Black 5 (RB-5) from synthetic wastewater. In the second study, a sustainable aminated/TEMPO cellulose nanofiber (Am/TEMPO-CNF) aerogel was fabricated and used to treat oxytetracycline (OTC) and chloramphenicol (CAP) contaminated water. The physiochemical properties of all adsorbents were studied using FTIR, SEM, TGA, elemental analyzer and N2 adsorption-desorption isothermal analyses. The contaminants were quantified using Ultraviolet–visible spectroscopy (UV-Vis) before and after the experiments. Kinetics, isothermal and thermodynamics modeling was applied to analyze the adsorption behavior and mechanism. In the third investigation, a novel In-situ UiO-66-NH2/TOCNF adsorbent was employed to remove the anionic azo dyes Orange II (ORII) and Congo Red (CR) from synthetic wastewater. We also looked at how pH, time, and initial concentration impacted CR and ORII adsorption. Research was conducted to assess the stability and adsorption potential under various situations by thermodynamics and regeneration.

Carbon capture and sequestration (CCS) is an engineering-based approach for mitigating excess anthropogenic CO2 emissions. Deep brine aquifers and basalt reservoirs have shown outstanding performance in CO2 storage based on their global widespread distribution and large storage capacity. Capillary trapping and mineral trapping are the two dominant mechanisms controlling the distribution, migration, and transportation of CO2 in deep brine aquifers and basalt reservoirs. Understanding the behavior of CO2 in a storage reservoir under realistic conditions is important for risk management and storage efficiency improvement. As a result, numerical simulations have been implemented to understand the relationship between fluid properties and multi-phase fluid dynamics. However, the physics-based simulations that focus on the uncertainties of fluid flow dynamics are complicated and computationally expensive. Machine learning method provides immense potential for improving computational efficiency for subsurface simulations, particularly in the context of parametric sensitivity. This work focuses on parametric uncertainty associated with multi-phase fluid dynamics that govern geologic CO2 storage. The effects of this uncertainty are interrogated through ensemble simulation methods that implement both physics-based and machine learning modeling strategies. This dissertation is a culmination of three projects: (1) a parametric analysis of capillary pressure variability effects on CO2 migration, (2) a reactive transport simulation in a basalt fracture system investigating the effects of carbon mineralization on CO2 migration, and (3) a parametric analysis based on machine learning methods of simultaneous effects of capillary pressure and relative permeability on CO2 migration. / Doctor of Philosophy / Carbon capture and sequestration (CCS) has been proposed as a technological approach to mitigate the deleterious effects of anthropogenic CO2 emissions. During CCS, CO2 is captured from power plants and then pumped in deep geologic reservoirs to isolate it from the atmosphere. Deep sedimentary formations and fractured basalt reservoirs are two options for CO2 storage. In sedimentary systems, CO2 is immobilized largely by physical processes, such as capillary and solubility trapping, while in basalt reservoirs, CO2 is transformed into carbonate minerals, thus rendering it fully immobilized. This research focuses on how a large range of capillary pressure variabilities and how CO2-basalt reactions affect CO2 migration. Specifically, the work presented utilizes numerical simulation and machine learning methods to study the relationship between capillary trapping and buoyancy in a sandstone formation, as well as the combined effects of capillary pressure and relative permeability on CO2 migration. In addition, the work also identifies a new reinforcing feedback between mineralization and relative permeability during reactive CO2 flow in a basalt fracture network. In aggregate, the whole of this work presents a new, multi-dimensional perspective on the multi-phase fluid dynamics that govern CCS efficacy in a range of geologic formations.

Neurons have an extremely high rate of energy consumption and use mitochondrial-derived ATP as the primary energy source to drive biochemical processes involved in various functions. Consequently, neurons produce reactive oxygen species (ROS) as 'by-products' of oxidative phosphorylation. Excessive levels of ROS are highly detrimental to neurons as ROS can directly oxidize and induce damage to cellular macromolecules including lipids, DNA and proteins. Hence, the high-energy demands of neurons, together with their high levels of ROS production, place them at risk during conditions of stress, which occur during aging and in neurodegenerative disorders including Alzheimer's and Huntington's disease. Uncoupling proteins (UCPs) belong to a family of inner mitochondrial membrane proteins initially identified as regulators of thermogenesis in fat cells wherein they uncouple energy-substrate oxidation from mitochondrial ATP production, resulting in the production of heat. UCPs also regulate ROS production from mitochondria by physiologically lowering the mitochondrial membrane potential below the critical level for ROS production. Because of their important role in co-regulating energy metabolism and ROS production, there has been considerable interest in the functions of UCPs. Neurons express at least three UCPs including the widely expressed UCP2 and the brain- specific UCP4 and UCP5. Despite a great deal of interest, to date neither the molecular mechanism nor the biochemical and physiological functions of brain UCPs are well understood. Our previous studies showed that UCP4 is highly expressed in subpopulations of neurons with high energy demands. Knockdown ofUCP4 expression in cultured primary neurons markedly enhances neuronal death suggesting that endogenous UCP4 is critical for neuronal survival. Expression of UCP4 shifts cellular ATP synthesis from oxidative phosphorylation to anaerobic glycolysis, which might be beneficial to cell survival. In this study, we investigated the underlying mechanism of UCP4-mediated metabolic adaptation in response to mitochondrial inhibition. We found that UCP4 enhances glucose uptake and glycolysis which may compensate for the reduced supply of ATP from compromised mitochondria. In addition, the activation of mitogen activated protein kinases (MAPKs) and several transcription factors play a role in augmenting nonoxidative synthesis of ATP in response to metabolic stress possibly by acting downstream of UCP4. Elucidating the underlying mechanism(s) whereby this brain UCP mediates metabolic adaptation in response to mitochondrial inhibition will likely lead to the development of novel preventative and therapeutic strategies for neurodegenerative disorders.