Bringing Lived Experience to Research on Health and Homelessness: Perspectives of Researchers and Lived Experience Partners.

Improving health and healthcare for people experiencing homelessness (PEH) has become a national research priority. It is critical for research related to homelessness to be guided by input from PEH themselves. We are a group of researchers and individuals who have personally experienced homelessness collaborating on a study focused on homelessness and housing. In this Fresh Focus, we describe our partnership, lessons learned from our work together, what we have gained from our collaboration, and considerations for future homelessness research-lived experience partnerships.

Calmodulin kinase 2 genetically interacts with Rch1p to negatively regulate calcium import into Saccharomyces cerevisiae after extracellular calcium pulse.

After a single extracellular 100 mM calcium pulse (final concentration), wild type S. cerevisiae exhibits a sharp peak in cytosolic calcium. The concentration drops rapidly in these cells as the calcium is sequestered away in the endoplasmic reticulum, Golgi, and vacuoles leaving resting cytosolic levels higher than their original state, followed by changes in gene expression. In cells lacking calmodulin kinase 2 (Cmk2p), a secondary rise in cytosolic calcium concentration is seen after extracellular calcium increases and the cytosolic calcium is subsequently sequestered. Utilizing double deletions, we demonstrate that Cmk2p is modulating the activity of Rch1p, a known inhibitor of Channel X which is a yeast plasma membrane channel through which calcium ions are transported after an extracellular calcium pulse. We hypothesize that Cmk2p is acting as a regulator of Channel X by activating Rch1p and without CMK2, Channel X inactivation does not occur fully.

Clonazolam Intoxication Case Report: Danger of Designer Benzodiazepines.

ABSTRACT: Clonazolam is a derivative of the Xanax active ingredient, alprazolam. Classified as a designer benzodiazepine, clonazolam availability has been rising because of its circulation on illegal internet drug markets and marginal cost in comparison to its parent analogs. Clonazolam's accessibility encourages abuse prevalence and use of designer benzodiazepines. In our case, a 14-year-old male was found unresponsive the morning after ingesting multiple tablets believed to be Xanax. Toxicology testing indicated 140 ng/mL of 8-aminoclonazolam, a clonazolam metabolite, in the decedent's system. Alprazolam was not identified. Pathological analysis determined cerebral and respiratory depression to be the mechanism of death, resulting from acute clonazolam intoxication. This case presents the first death induced by clonazolam alone. Current literature identifies a gap in designer benzodiazepine confirmatory testing and a lack of awareness within the forensic and medical communities. Knowledge of designer benzodiazepines is needed to better understand their potency and to help prevent future intoxications. We present this case to aid in the recognition of novel benzodiazepines by medical examiners and coroners, to encourage their consideration in suspected Xanax and other substance related investigations, and to be aware of the capabilities of toxicological testing to improve novel benzodiazepine identification and subsequent interpretation.

An Isochroman Analog of CD3254 and Allyl-, Isochroman-Analogs of NEt-TMN Prove to Be More Potent Retinoid-X-Receptor (RXR) Selective Agonists Than Bexarotene.

Bexarotene is an FDA-approved drug for the treatment of cutaneous T-cell lymphoma (CTCL); however, its use provokes or disrupts other retinoid-X-receptor (RXR)-dependent nuclear receptor pathways and thereby incites side effects including hypothyroidism and raised triglycerides. Two novel bexarotene analogs, as well as three unique CD3254 analogs and thirteen novel NEt-TMN analogs, were synthesized and characterized for their ability to induce RXR agonism in comparison to bexarotene (1). Several analogs in all three groups possessed an isochroman ring substitution for the bexarotene aliphatic group. Analogs were modeled for RXR binding affinity, and EC50 as well as IC50 values were established for all analogs in a KMT2A-MLLT3 leukemia cell line. All analogs were assessed for liver-X-receptor (LXR) activity in an LXRE system to gauge the potential for the compounds to provoke raised triglycerides by increasing LXR activity, as well as to drive LXRE-mediated transcription of brain ApoE expression as a marker for potential therapeutic use in neurodegenerative disorders. Preliminary results suggest these compounds display a broad spectrum of off-target activities. However, many of the novel compounds were observed to be more potent than 1. While some RXR agonists cross-signal the retinoic acid receptor (RAR), many of the rexinoids in this work displayed reduced RAR activity. The isochroman group did not appear to substantially reduce RXR activity on its own. The results of this study reveal that modifying potent, selective rexinoids like bexarotene, CD3254, and NEt-TMN can provide rexinoids with increased RXR selectivity, decreased potential for cross-signaling, and improved anti-proliferative characteristics in leukemia models compared to 1.

Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB).

Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid-or NEt-4IB-in addition to seven novel analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene (1), a FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Bexarotene treatment elicits side-effects by provoking or disrupting other RXR-dependent pathways. Analogs were assessed by the modeling of binding to RXR and then evaluated in a human cell-based RXR-RXR mammalian-2-hybrid (M2H) system as well as a RXRE-controlled transcriptional system. The analogs were also tested in KMT2A-MLLT3 leukemia cells and the EC50 and IC50 values were determined for these compounds. Moreover, the analogs were assessed for activation of LXR in an LXRE system as drivers of ApoE expression and subsequent use as potential therapeutics in neurodegenerative disorders, and the results revealed that these compounds exerted a range of differential LXR-RXR activation and selectivity. Furthermore, several of the novel analogs in this study exhibited reduced RARE cross-signaling, implying RXR selectivity. These results demonstrate that modification of partial agonists such as NEt-4IB and potent rexinoids such as bexarotene can lead to compounds with improved RXR selectivity, decreased cross-signaling of other RXR-dependent nuclear receptors, increased LXRE-heterodimer selectivity, and enhanced anti-proliferative potential in leukemia cell lines compared to therapeutics such as 1.

Mathematical modeling of fungal infection in immune compromised individuals: The effect of back mutation on drug treatment.

We present a mathematical model that describes treatment of a fungal infection in an immune compromised patient in which both susceptible and resistant strains are present with a mutation allowing the susceptible strain to become resistant as well as a back mutation allowing resistant fungus to again become susceptible. The resulting nonlinear differential equations model the biological outcome, in terms of strain growth and cell number, when an individual is treated with a fungicidal or fungistatic drug. The model demonstrates that under any levels of the drug both strains will be in stable co-existence and high levels of treatment will never completely eradicate the susceptible strain. A modified model is then described in which the drug is changed to one in which both strains are susceptible, and subsequently, at the appropriate level of treatment, complete eradication of both fungal strains ensues. We discuss the model and implications for treatment options within the context of an immune compromised patient.

Utility of amplification enhancers in low copy number DNA analysis.

One parameter that impacts the robustness and reliability of forensic DNA analyses is the amount of template DNA used in the polymerase chain reaction (PCR). With short tandem repeat (STR) typing, low copy number (LCN) DNA samples can present exaggerated stochastic effects during the PCR that result in heterozygote peak height imbalance, allele drop out, and increased stutter. Despite these effects, there has been little progress toward decreasing the formation of stutter products and heterozygote peak imbalance effects during PCR. In an attempt to develop a more robust system that is less refractory to stochastic effects, the PCR additives, betaine, DMSO, PEG, and PCRboost®, were investigated on low-quantity DNA samples. The effects of the additives were assessed by evaluating STR typing results. Of the four additives, the only positive effects were observed with betaine treatment. Betaine, at a final concentration of 1.25 mol/L, was found to improve the robustness of the amplification, specifically by decreasing stutter in a dual locus system. In contrast, the addition of 1.25 mol/L betaine to commercial STR amplification kits did not affect stutter ratios. However, the addition of betaine did lead to increased yield of PCR products in all commercial kits tested. The results support that betaine can improve amplification efficiency of LCN DNA samples.

The relevance of current forensic firearms examination techniques when applied to 3D printed firearms.

This research project had two major objectives. The first was to successfully print and fire the Liberator, a 3D-printed firearm, to assess its feasibility as a lethal weapon. The second objective was to identify any individual characteristics that might be deposited during the firing process by the firearm. The Liberator was printed using unchanged files downloaded from the internet using PLA and ABS filament. The Liberator was fired remotely into newspapers at the Allegheny County Medical Examiner's Office. The printing of the Liberator was both inexpensive and relatively quick with only minor hand modifications made after printing. The Liberator fractured beyond repair after firing but successfully fired and penetrated three newspapers. Neither the bullet nor the cartridge case exhibited any individual characteristics that could be used for identification purposes. Suspected thermoplastic deposits were identified on both the bullet and cartridge case, but additional testing must be done for confirmation purposes. In conclusion, the Liberator can be used reliably for one shot and will not yield any evidence for Firearms and Toolmark Examination.

Rexinoids Induce Differential Gene Expression in Human Glioblastoma Cells and Protein-Protein Interactions in a Yeast Two-Hybrid System.

Rexinoids are compounds that bind to the rexinoid X receptor (RXR) to modulate gene expression and have been proposed as a new class of therapeutics to treat Alzheimer's disease. Different rexinoids will initiate downstream effects that can be quite marked even though such compounds can be structurally similar and have comparable RXR binding affinities. RXR can both homo- and heterodimerize, and these protein-protein interactions and subsequent transactivating potential lead to differential gene expression, depending on the RXR dimeric partner, additional cofactors recruited, and downstream transcription factors that are up- or downregulated. Expression analysis was performed in the U87 human glioblastoma cell line treated with a panel of rexinoids, and our analysis demonstrated that rexinoids with similar RXR EC50 values can have pronounced differences in differential gene expression. Rexinoid binding likely leads to distinctive RXR conformations that cause major downstream gene expression alterations via modulation of RXR interacting proteins. Yeast two-hybrid analysis of RXR bait with two RXR interacting partners demonstrates that rexinoids drive differential binding of RXR to distinctive protein partners. Physiochemical analysis of the rexinoids reveals that the molecules cluster similarly to their gene expression patterns. Thus, rexinoids with similar RXR binding affinities drive differential gene expression by stimulating additional binding patterns in RXR and its homo- and heteropartners, driven by the physicochemical characteristics of these molecules.

Effective removal of co-purified inhibitors from extracted DNA samples using synchronous coefficient of drag alteration (SCODA) technology.

Various types of biological samples present challenges for extraction of DNA suitable for subsequent molecular analyses. Commonly used extraction methods, such as silica membrane columns and phenol-chloroform, while highly successful may still fail to provide a sufficiently pure DNA extract with some samples. Synchronous coefficient of drag alteration (SCODA), implemented in Boreal Genomics' Aurora Nucleic Acid Extraction System (Boreal Genomics, Vancouver, BC), is a new technology that offers the potential to remove inhibitors effectively while simultaneously concentrating DNA. In this initial study, SCODA was tested for its ability to remove various concentrations of forensically and medically relevant polymerase chain reaction (PCR) inhibitors naturally found in tissue, hair, blood, plant, and soil samples. SCODA was used to purify and concentrate DNA from intentionally contaminated DNA samples containing known concentrations of hematin, humic acid, melanin, and tannic acid. The internal positive control (IPC) provided in the Quantifiler™ Human DNA Quantification Kit (Life Technologies, Foster City, CA) and short tandem repeat (STR) profiling (AmpFℓSTR® Identifiler® Plus PCR Amplification Kit; Life Technologies, Foster City, CA) were used to measure inhibition effects and hence purification. SCODA methodology yielded overall higher efficiency of purification of highly contaminated samples compared with the QIAquick® PCR Purification Kit (Qiagen, Valencia, CA). SCODA-purified DNA yielded no cycle shift of the IPC for each sample and yielded greater allele percentage recovery and relative fluorescence unit values compared with the QIAquick® purification method. The Aurora provided an automated, minimal-step approach to successfully remove inhibitors and concentrate DNA from challenged samples.

Pressure cycling technology (PCT) reduces effects of inhibitors of the PCR.

A common problem in the analysis of forensic human DNA evidence, or for that matter any nucleic acid analysis, is the presence of contaminants or inhibitors. Contaminants may copurify with the DNA, inhibiting downstream PCR or they may present samples effectively as containing fewer templates than exist in the PCR, even when the actual amount of DNA is adequate. Typically, these challenged samples exhibit allele imbalance, allele dropout, and sequence-specific inhibition, leading to interpretational difficulties. Lessening the effects of inhibitors may increase the effective yield of challenged low template copy samples. High pressure may alter some inhibitors and render them less effective at reducing the yield of PCR products. In an attempt to enhance the amplicon yield of inhibited DNA samples, pressure cycling technology was applied to DNA exposed to various concentrations of hematin (0, 1.25, 2.5, 5, and 7 µM) and humic acid (0, 1.25, 2.5, 5, and 7 ng/µL). The effect of high pressure on the inhibitors, and subsequently the PCR process, was assessed by measuring DNA quantity by quantitative PCR and evaluating short tandem repeat typing results. The results support that pressure cycling technology reduces inhibitory effects and thus, in effect, enhances yield of contaminated amplified products of both hematin and humic acid contaminate samples. Based on the results obtained in this study, this method can improve the ability to type challenged or inhibited DNA samples.

Synthesis and biological evaluation of halogenated curcumin analogs as potential nuclear receptor selective agonists.

This report describes the synthesis of analogs of curcumin, and their analysis in acting as nuclear receptor specific agonists. Curcumin (CM), a turmeric-derived bioactive polyphenol found in curry, has recently been identified as a ligand for the vitamin D receptor (VDR), and it is possible that CM exerts some of its bioeffects via direct binding to VDR and/or other proteins in the nuclear receptor superfamily. Using mammalian-two-hybrid (M2H) and vitamin D responsive element (VDRE) biological assay systems, we tested CM and 11 CM synthetic analogs for their ability to activate VDR signaling. The M2H assay revealed that RXR and VDR association was induced by CM and several of its analogs. VDRE-based assays demonstrated that pure curcumin and eight CM analogs activated transcription of a luciferase plasmid at levels approaching that of the endocrine 1,25 dihydroxyvitamin D(3) (1,25D) ligand in human colon cancer cells (HCT-116). Additional experiments were performed in HCT-116 utilizing various nuclear receptors and hormone responsive elements to determine the receptor specificity of curcumin binding. CM did not appear to activate transcription in a glucocorticoid responsive system. However, CM along with several analogs elicited transcriptional activation in retinoic acid and retinoid X receptor (RXR) responsive systems. M2H assays using RXR-RXR, VDR-SRC1 and VDR-DRIP revealed that CM and select analogs stimulate RXR homodimerization and VDR-coactivator interactions. These studies may lead to the discovery of novel curcumin analogs that activate nuclear receptors, including RXR, RAR and VDR, resulting in similar health benefits as those for vitamins A and D, such as lowering the risk of epithelial and colon cancers.

Microbes in fingerprints: A source for dating crime evidence?

Interest in the human microbiome has grown in recent years because of increasing applications to biomedicine and forensic science. However, the potential for dating evidence at a crime scene based upon time-dependent changes in microbial signatures has not been established, despite a relatively straightforward scientific process for isolating the microbiome. We hypothesize that modifications in microbial diversity, abundance, and succession can provide estimates of the time a surface was touched for investigative purposes. In this proof-of-concept research, the sequencing and analysis of the 16 S rRNA gene from microbes present in fresh and aged latent fingerprints deposited by three donors with pre- and post-washed hands is reported. The stability of major microbial phyla is confirmed while the dynamics of less abundant groups is described up to 21 days post-deposition. Most importantly, a phylum is suggested as the source for possible biological markers to date fingerprints: Deinococcus-Thermus.

Development of Bexarotene Analogs for Treating Cutaneous T-Cell Lymphomas.

Bexarotene, a drug approved for treatment of cutaneous T-cell lymphoma (CTCL), is classified as a rexinoid by its ability to act as a retinoid X receptor (RXR) agonist with high specificity. Rexinoids are capable of inducing RXR homodimerization leading to the induction of apoptosis and inhibition of proliferation in human cancers. Numerous studies have shown that bexarotene is effective in reducing viability and proliferation in CTCL cell lines. However, many treated patients present with cutaneous toxicity, hypothyroidism, and hyperlipidemia due to crossover activity with retinoic acid receptor (RAR), thyroid hormone receptor (TR), and liver X receptor (LXR) signaling, respectively. In this study, 10 novel analogs and three standard compounds were evaluated side-by-side with bexarotene for their ability to drive RXR homodimerization and subsequent binding to the RXR response element (RXRE). In addition, these analogs were assessed for proliferation inhibition of CTCL cells, cytotoxicity, and mutagenicity. Furthermore, the most effective analogs were analyzed via qPCR to determine efficacy in modulating expression of two critical tumor suppressor genes, ATF3 and EGR3. Our results suggest that these new compounds may possess similar or enhanced therapeutic potential since they display enhanced RXR activation with equivalent or greater reduction in CTCL cell proliferation, as well as the ability to induce ATF3 and EGR3. This work broadens our understanding of RXR-ligand relationships and permits development of possibly more efficacious pharmaceutical drugs. Modifications of RXR agonists can yield agents with enhanced biological selectivity and potency when compared to the parent compound, potentially leading to improved patient outcomes.

An evaluation of the transfer of saliva-derived DNA.

Studies of DNA transfer have focused largely on the transfer of sloughed off epithelial cells from individuals' hands. This research examines primary, secondary, and tertiary transfer events involving DNA originating from saliva, a commonly encountered body fluid. More routine human behaviors were simulated to evaluate transfer, and the effects of drying time, moisture, and surface composition were investigated. The results agree with previous findings which indicate that the presence of moisture, as well as a smooth nonporous surface as the primary substrate, increases the efficiency of transfer. Previous transfer studies have found that the last individual to come into contact with an item is usually the major contributor to the resulting DNA mixture, unless conditions are simulated in which a "good shedder" serves as the primary depositor and a poor shedder serves as the secondary depositor. The results of this study indicate that when saliva is the source of the transferred DNA, the primary depositor is often the major contributor. These findings suggest that shedder status is less relevant with regard to touch DNA samples in a forensic setting and emphasize the need for caution when analyzing such samples.

Assessing compensation for loss of vacuolar function in Saccharomyces cerevisiae.

We analyzed how Saccharomyces cerevisiae cells compensate for the lack of a functional vacuole, an acidic membrane-bound degradative and ion storage compartment. We hypothesized that cells lacking a functional vacuole would compensate for the loss of the functions of the vacuole by altering gene expression and (or) metabolic flux. We used gene expression profiling and Biolog phenotype microarray analysis to determine the compensatory mechanisms of cells lacking vacuolar function. In steady state, vps33 and vps41 cells changed the transcriptional profile of some genes, but no complete pathways were upregulated or downregulated. We treated vps41 cells with calcium to tease out cellular compensation for loss of vacuole function under ionic stress; however, changes in gene expression were not utilized to compensate for loss of vacuole function under stress either, as genes whose transcriptional profiles were changed did not function together in any one cellular process. Phenotype microarray analysis indicated that logarithmically growing vps33 or vps41 cells did not seem to compensate for loss of vacuolar function but instead demonstrated additional pleiotropic phenotypes due to the function of the vacuole. Under rich media conditions, yeast utilize the vacuole to regulate stress, ion response, and peptide degradation. However, loss of the vacuole does not lead to observable compensation mechanisms.

Rexinoids Modulate Effector T Cell Expression of Mucosal Homing Markers CCR9 and α4ß7 Integrin and Direct Their Migration In Vitro.

Altering T cell trafficking to mucosal regions can enhance immune responses towards pathogenic infections and cancers at these sites, leading to better outcomes. All-trans-retinoic acid (ATRA) promotes T cell migration to mucosal surfaces by inducing transcription of the mucosal-homing receptors CCR9 and α4ß7 via binding to retinoic acid receptors (RARs), which heterodimerize with retinoid X receptors (RXRs) to function. However, the unstable nature and toxicity of ATRA limit its use as a widespread treatment modality for mucosal diseases. Therefore, identifying alternatives that could reduce or eliminate the use of ATRA are needed. Rexinoids are synthetically derived compounds structurally similar to ATRA. Originally named for their ability to bind RXRs, rexinoids can enhance RAR-mediated gene transcription. Furthermore, rexinoids are more stable than ATRA and possess an improved safety profile, making them attractive candidates for use in clinical settings. Here we show that select novel rexinoids act as ATRA mimics, as they cause increased CCR9 and α4ß7 expression and enhanced migration to the CCR9 ligand, CCL25 in vitro, even in the absence of ATRA. Conversely, other rexinoids act synergistically with ATRA, as culturing cells with suboptimal doses of both compounds resulted in CCR9 expression and migration to CCL25. Overall, our findings show that rexinoids can be used independently or synergistically with ATRA to promote mucosal homing of T cells in vitro, and lends support for the prospective clinical use of these compounds in immunotherapeutic approaches for pathogenic infections or cancers at mucosal surfaces.

The rexinoid V-125 reduces tumor growth in preclinical models of breast and lung cancer.

Rexinoids are ligands which activate retinoid X receptors (RXRs), regulating transcription of genes involved in cancer-relevant processes. Rexinoids have anti-neoplastic activity in multiple preclinical studies. Bexarotene, used to treat cutaneous T cell lymphoma, is the only FDA-approved rexinoid. Bexarotene has also been evaluated in clinical trials for lung and metastatic breast cancer, wherein subsets of patients responded despite advanced disease. By modifying structures of known rexinoids, we can improve potency and toxicity. We previously screened a series of novel rexinoids and selected V-125 as the lead based on performance in optimized in vitro assays. To validate our screening paradigm, we tested V-125 in clinically relevant mouse models of breast and lung cancer. V-125 significantly (p < 0.001) increased time to tumor development in the MMTV-Neu breast cancer model. Treatment of established mammary tumors with V-125 significantly (p < 0.05) increased overall survival. In the A/J lung cancer model, V-125 significantly (p < 0.01) decreased number, size, and burden of lung tumors. Although bexarotene elevated triglycerides and cholesterol in these models, V-125 demonstrated an improved safety profile. These studies provide evidence that our screening paradigm predicts novel rexinoid efficacy and suggest that V-125 could be developed into a new cancer therapeutic.

Mathematical modeling of fungal infection in immune compromised individuals: implications for drug treatment.

We present a mathematical model that describes treatment of a fungal infection in an immune compromised patient in which both susceptible and resistant strains are present. The resulting nonlinear differential equations model the biological outcome, in terms of strain growth and cell number, when an individual, who has both a susceptible and a resistant population of fungus, is treated with a fungicidal or fungistatic drug. The model demonstrates that when the drug is only successful at treating the susceptible strain, low levels of the drug cause both strains to be in stable co-existence and high levels eradicate the susceptible strain while allowing the resistant strain to persist or to multiply unchecked. A modified model is then described in which the drug is changed to one in which both strains are susceptible, and subsequently, at the appropriate level of treatment, complete eradication of both fungal strains ensues. We discuss the model and implications for treatment options within the context of an immune compromised patient.

Evaluating Novel RXR Agonists That Induce ApoE and Tyrosine Hydroxylase in Cultured Human Glioblastoma Cells.

There is considerable interest in identifying effective and safe drugs for neurodegenerative disorders. Cell culture and animal model work have demonstrated that modulating gene expression through RXR-mediated pathways may mitigate or reverse cognitive decline. However, because RXR is a dimeric partner for several transcription factors, activating off-target transcription is a concern with RXR ligands (rexinoids). This off-target gene modulation leads to unwanted side effects that can include low thyroid function and significant hyperlipidemia. There is a need to develop rexinoids that have binding specificity for subsets of RXR heterodimers, to drive desired gene modulation, but that do not induce spurious effects. Herein, we describe experiments in which we analyze a series of novel and previously reported rexinoids for their ability to modulate specific gene pathways implicated in neurodegenerative disorders employing a U87 cell culture model. We demonstrate that, compared to the FDA-approved rexinoid bexarotene (1), several of these compounds are equally or more effective at stimulating gene expression via LXREs or Nurr1/NBREs and are superior at inducing ApoE and/or tyrosine hydroxylase (TH) gene and protein expression, including analogs 8, 9, 13, 14, 20, 23, and 24, suggesting a possible therapeutic role for these compounds in Alzheimer's or Parkinson's disease (PD). A subset of these potent RXR agonists can synergize with a presumed Nurr1 ligand and antimalarial drug (amodiaquine) to further enhance Nurr1/NBREs-directed transcription. This novel discovery has potential clinical implications for treatment of PD since it suggests that the combination of an RXR agonist and a Nurr1 ligand can significantly enhance RXR-Nurr1 heterodimer activity and drive enhanced therapeutic expression of the TH gene to increase endogenous synthesis of dopamine. These data indicate that is it possible and prudent to develop novel rexinoids for testing of gene expression and side effect profiles for use in potential treatment of neurodegenerative disorders, as individual rexinoids can have markedly different gene expression profiles but similar structures.