Biology subjects

Lee, A. M.

Publications and source records attributed to Lee, A. M..

18 recordsLinked to original sources

bioRxiv2025

Cholinergic regulation of prolonged alcohol withdrawal differs by sex

Acute alcohol withdrawal encompasses somatic withdrawal signs and increased negative affect. In prolonged alcohol withdrawal the somatic withdrawal signs have resolved but the increased negative affect persists. We investigated acute and prolonged alcohol withdrawal after 9 daily injections of 2.5 g/kg alcohol plus 4-methypyrazole, an alcohol dehydrogenase inhibitor, in male and female C57BL/6J mice, and examined whether nicotinic acetylcholine receptor (nAChR) drugs could attenuate withdrawal-induced negative affect. Male mice showed changing somatic withdrawal signs over time and negative affect that persisted at least 21 days into withdrawal. Pre-treatment with mecamylamine, a non-specific nAChR antagonist, or varenicline, a nAChR partial agonist, reduced withdrawal-induced anxiety- and compulsive-like behavior in the marble-burying test during prolonged withdrawal. In contrast, female mice did not exhibit somatic withdrawal signs or anxiety- or compulsive-like behaviors. Instead, female mice showed a deficit in social interaction that was not attenuated by mecamylamine. Alcohol clearance and sedation were not different between sexes, indicating that differences in withdrawal signs and negative affect are not confounded by differences in alcohol metabolism. These findings suggest that cholinergic drugs may be a promising therapeutic for withdrawal-induced negative affect in male, but not female, mice.

pharmacology and toxicology↗

bioRxiv2025

Chronic alcohol drinking delays recovery from capsaicin- and nerve injury-induced hypersensitivity in mice

Chronic pain and alcohol use disorder (AUD) are major health concerns that significantly impair quality of life. Persistent pain is common in individuals with alcohol dependence, and alcohol is commonly used by chronic pain patients for self-medication. The neural mechanisms linking these conditions remain unclear. We hypothesized that chronic alcohol exposure induces hypersensitivity in multiple modalities and increases the duration of recovery in acute and persistent pain models. Using the two-bottle free-choice alcohol consumption paradigm in adult mice, alcohol-induced hypersensitivity (AIH), indicated by reduced mechanical withdrawal thresholds, developed after 4-6 weeks of alcohol consumption compared to age- and sex-matched water-consuming controls. Alcohol-consuming female mice, but not male mice, developed cold hypersensitivity after AIH emerged. To assess the impact of chronic alcohol consumption on acute and persistent pain, we used intraplantar capsaicin and sciatic nerve crush models, respectively. In the capsaicin model, water-treated, but not alcohol-treated, mice recovered from hypersensitivity by 24 hours post-injection. In the sciatic nerve crush model, alcohol-consuming mice exhibited slower recovery of mechanical withdrawal thresholds compared to water-consuming controls. While mechanical hypersensitivity in water-consuming mice returned to pre-surgical thresholds by 3-4 weeks post-surgery, recovery in alcohol-consuming mice was both delayed and partial. Surgical intervention did not impact alcohol intake. Overall, our results suggest that chronic voluntary alcohol consumption facilitates the transition to chronic pain by prolonging hypersensitivity and delaying recovery from injuries. HighlightsO_LIMagnitude of alcohol-induced mechanical hypersensitivity is similar across sex C_LIO_LIFemales, but not males, develop alcohol-induced cold sensitivity C_LIO_LIChronic alcohol prolongs acute inflammatory pain C_LIO_LIChronic alcohol prolongs nerve-injury induced neuropathic pain C_LI

pharmacology and toxicology↗

bioRxiv2025

Towards individualized deep brain stimulation: A stereoencephalography-based workflow for unbiased neurostimulation target identification

ObjectivesDeep brain stimulation (DBS) is increasingly being used to treat a variety of neuropsychiatric conditions, many of which exhibit idiosyncratic symptom presentations and neural correlates across individuals. Thus, we have utilized inpatient stereoelectroencephalography (sEEG) to identify personalized therapeutic stimulation sites for chronic implantation of DBS. Informed by our experience, we have developed a statistics-driven framework for stimulation testing to identify therapeutic targets. Materials and MethodsFourteen participants (major depressive disorder = 6, chronic pain = 6, obsessive-compulsive disorder = 2) underwent inpatient testing using sEEG and symptom monitoring to identify personalized stimulation targets for subsequent DBS implantation. We present a structured approach to this sEEG testing, integrating a Stimulation Testing Decision Tree with power analysis and effect size considerations to inform adequately powered results to detect therapeutic stimulation sites with statistical rigor. ResultsEffect sizes (Hedges g) of stimulation-induced symptom score changes ranged from -1.5 to +2.39. The standard deviation of sham trial responses was a strong predictor of stimulation response variability, as confirmed by a leave-one-out cross-validated linear regression (R2 = 0.67, permutation p<0.001). Thus, early sham trial data could be used to estimate the variability of stimulation responses for power analysis calculations. We show that approximately 10 sham trials were needed to robustly estimate sham variability. Power analysis (using a paired-t test) showed that for effect sizes [≥] 1.1, roughly 10 trials should be used per stimulation site for sufficiently powered results. ConclusionsThe presented workflow is adaptable to multiple indications and is specifically designed to overcome key challenges experienced during stimulation site testing. Through incorporating sham trials, effect size calculations, and tolerability testing, the described approach can be used to identify personalized and clinically efficacious stimulation sites.

neuroscience↗

bioRxiv2025

Central amygdalar PKCδ neurons mediate fentanyl withdrawal

Aversion to opioid withdrawal is a significant barrier to achieving lasting opioid abstinence. The central amygdala (CeA), a key brain region for pain, threat-detection, autonomic engagement, and valence assignment, is active during opioid withdrawal. However, the role of molecularly distinct CeA neural populations in withdrawal remains underexplored. Here, we investigated the activity dynamics, brain-wide connectivity, and functional contribution of Protein Kinase C-delta (PKC{delta})-expressing neurons in the CeA lateral capsule (CeLCPKC{delta}) during fentanyl withdrawal in mice. Mapping activity-dependent gene expression in CeLCPKC{delta} neurons revealed a highly withdrawal-active subregion in the anterior half of the CeA. Fiber photometry calcium imaging showed that opioid-naive CeLCPKC{delta} neurons respond to salient noxious and startling stimuli. In fentanyl-dependent mice, naloxone-precipitated withdrawal increased spontaneous neural activity and enhanced responses to noxious stimuli. Chronic inhibition of CeLCPKC{delta} neurons throughout fentanyl exposure, via viral overexpression of the potassium channel Kir2.1, attenuated withdrawal signs in fentanyl-dependent mice. Lastly, we identified putative opioid-sensitive inputs to CeLCPKC{delta} neurons using rabies-mediated monosynaptic circuit tracing and color-switching tracers to map mu-opioid receptor-expressing inputs to the CeLC. Collectively, these findings suggest that the hyperactivity of CeLCPKC{delta} neurons underlies the somatic signs of fentanyl withdrawal, offering new insights into the amygdala cell-types and circuits involved in opioid dependence.

neuroscience↗

bioRxiv2024

Therapeutic DBS for OCD Suppresses the Default Mode Network

BackgroundDeep brain stimulation (DBS) of the anterior limb of the internal capsule (ALIC) is an emerging treatment for severe, refractory obsessive-compulsive disorder (OCD). The therapeutic effects of DBS are hypothesized to be mediated by direct modulation of a distributed cortico-striato-thalmo-cortical network underlying OCD symptoms. However, the exact underlying mechanism by which DBS exerts its therapeutic effects still remains unclear. MethodIn five participants receiving DBS for severe, refractory OCD (3 responders, 2 non-responders), we conducted a DBS On/Off cycling paradigm during the acquisition of functional MRI to determine the network effects of stimulation across a variety of bipolar configurations. We also performed tractography using diffusion-weighted imaging (DWI) to relate the functional impact of DBS to the underlying structural connectivity between active stimulation contacts and functional brain networks. ResultsWe found that therapeutic DBS had a distributed effect, suppressing BOLD activity within regions such as the orbitofrontal cortex, dorsomedial prefrontal cortex, and subthalamic nuclei compared to non-therapeutic configurations. Many of the regions suppressed by therapeutic DBS were components of the default mode network (DMN). Moreover, the estimated stimulation field from the therapeutic configurations exhibited significant structural connectivity to core nodes of the DMN. ConclusionsTherapeutic DBS for OCD suppresses BOLD activity within a distributed set of regions within the DMN relative to non-therapeutic configurations. We propose that these effects may be mediated by interruption of communication through structural white matter connections surrounding the DBS active contacts.

neuroscience↗

bioRxiv2024

Human Anterior Insular Cortex Encodes Multiple Electrophysiological Representations of Anxiety-Related Behaviors

Anxiety is a common symptom across psychiatric disorders, but the neurophysiological underpinnings of these symptoms remain unclear. This knowledge gap has prevented the development of circuit-based treatments that can target the neural substrates underlying anxiety. Here, we conducted an electrophysiological mapping study to identify neurophysiological activity associated with self-reported state anxiety in 17 subjects implanted with intracranial electrodes for seizure localization. Participants had baseline anxiety traits ranging from minimal to severe. Subjects volunteered to participate in an anxiety induction task in which they were temporarily exposed to the threat of unpredictable shock during intracranial recordings. We found that anterior insular beta oscillatory activity was selectively elevated during epochs when unpredictable aversive stimuli were being delivered, and this enhancement in insular beta was correlated with increases in self-reported anxiety. Beta oscillatory activity within the frontoinsular region was also evoked selectively by cues-predictive of threat, but not safety cues. Anterior insular gamma responses were less selective than gamma, strongly evoked by aversive stimuli and had weaker responses to salient threat and safety cues. On longer timescales, this gamma signal also correlated with increased skin conductance, a measure of autonomic state. Lastly, we found that direct electrical stimulation of the anterior insular cortex in a subset of subjects elicited self-reported increases in anxiety that were accompanied by enhanced frontoinsular beta oscillations. Together, these findings suggest that electrophysiologic representations of anxiety- related states and behaviors exist within anterior insular cortex. The findings also suggest the potential of reducing anterior insular beta activity as a therapeutic target for refractory anxiety-spectrum disorders.

neuroscience↗

bioRxiv2023

Subregion and sex differences in ethanol activation of cholinergic and glutamatergic cells in the mesopontine tegmentum

Ethanol engages cholinergic signaling and elicits endogenous acetylcholine release. Acetylcholine input to the midbrain originates from the mesopontine tegmentum (MPT), which is composed of the laterodorsal tegmentum (LDT) and the pedunculopontine tegmental nucleus (PPN). We investigated the effect of acute and chronic ethanol administration on cholinergic and glutamatergic neuron activation in the PPN and LDT in male and female mice. We show that ethanol selectively activates neurons of the PPN and not the LDT in male mice. Acute 4.0 g/kg and chronic 15 daily injections of 2.0 g/kg i.p. ethanol induced Fos expression in cholinergic and glutamatergic PPN neurons in male mice, whereas cholinergic and glutamatergic neurons of the LDT were unresponsive. In contrast, acute or chronic ethanol at either dose or duration had no effect on the activation of cholinergic or glutamatergic neurons in the MPT of female mice. Female mice had higher level of baseline activation in cholinergic neurons compared with males. We also found a population of co-labeled cholinergic and glutamatergic neurons in the PPN and LDT which were highly active in the saline- and ethanol-treated groups in both sexes. These findings illustrate the complex differential effects of ethanol across dose, time point, MPT subregion and sex.

pharmacology and toxicology↗

bioRxiv2023

Simplicity: web-based visualization and analysis of high-throughput cancer cell line screens

High-throughput drug screens are a powerful tool for cancer drug development. However, the results of such screens are often made available only as raw data, which is intractable for researchers without informatic skills, or as highly processed summary statistics, which can lack essential information for translating screening results into clinically meaningful discoveries. To improve the usability of these datasets, we developed Simplicity, a robust and user-friendly web interface for visualizing, exploring, and summarizing raw and processed data from high-throughput drug screens. Importantly, Simplicity allows for easy recalculation of summary statistics at user-defined drug concentrations. This allows Simplicitys outputs to be used with methods that rely on statistics being calculated at clinically relevant doses. Simplicity can be freely accessed at https://oncotherapyinformatics.org/simplicity/.

pharmacology and toxicology↗

bioRxiv2023

How do life history traits influence the environment's effect on population synchrony? Insights from European birds and insects

Populations closer together in space are more likely to experience shared environmental fluctuations. This correlation in experienced environmental conditions is the main driver of spatial population synchrony, defined as the tendency for geographically separate populations of the same species to exhibit parallel fluctuations in abundance over time. Morans theorem states that spatially distinct populations are expected to show the same synchrony in their population dynamics as the synchrony in their environment. However, this is rarely the case in the wild, and the population synchrony of different species inhabiting the same area is rarely similar. These species-specific differences in how the environment synchronizes populations can be due to life history traits that make some species more susceptible to environmental stochasticity, such as reduced mobility or faster pace of life. In this study, we compiled long-term annual abundance datasets on European birds and insects (Lepidoptera sp. and Bombus sp.) to identify how environmental synchrony (i.e., positively spatially correlated fluctuations in the environment, also called the Moran effect) affects species population synchrony. As expected, the environment synchronized populations of both birds and insects. Populations experiencing correlated fluctuations in precipitation or temperature had higher synchrony in annual population growth rates. Birds were more strongly synchronized by temperature, while precipitation was a stronger driver of synchrony in insects. In birds, species with short generation times had a stronger synchronizing effect of the environment compared to species with long generation times. Moreover, in birds the effects of synchrony in the environment also depended on movement propensity, with a positive impact for resident and short-distance migration species. In insects, annual population synchrony was affected by species movement propensity and dietary niche breadth, but these traits did not modify the effects of environmental synchrony. Our study provides empirical support for the prediction that spatial correlation in population dynamics is more influenced by environmental stochasticity for life histories with lower mobility and faster pace of life, but only in birds. By quantifying spatial population synchrony across different levels of environmental synchrony and life history traits, our study improves the understanding of the Moran effect as well as factors that drive population persistence in the face of environmental change.

ecology↗

bioRxiv2023

Expression pattern of nicotinic acetylcholine receptor subunit transcripts in neurons and astrocytes in the ventral tegmental area and locus coeruleus

Acetylcholine is the endogenous agonist for the neuronal nicotinic acetylcholine receptor (nAChR) system, which is involved in attention, memory, affective behaviors, and substance use disorders. Brain nAChRs are highly diverse with 11 different subunits that can form multiple receptor subtypes, each with distinct receptor and pharmacological properties. Different neuronal cell types can also express different nAChR subtypes, resulting in highly complex cholinergic signaling. Identifying which nAChR subunit transcripts are expressed in cell types can provide an indication of which nAChR combinations are possible and which receptor subtypes may be most pharmacologically relevant to target. In addition to differences in expression across cell types, nAChRs also undergo changes in expression levels from adolescence to adulthood. In this study, we used fluorescent in situ hybridization to identify and quantify the expression of 4, 5, 6, {beta}2 and {beta}3 nAChR subunit transcripts in dopaminergic, GABAergic, glutamatergic, and noradrenergic neurons and astrocytes in the ventral tegmental area (VTA) and locus coeruleus (LC) in adult and adolescent, male and female C57BL/6J mice. There were distinct differences in the pattern of nAChR subunit transcript expression between the two brain regions. LC noradrenergic neurons had high prevalence of 6, {beta}2 and {beta}3 expression, with very low expression of 4, suggesting the 6(non-4){beta}2{beta}3 receptor as a main subtype in these neurons. VTA astrocytes from adult mice showed greater prevalence of 5, 6, {beta}2 and {beta}3 transcript compared with adolescent mice. These data highlight the complex nAChR expression patterns across brain region and cell type.

neuroscience↗

bioRxiv2023

Generation time and seasonal migration explain variation in spatial population synchrony across European bird species

O_LISpatial population synchrony is common among populations of the same species and is an important predictor of extinction risk. Despite the potential consequences for metapopulation persistence, we still largely lack understanding of what makes one species more likely to be synchronized than another given the same environmental conditions. C_LIO_LIGenerally, environmental conditions on a shared environment or a species sensitivity to the environment can explain the extent of synchrony. Populations that are closer together experience more similar fluctuations in their environments than those populations that are further apart and are therefore more synchronized. The relative importance of environmental and demographic stochasticity for population dynamics is strongly linked to species life history traits, such as pace of life, why may impact population synchrony. For populations that migrate, there may be multiple environmental conditions at different locations driving synchrony. However, the importance of life history and migration strategies in determining patterns of spatial population synchrony have rarely been explored empirically. We therefore hypothesize that generation time, a proxy for pace of life, and migration play an important role in determining spatial population synchrony. C_LIO_LIWe used population abundance data on breeding birds from four countries to investigate patterns of spatial population synchrony in growth rate and abundance. We investigated differences in synchrony across a gradient of generation times in resident, short-distance migrant, and long-distance migrant bird species. C_LIO_LISpecies with shorter generation times were more synchronized than species with longer generation times. Short-distance migrants were more synchronized than long-distance migrants and resident birds. C_LIO_LIOur results provide novel empirical links between spatial population synchrony and species traits known to be of key importance for population dynamics, generation time and migration characteristics. We show how these different mechanisms can be combined to understand species-specific causes of spatial population synchrony. Understanding these specific drivers of spatial population synchrony is important in the face of increasingly severe threats to biodiversity and could be key for successful future conservation outcomes. C_LI

ecology↗

bioRxiv2022

High-resolution Spatiotemporal Changes in Dominant Frequency and Structural Organization During Persistent Atrial Fibrillation

ObjectiveAnalyze changes in frequency activity and structural organization that occur over time with persistent atrial fibrillation (AF) BackgroundLittle is known about the frequency characteristics of the epicardium during transition from paroxysmal to persistent AF. Accurate identification of areas of high dominant frequency (DF) is often hampered by limited spatial resolution. Improvements in electrode arrays provide high spatiotemporal resolution, allowing for characterization of the changes that occur during this transition. MethodsAF was induced in adult Yorkshire swine by atrial tachypacing. DF mapping was performed using personalized mapping arrays. Histological analysis and late gadolinium enhanced magnetic resonance imaging were performed to determine structural differences in fibrosis. ResultsThe left atrial epicardium was associated with a significant increase in DF in persistent AF (6.5 {+/-} 0.2 vs. 7.4 {+/-} 0.5 Hz, P = 0.03). The organization index (OI) significantly decreased during persistent AF in both the left atria (0.3 {+/-} 0.03 vs. 0.2 {+/-} 0.03, P = 0.01) and right atria (0.33 {+/-} 0.04 vs. 0.23 {+/-} 0.02, P = 0.02). MRI analysis demonstrated increased ECV values in persistent AF (0.19 vs 0.34, paroxysmal vs persistent, P = 0.05). Tissue sections from the atria showed increase in fibrosis in pigs with persistent AF compared to paroxysmal AF. Staining demonstrated decreased myocardial fiber alignment and loss of anisotropy in persistent AF tissue. ConclusionsChanges in tissue organization and fibrosis are observed in the porcine model of persistent AF. Alterations in frequency activity and organization index can be captured with high resolution using flexible electrode arrays.

physiology↗

bioRxiv2020

Bidirectional sex-dependent regulation of α6 and β3 nicotinic acetylcholine receptors by protein kinase Cε

Nicotine and alcohol are the most commonly abused substances worldwide, and comorbid nicotine and alcohol addiction is highly prevalent. Nicotinic acetylcholine receptors (nAChRs) containing the 6 and {beta}3 subunits are expressed in neural reward circuits and are critical for both nicotine and alcohol reward. nAChRs are dynamically regulated by signaling molecules such as protein kinase C epsilon (PKC{varepsilon}), which impact transcription of 6 and {beta}3 subunit mRNA (Chrna6 and Chrnb3, respectively). Previous work found decreased expression of Chrna6 and Chrnb3 transcripts in the ventral midbrain of male PKC{varepsilon}-/- mice, who also consume less nicotine and alcohol compared to wild-type (WT) littermates. Here, we show that female PKC{varepsilon}-/- mice have enhanced expression of Chrna6 and Chrnb3 transcripts in the ventral midbrain, which functionally impacts nAChR-dependent behavior, as female but not male PKC{varepsilon}-/- mice exhibit locomotor hypersensitivity to nicotine. Female PKC{varepsilon}-/- mice show no differences in alcohol-induced sedation compared to WT littermates, while male PKC{varepsilon}-/- have enhanced sedation compared to WT mice, a phenotype that has previously been reported in 6-/- mice. Female PKC{varepsilon}-/- mice also show reduced depression-like behavior in response to systemic injections of varenicline compared to WT littermates, and this effect was absent in male mice. Additionally, we found that female PKC{varepsilon}-/- mice show altered alcohol and nicotine consumption patterns in chronic voluntary two bottle choice assays. Our data reveal a bidirectional effect of sex in the transcriptional regulation of nicotinic receptors by PKC{varepsilon}, and highlight the importance of studying both sexes in preclinical animal models.

neuroscience↗

bioRxiv2019

Flavor-specific enhancement of electronic cigarette liquid consumption and preference in mice

BackgroundThe use of electronic cigarettes has increased over the past decade. To determine how the abuse liability of electronic cigarette liquids (e-liquids) differs from nicotine alone, and to determine the impact of flavor, we compared nicotine-containing fruit- and tobacco-flavored e-liquids, and their nicotine-free versions, to nicotine alone in mouse models of oral consumption, reward and aversion. MethodsAdult male C57BL/6J mice voluntarily consumed oral nicotine, equivalent nicotine concentrations of fruit- and tobacco-flavored e-liquid, and equivalent dilutions of the nicotine-free versions in 2-bottle choice tests. Conditioned place preference and place aversion were assessed with peripherally administered e-liquids or nicotine. Serum nicotine and cotinine levels were measured after subcutaneous injections of e-liquid or nicotine. ResultsMice showed higher consumption and preference for the fruit-flavored e-liquid compared with nicotine alone. This increase was not due to the flavor itself as consumption of the nicotine-free fruit-flavored e-liquid was not elevated until the highest concentration tested. The increased consumption and preference were not observed with the tobacco-flavored e-liquid. The conditioned place preference, place aversion and nicotine pharmacokinetics of the fruit-flavored e-liquid were not significantly different from nicotine alone. ConclusionsOur data suggest that fruit, but not tobacco flavor, increased the oral consumption of e-liquid compared with nicotine alone. Moreover, this enhancement was not due to increased consumption of the flavor itself, altered rewarding or aversive properties after peripheral administration, or altered pharmacokinetics. This flavor-specific enhancement suggests that some flavors may lead to higher nicotine intake and increased use of e-liquids compared with nicotine alone. HighlightsO_LIFruit flavor, but not tobacco flavor, enhances e-liquid consumption and preference C_LIO_LIThe nicotine-free flavored e-liquid is not preferred over nicotine alone C_LIO_LIConditioning rewarding and aversive effects are equal between nicotine and e-liquid C_LI

pharmacology and toxicology↗

bioRxiv2019

Selective enhancement of alcohol aversion by nicotinic acetylcholine receptor drugs

The prevalence of alcohol use disorders (AUDs) has steadily increased in the United States over the last 30 years. Alcohol acts on multiple receptor systems including the nicotinic acetylcholine receptors (nAChRs), which are known to mediate alcohol consumption and reward. We previously reported that the preclinical drug sazetidine-A, a nAChR agonist, reduces alcohol consumption without affecting nicotine consumption in C57BL/6J mice. Here, we found that sazetidine-A enhances the expression of alcohol aversion without affecting the expression or acquisition of conditioned alcohol reward in C57BL/6J mice. Microinjection of sazetidine-A into the ventral midbrain targeting the ventral tegmental area (VTA) reduced binge alcohol consumption, implicating the neurocircuitries in this region in mediating the effects of sazetidine-A. Furthermore, sazetidine-A-induced reduction in alcohol consumption was mediated by non-4 containing nAChRs, as sazetidine-A reduced binge alcohol consumption in both 4 knock-out and wild-type mice. Finally, we found that in mice pre-treated with sazetidine-A, alcohol induced Fos transcript within Th-expressing but not Gad2-expressing neurons in the VTA as measured by increased Fos transcript expression. In summary, we find that sazetidine-A acts on non-4 nAChRs to enhance the expression of alcohol aversion, which may underlie the reduction in alcohol consumption induced by sazetidine-A. Elucidating the identity of non-4 nAChRs in alcohol aversion mechanisms will provide a better understanding the complex role of nAChRs in alcohol addiction and potentially reveal novel drug targets to treat AUDs.

neuroscience↗

bioRxiv2019

Discovering novel long non-coding RNA predictors of anticancer drug sensitivity beyond protein-coding genes

Large-scale cancer cell line screens have identified thousands of protein-coding genes (PCGs) as biomarkers of anticancer drug response. However, systematic evaluation of long non-coding RNAs (lncRNAs) as pharmacogenomic biomarkers has so far proven challenging. Here, we study the contribution of lncRNAs as drug response predictors beyond spurious associations driven by correlations with proximal PCGs, tissue-lineage or established biomarkers. We show that, as a whole, the lncRNA transcriptome is equally potent as the PCG transcriptome at predicting response to hundreds of anticancer drugs. Analysis of individual lncRNAs transcripts associated with drug response reveals nearly half of the significant associations are in fact attributable to proximal cis-PCGs. However, adjusting for effects of cis-PCGs revealed significant lncRNAs that augment drug response predictions for most drugs, including those with well-established clinical biomarkers. In addition, we identify lncRNA-specific somatic alterations associated with drug response by adopting a statistical approach to determine lncRNAs carrying somatic mutations that undergo positive selection in cancer cells. Lastly, we experimentally demonstrate that two novel lncRNA, EGFR-AS1 and MIR205HG, are functionally relevant predictors of anti-EGFR drug response.

bioinformatics↗

bioRxiv2019

Unequal interactions between alcohol and nicotine co-consumption: Suppression and enhancement of concurrent drug intake

RationaleAlcohol and nicotine addiction are prevalent conditions that co-occur. Despite the prevalence of co-use, factors that influence the suppression and enhancement of concurrent alcohol and nicotine intake are largely unknown.\n\nObjectivesOur goals were to assess how nicotine abstinence and availability influenced concurrent alcohol consumption, and to determine the impact of quinine adulteration of alcohol on aversion resistant alcohol consumption and concurrent nicotine consumption.\n\nMethodsMale and female C57BL/6J mice voluntarily consumed unsweetened alcohol, nicotine and water in a chronic 3-bottle choice procedure. In Experiment 1, nicotine access was removed for 1 week and re-introduced the following week, while the alcohol and water bottles remained available at all times. In Experiment 2, quinine (100-1000 M) was added to the 20% alcohol bottle, while the nicotine and water bottles remained unaltered.\n\nResultsIn Experiment 1, we found that alcohol consumption and preference were unaffected by the presence or absence of nicotine access in both male and female mice. In Experiment 2a, we found that quinine temporarily suppressed alcohol intake and enhanced concurrent nicotine, but not water, preference in both male and female mice. In Experiment 2b, chronic quinine suppression of alcohol intake increased nicotine consumption and preference in female mice without affecting water preference, whereas it increased water and nicotine preference in male mice.\n\nConclusionsQuinine suppression of alcohol consumption enhanced the preference for concurrent nicotine preference in male and female mice, suggesting that mice compensate for the quinine adulteration of alcohol by increasing their nicotine preference.

pharmacology and toxicology↗

bioRxiv2018

A Cross-Platform Comparison of Student’s Perceptions of the Learning Environment in an Introductory Microbiology Course

AbstractStudents positive perceptions of the learning environment increase retention and persistence in STEM disciplines. This study presents results from a Learning Environment Questionnaire administered at the beginning and end of the semester in a redesigned general/introductory microbiology course offered in traditional lecture, flipped and online sections. Split-sample t-tests and chi-squared tests were used for cross-section and within section analyses, respectively. The findings support the study hypothesis that student perceptions of the learning environment will vary as a function of platform. This work demonstrates the additional effect of the time in the semester when students complete the questionnaire and this effect on students perceptions over the course of the semester relative to their initial perceptions. The results of this study offer insight on student perceptions of the learning environment as universities embrace online education in introductory and gateway courses as a response to rising student enrollments and diminishing resources.

scientific communication and education↗