Methamphetamine and Inflammatory Cytokines Increase Neuronal Na+/K+-ATPase Isoform 3: Relevance for HIV Associated Neurocognitive Disorders

Methamphetamine (METH) abuse in conjunction with human immunodeficiency virus (HIV) exacerbates neuropathogenesis and accelerates neurocognitive impairments in the central nervous system (CNS), collectively termed HIV Associated Neurocognitive Disorders (HAND). Since both HIV and METH have been implicated in altering the synaptic architecture, this study focused on investigating alterations in synaptic proteins. Employing a quantitative proteomics approach on synaptosomes isolated from the caudate nucleus from two groups of rhesus monkeys chronically infected with simian immunodeficiency virus (SIV) differing by one regimen, METH treatment, we identified the neuron specific Na+/K+-ATPase alpha 1 isoform 3 (ATP1A3) to be up regulated after METH treatment, and validated its up regulation by METH in vitro. Further studies on signaling mechanisms revealed that the activation of ATP1A3 involves the extracellular regulated kinase (ERK) pathway. Given its function in maintaining ionic gradients and emerging role as a signaling molecule, changes in ATP1A3 yields insights into the mechanisms associated with HAND and interactions with drugs of abuse

CHRI sis at the NICU: The Medley with Midazolam

Approximately 1.5 million neonates undergo anesthesia for surgical procedures in the United States every year1. Midazolam is a commonly used anesthetic agent used in the Neonatal Intensive Care Unit (NICU). It is used to sedate neonates and facilitates complex procedures such as mechanical ventilation.2 The extensive use of midazolam has raised questions about whether it affects the cognitive development of infants. In 2014, the International Anesthesia Research Society released a statement saying, “Surgeries and procedures requiring anesthetic and sedative drugs that could reasonably be delayed should possibly be postponed because of the potential risk to the developing brain of infants, toddlers, and preschool children”. 3 Although some evidence shows that midazolam exposure could harm an infant’s cognitive development, little is known about what parts of the developing brain are directly affected by midazolam. Additionally, research has yet to uncover whether the effects of midazolam persist into adulthood. In order to examine the consequences of midazolam exposure, a holistic system biology approach should be implemented. Experimental data from four different levels ─ the molecular level, the physical trait level, the behavioral level, and “omics” level would help address these issues. Our objective is to investigate how prolonged exposure to midazolam affects cellular as well as behavioral functions. A rodent model was implemented to study the effects at infanthood, adolescence, and adulthood. Our molecular results revealed that midazolam could potentially cause disturbances in key brain protein levels. Additionally, midazolam could potentially contribute to social deficits as evidenced by behavioral results. Overall, the results all point to midazolam\u27s potential to delay proper neurodevelopment.https://digitalcommons.unmc.edu/surp2021/1028/thumbnail.jp

Activity patterns, time use, and travel of millennials: a generation in transition?

Millennials, defined in this study as those born between 1979 and 2000, became the largest population segment in the United States in 2015. Compared to recent previous generations, they have been found to travel less, own fewer cars, have lower driver’s licensure rates, and use alternative modes more. But to what extent will these differences in behaviour persist as millennials move through various phases of the lifecycle? To address this question, this paper presents the results of a longitudinal analysis of the 2003--2013 American Time Use Survey data series. In early adulthood, younger millennials (born 1988--1994) are found to spend significantly more time in-home than older millennials (born 1979--1985), which indicates that there are substantial differences in activity-time use patterns across generations in early adulthood. Older millennials are, however, showing activity-time use patterns similar to their prior generation counterparts as they age, although some differences -- particularly in time spent as a car driver -- persist. Millennials appear to exhibit a lag in adopting the activity patterns of predecessor generations due to delayed lifecycle milestones (e.g. completing their education, getting jobs, marrying, and having children) and lingering effects of the economic recession, suggesting that travel demand will resume growth in the future

Integrated Systems Analysis of Mixed Neuroglial Cultures Proteome Post Oxycodone Exposure

Opioid abuse has become a major public health crisis that affects millions of individuals across the globe. This widespread abuse of prescription opioids and dramatic increase in the availability of illicit opioids have created what is known as the opioid epidemic. Pregnant women are a particularly vulnerable group since they are prescribed for opioids such as morphine, buprenorphine, and methadone, all of which have been shown to cross the placenta and potentially impact the developing fetus. Limited information exists regarding the effect of oxycodone (oxy) on synaptic alterations. To fill this knowledge gap, we employed an integrated system approach to identify proteomic signatures and pathways impacted on mixed neuroglial cultures treated with oxy for 24 h. Differentially expressed proteins were mapped onto global canonical pathways using ingenuity pathway analysis (IPA), identifying enriched pathways associated with ephrin signaling, semaphorin signaling, synaptic long-term depression, endocannabinoid signaling, and opioid signaling. Further analysis by ClueGO identified that the dominant category of differentially expressed protein functions was associated with GDP binding. Since opioid receptors are G-protein coupled receptors (GPCRs), these data indicate that oxy exposure perturbs key pathways associated with synaptic function

Effect of Combined Methamphetamine and Oxycodone Use on the Synaptic Proteome in an In Vitro Model of Polysubstance Use

Polysubstance use (PSU) generally involves the simultaneous use of an opioid along with a stimulant. In recent years, this problem has escalated into a nationwide epidemic. Understanding the mechanisms and effects underlying the interaction between these drugs is essential for the development of treatments for those suffering from addiction. Currently, the effect of PSU on synapses-critical points of contact between neurons-remains poorly understood. Using an in vitro model of primary neurons, we examined the combined effects of the psychostimulant methamphetamine (METH) and the prescription opioid oxycodone (oxy) on the synaptic proteome using quantitative mass-spectrometry-based proteomics. A further ClueGO analysis and Ingenuity Pathway Analysis (IPA) indicated the dysregulation of several molecular functions, biological processes, and pathways associated with neural plasticity and structural development. We identified one key synaptic protein, Striatin-1, which plays a vital role in many of these processes and functions, to be downregulated following METH+oxy treatment. This downregulation of Striatin-1 was further validated by Western blot. Overall, the present study indicates several damaging effects of the combined use of METH and oxy on neural function and warrants further detailed investigation into mechanisms contributing to synaptic dysfunction

Oxaliplatin induces drug resistance more rapidly than cisplatin in H69 small cell lung cancer cells

Cisplatin produces good responses in solid tumours including small cell lung cancer (SCLC) but this is limited by the development of resistance. Oxaliplatin is reported to show activity against some cisplatin-resistant cancers but there is little known about oxaliplatin in SCLC and there are no reports of oxaliplatin resistant SCLC cell lines. Studies of drug resistance mainly focus on the cellular resistance mechanisms rather than how the cells develop resistance. This study examines the development of cisplatin and oxaliplatin resistance in H69 human SCLC cells in response to repeated treatment with clinically relevant doses of cisplatin or oxaliplatin for either 4 days or 2h. Treatments with 200ng/ml cisplatin or 400ng/ml oxaliplatin for 4 days produced sublines (H69CIS200 and H69OX400 respectively) that showed low level (approximately 2-fold) resistance after 8 treatments. Treatments with 1000ng/ml cisplatin or 2000ng/ml oxaliplatin for 2h also produced sublines, however these were not stably resistant suggesting shorter treatment pulses of drug may be more effective. Cells survived the first five treatments without any increase in resistance, by arresting their growth for a period and then regrowing. The period of growth arrest was reduced after the sixth treatment and the H69CIS200 and H69OX400 sublines showed a reduced growth arrest in response to cisplatin and oxaliplatin treatment suggesting that "regrowth resistance" initially protected against drug treatment and this was further upregulated and became part of the resistance phenotype of these sublines. Oxaliplatin dose escalation produced more surviving sublines than cisplatin dose escalation but neither set of sublines were associated with increased resistance as determined by 5-day cytotoxicity assays, also suggesting the involvement of regrowth resistance. The resistant sublines showed no change in platinum accumulation or glutathione levels even though the H69OX400 subline was more sensitive to buthionine sulfoximine treatment. The H69CIS200 cells were cross-resistant to oxaliplatin demonstrating that oxaliplatin does not have activity against low level cisplatin resistance. Relative to the H69 cells, the H69CIS200 and H69OX400 sublines were more sensitive to paclitaxel and taxotere suggests the taxanes may be useful in the treatment of platinum resistant SCLC. These novel cellular models of cisplatin and oxaliplatin resistant SCLC will be useful in developing strategies to treat platinum-resistant SCLC

A Holistic Systems Approach to Characterize the Impact of Pre- and Post-natal Oxycodone Exposure on Neurodevelopment and Behavior

Background: Increased risk of oxycodone (oxy) dependency during pregnancy has been associated with altered behaviors and cognitive deficits in exposed offspring. However, a significant knowledge gap remains regarding the effect of in utero and postnatal exposure on neurodevelopment and subsequent behavioral outcomes. Methods: Using a preclinical rodent model that mimics oxy exposure in utero (IUO) and postnatally (PNO), we employed an integrative holistic systems biology approach encompassing proton magnetic resonance spectroscopy (1H-MRS), electrophysiology, RNA-sequencing, and Von Frey pain testing to elucidate molecular and behavioral changes in the exposed offspring during early neurodevelopment as well as adulthood. Results: 1H-MRS studies revealed significant changes in key brain metabolites in the exposed offspring that were corroborated with changes in synaptic currents. Transcriptomic analysis employing RNA-sequencing identified alterations in the expression of pivotal genes associated with synaptic transmission, neurodevelopment, mood disorders, and addiction in the treatment groups. Furthermore, Von Frey analysis revealed lower pain thresholds in both exposed groups. Conclusions: Given the increased use of opiates, understanding the persistent developmental effects of these drugs on children will delineate potential risks associated with opiate use beyond the direct effects in pregnant women

Characterizing genomic alterations in cancer by complementary functional associations.

Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes

The COVID-19 pandemic and the future of telecommuting in the United States

This study focuses on an important transport-related long-term effect of the COVID-19 pandemic in the United States: an increase in telecommuting. Analyzing a nationally representative panel survey of adults, we find that 40–50% of workers expect to telecommute at least a few times per month post-pandemic, up from 24% pre-COVID. If given the option, 90–95% of those who first telecommuted during the pandemic plan to continue the practice regularly. We also find that new telecommuters are demographically similar to pre-COVID telecommuters. Both pre- and post-COVID, higher educational attainment and income, together with certain job categories, largely determine whether workers have the option to telecommute. Despite growth in telecommuting, approximately half of workers expect to remain unable to telecommute and between 2/3 and 3/4 of workers expect their post-pandemic telecommuting patterns to be unchanged from their pre-COVID patterns. This limits the contribution telecommuting can make to reducing peak hour transport demand