A Pilot Study Analyzing Solvents in Electronic Cigarette “E-liquid” Using High Performance Liquid Chromatography

Introduction: Electronic cigarettes, also known as an e-cigarette, are battery-powered devices that use a heating element to convert a liquid (“e-liquid”) into an inhalable aerosol. Their advertised use is as a nicotine delivery system minus the harmful chemicals. Since “e-liquids” and the electronic cigarettes are not regulated by the Food and Drug Administration, it is not well known under what conditions, if any, carcinogenic compounds are produced. There has been little research on the toxicity of electronic cigarettes. The aim of this study was to determine if formaldehyde or acetaldehyde are formed from the e-liquid by the high heat of the electronic cigarette. Materials and Methods: Vapors from 5 brands of e-liquid were produced using a Kangertech Dripbox which has a max output of 60 watts. The vapors were trapped in a solution containing acetonitrile and 2,4-dinitrophenylhydrazine (DNPH) to create DNPH derivatives of any volatile organic compounds that may have formed. The DNPH solution was measured using high-performance liquid chromatography with diode-array detection. Results: Each of the 5 e-liquids produced formaldehyde after being heated by the electronic cigarette. The levels of formaldehyde ranged from 8.28 µg/mL (8.28 ppm) to 36.08 µg/mL (36.08 ppm). Acetaldehyde was not confirmed as being present in the e-liquid or in the vapors of any of the 5 samples. Conclusion: Decomposition due to heat yields a significant amount of formaldehyde. These levels of formaldehyde are well above what the Center for Disease Control considers a high exposure level. Formaldehyde has been found in numerous studies to be carcinogenic to humans

Computational Design of β-Fluorinated Morphine Derivatives for pH-specific Binding

The opioid epidemic impacted over 12 million Americans in 2019. Although they are effective pain-relieving medications, they carry addictive and dangerous side effects. Opioids, like morphine, bind non-selectively in both central and peripheral tissues; however, dangerous side effects result from central activation. Inflamed conditions of injured tissues have a lower pH (pH=6-6.5) environment than healthy central tissue (pH=7.4). We aim to design a morphine derivative that binds selectively within inflamed tissue using computationally-based molecular extension and dissection techniques. Binding to the mu-opioid receptor (MOR) is dependent on protonation of the biochemically active amine group of morphine. Fluorination of a carbon beta to the tertiary amine group was used in order to reduce the pKa of the ligand through induction. By decreasing the pKa of morphine, protonation remains possible in lower pH environments of inflamed tissue, while remaining primarily deprotonated in healthy tissue. A cyclohexane and pyridine ring were removed to increase conformational flexibility when binding to the MOR and maintaining biological function. Electronic structure calculations were performed with Gaussian16 using the Keck Computational Research Cluster at Chapman University. The theoretical pKa values were determined at the M06-2X/aug-cc-pVDZ//SMD level of theory to calculate the ΔG°aq values for the amine deprotonation reactions. Multiple beta-fluorinated morphine derivatives were made computationally and modeled within the MOR using Maestro: Schrödinger. Derivatives show reductions in pKa and enhanced ligand protein interactions within the MOR. Beta-fluorination decreased the overall pKa values of the morphine derivatives (pKa: 6.1-7.8) relative to morphine. The reductions in pKa reduce the possibility of binding within healthy, central tissue

Computational Design of β-Fluorinated Morphine Derivatives for pH-specific Binding

Molecular extension and dissection techniques are used to design a morphine derivative that promotes selective binding in inflamed tissue due to its lower pH while avoiding dangerous activation in the brain. Morphine is used to treat pain associated with inflammation. While being effective analgesics, opioids carry the risk of central side effects, including addiction, respiratory depression, and sedation. Opioids are agonists that bind to the μ-opioid peptide receptor (MOR) within central and peripheral nerves and act via a G-protein coupled receptor pathway. Deprotonation of the tertiary amine induces a negative charge on the nitrogen, discouraging binding at physiological pH (pH=7.4). The addition of a fluorine atom on a carbon beta to the amine allows fluorine’s inductive effects to decrease the pKa. Decreasing the pKa of the biochemically active amine group promotes selective binding in peripheral opioid receptors within inflamed tissue (pH=6-6.5). Protonation remains possible in lower pH environments of inflamed tissue. Activation of peripheral receptors provides analgesia, and central receptors within the brain remain inactive. A cyclohexane (C) and pyridine ring (D) are removed to increase conformational flexibility when binding to the MOR and maintaining biological function. Electronic structure calculations were performed with Gaussian 16 using the Keck Computational Research Cluster at Chapman University. Theoretical pKa values are determined at the M06-2X/aug-cc-pVDZ//SMD level of theory to calculate the ΔG°aq values for the amine deprotonation reactions. The pKa of morphine is determined as 8.0 via computational analysis and used as a benchmark value to compare the beta-fluorinated derivatives. Beta-fluorination decreased the overall pKa values of the morphine derivatives (pKa: 6.1-7.83) relative to morphine. The beta-fluorinated derivatives have lower pKa values with respect to the C and D dissected derivatives. Molecular extension and dissection techniques are used to design a morphine derivative that promotes selective binding in inflamed tissue due to its lower pH while avoiding dangerous activation in the brain. Morphine is an opioid used to treat pain associated with inflammation yet it has severe central side effects, including addiction and respiratory depression. Opioid agonists that bind to the μ-opioid peptide receptor (MOR) within central and peripheral nerves and act via a G-protein coupled receptor pathway. Deprotonation of the tertiary amine induces a negative charge on the nitrogen, discouraging binding at physiological pH (pH=7.4). Adding a fluorine on a carbon beta to the amine allows fluorine’s inductive effects to decrease the pKa. This promotes selective binding in peripheral opioid receptors within inflamed tissue (pH=6-6.5); protonation remains possible in lower pH environments. Peripheral receptor activation provides analgesia while central receptors remain inactive. A cyclohexane (C) and pyridine ring (D) are removed, increasing conformational flexibility while maintaining biological function. Electronic structure calculations were performed with Gaussian 16 using the Keck Computational Research Cluster. Theoretical pKa values are determined at the M06-2X/aug-cc-pVDZ//SMD level of theory to calculate the ΔG°aq values for the amine deprotonation reactions. The pKa of morphine (8.0) is determined via computational analysis and used as a benchmark value to compare the beta-fluorinated derivatives. Beta-fluorination decreased the overall pKa values of the morphine derivatives (pKa: 6.1-7.83) relative to morphine. The beta-fluorinated derivatives have lower pKa values with respect to the C and D dissected derivatives

Modelling the Accessibility of Adult Psychology Services Using Discrete Event Simulation

With a growing number of people seeking treatment for mental health problems, mental health services are consequently coming under increased pressure resulting in longer waiting times and worsening of mental health problems. Service underfunding, overworked staff, and the looming threat of further demand due to the COVID-19 pandemic only add to the concerns. Hence it is imperative the efficiencies of these services are maximised to allow better access to quality treatment. We created a Discrete Event Simulation model to replicate the current clinical approach taken in an adult psychology clinic in the U.K.'s National Health Service. The model identifies bottlenecks in the service, and provides results on how different staffing scenarios could alleviate challenges

Computational Design of β-Fluorinated Morphine Derivatives for pH-specific Binding

Opioids such as morphine are important pain-relieving drugs but also carry a risk of harmful side effects including addiction. Morphine is active in both healthy and inflamed tissue, however, decreasing the pKa of the biochemically-active amine group can promote selective binding in the more acidic conditions of inflamed tissue and reduce harmful side effects associated with opioids. Herein, we explore the impact of fluorination on the pKa of fluoromorphine derivatives to identify which will bind selectively in inflamed tissue. Theoretical pKa values are determined at the M06-2X(SMD)/aug-cc-pVDZ level of theory to calculate the ΔGaq role= presentation style= box-sizing: border-box; margin: 0px; padding: 0px; display: inline-block; line-height: normal; font-size: 16.2px; word-spacing: normal; overflow-wrap: normal; white-space: nowrap; float: none; direction: ltr; max-width: none; max-height: none; min-width: 0px; min-height: 0px; border: 0px; position: relative; \u3eΔGaq values for the amine deprotonation reactions

Experimental and theoretical evidence for molecular forces driving surface segregation in photonic colloidal assemblies

Surface segregation in binary colloidal mixtures offers a simple way to control both surface and bulk properties without affecting their bulk composition. Here, we combine experiments and coarse-grained molecular dynamics (CG-MD) simulations to delineate the effects of particle chemistry and size on surface segregation in photonic colloidal assemblies from binary mixtures of melanin and silica particles of size ratio (Dlarge/Dsmall) ranging from 1.0 to similar to 2.2. We find that melanin and/or smaller particles segregate at the surface of micrometer-sized colloidal assemblies (supraballs) prepared by an emulsion process. Conversely, no such surface segregation occurs in films prepared by evaporative assembly. CG-MD simulations explain the experimental observations by showing that particles with the larger contact angle (melanin) are enriched at the supraball surface regardless of the relative strength of particle-interface interactions, a result with implications for the broad understanding and design of colloidal particle assemblies

Changes in epithelial proportions and transcriptional state underlie major premenopausal breast cancer risks

The human breast undergoes lifelong remodeling in response to estrogen and progesterone, but hormone exposure also increases breast cancer risk. Here, we use single-cell analysis to identify distinct mechanisms through which breast composition and cell state affect hormone signaling. We show that prior pregnancy reduces the transcriptional response of hormone-responsive (HR+) epithelial cells, whereas high body mass index (BMI) reduces overall HR+ cell proportions. These distinct changes both impact neighboring cells by effectively reducing the magnitude of paracrine signals originating from HR+ cells. Because pregnancy and high BMI are known to protect against hormone-dependent breast cancer in premenopausal women, our findings directly link breast cancer risk with person-to-person heterogeneity in hormone responsiveness. More broadly, our findings illustrate how cell proportions and cell state can collectively impact cell communities through the action of cell-to-cell signaling networks

Modelling the accessibility of adult psychology services using discrete event simulation

With a growing number of people seeking treatment for mental health problems, mental health services are consequently coming under increased pressure resulting in longer waiting times and worsening of mental health problems. Service underfunding, overworked staff, and the looming threat of further demand due to the COVID-19 pandemic only add to the concerns. Hence it is imperative the efficiencies of these services are maximised to allow better access to quality treatment. We created a Discrete Event Simulation model to replicate the current clinical approach taken in an adult psychology clinic in the U.K.'s National Health Service. The model identifies bottlenecks in the service, and provides results on how different staffing scenarios could alleviate challenges

Human Immunodeficiency Virus (HIV)-Infected CCR6+ Rectal CD4+ T Cells and HIV Persistence On Antiretroviral Therapy.

BackgroundIdentifying where human immunodeficiency virus (HIV) persists in people living with HIV and receiving antiretroviral therapy is critical to develop cure strategies. We assessed the relationship of HIV persistence to expression of chemokine receptors and their chemokines in blood (n = 48) and in rectal (n = 20) and lymph node (LN; n = 8) tissue collected from people living with HIV who were receiving suppressive antiretroviral therapy.MethodsCell-associated integrated HIV DNA, unspliced HIV RNA, and chemokine messenger RNA were quantified by quantitative polymerase chain reaction. Chemokine receptor expression on CD4+ T cells was determined using flow cytometry.ResultsIntegrated HIV DNA levels in CD4+ T cells, CCR6+CXCR3+ memory CD4+ T-cell frequency, and CCL20 expression (ligand for CCR6) were highest in rectal tissue, where HIV-infected CCR6+ T cells accounted for nearly all infected cells (median, 89.7%). Conversely in LN tissue, CCR6+ T cells were infrequent, and there was a statistically significant association of cell-associated HIV DNA and RNA with CCL19, CCL21, and CXCL13 chemokines.ConclusionsHIV-infected CCR6+ CD4+ T cells accounted for the majority of infected cells in rectal tissue. The different relationships between HIV persistence and T-cell subsets and chemokines in rectal and LN tissue suggest that different tissue-specific strategies may be required to eliminate HIV persistence and that assessment of biomarkers for HIV persistence may not be generalizable between blood and other tissues