Corticosterone Regulates Both Naturally Occurring and Cocaine‐Induced Dopamine Signaling by Selectively Decreasing Dopamine Uptake

Stressful and aversive events promote maladaptive reward‐seeking behaviors such as drug addiction by acting, in part, on the mesolimbic dopamine system. Using animal models, data from our laboratory and others show that stress and cocaine can interact to produce a synergistic effect on reward circuitry. This effect is also observed when the stress hormone corticosterone is administered directly into the nucleus accumbens (NAc), indicating that glucocorticoids act locally in dopamine terminal regions to enhance cocaine\u27s effects on dopamine signaling. However, prior studies in behaving animals have not provided mechanistic insight. Using fast‐scan cyclic voltammetry, we examined the effect of systemic corticosterone on spontaneous dopamine release events (transients) in the NAc core and shell in behaving rats. A physiologically relevant systemic injection of corticosterone (2 mg/kg i.p.) induced an increase in dopamine transient amplitude and duration (both voltammetric measures sensitive to decreases in dopamine clearance), but had no effect on the frequency of transient release events. This effect was compounded by cocaine (2.5 mg/kg i.p.). However, a second experiment indicated that the same injection of corticosterone had no detectable effect on the dopaminergic encoding of a palatable natural reward (saccharin). Taken together, these results suggest that corticosterone interferes with naturally occurring dopamine uptake locally, and this effect is a critical determinant of dopamine concentration specifically in situations in which the dopamine transporter is pharmacologically blocked by cocaine

Carbon isotopic signature of coal-derived methane emissions to the atmosphere: from coalification to alteration

Currently, the atmospheric methane burden is rising rapidly, but the extent to which shifts in coal production contribute to this rise is not known. Coalbed methane emissions into the atmosphere are poorly characterised, and this study provides representative δ13CCH4 signatures of methane emissions from specific coalfields. Integrated methane emissions from both underground and opencast coal mines in the UK, Australia and Poland were sampled and isotopically characterised. Progression in coal rank and secondary biogenic production of methane due to incursion of water are suggested as the processes affecting the isotopic composition of coal-derived methane. An averaged value of −65 ‰ has been assigned to bituminous coal exploited in open cast mines and of −55 ‰ in deep mines, whereas values of −40 and −30 ‰ can be allocated to anthracite opencast and deep mines respectively. However, the isotopic signatures that are included in global atmospheric modelling of coal emissions should be region- or nation-specific, as greater detail is needed, given the wide global variation in coal type

Small PARP inhibitor PJ-34 induces cell cycle arrest and apoptosis of adult T-cell leukemia cells

A grant from the One-University Open Access Fund at the University of Kansas was used to defray the author’s publication fees in this Open Access journal. The Open Access Fund, administered by librarians from the KU, KU Law, and KUMC libraries, is made possible by contributions from the offices of KU Provost, KU Vice Chancellor for Research & Graduate Studies, and KUMC Vice Chancellor for Research. For more information about the Open Access Fund, please see http://library.kumc.edu/authors-fund.xml.Background HTLV-I is associated with the development of an aggressive form of lymphocytic leukemia known as adult T-cell leukemia/lymphoma (ATLL). A major obstacle for effective treatment of ATLL resides in the genetic diversity of tumor cells and their ability to acquire resistance to chemotherapy regimens. As a result, most patients relapse and current therapeutic approaches still have limited long-term survival benefits. Hence, the development of novel approaches is greatly needed. Methods In this study, we found that a small molecule inhibitor of poly (ADP-ribose) polymerase (PARP), PJ-34, is very effective in activating S/G2M cell cycle checkpoints, resulting in permanent cell cycle arrest and reactivation of p53 transcription functions and caspase-3-dependent apoptosis of HTLV-I-transformed and patient-derived ATLL tumor cells. We also found that HTLV-I-transformed MT-2 cells are resistant to PJ-34 therapy associated with reduced cleaved caspase-3 activation and increased expression of RelA/p65. Conclusion Since PJ-34 has been tested in clinical trials for the treatment of solid tumors, our results suggest that some ATLL patients may be good candidates to benefit from PJ-34 therapy

Sensory Communication

Contains table of contents for Section 2, an introduction and reports on twelve research projects.National Institutes of Health Grant 5 R01 DC00117National Institutes of Health Contract 2 P01 DC00361National Institutes of Health Grant 5 R01 DC00126National Institutes of Health Grant R01-DC00270U.S. Air Force - Office of Scientific Research Contract AFOSR-90-0200National Institutes of Health Grant R29-DC00625U.S. Navy - Office of Naval Research Grant N00014-88-K-0604U.S. Navy - Office of Naval Research Grant N00014-91-J-1454U.S. Navy - Office of Naval Research Grant N00014-92-J-1814U.S. Navy - Naval Training Systems Center Contract N61339-93-M-1213U.S. Navy - Naval Training Systems Center Contract N61339-93-C-0055U.S. Navy - Naval Training Systems Center Contract N61339-93-C-0083U.S. Navy - Office of Naval Research Grant N00014-92-J-4005U.S. Navy - Office of Naval Research Grant N00014-93-1-119

The severity of pandemic H1N1 influenza in the United States, from April to July 2009: A Bayesian analysis

Background: Accurate measures of the severity of pandemic (H1N1) 2009 influenza (pH1N1) are needed to assess the likely impact of an anticipated resurgence in the autumn in the Northern Hemisphere. Severity has been difficult to measure because jurisdictions with large numbers of deaths and other severe outcomes have had too many cases to assess the total number with confidence. Also, detection of severe cases may be more likely, resulting in overestimation of the severity of an average case. We sought to estimate the probabilities that symptomatic infection would lead to hospitalization, ICU admission, and death by combining data from multiple sources. Methods and Findings: We used complementary data from two US cities: Milwaukee attempted to identify cases of medically attended infection whether or not they required hospitalization, while New York City focused on the identification of hospitalizations, intensive care admission or mechanical ventilation (hereafter, ICU), and deaths. New York data were used to estimate numerators for ICU and death, and two sources of data - medically attended cases in Milwaukee or self-reported influenza-like illness (ILI) in New York - were used to estimate ratios of symptomatic cases to hospitalizations. Combining these data with estimates of the fraction detected for each level of severity, we estimated the proportion of symptomatic patients who died (symptomatic case-fatality ratio, sCFR), required ICU (sCIR), and required hospitalization (sCHR), overall and by age category. Evidence, prior information, and associated uncertainty were analyzed in a Bayesian evidence synthesis framework. Using medically attended cases and estimates of the proportion of symptomatic cases medically attended, we estimated an sCFR of 0.048% (95% credible interval [CI] 0.026%-0.096%), sCIR of 0.239% (0.134%-0.458%), and sCHR of 1.44% (0.83%-2.64%). Using self-reported ILI, we obtained estimates approximately 7-96lower. sCFR and sCIR appear to be highest in persons aged 18 y and older, and lowest in children aged 5-17 y. sCHR appears to be lowest in persons aged 5-17; our data were too sparse to allow us to determine the group in which it was the highest. Conclusions: These estimates suggest that an autumn-winter pandemic wave of pH1N1 with comparable severity per case could lead to a number of deaths in the range from considerably below that associated with seasonal influenza to slightly higher, but with the greatest impact in children aged 0-4 and adults 18-64. These estimates of impact depend on assumptions about total incidence of infection and would be larger if incidence of symptomatic infection were higher or shifted toward adults, if viral virulence increased, or if suboptimal treatment resulted from stress on the health care system; numbers would decrease if the total proportion of the population symptomatically infected were lower than assumed.published_or_final_versio

Histone Deacetylase Inhibitors Selectively Target Homology Dependent DNA Repair Defective Cells and Elevate Non-Homologous Endjoining Activity

Background: We have previously used the ATAD5-luciferase high-throughput screening assay to identify genotoxic compounds with potential chemotherapeutic capabilities. The successful identification of known genotoxic agents, including the histone deacetylase inhibitor (HDACi) trichostatin A (TSA), confirmed the specificity of the screen since TSA has been widely studied for its ability to cause apoptosis in cancer cells. Because many cancers have acquired mutations in DNA damage checkpoints or repair pathways, we hypothesized that these cancers may be susceptible to treatments that target compensatory pathways. Here, we used a panel of isogenic chicken DT40 B lymphocyte mutant and human cell lines to investigate the ability of TSA to define selective pathways that promote HDACi toxicity. Results: HDACi induced a DNA damage response and reduced viability in all repair deficient DT40 mutants although ATM-nulls were least affected. The most dramatic sensitivity was observed in mutants lacking the homology dependent repair (HDR) factor BLM or the non-homologous end-joining (NHEJ) and HDR factors, KU/RAD54, suggesting an involvement of either HDR or NHEJ in HDACi-induced cell death. To extend these findings, we measured the frequencies of HDR and NHEJ after HDACi treatment and monitored viability in human cell lines comparably deficient in HDR or NHEJ. Although no difference in HDR frequency was observed between HDACi treated and untreated cells, HDR-defective human cell lines were clearly more sensitive than wild type. Unexpectedly, cells treated with HDACis showed a significantly elevated NHEJ frequency. Conclusions: HDACi targeting drugs induced significant increases in NHEJ activity in human cell lines but did not alter HDR frequency. Moreover, HDR is required for cellular resistance to HDACi therapy; therefore, NHEJ does not appear to be a critical axis for HDACi resistance. Rather, HDACi compounds induced DNA damage, most likely double strand breaks (DSBs), and HDR proficiency is correlated with cell survivalclose4

Optopneumatic Detector with Platinum Flow Sensor

In optopneumatic detectors, operating on principle of the gaseous infrared detectors, the radiation absorbed in the gas is changed into pressure fluctuation, followed by periodic flow of the gas between detector chambers. This flow is usually measured by means of hot-wire or hot-film anemometers. Their parameters in a great measure determine the quality of the whole detector. The flow sensor used in optopneumatic detectors should have short time constant, high sensitivity, possibility to distinguish the flow direction, and high chemical resistance to the gas which the detector is filled with. To meet these requirements, micro-electro-mechanical system flowmeter consisting of two platinum hot films placed in series in the flow direction was made. Platinum film of 0.3 μm thickness was deposited by magnetron spattering on thin membrane, which was composed of polysilicon substrate (0.5 μm) and two $Si_{3}N_{4}$ layers with thickness of 0.1 μm. The obtained platinum elements have resistance of 32 Ω and temperature coefficient of resistance of 2.31× $10^{-3}$/°C. Hot film does not change its parameters up to 350°C, whereas typical working temperature of such films ranged from 150 to 200°C. Anemometer characteristics and voltage-current dependences were determined in this work. The linear range of operation from 0 to 10 ml/min and sensitivity suitable for optopneumatic detectors were found. The time constant of the flowmeter is equal to 11 ms (95% of final signal), that enables the detector to operate with frequency up to 100 Hz. The flowmeters were applied in detectors filled with sulphur dioxide and were tested for six months at temperature of hot-film about 150°C. During that time no changes of their parameters were observed

Mobile GC-MS devices

Jednym z kierunków rozwoju analizy chemicznej–szczególnie w przypadku zanieczyszczeń środowiska – jest dążenie do wykonywania analiz w miejscach, w których istnieje potrzeba wykrycia substancji chemicznych, ich identyfikacji i oznaczenia ilościowego. Skutkuje to coraz większym zainteresowaniem przyrządami przenośnymi lub przewoźnymi, w których skład wchodzi chromatograf gazowy. Przyrządy mobilne, przeznaczone do stosowania poza laboratorium, charakteryzują się mniejszymi wymiarami i masami niż chromatografy laboratoryjne. Są to przyrządy przystosowane do przewożenia w samochodach lub takie, które może przenosić jedna osoba. W niniejszym przeglądzie opisujemy mobilne przyrządy stanowiące połączenie chromatografu gazowego ze spektrometrem mas. Aby umożliwić wykonywanie analiz za pomocą przyrządów GC-MS w terenie, konieczne jest przystosowanie kolumny chromatograficznej do małych wymiarów przyrządu i do pracy w reżimie szybkiej chromatografii gazowej, zminiaturyzowanie detektorów mas, a także dopasowanie sposobu zaopatrzenia w energię elektryczną oraz gazy nośne do warunków polowych. W pracy tej podano przy- kłady komercyjnie dostępnych mobilnych przyrządów GC-MS wraz z ich zastosowaniami.One of the directions of development of chemical analysis is the pursuit of analysis, especially in the case of environmental pollution, where is a need to detect, identify and quantify chemicals. This results in a growing interest in portable or mobile devices, which include a gas chromatographs. Out-of-laboratory mobile instruments are characterized by smaller dimensions and masses than laboratory chromatographs. These are instruments carried in cars or which can be carried by one person. In this review we describe mobile devices that combine gas chromatograph with mass spectrome- ter. The process of transferring GC-MS analytical capabilities into the field consists of adjusting the chromatographic column to small dimensions of the instrument and working as fast chromatography, miniaturization of mass detectors as well as adjusting the way of supplying electricity and carrier gases to field conditions. This work also presents some examples of commercially available GC-MS mobile devices and their applications