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A defining characteristic of individuals diagnosed with alcohol use disorder (AUD) is that negative outcomes related to drinking do not lead them to reduce their alcohol use. In rodent models of AUD, this characteristic has been studied by adding the bitter tastant quinine to an ethanol solution. In this study, we extended this approach to a nonhuman primate model in which the ability of quinine to decrease the choice of a 4% ethanol solution vs. water was measured. Five adult female rhesus monkeys with 7.3 years of experience drinking ethanol were given access to a 4% ethanol solution and water for 3 h per day. When ethanol choice was stable, a single quinine concentration (0.03-5.6 g /L) was added to the ethanol solution for 1 day until a quinine concentration-effect curve was generated. After determining the quinine concentration that reduced ethanol choice by half (the quinine EC 50 ), the relative reinforcing strength of ethanol was manipulated by adding quinine or sucrose to the water alternative depending on the monkey's baseline choice. Adding quinine to ethanol produced a concentration-dependent decrease in ethanol choice and intake. Importantly, water intake increased, indicating an effect on response allocation rather than simply a decrease in fluid consumption. Consistent with this conclusion, the addition of quinine or sucrose to the water alternative resulted in predictable increases and decreases, respectively, in ethanol choice. These studies establish a model of punishment of ethanol choice in nonhuman primates that can be used to understand the contextual, biologic and pharmacologic factors that influence sensitivity to the punishment of alcohol drinking.

Nonhuman primate models of alcohol use disorder (AUD) frequently utilize schedule-induced polydipsia to initiate ethanol drinking. Previous research has demonstrated that specific characteristics of drinking during the final phase of induction, in which monkeys consume 1.5 g/kg of ethanol per day, can predict whether monkeys become heavy or light drinkers when they subsequently have free access to ethanol (22 hours per day; Baker, Farro, Gonzales, Helms, & Grant, 2017; Grant et al., 2008). A monkey's position in the social dominance hierarchy is another factor associated with ethanol drinking in nonhuman primates; lower social status is associated with higher ethanol intakes. In the present study, characteristics of drinking during induction were measured in 12 male cynomolgus monkeys living in three established social groups (4 monkeys per group). All monkeys were induced to consume water, then increasing doses of ethanol (0.5, 1.0, and 1.5 g/kg) for 30 sessions per dose using a 300-s fixed-time schedule of food pellet delivery. Drinking sessions occurred five days per week and monkeys were group-housed on the other two days. Contrary to our hypothesis that subordinate monkeys would show characteristics of drinking during the last phase of induction that were predictive of later heavy drinking, no significant differences were observed between dominant and subordinate monkeys in any phase of induction. When ethanol availability was subsequently increased to 22 hours per day for 5 weeks, the intakes of subordinate- and dominant-ranked monkeys diverged, with higher intakes on average in subordinates. Several factors unique to the conditions of induction may have obscured any influence of social rank, including the limited duration of sessions and limited maximal ethanol intake. The data support the conclusion that the effects of social rank on ethanol consumption require unrestricted access to ethanol.

Most individuals with cocaine use disorder also use alcohol; however, little is known about the behavioural and pharmacological mechanisms that promote co-abuse. For example, although studies in humans and animals have documented that chronic use of either alcohol or cocaine alone decreases D2-like receptor (D2R) availability, effects of co-abuse of these substances on dopamine receptor function have not been characterized. These studies examined the effects of long-term cocaine self-administration in 12 male rhesus monkeys who also consumed either ethanol or an ethanol-free solution each day (n = 6 per group). Specifically, all monkeys self-administered cocaine (0.1 mg/kg per injection) 5 days per week in the morning. In the afternoon, six monkeys consumed 2.0 g/kg ethanol over 1 h to model binge drinking and six monkeys drank an ethanol-free solution. Assessment of D2R availability using positron emission tomography (PET) and [

Background Although most individuals with cocaine use disorder also abuse alcohol, little is known about the behavioral and pharmacological mechanisms that promote co-abuse. For example, it is unclear whether prior experience with alcohol renders individuals more sensitive to cocaine when it is subsequently experienced. Methods This study examined the effects of chronic ethanol consumption on subsequent cocaine reinforcement in rhesus monkeys. Six monkeys consumed 2.0 g/kg ethanol in a binge-drinking paradigm and 6 monkeys drank a non-alcoholic solution 5 days per week. After 9 months, each monkey’s sensitivity to acquiring cocaine self-administration was determined. Monkeys performed an operant response resulting in food pellet delivery under a fixed-ratio 30 schedule of reinforcement. Saline, then ascending doses of cocaine, were substituted for food pellets until a cocaine dose was reached at which the number of cocaine injections delivered differed significantly from saline injections delivered. Following acquisition, a complete cocaine dose-effect curve was generated to determine whether ethanol consumption altered the reinforcing potency of cocaine determined by calculating the ED50 of the ascending limb of each subject’s curve. Results Although individual variability was observed, the cocaine dose which initially served as a reinforcer did not differ between ethanol-drinking and control groups and, within the ethanol-drinking group, was not related to the amount of ethanol consumed. Moreover, the reinforcing potency of cocaine did not differ between groups. Conclusion Taken together, the data suggest that a history of binge-like alcohol consumption does not affect sensitivity to cocaine when it is subsequently first experienced.

A fundamental question for alcohol use disorder is how naïve brain networks are reorganized in response to the consumption of alcohol. The current study aimed to determine the progression of alcohol’s effect on functional brain networks during the transition from naïve, to early, to chronic consumption. Resting-state brain networks of six female monkeys were acquired using magnetoencephalography prior to alcohol exposure, after early exposure, and after free-access to alcohol using a well-established model of chronic heavy alcohol use. Functional brain network metrics were derived at each time point. Assortativity, average connection frequency, and number of gamma connections changed significantly over time. All metrics remained relatively stable from naïve to early drinking, and displayed significant changes following increased quantity of alcohol consumption. The assortativity coefficient was significantly less negative (p=.043), connection frequency increased (p=.03), and gamma connections increased (p=.034). Further, brain regions considered hubs (p=.037) and members of the Rich Club (p=.012) became less common across animals following the introduction of alcohol. The minimum degree of the Rich Club prior to alcohol exposure was significantly predictive of future free-access drinking (r=-.88, p

PURPOSE/OBJECTIVE(S) The role of cellular senescence in radiation induced pulmonary fibrosis (RIPF) is unknown. Furthermore, clearance of senescent cells (SCs) could be an effective therapeutic strategy; however, the identification and targeted removal of only senescent cells by senolytic drugs is difficult. We isolated a pure population of radiation induced senescent and non-senescent cells using tdTOMp16+ mice and examined induction of fibrosis in target cells. MATERIALS/METHODS A stromal cell line was established from explanted tdTOMp16+ mouse bone marrow. The tdTOMp16+ stromal cell line was irradiated to each of several doses by Cesium Gamma Cell dose rate 300 cGy/min including 1.0 Gy, 2.5 Gy, 5 Gy, and 7.5 Gy under growth conditions of either 50% or 100% confluence. The number and percent of senescent cells, by p16 promoter linked to the red fluorochrome biomarker was quantitated. Irradiated red, irradiated non-red, and non-irradiated cells were sorted and cultured as single cells in 96-well plates, then monitored for cell division over four weeks. The expression of senescence markers, p16 and p21, was evaluated by qPCR, and SA-β-gal by fluorogenic substrate. To examine the effect of senescent cells on a target fibrosis-prone C57BL/6 line, sorted irradiated red, irradiated non-red, and non-irradiated cells were placed on the top level of transwells, and after 2 weeks induction of biomarkers of fibrosis including Ctgf, TGF-β, collagen 1a, and collagen 3 was measured in target cells in the lower level by qPCR. RESULTS After 5 Gy irradiation at 50% cell density, ∼9% of tdTOMp16+ cells became senescent (stably red in color) after 10 days, thus, defining the optimal conditions. Then, in bulk cultures, red cells were sorted by fluorescence automated cell sorter (FACS) to a pure population of red tdTOMp16+ cells. When cultured as single cells, none of 960 irradiated red cells divided after 2 weeks, 137 of these cells remained intact, and assume large and flat morphology. In contrast, 50 of 800 non-red irradiated cells divided, and 104 of 560 non-irradiated control cells divided. There was significant detection of senescent cell markers including: SA-β-gal, p16, and p21 in irradiated sorted red cells compared to irradiated non-red cells (P = 0.0096, P < 0.0001 and P = 0.0001 respectively based on scoring of 1000 cells in triplicate experiments for SA-β-gal and analyses from three independent experiments). Induction of biomarkers of fibrosis Ctgf, TGF-β, collagen 1a, and collagen 3 in C57BL/6 stromal target cells was significant by irradiated red, but not irradiated non-red or non-irradiated cells (P = 0.037, P = 0.14, P = 0.015, and P = 0.0259). CONCLUSION The data indicate that sorted irradiated red senescent tdTOMp16 stromal cells can be isolated as a pure non-dividing population and induce fibrotic markers in target cells in non-contact transwell cultures. This unique system can now be used to define the mechanism of senescent cell-induced radiation fibrosis, and the effects of senolytic drugs.

Purpose/Objective(s) We delivered intraoral (gavage) of LR-IL-22 (Zhang, et al., In Vivo, 34: 139-150, 2020) prior to whole abdominal irradiation (WAI) of C57BL/6J mice and quantitated survival, intestinal barrier integrity, and levels of irradiation-induced inflammatory cytokines. We measured the effect on fractionated WAI of LR-IL-22 in transgenic C57BL/6J-MUC1 (human-MUC1) female mice with widespread intra-abdominal cisplatin-resistant ovarian cancer. Materials/Methods C57BL/6J mice were irradiated to 19.75 Gy WAI, then evaluated for the primary endpoint of improved 30-day survival. Fluorescent beads (F13083 FluoSpheres™ Polystyrene Microspheres, 1.0 μm, red fluorescent (580/605), for tracer studies) were administered intraorally three hours prior to sacrifice at days 2 or 5 after WAI, and blood was assayed for beads. Luminex assay of plasma and intestinal cells were also assayed at days 0, 1, 2, 3, and 5 after WAI for radiation-induced inflammatory cytokines. Murine ovarian cancer 2F8cis cells were injected intraperitoneally into female transgenic C57BL/6J-MUC1 mice (1 × 106 cells per mouse). Seventy-two hours later, mice were irradiated to 16 Gy WAI and followed for tumor growth. In a separate experiment, female mice harboring 2F8cis tumors were irradiated to 6 Gy WAI daily for 4 successive days. Overall survival was compared between groups: irradiation only, LR-IL-22 gavage three hours prior to each fraction, and/or weekly anti-PD-L1 antibody treatment. Results Mice receiving LR-IL-22 (109 bacteria in 100 µL of saline) 24-hours and 3-hours prior to a single fraction of 19.75 Gy WAI, and 24-hours following irradiation, showed improved survival and barrier integrity compared to those receiving control LR or IL-22 protein (P = 0.0167 or 0.0276, n = 15). LR-IL-22 gavage maintained intestinal barrier integrity and decreased levels of intestinal pro-inflammatory cytokines, including KC (CXCL1) (P = 0.002), and IFN- γ (P = 0.0024), as well as profibrotic plasma Eotaxin (CCL11) (P = 0.0088). In MUC1 transgenic female mice with tumors, nonirradiated mice had over 100 disseminated tumor nodules throughout the abdomen at day 10, while control WAI mice or those treated with intraoral LR-IL-22 had less than 10 nodules at day 10 (P = 0.0471); furthermore, LR-IL-22 treated mice showed reduced intestinal edema. C57BL/6J-MUC1 female mice with intra-abdominal 2F8cis tumor showed significantly improved 30-day survival by adding LR-IL-22 and anti-PD-L1 to 6 Gy × 4 WAI (P = 0.0004). Conclusion Intraoral LR-IL-22 prior to WAI protects the intestine from radiation-induced toxicity and facilitates fractionated therapeutic WAI to improve survival in cis-platinum resistant ovarian cancer. Author Disclosure D.F. Hamade: None. M. Epperly: None. R. Fisher: None. W. Hou: None. J.S. Greenberger: None.

Alcohol use disorder (AUD) persists as a devastating public health problem; widely effective pharmacological treatments are needed. Evidence from rodent models suggests that stimulating brain receptors for the neuropeptide nociceptin/orphanin FQ (NOP) can decrease ethanol drinking. We characterized the effects of the mu opioid peptide (MOP) receptor agonist buprenorphine and the buprenorphine analog (2S)-2-[(5R,6R,7R,14S)-N-cyclopropylmethyl-4,5-epoxy-6,14-ethano-3-hydroxy-6 methoxymorphinan-7-yl]-3,3-dimethylpentan-2-ol (BU08028), which stimulates MOP and NOP receptors, in a translational nonhuman primate model of AUD. Rhesus monkeys drank a 4% ethanol solution 6 h per day, 5 days per week via an operant behavioral panel in their home cages. To assess behavioral selectivity, monkeys responded via a photo-optic switch to earn food pellets. After characterizing the acute effects of BU08028 (0.001–0.01 mg/kg, i.m.) and buprenorphine (0.003–0.056 mg/kg, i.m.), the drugs were administered chronically using a model of pharmacotherapy assessment that incorporates clinical aspects of AUD and treatment. Acutely, both drugs decreased ethanol drinking at doses that did not affect food-maintained responding. During chronic treatment, effects of BU08028 and buprenorphine were maintained for several weeks without development of tolerance or emergence of adverse effects. BU08028 was ~0.5 and 1.0 log units more potent in acute and chronic studies, respectively. The selective NOP receptor agonist SCH 221510 also selectively decreased ethanol intakes when given acutely (0.03–1.0 mg/kg, i.m.), whereas the MOP antagonist naltrexone (1.7–5.6 mg/kg, i.m.) decreased both ethanol intake and food pellets delivered. These data demonstrate that bifunctional MOP/NOP agonists, which may have therapeutic advantages to MOP-selective drugs, can decrease alcohol drinking in nonhuman primates.

Dysregulation of microtubules is commonly associated with several psychiatric and neurological disorders, including addiction and Alzheimer’s disease. Imaging of microtubules in vivo using positron emission tomography (PET) could provide valuable information on their role in the development of disease pathogenesis and aid in improving therapeutic regimens. We developed [11C]MPC-6827, the first brain-penetrating PET radiotracer to image microtubules in vivo in the mouse brain. The aim of the present study was to assess the reproducibility of [11C]MPC-6827 PET imaging in non-human primate brains. Two dynamic 0–120 min PET/CT imaging scans were performed in each of four healthy male cynomolgus monkeys approximately one week apart. Time activity curves (TACs) and standard uptake values (SUVs) were determined for whole brains and specific regions of the brains and compared between the “test” and “retest” data. [11C]MPC-6827 showed excellent brain uptake with good pharmacokinetics in non-human primate brains, with significant correlation between the test and retest scan data (r = 0.77, p = 0.023). These initial evaluations demonstrate the high translational potential of [11C]MPC-6827 to image microtubules in the brain in vivo in monkey models of neurological and psychiatric diseases.

We show that a spacecraft launched from Earth towards Mars following a Hohmann minimum energy transfer trajectory has a strong tendency to remain well-connected magnetically to Earth, in the early phase of the transfer, or to Mars in the late phase, via the Parker spiral magnetic field. On the return trip, the spacecraft would remain reasonably well-connected magnetically first to Mars and later to Earth. Moreover, good magnetic connectivity occurs on all Hohmann transfers between neighboring planets in the inner solar system out to Mars. We call this hitherto unnamed circumstance the Hohmann–Parker effect. We show consequences of the effect by means of simultaneous cosmic radiation proxy observations made near Earth, near Mars, and at the Mars Science Laboratory on the transfer from Earth to Mars in 2011/2012. We support the observations with simulations of the large-scale magnetic field of the inner heliosphere during this period and compare the results with our predictions. The implications of the Hohmann–Parker effect are discussed. & 2013 Published by Elsevier Ltd.

Senescence is an irreversible cell cycle arrest induced by various triggers, including aging and irradiation. Fanconi Anemia (FA) is a genetic disorder associated with defects in 22 proteins in the scaffold DNA double strand break repair. FA mice develop anemia and marrow failure and have been considered as a potential model for accelerated aging. Fancd2-/- murine bone marrow (BM) stromal cell lines are radiosensitive in clonogenic survival curves compared to wild type (Berhane et al, Radiat Res, 2014). We tested the Fanca-/- mouse model for irradiation induced senescence. 129Sv Fanca+/+ and Fanca-/- BM stromal cell lines were irradiated to 5Gy, then assayed for senescence at various timepoints. Cells were stained with a chromogenic beta-galactosidase assay. Cells were also stained by immunofluorescence (IF) to determine percent of cells positive for p16 and p21. For total body irradiation (TBI) studies, 129Sv Fanca+/+ and Fanca-/- mice were given 7Gy. Organs were harvested at Day 7, then assayed for senescence. Statistical analysis was carried out using student's t-test. Baseline levels of beta-gal positive Fanca-/- BM stromal cells were not significantly different from Fanca+/+ (respectively, 0.88% ± 0.22% vs 0.74% ± 0.23%). Fanca-/- and Fanca+/+ IF also showed no significant differences in baseline p16 levels (4.98%±2.5 vs 14.37%± 4.06%) and p21 levels (14.57% ± 7.61% vs. 11.7% ± 3.48%). In contrast, Fanca-/- cells showed significantly higher beta-gal staining compared to Fanca+/+ at days 1, 3, and 5 after irradiation (p=0.0042, p Citation Format: Aranee P. Sivananthan, Xichen Zhang, Wen Hou, Donna Shields, Renee Fisher, Michael Epperly, Joel S. Greenberger. Increased irradiation-induced senescence in Fanconi anemia (FA) mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 842.

A unique rapid response system was designed to provide social, psychological, emotional, and professional support for health care providers who are "second victims"--traumatized as a result of their involvement in an unanticipated adverse event, medical error, or patient-related injury.

IBEX provides the observations needed for detailed modeling and in-depth understanding of the interstellar interaction (McComas et al. in Physics of the Outer Heliosphere, Third Annual IGPP Conference, pp. 162–181, 2004; Space Sci. Rev., 2009a, this issue). From mission design to launch and acquisition, this goal drove all flight system development. This paper describes the management, design, testing and integration of IBEX’s flight system, which successfully launched from Kwajalein Atoll on October 19, 2008. The payload is supported by a simple, Sun-pointing, spin-stabilized spacecraft with no deployables. The spacecraft bus consists of the following subsystems: attitude control, command and data handling, electrical power, hydrazine propulsion, RF, thermal, and structures. A novel 3-step orbit approach was employed to put IBEX in its highly elliptical, 8-day final orbit using a Solid Rocket Motor, which provided large delta-V after IBEX separated from the Pegasus launch vehicle; an adapter cone, which interfaced between the SRM and Pegasus; Motorized Lightbands, which performed separation from the Pegasus, ejection of the adapter cone, and separation of the spent SRM from the spacecraft; a ShockRing isolation system to lower expected launch loads; and the onboard Hydrazine Propulsion System. After orbit raising, IBEX transitioned from commissioning to nominal operations and science acquisition. At every phase of development, the Systems Engineering and Mission Assurance teams supervised the design, testing and integration of all IBEX flight elements.

This article presents a model for determining the composition of a United States peacekeeping force deployed to Bosnia. The model, which is loosely based on Quality Function Deployment (QFD), uses three matrices in series to relate the interests of stakeholders involved in the conflict to the composition of the US force deployed in Bosnia. In addition, we have used AHP to determine the weighted importance of various stakeholders and the intensity of the relationship between the variables involved in the model. The recommendations of the model are more or less validated by the actual force composition currently deployed in Bosnia. The advantage of the model is to add “fine tuning” and precision to an otherwise ad hoc decision making process concerning the deployment of armed forces. The model can be used in other force composition planning scenarios.

The Radiation Assessment Detector (RAD) on the Mars Science Laboratory (MSL) is an energetic particle detector designed to measure a broad spectrum of energetic particle radiation. It will make the first-ever direct radiation measurements on the surface of Mars, detecting galactic cosmic rays, solar energetic particles, secondary neutrons, and other secondary particles created both in the atmosphere and in the Martian regolith. The radiation environment on Mars, both past and present, may have implications for habitability and the ability to sustain life. Radiation exposure is also a major concern for future human missions. The RAD instrument combines charged- and neutral-particle detection capability over a wide dynamic range in a compact, low-mass, low-power instrument. These capabilities are required in order to measure all the important components of the radiation environment. RAD consists of the RAD Sensor Head (RSH) and the RAD Electronics Box (REB) integrated together in a small, compact volume. The RSH contains a solid-state detector telescope with three silicon PIN diodes for charged particle detection, a thallium doped Cesium Iodide scintillator, plastic scintillators for neutron detection and anti-coincidence shielding, and the front-end electronics. The REB contains three circuit boards, one with a novel mixed-signal ASIC for processing analog signals and an associated control FPGA, another with a second FPGA to communicate with the rover and perform onboard analysis of science data, and a third board with power supplies and power cycling or “sleep”-control electronics. The latter enables autonomous operation, independent of commands from the rover. RAD is a highly capable and highly configurable instrument that paves the way for future compact energetic particle detectors in space.

In contrast to traditional drugs that generally act by altering existing gene product function, gene therapy aims to target the root cause of the disease by altering the genetic makeup of the cell to treat the disease. Researchers have adapted several classes of viruses as gene-transfer vectors, taking advantage of natural viral mechanisms designed to efficiently and effectively deliver DNA to the host-cell nucleus. Among these, the human herpesviruses are excellent candidate vectors for a variety of applications. Herpes simplex virus type 1 (HSV-1) is a particularly attractive gene-transfer vehicle because natural infection in humans includes a latent state in which the viral genome persists in a nonintegrated form without causing disease in an immune-competent host. HSV-1 is a large DNA virus with a broad host range that can be engineered to accommodate multiple or large therapeutic transgenes (4). HSV vectors may be generally useful for gene transfer to a variety of tissues in which short-term or extended transgene expression of therapeutic transgenes achieve a therapeutic effect. We have used therapeutic vectors to successfully treat human disease models in animals, including cancer, Parkinson's disease, and nerve damage (5-10).

This paper presents a radiation hardened digital oscilloscope tailored for space applications. The waveform capture system (WCS) was designed as a data acquisition system for a time of flight instrument on the European Rosetta cometary mission. The WCS is a radiation hardened low power, single board solution, providing 11 bits of accuracy, sub-nanosecond resolution, and complete command and data handling. This paper details the design and evolution of the WCS, as well as presenting results from recent testing of the engineering qualification module with the time of flight instrument.