A plastic scintillator and HPGe ß-γ coincidence detection system.

A network of specialist laboratories support the International Monitoring System (IMS) of the Comprehensive Nuclear-Test-Ban Treaty (CTBT) with re-measurements of radionuclide samples, including xenon gas. The measurement of four xenon fission product radionuclides (133Xe, 135Xe, 131mXe and 133mXe) can be used to detect an underground nuclear explosion. Laboratories use a range of techniques to measure the radionuclides, including beta-gamma (ß-γ) coincidence spectrometry. These highly-sensitive measurements are capable of detecting concentrations of down to 500 atoms of 133Xe in a few cm3 of xenon. In some detector systems, detection of the metastable isomers (131mXe and 133mXe) can be more challenging due to interferences between the signatures of different radionuclides. Recent work has shown that using high-purity Germanium (HPGe) high-resolution gamma detectors, these interferences can be reduced, lowering the dependence of the detection limits on radionuclide sample isotopic composition. One downside of these detectors is the reduction in detection efficiency, which impacts the overall detection sensitivity; so assessing different detector systems is a priority for radionuclide laboratories. This work presents a coincidence detector system comprising of a plastic scintillator gas cell and a large-crystal high-purity germanium detector. The energy resolution, coincidence detection efficiency, MDA and interference factors are determined from measurements of synthetic radioxenon gas samples.

Subunit-selective PI3-kinase control of action strategies in the medial prefrontal cortex.

PI3-kinase (PI3K) is an intracellular signaling complex that is stimulated upon cocaine exposure and linked with the behavioral consequences of cocaine. We recently genetically silenced the PI3K p110ß subunit in the medial prefrontal cortex following repeated cocaine in mice, reinstating the capacity of these mice to engage in prospective goal-seeking behavior. In the present short report, we address two follow-up hypotheses: 1) The control of decision-making behavior by PI3K p110ß is attributable to neuronal signaling, and 2) PI3K p110ß in the healthy (i.e., drug-naïve) medial prefrontal cortex has functional consequences in the control of reward-related decision-making strategies. In Experiment 1, we found that silencing neuronal p110ß improved action flexibility following cocaine. In Experiment 2, we reduced PI3K p110ß in drug-naïve mice that were extensively trained to respond for food reinforcers. Gene silencing caused mice to abandon goal-seeking strategies, unmasking habit-based behaviors that were propelled by interactions with the nucleus accumbens. Thus, PI3K control of goal-directed action strategies appears to act in accordance with an inverted U-shaped function, with "too much" (following cocaine) or "too little" (following p110ß subunit silencing) obstructing goal seeking and causing mice to defer to habit-like response sequences.

Third international challenge to model the medium- to long-range transport of radioxenon to four Comprehensive Nuclear-Test-Ban Treaty monitoring stations.

In 2015 and 2016, atmospheric transport modeling challenges were conducted in the context of the Comprehensive Nuclear-Test-Ban Treaty (CTBT) verification, however, with a more limited scope with respect to emission inventories, simulation period and number of relevant samples (i.e., those above the Minimum Detectable Concentration (MDC)) involved. Therefore, a more comprehensive atmospheric transport modeling challenge was organized in 2019. Stack release data of Xe-133 were provided by the Institut National des Radioéléments/IRE (Belgium) and the Canadian Nuclear Laboratories/CNL (Canada) and accounted for in the simulations over a three (mandatory) or six (optional) months period. Best estimate emissions of additional facilities (radiopharmaceutical production and nuclear research facilities, commercial reactors or relevant research reactors) of the Northern Hemisphere were included as well. Model results were compared with observed atmospheric activity concentrations at four International Monitoring System (IMS) stations located in Europe and North America with overall considerable influence of IRE and/or CNL emissions for evaluation of the participants' runs. Participants were prompted to work with controlled and harmonized model set-ups to make runs more comparable, but also to increase diversity. It was found that using the stack emissions of IRE and CNL with daily resolution does not lead to better results than disaggregating annual emissions of these two facilities taken from the literature if an overall score for all stations covering all valid observed samples is considered. A moderate benefit of roughly 10% is visible in statistical scores for samples influenced by IRE and/or CNL to at least 50% and there can be considerable benefit for individual samples. Effects of transport errors, not properly characterized remaining emitters and long IMS sampling times (12-24 h) undoubtedly are in contrast to and reduce the benefit of high-quality IRE and CNL stack data. Complementary best estimates for remaining emitters push the scores up by 18% compared to just considering IRE and CNL emissions alone. Despite the efforts undertaken the full multi-model ensemble built is highly redundant. An ensemble based on a few arbitrary runs is sufficient to model the Xe-133 background at the stations investigated. The effective ensemble size is below five. An optimized ensemble at each station has on average slightly higher skill compared to the full ensemble. However, the improvement (maximum of 20% and minimum of 3% in RMSE) in skill is likely being too small for being exploited for an independent period.

A molecularly integrated amygdalo-fronto-striatal network coordinates flexible learning and memory.

Behavioral flexibility-that is, the ability to deviate from established behavioral sequences-is critical for navigating dynamic environments and requires the durable encoding and retrieval of new memories to guide future choice. The orbitofrontal cortex (OFC) supports outcome-guided behaviors. However, the coordinated neural circuitry and cellular mechanisms by which OFC connections sustain flexible learning and memory remain elusive. Here we demonstrate in mice that basolateral amygdala (BLA)→OFC projections bidirectionally control memory formation when familiar behaviors are unexpectedly not rewarded, whereas OFC→dorsomedial striatum (DMS) projections facilitate memory retrieval. OFC neuronal ensembles store a memory trace for newly learned information, which appears to be facilitated by circuit-specific dendritic spine plasticity and neurotrophin signaling within defined BLA-OFC-DMS connections and obstructed by cocaine. Thus, we describe the directional transmission of information within an integrated amygdalo-fronto-striatal circuit across time, whereby novel memories are encoded by BLA→OFC inputs, represented within OFC ensembles and retrieved via OFC→DMS outputs during future choice.

Next-generation particulate monitoring.

Operated by the Comprehensive Nuclear-Test-Ban Treaty Organisation, the International Monitoring System is used by almost 200 nations to monitor for nuclear weapons tests. The IMS is still under development, and the Comprehensive Nuclear-Test-Ban Treaty has not yet entered into force, however the radionuclide component has proved instrumental in radically changing both nuclear verification science and researchers' understanding of the dynamic global radiation background. After more than 20 years, the network is mostly complete, however the technology utilised for the particulate monitoring component remains practically the same, despite a number of laboratories developing coincidence systems that can offer orders of magnitude improvements in detection sensitivity and reliability. This paper describes the status of the technology, and the advantages of implementing this within the International Monitoring System. Furthermore, the performance of a prototype system developed by the Comprehensive Nuclear-Test-Ban Treaty Organisation is presented, and the implications of introducing this technology considered.

Brain systems in cocaine abstinence-induced anxiety-like behavior in rodents: A review.

Cocaine use disorder (CUD) is a significant public health issue that generates substantial personal, familial, and economic burdens. Still, there are no FDA-approved pharmacotherapies for CUD. Cocaine-dependent individuals report anxiety during withdrawal, and alleviation of anxiety and other negative affective states may be critical for maintaining drug abstinence. However, the neurobiological mechanisms underlying abstinence-related anxiety in humans or anxiety-like behavior in rodents are not fully understood. This review summarizes investigations regarding anxiety-like behavior in mice and rats undergoing cocaine abstinence, as assessed using four of the most common anxiety-related assays: the elevated plus (or its derivative, the elevated zero) maze, open field test, light-dark transition test, and defensive burying task. We first summarize available evidence that cocaine abstinence generates anxiety-like behavior that persists throughout protracted abstinence. Then, we examine investigations concerning neuropeptide, neurotransmitter, and neuromodulator systems in cocaine abstinence-induced anxiety-like behavior. Throughout, we discuss how differences in sex, rodent strain, cocaine dose and dosing strategy and abstinence duration interact to generate anxiety-like behavior.

The PI3-Kinase p110ß Isoform Controls Severity of Cocaine-Induced Sequelae and Alters the Striatal Transcriptome.

BACKGROUND: The PI3-kinase (PI3K) complex is a well-validated target for mitigating cocaine-elicited sequelae, but pan-PI3K inhibitors are not viable long-term treatment options. The PI3K complex is composed of p110 catalytic and regulatory subunits, which can be individually manipulated for therapeutic purposes. However, this possibility has largely not been explored in behavioral contexts. METHODS: Here, we inhibited PI3K p110ß in the medial prefrontal cortex (mPFC) of cocaine-exposed mice. Behavioral models for studying relapse, sensitization, and decision-making biases were paired with protein quantification, RNA sequencing, and cell type-specific chemogenetic manipulation and RNA quantification to determine whether and how inhibiting PI3K p110ß confers resilience to cocaine. RESULTS: Viral-mediated PI3K p110ß silencing reduced cue-induced reinstatement of cocaine seeking by half, blocked locomotor sensitization, and restored mPFC synaptic marker content after exposure to cocaine. Cocaine blocked the ability of mice to select actions based on their consequences, and p110ß inhibition restored this ability. Silencing dopamine D2 receptor-expressing excitatory mPFC neurons mimicked cocaine, impairing goal-seeking behavior, and again, p110ß inhibition restored goal-oriented action. We verified the presence of p110ß in mPFC neurons projecting to the dorsal striatum and orbitofrontal cortex and found that inhibiting p110ß in the mPFC altered the expression of functionally defined gene clusters within the dorsal striatum and not orbitofrontal cortex. CONCLUSIONS: Subunit-selective PI3K silencing potently mitigates drug seeking, sensitization, and decision-making biases after exposure to cocaine. We suggest that inhibiting PI3K p110ß provides neuroprotection against cocaine by triggering coordinated corticostriatal adaptations.

Improving the sensitivity and reliability of radionuclide measurements at remote international monitoring stations.

The Comprehensive Nuclear-Test-Ban Treaty is supported by a global network of monitoring stations that perform high-resolution gamma-spectrometry on air filter samples. The UK CTBT Radionuclide Laboratory has utilised cosmic veto systems to improve the sensitivity of measurements since 2010. During this study, a second detector system (with a cosmic veto) was deployed at the CTBT IMS station RN67, alongside the standard detector. This is an incredibly remote IMS station on the island of St Helena in the South Atlantic. A duplicate system was also tested at AWE to benchmark the remote systems performance. The cosmic veto system improved detection sensitivities by up to 10% across a range of radionuclides. As a system to re-measure samples 7 days after the primary measurement, detection sensitivities were improved by an order of magnitude, allowing a potentially crucial confirmation of signatures when timely transport to a laboratory is not feasible. Utilising the second detector in coincidence with the primary detector system (which would require reengineering of the shield), sensitivity improvements of up to two orders of magnitude can be achieved. These improvements are maintained even when the measurement takes place without any decay, potentially allowing a highly sensitive treaty measurement within 2 h of the end of collection.

Involvement of the rodent prelimbic and medial orbitofrontal cortices in goal-directed action: A brief review.

Goal-directed action refers to selecting behaviors based on the expectation that they will be reinforced with desirable outcomes. It is typically conceptualized as opposing habit-based behaviors, which are instead supported by stimulus-response associations and insensitive to consequences. The prelimbic prefrontal cortex (PL) is positioned along the medial wall of the rodent prefrontal cortex. It is indispensable for action-outcome-driven (goal-directed) behavior, consolidating action-outcome relationships and linking contextual information with instrumental behavior. In this brief review, we will discuss the growing list of molecular factors involved in PL function. Ventral to the PL is the medial orbitofrontal cortex (mOFC). We will also summarize emerging evidence from rodents (complementing existing literature describing humans) that it too is involved in action-outcome conditioning. We describe experiments using procedures that quantify responding based on reward value, the likelihood of reinforcement, or effort requirements, touching also on experiments assessing food consumption more generally. We synthesize these findings with the argument that the mOFC is essential to goal-directed action when outcome value information is not immediately observable and must be recalled and inferred.

Reward-Related Expectations Trigger Dendritic Spine Plasticity in the Mouse Ventrolateral Orbitofrontal Cortex.

An essential aspect of goal-directed decision-making is selecting actions based on anticipated consequences, a process that involves the orbitofrontal cortex (OFC) and potentially, the plasticity of dendritic spines in this region. To investigate this possibility, we trained male and female mice to nose poke for food reinforcers, or we delivered the same number of food reinforcers non-contingently to separate mice. We then decreased the likelihood of reinforcement for trained mice, requiring them to modify action-outcome expectations. In a separate experiment, we blocked action-outcome updating via chemogenetic inactivation of the OFC. In both cases, successfully selecting actions based on their likely consequences was associated with fewer immature, thin-shaped dendritic spines and a greater proportion of mature, mushroom-shaped spines in the ventrolateral OFC. This pattern was distinct from spine loss associated with aging, and we identified no effects on hippocampal CA1 neurons. Given that the OFC is involved in prospective calculations of likely outcomes, even when they are not observable, constraining spinogenesis while preserving mature spines may be important for solidifying durable expectations. To investigate causal relationships, we inhibited the RNA-binding protein fragile X mental retardation protein (encoded by Fmr1), which constrains dendritic spine turnover. Ventrolateral OFC-selective Fmr1 knockdown recapitulated the behavioral effects of inducible OFC inactivation (and lesions; also shown here), impairing action-outcome conditioning, and caused dendritic spine excess. Our findings suggest that a proper balance of dendritic spine plasticity within the OFC is necessary for one's ability to select actions based on anticipated consequences.SIGNIFICANCE STATEMENT Navigating a changing environment requires associating actions with their likely outcomes and updating these associations when they change. Dendritic spine plasticity is likely involved, yet relationships are unconfirmed. Using behavioral, chemogenetic, and viral-mediated gene silencing strategies and high-resolution microscopy, we find that modifying action-outcome expectations is associated with fewer immature spines and a greater proportion of mature spines in the ventrolateral orbitofrontal cortex (OFC). Given that the OFC is involved in prospectively calculating the likely outcomes of one's behavior, even when they are not observable, constraining spinogenesis while preserving mature spines may be important for maintaining durable expectations.

Dietary trehalose enhances virulence of epidemic Clostridium difficile.

Clostridium difficile disease has recently increased to become a dominant nosocomial pathogen in North America and Europe, although little is known about what has driven this emergence. Here we show that two epidemic ribotypes (RT027 and RT078) have acquired unique mechanisms to metabolize low concentrations of the disaccharide trehalose. RT027 strains contain a single point mutation in the trehalose repressor that increases the sensitivity of this ribotype to trehalose by more than 500-fold. Furthermore, dietary trehalose increases the virulence of a RT027 strain in a mouse model of infection. RT078 strains acquired a cluster of four genes involved in trehalose metabolism, including a PTS permease that is both necessary and sufficient for growth on low concentrations of trehalose. We propose that the implementation of trehalose as a food additive into the human diet, shortly before the emergence of these two epidemic lineages, helped select for their emergence and contributed to hypervirulence.

Incorporating X-ray summing into gamma-gamma signature quantification.

A method for quantifying coincidence signatures has been extended to incorporate the effects of X-ray summing, and tested using a high-efficiency γ-γ system. An X-ray library has been created, allowing all possible γ, X-ray and conversion electron cascades to be generated. The equations for calculating efficiency and cascade summing corrected coincidence signature probabilities have also been extended from a two γ, two detector 'special case' to an arbitrarily large system. The coincidence library generated is fully searchable by energy, nuclide, coincidence pair, γ multiplicity, cascade probability and the half-life of the cascade, allowing the user to quickly identify coincidence signatures of interest. The method and software described is inherently flexible, as it only requires evaluated nuclear data, an X-ray library, and accurate efficiency characterisations to quickly and easily calculate coincidence signature probabilities for a variety of systems. Additional uses for the software include the fast identification of γ coincidence signals with required multiplicities and branching ratios, identification of the optimal coincidence signatures to measure for a particular system, and the calculation of cascade summing corrections for single detector systems.

A high-efficiency HPGe coincidence system for environmental analysis.

The Comprehensive Nuclear-Test-Ban Treaty (CTBT) is supported by a network of certified laboratories which must meet certain sensitivity requirements for CTBT relevant radionuclides. At the UK CTBT Radionuclide Laboratory (GBL15), a high-efficiency, dual-detector gamma spectroscopy system has been developed to improve the sensitivity of measurements for treaty compliance, greatly reducing the time required for each sample. Utilising list-mode acquisition, each sample can be counted once, and processed multiple times to further improve sensitivity. For the 8 key radionuclides considered, Minimum Detectable Activities (MDA's) were improved by up to 37% in standard mode (when compared to a typical CTBT detector system), with the acquisition time required to achieve the CTBT sensitivity requirements reduced from 6 days to only 3. When utilising the system in coincidence mode, the MDA for (60) Co in a high-activity source was improved by a factor of 34 when compared to a standard CTBT detector, and a factor of 17 when compared to the dual-detector system operating in standard mode. These MDA improvements will allow the accurate and timely quantification of radionuclides that decay via both singular and cascade γ emission, greatly enhancing the effectiveness of CTBT laboratories.

Maximising the sensitivity of a γ spectrometer for low-energy, low-activity radionuclides using Monte Carlo simulations.

Monte-Carlo simulations have been utilised to determine the optimum material and thickness for a γ spectrometer to be used for the assay of radionuclides that emit radiation in the 50-300 keV energy range. Both HPGe and LaBr3(Ce) materials were initially considered for use, however the additional background radiation and lack of resolution in the latter drove the selection of HPGe for further optimisation. Multiple thicknesses were considered for the HPGe detector, with the aim of improving the sensitivity of the system by maximising the efficiency for low energy emissions, and reducing the probability of interaction with (and therefore the continuum from) higher energy photons. The minimum amount of material needed to achieve this was found to be 15 mm for a source that is dominated by high energy (>2.614 MeV) photons, and 20-30 mm for a typical reference source (with photons of energy 59.54 keV-2.614 MeV).

Consumption of fa cai Nostoc soup: a potential for BMAA exposure from Nostoc cyanobacteria in China?

Grown in arid regions of western China the cyanobacterium Nostoc flagelliforme--called fa cai in Mandarin and fat choy in Cantonese--is wild-harvested and used to make soup consumed during New Year's celebrations. High prices, up to $125 USD/kg, led to overharvesting in Inner Mongolia, Ningxia, Gansu, Qinghai, and Xinjiang. Degradation of arid ecosystems, desertification, and conflicts between Nostoc harvesters and Mongol herdsmen concerned the Chinese environmental authorities, leading to a government ban of Nostoc commerce. This ban stimulated increased marketing of a substitute made from starch. We analysed samples purchased throughout China as well as in Chinese markets in the United States and the United Kingdom. Some were counterfeits consisting of dyed starch noodles. A few samples from California contained Nostoc flagelliforme but were adulterated with starch noodles. Other samples, including those from the United Kingdom, consisted of pure Nostoc flagelliforme. A recent survey of markets in Cheng Du showed no real Nostoc flagelliforme to be marketed. Real and artificial fa cai differ in the presence of beta-N-methylamino-L-alanine (BMAA). Given its status as a high-priced luxury food, the government ban on collection and marketing, and the replacement of real fa cai with starch substitutes consumed only on special occasions, it is anticipated that dietary exposure to BMAA from fa cai will be reduced in the future in China.

Molecular aspects of iron absorption and HFE expression.

Hereditary hemochromatosis, a disease of iron overload, occurs in about 1 in 200-400 Caucasians. The gene mutated in this disorder is termed HFE. The product of this gene, HFE protein, is homologous to major histocompatibility complex class I proteins, but HFE does not present peptides to T cells. Based on recent structural, biochemical, and cell biological studies, transferrin receptor (TfR) is a ligand for HFE. This association directly links HFE protein to the TfR-mediated regulation of iron homeostasis. Although evidence is accumulating that binding of HFE to TfR is critical for the effects of HFE, the final pieces in the HFE puzzle have not been established. This review focuses on recent advances in HFE research and presents a hypothetical model of HFE function.

Increased hepatic oxidative DNA damage in patients with hepatocellular carcinoma.

Since oxidative DNA damage plays a role in experimental carcinogen-induced cancers, the purpose of the present study was to determine if hepatic oxidative DNA damage was increased in patients with HCC compared to patients with benign hepatic tumors or hepatic metastases (non-HCC) or to patients with end-stage alcoholic liver disease undergoing liver transplantation. Oxidative DNA damage was assessed by 8-hydroxy-2'-deoxyguanosine (8-OH-dG). Results showed that peritumoral 8-OH-dG was markedly increased in HCC (N= 51) (180 +/- 74 vs 32 +/- 58-OH-dG/10(6)dG for tumor, P < 0.005) in contrast to patients with non-HCC (N = 17), in whom the peritumoral 8-OH-dG did not differ from that in tumor (39 +/- 7 vs. 31 +/- 108-OH-dG/10(6)dG). Oxidative DNA damage can be both mutagenic and carcinogenic; our data suggested it will be important in future studies to determine the chronology of this type of liver injury relative to hepatocarcinogenesis.

Report of a new DRB1*13 allele: DRB1*1336.

This brief communication describes the characterization of a new allele, DRB1*1336.

Changes in serum lipoprotein profile during interferon therapy in chronic hepatitis C.

OBJECTIVES: Therapy with a interferon is associated with a rise in serum triglyceride levels, although this effect has not been well studied with newer forms of interferon or interferon in combination with ribavirin. METHODS: Review of combined data obtained from several prospective, randomized controlled clinical trials conducted in the clinical studies unit of a tertiary care referral center among patients with chronic hepatitis C undergoing treatment with various forms of a interferon, with or without the addition of ribavirin. Serum levels of triglycerides and cholesterol were measured before and during therapy. Changes in these levels were correlated with baseline characteristics. RESULTS: At baseline, the mean serum triglyceride level among 152 patients studied was 130 mg/dL (range 32-620) and was elevated above normal in three patients (2%). During therapy, triglyceride levels rose significantly early on and began to decline spontaneously after 12 wk, returning to baseline after stopping treatment. Triglyceride levels rose above 500 mg/dL in 18 patients (12%) and above 1000 mg/dL in two patients (1.3%) although none experienced acute complications or clinical symptoms. Serum cholesterol levels did not change significantly during therapy (mean at baseline 172 vs 168 mg/dL at 24 wk). Factors correlated with the rise in triglycerides included baseline triglyceride levels, HCV genotype, and the type of interferon used. CONCLUSIONS: Serum triglyceride levels increase consistently in patients with chronic hepatitis C treated with all forms of a interferon, often to very high levels. These changes do not seem to be associated with clinical signs or complications and triglyceride levels decline while patients are still on therapy and return to normal after stopping.