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Discovery of analgesics void of abuse liability is critical to battle the opioid crisis in the United States. Among many strategies to achieve this goal, targeting more than one opioid receptor seems promising to minimize this unwanted side effect while achieving a reasonable therapeutic profile. In the process of understanding the structure-activity relationship of nalfurafine, we identified a potential analgesic agent, NMF, as a dual kappa opioid receptor/delta opioid receptor agonist with minimum abuse liability. Further characterizations, including primary in vitro ADMET studies (hERG toxicity, plasma protein binding, permeability, and hepatic metabolism), and in vivo pharmacodynamic and toxicity profiling (time course, abuse liability, tolerance, withdrawal, respiratory depression, body weight, and locomotor activity) further confirmed NMF as a promising drug candidate for future development.

Background Opioid withdrawal is a key driver of opioid addiction and an obstacle to recovery. However, withdrawal effects on opioid reinforcement and mesolimbic neuroadaptation are understudied, and the role of sex is largely unknown. Methods Male (n = 13) and female (n = 12) rats responded under a fentanyl-versus-food choice procedure during daily 2-hour sessions. In addition to the daily choice sessions, rats were provided extended access to fentanyl during 12-hour self-administration sessions. After 2 weeks of this self-administration regimen, the nucleus accumbens and ventral tegmental area of a subset of rats were subjected to RNA sequencing. In the remaining rats, a third week of this self-administration regimen was conducted, during which methadone effects on fentanyl-versus-food choice were determined. Results Before opioid dependence, male and female rats similarly allocated responding between fentanyl and food. Abstinence from extended fentanyl access elicited similar increases in somatic withdrawal signs in both sexes. Despite similar withdrawal signs and extended-access fentanyl intake, opioid withdrawal was accompanied by a maladaptive increase in fentanyl choice in males, but not females. Behavioral sex differences corresponded with a greater number of differentially expressed genes in the nucleus accumbens and ventral tegmental area of opioid-withdrawn females relative to males. Methadone blocked withdrawal-associated increases in fentanyl choice in males but failed to further decrease fentanyl choice in females. Conclusions These results provide foundational evidence of sex-specific neuroadaptations to opioid withdrawal, which may be relevant to the female-specific resilience to withdrawal-associated increases in opioid choice and aid in the identification of novel therapeutic targets.

RationaleStrategies are needed to decrease the abuse liability of mu opioid receptor (MOR) agonists. One strategy under consideration is to combine MOR agonists with kappa opioid receptor (KOR) agonists.ObjectivesThe effects of KOR-agonists (U50488, nalfurafine) on fentanyl-versus-food choice were compared under conditions where the KOR agonists were added to the self-administered fentanyl (contingent delivery) or administered as pretreatments (non-contingent delivery) in male and female rats. The effects of increasing and decreasing the magnitude of the alternative food reinforcer were also determined.MethodsRats were trained to respond under a concurrent schedule of fentanyl (0, 0.32-10 μg/kg/infusion) and food reinforcement. In Experiment 1, U50488 and nalfurafine were co-administered with fentanyl as fixed-proportion mixtures (contingent administration). In Experiment 2, U50488 (1-10 mg/kg) and nalfurafine (3.2-32 μg/kg) were administered as acute pretreatments (non-contingent administration). nor-BNI (32 mg/kg) was administered prior to contingent and non-contingent KOR-agonist treatment in Experiment 3. Experiment 4 evaluated the effects of increasing and decreasing the magnitude of the non-drug reinforcer.ResultsBoth U50488 and nalfurafine decreased fentanyl choice when administered contingently, demonstrating that KOR agonists punish opioid choice. Non-contingent U50488 and nalfurafine administration decreased rates of fentanyl and food self-administration without altering fentanyl choice. Both contingent and non-contingent U50488 and nalfurafine effects on fentanyl choice were attenuated by nor-BNI. Fentanyl choice was sensitive to increases and decreases in the magnitude of the non-drug reinforcer.ConclusionsThese results demonstrate that the effects of KOR agonists on fentanyl reinforcement are dependent upon the contingencies under which they are administered.

Opioid-targeted vaccines represent an emerging treatment strategy for opioid use disorder. To determine whether concurrent vaccination against two commonly abused opioids (fentanyl and heroin) would confer broader spectrum opioid coverage, the current study evaluated dual fentanyl/heroin conjugate vaccine effectiveness using a warm water tail-withdrawal and a fentanyl/heroin-vs-food choice procedure in male and female rats across a 105-day observation period. Vaccine administration generated titers of high-affinity antibodies to both fentanyl and heroin sufficient to decrease the antinociceptive potency of fentanyl (25-fold), heroin (4.6-fold), and a 1:27 fentanyl/heroin mixture (7.5-fold). Vaccination did not alter the antinociceptive potency of the structurally dissimilar opioid agonist methadone. For comparison, continuous treatment with a naltrexone dose (0.032 mg/kg/h) shown previously to produce clinically relevant plasma-naltrexone levels decreased the antinociceptive potency of fentanyl, heroin, and the 1:27 fentanyl/heroin mixture by approximately 20-fold. Naltrexone treatment also shifted the potency of 1:27 fentanyl/heroin mixture in a drug-vs-food choice self-administration procedure 4.3-fold. In contrast, vaccination did not attenuate 1:27 fentanyl/heroin mixture self-administration in the drug-vs-food choice procedure. These data demonstrate that a vaccine can simultaneously attenuate the thermal antinociceptive effects of two structurally dissimilar opioids. However, the vaccine did not attenuate fentanyl/heroin mixture self-administration, suggesting a greater magnitude of vaccine responsiveness is required to decrease opioid reinforcement relative to antinociception.

The high efficacy mu-opioid receptor (MOR) agonist methadone is an effective opioid use disorder (OUD) medication used exclusively in opioid-dependent patients. However, methadone has undesirable effects that limit its clinical efficacy. Intermediate efficacy MOR agonists may treat OUD with fewer undesirable effects. We compared the effects of methadone with the intermediate efficacy MOR agonist TRV130 (oliceridine) on fentanyl-vs.-food choice and somatic withdrawal signs in opioid-dependent and post-opioid-dependent rats. Male rats (n = 20) were trained under a fentanyl-vs.-food choice procedure. Rats were then provided extended fentanyl (3.2 µg/kg/infusion) access (6 p.m.-6 a.m.) for 10 days to produce opioid dependence/withdrawal. Rats were treated with vehicle (n = 7), TRV130 (3.2 mg/kg; n = 8), or methadone (3.2 mg/kg; n = 5) three times per day after each extended-access session (8:30 a.m., 11 a.m., 1:30 p.m.). Withdrawal sign scoring (1:55 p.m.) and choice tests (2-4 p.m.) were conducted daily. Vehicle, TRV130, and methadone effects on fentanyl choice were redetermined in post-opioid-dependent rats. Vehicle-, TRV130-, and methadone-treated rats had similar fentanyl intakes during extended access. Vehicle-treated rats exhibited increased withdrawal signs and decreased bodyweights. Both methadone and TRV130 decreased these withdrawal signs. TRV130 was less effective than methadone to decrease fentanyl choice and increase food choice in opioid-dependent rats. Neither methadone nor TRV130 decreased fentanyl choice in post-opioid-dependent rats. Results suggest that higher MOR activation is required to reduce fentanyl choice than withdrawal signs in fentanyl-dependent rats. Additionally, given that TRV130 did not precipitate withdrawal in opioid-dependent rats, intermediate efficacy MOR agonists like TRV130 may facilitate the transition of patients with OUD from methadone to lower efficacy treatments like buprenorphine.

Laser ultrasonics is a remote nondestructive evaluation technique suitable for real-time monitoring of fabrication processes in semiconductor metrology, advanced manufacturing, and other applications where non-contact, high fidelity measurements are required. Here we investigate laser ultrasonic data processing approaches to reconstruct images of subsurface side drilled holes in aluminum alloy specimens. We demonstrate through simulation that the model-based linear sampling method (LSM) can perform accurate shape reconstruction of single and multiple holes and produce images with well-defined boundaries. We experimentally confirm that LSM produces images that represent the internal geometric features of an object, some of which may be missed by conventional imaging.

This study explores the evolutionary history of ecological niche characters in the Eurasian snowfinch lineage. Specifically, we use new analytical approaches to reconstruct ecological niche evolution, taking uncertainty in knowledge of the ecological niche limits into account. We found an overall pattern of niche conservatism in relation to both temperature and precipitation characteristics of niches, but for one dramatic niche evolution event, in Montifringilla nivalis. Interestingly, this species is also that which has by far the broadest geographic distribution among snowfinches. We conclude that an evolutionary change in niche characteristics perhaps within M. nivalis (i.e., present in some and not all of its populations) made possible the broad, westward range expansion of that species, thus changing the distributional potential of the snowfinch lineage dramatically.

Biodiversity remains relatively unknown and understudied in many parts of the developing world with significant information gaps, in stark contrast to many areas in the developed world, where knowledge about biodiversity can approach encyclopedic. Access to resources, such as funding, data, information, expertise, and biological collections (often collected by colonial-era scientists from across the developing world), is often quite limited for developing-world scientists. The life of a biodiversity scientist in the developing world is therefore one of manifold dilemmas and challenges, as well as numerous opportunities. Although collaborations exist between developing-world scientists and developed-world scientists, too many of those collaborations are not deep or permanent, and developing-world scientists are too often relegated to a subordinate role. The focus in this contribution is on providing suggestions for how to open and build access to resources for developing-world scientists. Everyone benefits if developing-world and developed-world scientists work together collaboratively to pose interesting and novel questions, generate new data, update existing data, carry out analyses, and arrive at interesting insights and interpretations. In this way, the biodiversity science community can replace “parachute” science with “global science.”

Lens-coupled X-ray computed tomography (X-ray CT) using a transparent scintillator imaged on a CCD camera obtains higher spatial resolution than the more commonly employed phosphor-enhanced amorphous silicon (A-Si) panels. A-Si panels are limited to resolution typically greater than ~200 microns, have a limited working life due to degradation with dose, and provide intrinsically low efficiency with thin (few hundred microns thick) phosphor coatings. Demanding applications such as imaging the interior of complex additively manufactured components require high throughput and high resolution, best achieved with a lens-coupled system. However, for large fields-of-view, very large area but thin transparent scintillators are required – a format difficult to fabricate with high light yield single crystals – therefore, glass scintillators with both modest X-ray interaction and light yield have been used for years. We have developed a new polycrystalline transparent ceramic scintillator, Gd0.3Lu1.6Eu0.1O3, or “GLO,” that offers excellent stopping power and light yield for improved contrast in sizes up to 14” x 14” plates, with thicknesses in the 2-10 mm range, and we are implementing it in systems to increase imaging throughput for 9 MeV Bremsstrahlung X-ray CT. CT imaging performance will be described.

Orphan legume crops play an important role in smallholder farmers’ food systems. Though less documented, they have the potential to contribute to adequate nutrition in vulnerable communities. Unfortunately, data are scarce about the potential of those crops to withstand current and future climate variations. Using Macrotyloma geocarpum as an example, we used genetically informed ecological niche models to explore the role of ecology on the current and future distributions of genetic populations of Kersting’s groundnut. Three main conclusions emerged: i) the models had good predictive power, indicating that M. geocarpum’s distribution was correlated with both climatic and soil layers; ii) identity and similarity tests revealed that the two genetic groups while overlapping, are each, locally adapted and display differences in climate suitability; iii) by integrating the genetic information in niche modeling, niches projections show divergence in the response of the species and genetic populations to ongoing climate change. This study highlights the importance of incorporating genetic data into ENM approaches to obtain a finer information of species’ future distribution, and explores the implications for agricultural adaptation, with a particular focus on identifying priority actions in orphan crops conservation and breeding.

Background and Purpose: Maintenance treatment with opioid agonists (buprenorphine, methadone) decreases opioid use and relapse. We recently modelled maintenance treatment in rats and found that chronic delivery of buprenorphine or the μ opioid receptor partial agonist TRV130 decreased relapse to oxycodone seeking and taking. Here, we tested the buprenorphine analogue BU08028 on different heroin relapse-related measures and heroin versus food choice. Experimental Approach: For relapse assessment, we trained male and female rats to self-administer heroin (6 h·day−1, 14 days) in Context A and then implanted osmotic minipumps containing BU08028 (0, 0.03 or 0.1 mg·kg−1·d−1). Effects of chronic BU08028 delivery were tested on (1) incubation of heroin-seeking in a non-drug Context B, (2) extinction responding reinforced by heroin-associated discrete cues in Context B, (3) reinstatement of heroin-seeking induced by re-exposure to Context A and (4) re-acquisition of heroin self-administration in Context A. For choice assessment, we tested the effect of chronic BU08028 delivery on heroin versus food choice. Key Results: Chronic BU08028 delivery decreased incubation of heroin seeking. Unexpectedly, BU08028 increased re-acquisition of heroin self-administration selectively in females. Chronic BU08028 had minimal effects on context-induced reinstatement and heroin versus food choice in both sexes. Finally, exploratory post hoc analyses suggest that BU08028 decreased extinction responding selectively in males. Conclusions and Implications: Chronic BU08028 delivery had both beneficial and detrimental, sex-dependent, effects on different triggers of heroin relapse and minimal effects on heroin choice in both sexes. Results suggest that BU08028 would not be an effective opioid maintenance treatment in humans.

Fast neutrons accessible from 14-MeV D-T neutron generators have higher transmission through high-Z materials compared to radiography X-rays due to a more uniform attenuation as a function of material Z. These neutrons can therefore image low-Z materials even when shielded by high-Z materials. The constraints in portable fast-neutron digital imaging systems include limited neutron output, limited light produced by neutron imaging scintillators, and lower resolution images due to large source spot size and required scintillator thickness. In addition, digital panel dark-noise counts can be 100x higher than the image signal, and variations across the panel can also be comparable to this signal. We will discuss recent efforts to develop a portable neutron-radiography system, including improved neutron scintillator, mitigation of digital panel noise, and new portable D-T neutron generators. We will also present MCNP efforts to model the system, including neutron scattering effects.

Additive Manufacturing (AM) presents significant industry-specific advantages allowing the creation of complex geometries and internal features that cannot be produced using conventional manufacturing processes. However, a current limitation of AM is the degraded dimensional control and surface integrity of specific surfaces. The parts are constructed through layer-by-layer approach, each layer presenting a characteristic ‘fingerprint’. The functional performance of the final part is influenced by the morphology of the outer surface as well as by the surface quality introduced at intermediate layers. Surface texture metrology therefore can play an enabling role in AM-related manufacture and research. The use of optical topography measurement instrumentation allows for a high level of detail in the acquisition of topographic information. Some of the most commonly used optical measuring instruments are Vertical Scanning Interferometry (CSI), Imaging Confocal Microscopy (CONF), and Focus Variation (FV), each one has benefits and drawbacks in terms of acquisition time and measurement resolution. AM surfaces overall present complex topographical features, requiring the acquisition of large surface areas and large z-scans which considerably increases the acquisition time. Speed is a key factor in industrial practice, and time optimization is required for quality control and surface analysis before down-stream processes. This paper reports on the measurement and characterisation of the surface texture of metal powder bed fusion AM parts. All measurements were performed in the same SENSOFAR S-NEOX instrument using the commonly used optical technologies (CSI, CONF, and FV) and the latest step in confocal measurement technology called Continuous Confocal (C-CONF). The resolution and acquisition time of each technique is analysed in order to check the suitability of each method to characterize and describe the AM surface microstructures in a time-efficient way.

We review the biology and ecology of the endemic New Zealand genus Alseuosmia A. Cunn. The taxonomy of the genus has a complicated history with considerable debate about both its relationsh...

Characterisation of freeform surfaces is an increasingly importance area of metrology. Currently the characterisation of surfaces is performed using data that can be represented by a height map. Modern measurement devices allow the acquisition of surfaces with complex shapes that cannot properly be analysed using the current texture parameters definition. In this paper a method to characterise both freeform surfaces and surfaces with re-entrant features is proposed. Two surface approximation methods are investigated: triangular mesh and Bezier surface. The proposed method will be compared with a method able to extract the ISO 25178-2 areal texture parameters from a triangular mesh.

Hass avocado cultivation in Colombia has grown rapidly in area in recent years. It is being planted in marginal areas, which leads to low yields, and in many cases is related to diseases. Ecological niche modeling (ENM) can offer a view of the potential geographic and environmental distribution of diseases, and thus identify areas with suitable or unsuitable conditions for their development. The aim of the study was to assess current and potential distribution of the major diseases on Hass avocado in Colombia. Areas planted with Hass avocado in Antioquia, Colombia were sampled for diseases including the following pathogens: Phytophthora cinnamomi, Verticillium sp., Lasiodiplodia theobromae, Phytophthora palmivora, Colletotrichum gloeosporioides sensu lato, Pestalotia sp., and Capnodium sp., and one disorder hypoxia-anoxia. These pathogens were selected based on their relevance (incidence-severity) and capacity to cause damage in different tissues of avocado plants. Severity and incidence of each disease were related to environmental information from vegetation indices and topographic variables using maximum entropy modeling approaches (MaxEnt). Models were calibrated only across areas sampled, and then transferred more broadly to areas currently planted, and to potential zones for planting. Combinations of best performance and low omission rates were the basis for model selection. Results show that Hass avocado has been planted in areas highly conducive for many pathogens, particularly for Phytophthora cinnamomi and hypoxia-anoxia disorder. Ecological niche modeling approaches offer an alternative toolset for planning and making assessments that can be incorporated into disease management plans.

The current opioid crisis remains a significant public health issue and there is a critical need for biomedical research to develop effective and easily deployable candidate treatments. One emerging treatment strategy for opioid use disorder includes immunopharmacotherapies or opioid-targeted vaccines. The present study determined the effectiveness of a fentanyl-tetanus toxoid conjugate vaccine to alter fentanyl self-administration using a fentanyl-vs.-food choice procedure in male and female rats under three experimental conditions. For comparison, continuous 7-day naltrexone (0.01–0.1 mg/kg/h) and 7-day clonidine (3.2–10 μg/kg/h) treatment effects were also determined on fentanyl-vs.-food choice. Male and female rats responded for concurrently available 18% diluted Ensure® (liquid food) and fentanyl (0–10 μg/kg/infusion) infusions during daily sessions. Under baseline and saline treatment conditions, fentanyl maintained a dose-dependent increase in fentanyl-vs.-food choice. First, fentanyl vaccine administration significantly blunted fentanyl reinforcement and increased food reinforcement for 15 weeks in non-opioid dependent rats. Second, surmountability experiments by increasing the unit fentanyl dose available during the self-administration session 10-fold empirically determined that the fentanyl vaccine produced an approximate 22-fold potency shift in fentanyl-vs.-food choice that was as effective as the clinically approved treatment naltrexone. Clonidine treatment significantly increased fentanyl-vs.-food choice. Lastly, fentanyl vaccine administration prevented the expression of withdrawal-associated increases in fentanyl-vs.-food choice following introduction of extended 12 h fentanyl access sessions. Overall, these results support the potential and further consideration of immunopharmacotherapies as candidate treatments to address the current opioid crisis.

Clinical evidence suggest that men are more sensitive than women to the abuse-related effects of mu-opioid agonists. In contrast, preclinical studies suggest the opposite sex difference. The aim of the present study was to clarify this discrepancy using a fentanyl vs. diluted Ensure® choice procedure to assess sex differences in opioid reinforcement. Sex differences in intravenous (IV) fentanyl self-administration were examined under a fixed-ratio (FR5) schedule, a multi-day progressive-ratio (PR) schedule for behavioral economic analysis, and a concurrent (choice) schedule of fentanyl and diluted Ensure® reinforcement in Sprague–Dawley male and female rats. The fentanyl dose-effect function under the FR5 schedule was significantly shifted upward in females compared to males. Similarly, the reinforcing effectiveness of both fentanyl (3.2 and 10 µg/kg per injection, IV) and diluted Ensure® (18 and 56%) were greater in females than in males as assessed using behavioral economic analysis, irrespective of dose or concentration. However, under a fentanyl vs. foodchoice procedure, males chose 3.2 µg/kg per injection fentanyl injections over 18%, but not 56%, diluted Ensure® at a higher percentage compared to females. Overall, these results suggest that the expression of sex differences in opioid reinforcement depends upon the schedule of reinforcement and that preclinical opioid vs. food choice procedures provide a translationally relevant measure (i.e., behavioral allocation) consistent with the direction of sex differences reported in the clinical literature.

Production of nitric oxide (NO) has been demonstrated in several malignancies, however its role remains not fully understood, specifically in relation to the metabolic and functional implications that it may have on immune cells participating in tumorigenesis. Here, we show that inducible NO synthase (iNOS) is expressed in cancers of the colon and the prostate, mainly by tumour cells, and NO generation is evidenced by widespread nitrotyrosine (NT) staining in tumour tissue. Furthermore, presence of NT is observed in the majority of tumour-associated macrophages (TAMs), despite low iNOS expression by these cells, suggesting that NO from the tumour microenvironment affects TAMs. Indeed, using a co-culture model, we demonstrate that NO produced by colon and prostate cancer cells is sufficient to induce NT formation in neighbouring macrophages. Moreover, exposure to exogenous NO promotes mitochondria-dependent and -independent changes in macrophages, which orientate their polarity towards an enhanced pro-inflammatory phenotype, whilst decreasing antigen-presenting function and wound healing capacity. Abrogating endogenous NO generation in murine macrophages, on the other hand, decreases their pro-inflammatory phenotype. These results suggest that the presence of NO in cancer may regulate TAM metabolism and function, favouring the persistence of inflammation, impairing healing and subverting adaptive immunity responses.

Orphan legume crops play an important role in smallholder farmers’ food systems. Though less documented, they have the potential to contribute to adequate nutrition in vulnerable communities. Unfortunately, data are scarce about the potential of those crops to withstand current and future climate variations. Using Macrotyloma geocarpum as an example, we used ecological niche modeling to explore the role of ecology on the current and future distributions of genetic populations of Kersting’s groundnut. Our findings showed that: (1) the models had good predictive power, indicating that M. geocarpum’s distribution was correlated with both climatic and soil layers; (2) identity and similarity tests revealed that the two genetic groups have identical and similar environmental niches; (3) by integrating the genetic information in niche modeling, niches projections show divergence in the response of the species and genetic populations to ongoing climate change. This study highlights the importance of incorporating genetic data into Ecological Niche Modeling (ENM) approaches to obtain a finer information of species’ future distribution, and explores the implications for agricultural adaptation, with a particular focus on identifying priority actions in orphan crops conservation and breeding.

Rationale and ObjectivePain-related factors increase risk for opioid addiction, and opioid-induced pain relief may function as a negative reinforcer to increase opioid taking and seeking. However, experimental pain-related manipulations generally do not increase opioid self-administration in rodents. This discrepancy may reflect insufficient learning of pain-relief contingencies or confounding effects of pain-related behavioral impairments. Here we determined if pairing noxious stimuli with opioid self-administration would promote pain-related reinstatement of opioid seeking or increase opioid choice over food.MethodsIn Experiment 1, rats self-administered fentanyl in the presence or absence of repeated intraplantar capsaicin injections in distinct contexts to model context-specific exposure to cutaneous nociception. After capsaicin-free extinction in both contexts, we tested if capsaicin would reinstate fentanyl seeking. In Experiment 2, rats self-administered heroin after intraperitoneal (i.p.) lactic acid injections to model acute visceral inflammatory pain. After lactic acid-free extinction, we tested if lactic acid would reinstate heroin seeking. In Experiment 3, we tested if repeated i.p. lactic acid or intraplantar Complete Freund’s Adjuvant (CFA; to model sustained inflammatory pain) would increase fentanyl choice over food.ResultsIn Experiments 1-2, neither capsaicin nor lactic acid reinstated opioid seeking after extinction, and lactic acid did not increase heroin-induced reinstatement. In Experiment 3, lactic acid and CFA decreased reinforcement rate without affecting fentanyl choice.ConclusionsResults extend the range of conditions across which pain-related manipulations fail to increase opioid seeking in rats and suggest that enhanced opioid-addiction risk in humans with chronic pain involves factors other than enhanced opioid reinforcement and relapse.

BackgroundOpioid withdrawal is a key driver of opioid addiction and an obstacle to recovery. However, withdrawal effects on opioid reinforcement and mesolimbic neuroadaptation are understudied and the role of sex is largely unknown.MethodsMale (n=10) and female (n=9) rats responded under a fentanyl-vs.-food “choice” procedure during daily 2h sessions. In addition to the daily choice sessions, rats were provided extended access to fentanyl during 12h sessions. After two weeks of this self-administration regimen, the nucleus accumbens (NAc) and ventral tegmental area (VTA) of a subset of rats were subjected to RNA sequencing. In the remaining rats, a third week of this self-administration regimen was conducted, during which methadone effects on fentanyl-vs.-food choice were determined.ResultsPrior to opioid dependence, male and female rats similarly allocated responding between fentanyl and food. Abstinence from extended fentanyl access elicited a similar increase in somatic withdrawal signs in both sexes. Despite similar withdrawal signs and extended access fentanyl intake, opioid withdrawal was accompanied by a maladaptive increase in fentanyl choice in males, but not females. Behavioral sex differences corresponded with transcriptional hyperfunction in the NAc and VTA of opioid-withdrawn females relative to males. Methadone blocked withdrawal-associated increases in fentanyl choice in males, but failed to further decrease fentanyl choice in females.ConclusionsThese results provide foundational evidence of sex-specific neuroadaptations to opioid withdrawal, which may be relevant to the female-specific resilience to withdrawal-associated increases in opioid choice and aid in the identification of novel therapeutic targets.

Background Preclinical drug self-administration procedures are commonly used to investigate expression, mechanisms, and treatment of substance use disorders. New method The aims were to back-translate an intravenous drug-vs-food choice procedure primarily utilized in monkeys to male and female rats and to develop a surgical method for sustained intravenous catheter patency suitable for long-term drug-choice studies. Results The surgical protocol resulted in a median intravenous jugular catheter patency in male and female rats of 126 days (range: 25–365 days). Drug-vs-food choice was established with opioids (fentanyl and heroin), psychostimulants (cocaine, methamphetamine, and amphetamine), and an opioid/psychostimulant mixture (fentanyl + methamphetamine). The average time from catheter implantation to stable choice behavior across all drugs was 27 sessions (range: 16–44 sessions). Choice behavior stabilized more quickly for cocaine and fentanyl than for other drugs. Manipulations of both environmental variables (e.g., response requirement or food reinforcer magnitude) and pharmacological variables (e.g., extended access drug self-administration or continuous buprenorphine treatment via osmotic pump) significantly shifted opioid-vs-food choice consistent with previous monkey studies. Comparison with existing methods Duration of intravenous catheter patency in rats was suitable for long-term, within-subject drug choice studies. Effects of environmental and pharmacological manipulations in rats confirmed and extended previous results from monkeys. Conclusions The concordance of behavioral results between rats and monkeys using the present drug-vs-food choice procedure supports its utility to improve our basic understanding of the expression and mechanisms of substance use disorders towards to development of more effective therapeutics.

Nalfurafine is a G protein signaling-biased kappa opioid receptor (KOR) agonist approved in Japan for second-line treatment of uremic pruritus. Neither nalfurafine nor any other KOR agonist is currently approved anywhere for treatment of pain, but recent evidence suggests that G protein signaling-biased KOR agonists may have promise as candidate analgesics/antipruritics with reduced side effects compared to nonbiased or s-arrestin-signaling-biased KOR agonists. This study compared nalfurafine effects in rats using assays of pain-stimulated and pain-depressed behavior used previously to evaluate other candidate analgesics. Nalfurafine effects were also examined in complementary assays of itch-stimulated and itch-depressed behavior. Intraperitoneal lactic acid (IP acid) and intradermal serotonin (ID 5HT) served as noxious and pruritic stimuli, respectively, in male Sprague Dawley rats to stimulate stretching (IP acid) or scratching (ID 5HT) or to depress positively reinforced operant responding in an assay of intracranial self-stimulation (ICSS; both stimuli). Nalfurafine was equipotent to decrease IP acid-stimulated stretching and ID 5HT-stimulated scratching; however, doses of nalfurafine that decreased these pain/itch-stimulated behaviors also decreased control ICSS performance. Moreover, nalfurafine failed to alleviate either IP acid- or ID 5HT-induced depression of ICSS. These results suggest that nalfurafine-induced decreases in pain/itch-stimulated behaviors may reflect nonselective decreases in motivated behavior rather than analgesia or antipruritus against the noxious and pruritic stimuli used here. This conclusion agrees with the absence of clinical data for nalfurafine analgesia and the weak clinical data for nalfurafine antipruritus. Nalfurafine bias for G protein signaling may not be sufficient for clinically safe and reliable analgesia or antipruritus.

Ecological niche modelling (ENM) is used widely to aid in conservation planning and management, often focusing on rare species characterized by the biased observations associated with restricted geographic ranges, habitat specialization, small population size and limited natural history information. Generating reliable ENMs for such species is a challenge, however, owing to issues that arise from spatial sampling bias, such as model inaccuracy and overfitting. Here, using virtual scenarios, we assess the utility of integrating occurrence data for closely related species with varying degrees of niche overlap into ENMs of focal species. We consider two approaches to merge related and focal species models: integrating occurrences of focal and related species directly as inputs with which to generate ENMs, vs. creating ENMs based on occurrences of focal and related species separately and merging results based on Bayesian inference approaches. Both single, integrated models and Bayesian inference approaches performed better than models based on focal species only when niche overlap between the focal and related species was large, across ENM algorithms examined. While assessing sensitivity and specificity separately, the performances of the two integration approaches over different ENM algorithms were complicated. The results of the study offer a novel way forward in managing the challenge of creating useful, predictive models even for the rarest species, taking advantage of the reasonably general property of niche conservatism over small-to-moderate amounts of evolutionary time.

Strategies to reduce the misuse of mu opioid agonists are critically needed. Previous work has shown that kappa opioid agonists can diminish the abuse-related effects and augment the antinociceptive effects of mu agonists. However, use of traditional kappa agonists is limited by their dysphoric side effects. The current study examined the effects of nalfurafine, a clinically available atypical kappa agonist, on the reinforcing, thermal antinociceptive, and respiratory-depressant effects of oxycodone in male rats. To determine oxycodone/nalfurafine mixture proportions to be examined intravenously across procedures, a progressive ratio (PR) self-administration procedure compared the reinforcing effects of oxycodone (56 μg/kg/inj) available alone or as a mixture with co-administered nalfurafine (0.32, 1, or 3.2 μg/kg/inj), corresponding to oxycodone/nalfurafine proportions of 175:1, 56:1, and 18:1, respectively. Next, PR and thermal antinociception dose-effect functions were each determined for oxycodone, nalfurafine, and the same oxycodone/nalfurafine mixture proportions. Finally, the respiratory-depressant effects of equi-antinociceptive doses of oxycodone, nalfurafine, and the mixtures were compared. Nalfurafine decreased the reinforcing effects of oxycodone, and the 18:1 mixture did not function as a reinforcer. Oxycodone and nalfurafine each produced dose-dependent antinociception, and the mixtures produced additive antinociception. In addition, antinociceptive doses of the 56:1 and 18:1 mixtures did not produce respiratory depression. These results suggest that nalfurafine may augment the thermal antinociceptive effects while reducing the reinforcing and respiratory-depressant effects of oxycodone.

Aims Evidence indicates that obese individuals exhibit alterations in brain-reward function that are anatomically and functionally similar to what has been observed in drug addicts, which could theoretically make obese individuals vulnerable to drug abuse and drug abusers vulnerable to overeating. However, few studies have investigated the cross-generality of these phenotypes. We recently reported that the reinforcing effectiveness (i.e., value) of a fat was greater in obese Zucker rats than in their lean counterparts, but found no differences in the reinforcing effectiveness of cocaine between groups, suggesting psychostimulant reinforcement is similar in lean and obese Zucker rats. However, it is unknown if other aspects of reinforcement such as cocaine's potency as a reinforcer or its reinstating effects differ in lean and obese Zucker rats. Methods The current study compared cocaine's potency as a reinforcer in lean and obese Zucker rats self-administering intravenous cocaine (0.06–1.0 mg/kg/inj), and subsequently tested these subjects in cue- (light) and drug-primed (intraperitoneal cocaine; 10 mg/kg) reinstatement of extinguished operant responding. Results All rats acquired cocaine self-administration and generated “inverted-U” dose-response functions. Following extinction of responding, the cue- and drug-primes increased lever-pressing in both groups (i.e., reinstatement). No significant differences in the reinforcing potency or reinstating effects of cocaine were observed as a function of obesity. Conclusions These results, combined with our previous observations, demonstrate that cocaine's reinforcing effects are comparable in lean and obese Zucker rats and do not support the hypothesis that obesity is associated with an altered reinforcing effect of psychostimulants.

The field of biodiversity informatics has developed rapidly in recent years with broad availability of large-scale information resources. However, online biodiversity information are biased (Boakes et al. 2010, Stropp et al. 2016) as a result of the relatively slow capture and digitization of existing data resources. The West African Plants (WAP) initiative approach to data capture is a prototype of a novel solution to the challenge of the traditional model, in which the institutional “owner” of the specimens is responsible for digital capture of associated data. The WAP Initiative is a consortium of West African researchers in botany, in coordination with six institutions across Europe and North America; its goal is to digitize and mobilize available, high-quality, primary biodiversity occurrence data resources for West African plant diversity (http://jrsbiodiversity.org/grants/university-of-ghana-herbaria/). Here, we developed customized workflows for data capture in formats directly and permanently useful to the “owner” herbarium, and digitized significant new biodiversity records adding to the information available for the plants of the region. Data records were captured strictly in accordance with DarwinCore standards, achieved either by (a) capturing data records from existing images (e.g., images supplied by Naturalis Bodiversity Centre), or (b) capturing data from images taken quickly and efficiently by project personnel in West African Herbaria. Digitization of images and data began in 2015 in West African partner institutions, and by middle of 2018 resulted in 190,953 records of species in 1965 genera and 331 families from 16 West African countries (Fig. 1). Our approach is cost-effective, allows development of information resources even for regions in which political situations make it impossible, and it provides a historical context against which to compare newer data as the latter become available (Peterson et al. 2016). Further measures of success of the initiative will center on whether the institutions “owning” the specimens follow through and put the new data records online. Already, several project institutions have put initial project data online as part of their GBIF data contributions, but—of course—success would consist of all project-generated data being completely available online. Note that this model is the reverse of the traditional model, in which the institutions holding the specimens create the information resources that are used by the rest of the world. This new paradigm in specimen digitization has considerable promise to accelerate and improve the process of generating biodiversity information, and can be replicated and applied in many biodiversity-rich, information-poor regions to remedy the oft-cited massive gaps in information availability.

Ecological niche models have seen intensive exploration as a tool in biodiversity conservation and evaluation of areas for designing protected natural areas systems, including projections of potential distributions under future conditions. Cloud forest is the most endangered ecosystem in Mexico, and yet ranks high in terms of diversity and endemism. This study focuses on 12 endangered and range-restricted tree species in Mexican cloud forests, exploring patterns of distribution and diversity under 2 future emissions scenarios (representative concentration pathways 4.5 and 8.5) as anticipated by 20 general circulation models. Our results indicate a likely strong reduction in species’ distributional areas and —consequently— species diversity manifested in different cloud forest patches across the country. The genus Quercus resulted the most sensitive to climate change. We identified cloud forest patches that are most vulnerable to climate change effects, which can and should focus priorities for protection of this ecosystem, particularly in the Sierra Madre Oriental, where cloud forest is presently lacking any protection.

BackgroundThe current opioid crisis has reinvigorated preclinical research in the evaluation of non-opioid candidate treatments for opioid use disorder (OUD). Emerging evidence suggests 5-HT2C receptor agonists may attenuate the abuse-related effects of opioids. This study evaluated effectiveness of 7-day treatment with the clinically available 5-HT2C agonist lorcaserin on heroin-vs.-food choice in rhesus monkeys. Lorcaserin effects were compared to effects produced by saline substitution and by 7-day treatment with the opioid antagonist naltrexone.MethodsAdult male (1) and female (6) rhesus monkeys were trained to respond under a concurrent schedule of food delivery (1g pellets, fixed-ratio 100 schedule) and intravenous heroin injections (0-0.032 mg/kg/injection, fixed-ratio 10 schedule) during daily 2h sessions. Heroin choice dose-effect functions were determined daily before and following 7-day saline substitution or 7-day continuous treatment with naltrexone (0.0032-0.032 mg/kg/h, IV) or lorcaserin (0.032-0.32 mg/kg/h, IV).ResultsUnder baseline conditions, increasing heroin doses maintained a dose-dependent increase in heroin choice. Both saline substitution and 7-day naltrexone treatment significantly attenuated heroin choice and produced a reciprocal increase in food choice. Continuous lorcaserin treatment significantly increased heroin choice.ConclusionsIn contrast to saline substitution and naltrexone, lorcaserin treatment was ineffective to reduce heroin-vs.-food choice. These preclinical results do not support the therapeutic potential of lorcaserin as a candidate OUD treatment.

In India, biodiversity data and information are gaining significance for sustainable development and preparing National Biodiversity Strategies and Action Plans (NBSAPs). Civil societies and individuals are seeking open access to data and information generated with public funds, whereas sensitivity requirements often demand restrictions on the availability of sensitive data. In India, the traditional classification of data for sharing was based on the "Open Series Data" model; i.e. data not specifically included remains inaccessible. The National Data Sharing and Accessibility Policy (NDSAP Anonymous 2012Suppl. material 1) published in 2012 produced a new data sharing framework more focused on the declaration of data as closed. NDSAP is a clear statement that data that are produced by the Government of India should be shared openly. Although much of the verbiage is focused on sharing within the Government to meet national goals, the document does include clear statements about sharing with the public. The policy is intended to apply "to all data and information created, generated, collected and archived using public funds provided by the Government of India". The policy is quite clear that it should apply to all such data, and that such data should be categorized into open-access, registered-access, or restricted-access. NDSAP indicates that all Government of India-produced/funded data is to be opened to the broader community, but provides three access categories (open, registered, restricted). Although NDSAP does not offer much guidance about what sorts of data should fall in each of the categories, it clearly focuses on data sensitive in terms of national security (i.e., data that must be restricted), such as high-resolution satellite imagery of disputed border regions. Institutions collecting biodiversity data usually include primary, research-grade data in the restricted-access category and secondary / derived data (e.g., vegetation maps, species distribution maps) in the open or registered-access category. The conservative approach of not making bioidiversity data easily accessible, is not in accordance with the NDSAP policy, which emphasizes the openness of data. It also counters the main currents in science, which are shifting massively in the direction of opening access to data. Though NDSAP was intended for full implementation by 2014, its uptake by the institutions engaged in primary biodiversity data collection has been slow mainly because: providing primary data in some cases can endanger elements of the natural world; and many researchers wish to keep the data that result from their research activities shielded from full, open access out of a desire to retain control of those data for future analysis or publication. providing primary data in some cases can endanger elements of the natural world; and many researchers wish to keep the data that result from their research activities shielded from full, open access out of a desire to retain control of those data for future analysis or publication. Biodiversity data collected as part of institutional activities belong, in some sense, to the institution, and the institution should value such data over the long term. If institutions curate their biodiversity data for posterity, they can reap the benefits. Imagine the returns if biodiversity data from current ongoing projects were to be compared to data collected 50-100 years later. Thus, organizations should emphasize the long-term view of institutionalizing data resources through fair data restrictions and emphasise on public access, rather than on individual rights and control. This approach may be debatable, but we reckon that it will translate into massive science pay-offs.

Beginning in 2012, the JRS Biodiversity Foundation funded the University of Kansas to carry out a series of courses covering the breadth of the field of biodiversity informatics in cities across Africa. The Biodiversity Informatics Training Curriculum (BITC) was created from these events that used in-person courses taught by world experts in biodiversity informatics fields. The courses reached 120+ students and young professionals from 23 countries across Africa, and the digital videos of the courses reached thousands of viewers and users worldwide. BITC1 concluded in 2015 and a biodiversity informatics "curriculum" was published in the form of a compendium of BITC course materials (Peterson and Ingenloff 2016)—this curriculum has now been used as the basis for multiple programs of study around the world. BITC2 is now funded, again thanks to the JRS Biodiversity Foundation—this second version involves longer, more thematically oriented courses to be held in three east and southern African countries. The first will be held in Rwanda, in September 2019, and will focus on "Measuring Essential Biodiversity Variables and Ecosystem Services." BITC2 courses will begin with an open symposium, and then will proceed with intensive, hands-on, goal-oriented workshops with a small number of participants. The overall objective of the BITC is a community-oriented and community-run set of training events that can provide avenues to advanced study, international collaboration, and region-wide integration of efforts in biodiversity informatics. BITC2 has four main goals: implement new training dimensions in both an open symposium forum and an intensive, goal-and-product-focused approach that we tested in the later courses of BITC1; expand access to learning resources via subtitling and translation; build collaborative BITC communities via social media platforms; and build within-Africa capacity in biodiversity informatics via high-level involvement of a number of African scientists and educators. implement new training dimensions in both an open symposium forum and an intensive, goal-and-product-focused approach that we tested in the later courses of BITC1; expand access to learning resources via subtitling and translation; build collaborative BITC communities via social media platforms; and build within-Africa capacity in biodiversity informatics via high-level involvement of a number of African scientists and educators. These goals will be achieved via three, once-yearly symposium/course combination events which will be organized and implemented by combined leadership teams from the UK, USA, and African countries, and are intended to provide a combined total of 30-33 days of training to 36-42 trainees. Here we present the format of the BITC1 and BITC2 courses, and the positive and negative outcomes that have resulted, with an eye to optimal design of future such initiatives.

Producing components using metal additive manufacturing processes, such as powder bed fusion, presents manufacturing and measurement challenges, but also significant opportunities. The as-built surface may include overhanging (re-entrant) features not intentionally included in the design, but that aid in component functionality. In addition, the additive manufacturing process presents opportunities to design and manufacture re-entrant features intentionally. Re-entrant features increase the specific surface area and, in addition, produce mechanical locking to the surface. These re-entrant features may be intended to improve surface performance in areas such as biological cell attachment, coating adhesion, electrical capacitance and battery plate design, fluid flow and material cooling. Re-entrant features may prove difficult or impossible to measure and characterise using conventional line-of-sight surface metrology instrumentation, however the correct measurement of these surfaces may be vital for functional optimisation. X-ray computed tomography does have the ability to image internal and re-entrant features. This paper reports on the measurement of re-entrant features using X-ray computed tomography and the extraction of actual surface area information (including re-entrant surfaces) from sample additively manufactured surfaces. A proposed new surface texture parameter, Sdrprime, is discussed. This parameter is applicable to true 3D data, including re-entrant features, and is intended to relate directly to the component surface functional performance. The errors produced when using line-of-sight instruments and height map parameter generation per ISO 25178-2 to evaluate surfaces that include re-entrant features are discussed. Measurement results for electron beam melting and selective laser melting additively manufactured components, together with simulated structured surfaces, are presented.

Ecological niche models are popular tools used in fields such as ecology, biogeography, conservation biology, and epidemiology. These models are used commonly to produce representations of species’ potential distributions, which are then used to answer other research questions; for instance, where species richness is highest, where potential impacts of climate change can be anticipated, or where to expect spread of invasive species or disease vectors. Although these representations of potential distributions are variable which contributes to uncertainty in these predictions, model variability is neglected when presenting results of ecological niche model analyses. Here, we present examples of how to quantify and represent variability in models, particularly when models are transferred in space and time. To facilitate implementations of analyses of variability, we developed R functions and made them freely available. We demonstrate means of understanding how much variation exists and where this variation is manifested in geographic space. Representing model variability in geographic space gives a reference of the uncertainty in predictions, so analyzing this aspect of model outcomes must be a priority when policy is to be set or decisions taken based on these models. Our open access tools also facilitate post modeling process that otherwise could take days of manual work.