11-O-Debenzoyltashironin (1) is a member of the neurotrophic sesquiterpenes, trace plant metabolites that enhance neurite outgrowth in cultured neurons. We report its synthesis in six steps from a ...butenolide heterodimer via its likely biosynthetic precursor, 3,6-dideoxy-10-hydroxypseudoanisatin, here identified as the chain tautomer of 1. Access to the tashironin chemotype fills a gap in a comparison set of convulsive and neurotrophic sesquiterpenes, which we hypothesized to share a common target. Here we show that both classes mutually hyperexcite rat cortical neurons, consistent with antagonism of inhibitory channels and a mechanism of depolarization-induced neurite outgrowth.
Oxide-dispersion-strengthened (ODS) alloys have long been considered for high temperature turbine, spacecraft, and nuclear reactor components due to their high temperature strength and radiation ...resistance. Conventional synthesis approaches of ODS alloys involve ball milling of powders and consolidation. In this work, a process-synergistic approach is used to introduce oxide particles during laser powder bed fusion (LPBF). Chromium (III) oxide (Cr
O
) powders are blended with a cobalt-based alloy, Mar-M 509, and exposed to laser irradiation, resulting in reduction-oxidation reactions involving metal (Ta, Ti, Zr) ions from the metal matrix to form mixed oxides of increased thermodynamic stability. A microstructure analysis indicates the formation of nanoscale spherical mixed oxide particles as well as large agglomerates with internal cracks. Chemical analyses confirm the presence of Ta, Ti, and Zr in agglomerated oxides, but primarily Zr in the nanoscale oxides. Mechanical testing reveals that agglomerate particle cracking is detrimental to tensile ductility compared to the base alloy, suggesting the need for improved processing methods to break up oxide particle clusters and promote their uniform dispersion during laser exposure.
NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative diseases, epilepsy, traumatic brain injury, substance abuse disorder ...(SUD), and major depressive disorder (MDD). (S)-ketamine was the first of a novel class of antidepressants, rapid-acting antidepressants, to be approved for medical use. The stereoisomer, (R)-ketamine (arketamine), is currently under development for treatment-resistant depression (TRD). The compound has demonstrated efficacy in multiple animal models. Two clinical studies disclosed efficacy in TRD and bipolar depression. A study by the drug sponsor recently failed to reach a priori clinical endpoints but post hoc analysis revealed efficacy. The clinical value of (R)-ketamine is supported by experimental data in humans and rodents, showing that it is less sedating, does not produce marked psychotomimetic or dissociative effects, has less abuse potential than (S)-ketamine, and produces efficacy in animal models of a range of neurological and psychiatric disorders. The mechanisms of action of the antidepressant effects of (R)-ketamine are hypothesized to be due to NMDA receptor antagonism and/or non-NMDA receptor mechanisms. We suggest that further clinical experimentation with (R)-ketamine will create novel and improved medicines for some of the neurological and psychiatric disorders that are underserved by current medications.
AMPA-glutamate receptors (AMPARs) are expressed throughout the CNS and mediate the majority of fast excitatory synaptic transmission. Ampakines are orally available small molecules that bind ...allosterically to AMPARs and enhance excitatory currents elicited by the endogenous agonist glutamate. In preclinical studies, ampakines are effective in ameliorating symptoms in a battery of neurodegenerative and neuropsychiatric diseases in which excitatory transmission is compromised. However, the development of ampakines as medicines was slowed by the emergence of neurotoxicity and seizures in rodents due to some ampakines. Here, we describe the preclinical pharmacology of a novel ampakine, N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzoc1,2,5 oxadiazole-5-carboxamide (CX1739), that does not induce seizures in animals or humans at efficacious doses. CX1739 dose-dependently enhanced long-term potentiation in vivo in rats, a process thought to be a molecular substrate of learning and memory. Correspondingly, CX1739 dose-dependently enhanced performance in assays that probed multiple aspects of cognition—the novel object recognition test, the win shift radial arm maze, and the five-choice serial reaction time task in rats. CX1739 also abrogated amphetamine-induced locomotor activity, demonstrating that it may be given in conjunction with stimulants for pro-cognitive gains while mitigating the side effects of stimulant-based ADHD medications. CX1739 also rapidly reversed opioid-induced respiratory depression. While efficacy in these tests occurred at doses of 0.03–18 mg/kg, there were no adverse events detected in safety studies in rats up to 2000 mg/kg. These preclinical findings suggest that CX1739 can be translated safely into the clinical setting to potentially treat dementia, neuropsychiatric disorders, and the life-threatening complication of opiate-induced suppression of endogenous inspiratory breathing rhythms.
Display omitted
The ‘neurotrophic sesquiterpenes’ refer to a group of molecules derived from the Illicium genus of flowering plant. They display neurotrophic effects in cultured neuron preparations ...and have been suggested to be cognitive enhancers and potential therapeutics for neurodegenerative disorders and dementias. Recent synthetic advances generated sufficient quantities of jiadifenolide for in vivo investigation into its biological effects. Jiadifenolide did not induce convulsions in mice nor did it enhance or diminish convulsions induced by pentylenetetrazole. Other negative allosteric modulators of GABAA receptors, picrotoxin, tetramethylenedisulfotetramine (TETS), and bilobalide all induced convulsions. Either i.p. or i.c.v. dosing generated micromolar plasma and brain levels of jiadifenolide but only small effects on locomotion of mice. However, jiadifenolide decreased d-amphetamine-induced hyperlocomotion in mice, an antipsychotic-like drug effect. Jiadifenolide did not significantly alter body temperature or behavior in the forced-swim test in mice. Molecular simulation data suggested a potential site in the pore/M2 helix region that is at an overlapping, yet lower position than those observed for other ‘cage convulsant’ compounds such as TETS and picrotoxin. We hypothesize that a position nearer to the entrance of the pore channel may allow for easier displacement of jiadifenolide from its blocking location leading to lower potency and lower side-effect liability. Like jiadifenolide, memantine (Namenda), one of the few drugs used in the symptomatic treatment of dementias, occupies a unique site on the NMDA receptor complex that creates low binding affinity that is associated with its reduced side-effect profile. Given the potential therapeutic applications of jiadifenolide and its relatively inert effects on overt behavior, the possibility of clinical utility for jiadifenolide and related compounds becomes intriguing.
A clinical case of a 19-year-old male patient with pharmacoresistant seizures occurring following parieto-occipital tumor-resection at age 6 is described. Seizure surgery work-up included prolonged ...video EEG monitoring and head CT without contrast. Seizure focus was localized to the left temporal lobe, and we felt that the patient was an excellent candidate for seizure surgery. The patient underwent a left frontotemporal craniotomy for removal of the seizure focus with intraoperative electrocorticography (ECoG) conducted pre and post resection. ECoG recordings pre- and post-resection confirmed resolution of seizure generation. Imaging obtained immediately postoperatively showed complete resection of the residual tumor with no evidence of recurrence in follow-ups. A year after the surgery the patient is seizure-free but remains on seizure medication. With the patient's consent the excised epileptogenic tissue was used for ex-vivo research studies. The microelectrode recordings confirmed epileptiform activity in the excised tissue incubated in excitatory artificial cerebrospinal fluid. The epileptiform activity in the epileptogenic tissue was suppressed by addition of KRM–II–81, a novel α2/3 subtype preferring GABAA receptor (GABAAR) potentiator with previously demonstrated antiepileptic efficacy in multiple animal models of epilepsy and with reduced potential for CNS side-effects compared to classical benzodiazepine GABAAR potentiators. These findings support the proposition that KRM–II–81 might reduce seizure burden in pharmacoresistant patients.
Sharing space with large carnivores on a human-dominated continent like Europe results in multiple conflictful interactions with human interests, of which depredation on livestock is the most ...widespread. We conducted an analysis of the impact by all four European large carnivores on sheep farming in 10 European countries, during the period 2010–2015. We ran a hierarchical Simultaneous Autoregressive model, to assess the influence of several ecological factors on the reported depredation levels. About 35,000 (SD = 4110) sheep kills were compensated in the ten countries as caused by large carnivores annually, representing 0.5% of the total sheep stock. Of them, 45% were recognized as killed by wolves, 24% by wolverines, 19% by lynx and 12% by bears. We found a positive relationship between wolf distribution and the number of compensated sheep, but not for the other three species. Depredation levels were lower in the areas where large carnivore presence has been continuous compared to areas where they disappeared and returned in the last 50 years. Our study shows that a few large carnivores can produce high damage, when the contribution of environmental, social, and economic systems predisposes for it, whereas large populations can produce a limited impact when the same components of the system reduce the probability that depredations occur. Time of coexistence plays in favour of a progressive reduction in the associated costs, provided that the responsible agencies focus their attention both on compensation and co-adaptation.
Context
Many carnivores are attracted to rugged terrain, rocky areas, and conspicuous relief features. However, most of the previous research is limited to general topographical habitat ...characteristics and rarely consider the effects of microhabitat characteristics.
Objectives
We used the Eurasian lynx (
Lynx lynx
) as a model species to investigate the effects of microhabitat characteristics and human infrastructure on habitat selection. We also tested whether there is evidence for a functional response in habitat selection across a large gradient of habitat availability.
Methods
We developed a new approach for detecting rocky outcrops from airborne LiDAR data. In combination with other remote sensing techniques and GPS-telemetry data, we assessed lynx habitat selection and functional responses across two geologically contrasting areas in Europe.
Results
We detected > 1 million rocky outcrops and confirmed their strong selection by lynx. Lynx also selected steep, rugged, and rocky areas, especially for day-resting sites. Furthermore, lynx avoided paths during the day but selected them and other linear anthropogenic infrastructure during the night, indicating the behaviour-specific impact of human infrastructure. We also observed a functional response in the selection of rocky and rugged areas, as lynx’ selection of such habitats increased with their lower availability. This highlights the importance of preserving such terrains, especially when they are rare in a landscape.
Conclusions
Our results highlight the importance of incorporating remote sensing techniques and data on microhabitat features in animal habitat selection research. We also recommend caution when developing new infrastructure for human recreation or promoting its use near geomorphological features and in rugged terrain.
Automatic methods for detecting and delineating relief features allow remote and low-cost mapping, which has an outstanding potential for wildlife ecology and similar research. We applied a ...filled-DEM (digital elevation model) method using LiDAR (Light Detection and Ranging) data to automatically detect dolines and other karst depressions in a rugged terrain of the Dinaric Mountains, Slovenia. Using this approach, we detected 9711 karst depressions in a 137 km2 study area and provided their basic morphometric characteristics, such as perimeter length, area, diameter, depth, and slope. We performed visual validation based on shaded relief, which indicated 83.5% accordance in detecting depressions. Although the method has some drawbacks, it proved suitable for detection, general spatial analysis, and calculation of morphometric characteristics of depressions over a large scale in remote and forested areas. To demonstrate its applicability for wildlife research, we applied it in a preliminary study in combination with GPS-telemetry data to assess the selection of these features by two wild felids, the Eurasian lynx (Lynx lynx) and the European wildcat (Felis silvestris). Both species selected for vicinity of karst depressions, among which they selected for larger karst depressions. Lynx also regularly killed ungulate prey near these features, as we found more than half of lynx prey remains inside or in close vicinity of karst depressions. These results illustrate that karstic features could play an important role in the ecology of wild felids and warrant further research, which could be considerably assisted with the use of remote detection of relief features.
As large carnivores recover throughout Europe, their distribution needs to be studied to determine their conservation status and assess the potential for human‐carnivore conflicts. However, efficient ...monitoring of many large carnivore species is challenging due to their rarity, elusive behavior, and large home ranges. Their monitoring can include opportunistic sightings from citizens in addition to designed surveys. Two types of detection errors may occur in such monitoring schemes: false negatives and false positives. False‐negative detections can be accounted for in species distribution models (SDMs) that deal with imperfect detection. False‐positive detections, due to species misidentification, have rarely been accounted for in SDMs. Generally, researchers use ad hoc data‐filtering methods to discard ambiguous observations prior to analysis. These practices may discard valuable ecological information on the distribution of a species. We investigated the costs and benefits of including data types that may include false positives rather than discarding them for SDMs of large carnivores. We used a dynamic occupancy model that simultaneously accounts for false negatives and positives to jointly analyze data that included both unambiguous detections and ambiguous detections. We used simulations to compare the performances of our model with a model fitted on unambiguous data only. We tested the 2 models in 4 scenarios in which parameters that control false‐positive detections and true detections varied. We applied our model to data from the monitoring of the Eurasian lynx (Lynx lynx) in the European Alps. The addition of ambiguous detections increased the precision of parameter estimates. For the Eurasian lynx, incorporating ambiguous detections produced more precise estimates of the ecological parameters and revealed additional occupied sites in areas where the species is likely expanding. Overall, we found that ambiguous data should be considered when studying the distribution of large carnivores through the use of dynamic occupancy models that account for misidentification.
Uso de Detecciones Ambiguas para Mejorar las Estimaciones a partir de Modelos de Distribución de Especies
Resumen
Conforme los carnívoros mayores se recuperan en toda Europa, su distribución requiere ser estudiada para determinar su estado de conservación y para evaluar el potencial de conflictos entre humanos y carnívoros. Sin embargo, el monitoreo eficiente de muchas especies de carnívoros mayores es complicada debido a su rareza, comportamiento elusivo y las grandes extensiones de su ámbito de hogar. Su monitoreo puede incluir avistamientos oportunistas por parte de los ciudadanos, además de los censos diseñados. Pueden ocurrir dos tipos de errores de detección en dichos métodos de monitoreo: negativos falsos y negativos positivos. La detección de los falsos negativos puede justificarse en los modelos de distribución de especies (MDE) que manejan la detección imperfecta. La detección de falsos positivos por causa de la identificación errónea rara vez se justifica en los MDE. Los investigadores usan generalmente métodos con filtración de datos ad hoc para descartar las observaciones ambiguas previo al análisis. Estas prácticas pueden descartar información ecológica variable sobre la distribución de una especie. Investigamos los costos y beneficios de la inclusión de tipos de datos que podrían contener falsos positivos en lugar de descartarlos de los MDE para carnívoros mayores. Usamos un modelo dinámico de ocupación que justificó simultáneamente los falsos positivos y falsos negativos para analizar en conjunto los datos que incluían tanto las detecciones no ambiguas como las ambiguas. Usamos simulaciones para comparar el desempeño de nuestro modelo con el de un modelo ajustado solamente para datos no ambiguos. Probamos los dos modelos en cuatro escenarios en los que variaron los parámetros que controlan la detección de falsos positivos y de detecciones verdaderas. Aplicamos nuestro modelo a datos del monitoreo del lince euroasiático (Lynx lynx) en los Alpes. La suma de las detecciones ambiguas incrementó la precisión de las estimaciones de los parámetros. Para el lince euroasiático, la incorporación de las detecciones ambiguas produjo estimaciones más precisas de los parámetros ecológicos y reveló sitios ocupados adicionales en áreas en donde la especie probablemente se esté expandiendo. En general, encontramos que los datos ambiguos deberían ser considerados cuando se estudia la distribución de carnívoros mayores por medio del uso de modelos dinámicos de ocupación que justifican la identificación errónea.
摘要
随着欧洲大型食肉动物的恢复, 我们需要研究这些物种的分布以确定它们的保护现状, 并评估人兽冲突的可能性。然而, 由于大型食肉动物的稀有性、回避行为和较大的活动范围, 对它们进行有效监测困难重重。大型食肉动物的监测除了设计调查外, 还可以包含公民的偶然目击。这样的监测方案可能出现两类检测误差: 假阴性和假阳性。假阴性的监测结果可用于物种分布模型分析, 该模型可处理有缺陷的监测。而因物种鉴定错误产生的假阳性结果在物种分布模型中却很少被考虑在内。通常情况下, 研究者在分析前会用特定的数据过滤方法来去除不确定的观察数据。这种做法也可能丢掉对物种分布有价值的生态学信息。我们研究了保留可能含有假阳性发现的数据类型 (而不是丢弃这些数据) 对大型食肉动物物种分布模型的利弊。我们利用同时考虑假阴性和阳性的动态占有模型, 共同分析了包含确定发现和不确定发现的数据。通过模拟, 我们比较了这个模型和仅用真实数据拟合的模型的表现。我们选择了不同的控制假阳性和真阳性的参数, 在四种情况下检验了这两个模型。我们还将这一模型应用于欧洲阿尔卑斯山脉的欧亚猞猁 (Lynx lynx) 的监测数据, 加入不确定的发现数据可以提高参数估计的精确度。对欧亚猞猁来说, 加入不确定的发现可以对生态学参数作出更精确的估计, 揭示这个物种的分布范围可能正在扩张。总之, 我们的研究表明, 在研究大型食肉动物的分布时, 可以用考虑到物种鉴定错误的动态占有模型来利用不确定的数据。翻译: 胡怡思; 审校: 聂永刚
Article impact statement: Use of ambiguous detections can improve understanding of large‐carnivore distribution dynamics.
PDF
