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Geodiversity, encompassing various geophysical elements, can have an important impact on species distribution and affect animal behaviour patterns. Although many wild felids are attracted to rugged terrain and conspicuous relief features, most previous research was limited to general topographical characteristics (e.g., slope or terrain ruggedness) and rarely considered the effects of specific microhabitat characteristics. This gap is primarily due to the limited availability of high-resolution digital terrain models (DTMs) and relief features data at larger scales. However, LiDAR DTMs can be used in combination with various automatic methods to detect relief features, enabling non-contact and accurate mapping of large, remote and densely-forested areas. Here, we investigated the selection patterns of various karstic relief features, as well as topographic, anthropogenic and vegetation characteristics, by two sympatric felids, the Eurasian lynx (Lynx lynx) and the European wildcat (Felis silvestris), in the Dinaric Mountains, Slovenia. We used LiDAR DTM to calculate topographic characteristics and detect karst relief features based on automatic methods. We compared the selection of these features between the GPS-collared lynx and wildcats under a use-availability approach. We also investigated the differences in the selection of these features by lynx based on their origin and experience (remnant vs. translocated and naive vs. experienced, respectively). We observed significant impact of relief features on space use by both felids and detected distinct selection patterns between the two species. Lynx selected rugged terrain and proximity of caves, cliffs, karst depressions, ridges, small rocky outcrops, and roads, but avoided human settlements and forest edges. Wildcats selected areas with lower surface slope, closer to main roads, forest edges, caves and ridges, but avoided cliffs, forest roads and human settlements. We observed stronger selection/avoidance patterns among the translocated compared to the remnant lynx, while the differences in experience levels were less important. Our study demonstrates the potential of integrating remote sensing techniques and information on geodiversity into the study of animal spatial ecology. Furthermore, our results indicate that specific relief features provide important abiotic microhabitats for felids and may influence habitat segregation between sympatric species. Our findings provide further evidence for the importance of geodiversity conservation and the need to incorporate abiotic microhabitat features in wildlife habitat selection studies.

Abstract Integrating data across studies with traditional microsatellite genetic markers requires careful calibration and represents an obstacle for investigation of wide-ranging species where populations require transboundary management. We used the “yardstick” method to compare results published across Europe since 2002 and new wolf (Canis lupus) genetic profiles from the Carpathian Mountains in Central Europe and the Dinaric Mountains in Southeastern Europe, with the latter as our reference population. We compared each population with Dinaric wolves, considering only shared markers (range 4–17). For each population, we calculated standard genetic diversity indices plus calibrated heterozygosity (Hec) and allelic richness (Ac). Hec and Ac in Dinaric (0.704 and 9.394) and Carpathian wolves (0.695 and 7.023) were comparable to those observed in other large and mid-sized European populations, but smaller than those of northeastern Europe. Major discrepancies in marker choices among some studies made comparisons more difficult. However, the yardstick method, including the new measures of Hec and Ac, provided a direct comparison of genetic diversity values among wolf populations and an intuitive interpretation of the results. The yardstick method thus permitted the integration of diverse sources of publicly available microsatellite data for spatiotemporal genetic monitoring of evolutionary potential.

Artificial feeding of wildlife is a widespread, but controversial, management practice with many positive and negative effects. Besides the effects on the target species, it can also affect other (non-target) species by modulating interspecific interactions. Previous research showed that the presence of artificial feeding sites for bears and ungulates increases the risk of kleptoparasitism by the brown bear (Ursus arctos) on kills made by Eurasian lynx (Lynx lynx). However, it remains unknown whether lynx adjust their behaviour to the distribution of artificial feeding sites, which also attract potential prey (ungulates) for lynx. Using GPS telemetry data, we explored the spatiotemporal lynx response to such sites and studied how this response varied with experience level, i.e. between adult resident individuals ('experienced lynx') and juveniles and/or translocated individuals ('naïve lynx'). We found that lynx experience played an important role in the use of artificial feeding sites. Specifically, while both experienced and naïve lynx selected feeding sites while moving within their home range, the attraction was stronger among the naïve lynx. Considering the distribution of kill sites, naïve lynx killed prey closer to the artificial feeding sites than expected, while experienced lynx avoided them. Finally, the proximity to artificial feeding sites by experienced lynx showed an annual variation, matching the seasonal kleptoparasitism risk, with overall closer proximity to feeding sites during the winter, when bears are less active, which is also when ungulates are more concentrated around feeding sites. Our study suggests that, despite the relatively recent introduction of artificial feeding in the ecosystems, wildlife can learn to respond to the altered interactions with other species. However, this appears to be a learning process with manifold management and conservation implications. A better understanding of species interactions and space use in the context of resource manipulation is increasingly relevant as the use of anthropogenic food by wildlife is nowadays substantial and widespread across most parts of the world.

Wolves have large spatial requirements and their expansion in Europe is occurring over national boundaries, hence the need to develop monitoring programs at the population level. Wolves in the Alps are defined as a functional population and management unit. The range of this wolf Alpine population now covers seven countries: Italy, France, Austria, Switzerland, Slovenia, Liechtenstein and Germany, making the development of a joint and coordinated monitoring program particularly challenging. In the framework of the Wolf Alpine Group (WAG), researchers developed uniform criteria for the assessment and interpretation of field data collected in the frame of different national monitoring programs. This standardization allowed for data comparability across borders and the joint evaluation of distribution and consistency at the population level. We documented the increase in the number of wolf reproductive units (packs and pairs) over 21 years, from 1 in 1993–1994 up to 243 units in 2020–2021, and examined the pattern of expansion over the Alps. This long-term and large-scale approach is a successful example of transboundary monitoring of a large carnivore population that, despite administrative fragmentation, provides robust indexes of population size and distribution that are of relevance for wolf conservation and management at the transnational Alpine scale.

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.

Ampakines—positive allosteric modulators of AMPA-type glutamate receptors (AMPARs)—are drug candidates that have shown substantial promise in pre-clinical models of various neurodegenerative and neuropsychiatric diseases. Much of the study of ampakines has focused on how these drugs modulate neuronal AMPARs to achieve certain therapeutic effects. However, astrocytes also express functional AMPARs and their physiology may be sensitive to modulation by ampakines. Herein, we investigate the effects of multiple ampakines on calcium levels in cortical astrocytes. We find that ampakines augment cytosolic calcium elevations in astrocytes to an extent far greater than that achieved by AMPA alone. This effect is amenable to competitive AMPAR blockade. Furthermore, calcium induction is sensitive to phospholipase Cβ antagonism and blockade of inositol triphosphate receptors located on the endoplasmic reticulum. Low-impact ampakines exerted weaker effects on cytosolic calcium levels in astrocytes and higher concentrations were required to observe an effect. Furthermore, high doses of the low-impact ampakine, CX717, were not toxic to cortical astrocytes at high concentrations, which may serve to differentiate low-impact ampakines from classical AMPAR positive modulators like cyclothiazide. As ampakines are further developed for clinical use, it would be prudent to determine the extent to and manner by which they affect astrocytes, as these effects may also underpin their therapeutic utility in CNS pathologies.

Ampakines are a class of orally available positive allosteric modulators of the AMPA-glutamate receptor (AMPAR) and have therapeutic implications for neurological/neuropsychiatric disorders in which AMPAR signaling is compromised. Low-impact ampakines are a distinct subclass of drugs that only modestly offset receptor desensitization and do not alter agonist binding affinity and thus lack the neurotoxicity and epileptogenic effects associated with other AMPAR modulators. In these studies, we describe the pre-clinical pharmacology of ampakine 1-(benzofurazan-5-ylcarbonyl)morpholine (CX717). CX717 modestly offsets desensitization in hippocampal patches and augments synaptic transmission in vivo. CX717 also enhances long-term potentiation in rats, which is crucial for learning and memory. CX717 enhances performance in the eight-arm radial maze and abrogates amphetamine-induced locomotor activity while being devoid of cataleptic activity in rats. CX717 also ameliorates alfentanil-induced respiratory depression in rats and is not toxic to cultured rat neurons. CX717 is active at doses of 0.3–10 mg/kg and lacked serious adverse events in safety studies in mice up to 2000 mg/kg. CX717 was also previously shown to be safe in humans and effective in reversing opiate-induced respiratory depression and hyperactivity and inattentiveness in adults with ADHD. These findings support the continued clinical investigation of CX717 in the treatment of ADHD, dementia, and opiate-induced respiratory depression.

Traumatic brain injury (TBI) has reached epidemic proportions worldwide. The consequences of TBI can be severe even with repetitive mild trauma. If death and coma are avoided, the consequences of TBI in the long term typically involve dizziness, sleep disturbances, headache, seizures, cognitive impairment, focal deficits, depression, and anxiety. The severity of brain injury is a significant predictor of outcome. However, the heterogenous nature of the injury makes prognosis difficult. The present review of the literature focuses on the genetics of TBI including genome wide (GWAS) data and candidate gene associations, among them brain-derived neurotrophic factor (BDNF) with TBI and development of post-traumatic epilepsy (PTE). Molecular biomarkers of TBI are also discussed with a focus on proteins and the inflammatory protein IL1-β. The secondary medical sequela to TBI of cognitive impairment, PTE, headache and risk for neurodegenerative disorders is also discussed. This overview of TBI concludes with a review and discussion of the medical management of TBI and the medicines used for and being developed at the preclinical and clinical stages for the treatment of TBI and its host of life-debilitating symptoms.

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)benzo[c][1,2,5] 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.

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.

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.

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 (Cr2O3) 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.

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.