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Purpose The aim of our research work was to develop dermally applicable, lidocaine hydrochloride (LID-HCl)-containing semisolid in situ film-forming systems (FFSs) using the Quality by Design (QbD) approach to increase drug permeation into the skin. Methods Silicones were used to improve the properties of formulations and to increase the permeation through the skin. The QbD approach was applied to ensure quality-based development. With initial risk assessment, the critical material attributes (CMAs) and the critical process parameters (CPPs) were identified to ensure the required critical quality attributes (CQAs). Results During the initial risk assessment, four high-risk CQAs, namely in vitro drug release, in vitro drug permeation, drying properties, and mechanical properties, and three medium-risk CQAs, namely pH, viscosity, and film appearance were identified and investigated. Moreover, four high-risk CMAs were also considered during the formulation: permeation enhancing excipients, drying excipients, film-forming excipients, and emollients. During the experiments, LID-HCl influenced these critical parameters highly, thereby reducing the drying time. The formulation containing 25% silicone showed the best mechanical properties (49 mN skin adhesion, 20.3% film flexibility, 1.27 N film burst strength), which could predict better patient adherence. In addition, in vitro permeation studies showed that formulation containing 50% silicone has the fastest permeation rate. The flux of diffused API was 6.763 µg/cm2/h, which is much higher compared to the silicone-free formulation (1.5734 µg/cm2/h), and it can already be observed in the lower part of the dermis in 0.5 hour. Conclusion Our results show that LID-HCl has great influence on the critical parameters of FFSs. The silicone content can improve the applicability of formulations and has a favorable effect on the permeation rate of LID-HCl into the skin.

Human brains process lexical meaning separately from emotional prosody of speech at higher levels of the processing hierarchy. Recently we demonstrated that dog brains can also dissociate lexical and emotional prosodic information in human spoken words. To better understand the neural dynamics of lexical processing in the dog brain, here we used an event-related design, optimized for fMRI adaptation analyses on multiple time scales. We investigated repetition effects in dogs’ neural (BOLD) responses to lexically marked (praise) words and to lexically unmarked (neutral) words, in praising and neutral prosody. We identified temporally and anatomically distinct adaptation patterns. In a subcortical auditory region, we found both short- and long-term fMRI adaptation for emotional prosody, but not for lexical markedness. In multiple cortical auditory regions, we found long-term fMRI adaptation for lexically marked compared to unmarked words. This lexical adaptation showed right-hemisphere bias and was age-modulated in a near-primary auditory region and was independent of prosody in a secondary auditory region. Word representations in dogs’ auditory cortex thus contain more than just the emotional prosody they are typically associated with. These findings demonstrate multilevel fMRI adaptation effects in the dog brain and are consistent with a hierarchical account of spoken word processing.

The dog (Canis familiaris) is a promising non-invasive translational model of human cognitive neuroscience including sleep research. Studies on the relationship between sleep and cognition in dogs and other canines are only just emerging, but still very scarce. Here we provide insight into canine sleep and sleep-related physiological and cognitive/behavioral phenomena. We show that dogs do not only fulfil all behavioral and polygraphic criteria of sleep, but are characterized by sleep homeostasis, diurnal pattern of activity, circadian rhythms, ultradian sleep cycles, socio-ecologically and environmentally shaped wake-sleep structure, sleep-related memory improvement, as well as specific sleep disorders. Developmental patterns of sleep-related physiological indices, as well as parallel trends in age-dependent changes in cognition and sleep were evidenced in dogs.

Emotionally expressive non-verbal vocalizations can play a major role in human-robot interactions. Humans can assess the intensity and emotional valence of animal vocalizations based on simple acoustic features such as call length and fundamental frequency. These simple encoding rules are suggested to be general across terrestrial vertebrates. To test the degree of this generalizability, our aim was to synthesize a set of artificial sounds by systematically changing the call length and fundamental frequency, and examine how emotional valence and intensity is attributed to them by humans. Based on sine wave sounds, we generated sound samples in seven categories by increasing complexity via incorporating different characteristics of animal vocalizations. We used an online questionnaire to measure the perceived emotional valence and intensity of the sounds in a two-dimensional model of emotions. The results show that sounds with low fundamental frequency and shorter call lengths were considered to have a more positive valence, and samples with high fundamental frequency were rated as more intense across all categories, regardless of the sound complexity. We conclude that applying the basic rules of vocal emotion encoding can be a good starting point for the development of novel non-verbal vocalizations for artificial agents.

In the present study, an electroless nickel (EN) plating method is applied for the coating of silicon carbide (SiC) particles. The particles of SiC(Ni) were added to the Sn–3.0Ag–0.5Cu matrix for the production of SAC305/SiC(Ni) composite by the powder metallurgy route. SAC305/xSi(Ni) composite was prepared by a planetary ball milling of the starting powder, followed by compacting and sintering. Nickel-coated silicon carbide particles and the lead-free solder matrix react together, forming different phases during sintering at temperature 200°C for 3 h. The microstructure, mechanical (compressive strength, microhardness, wettability, and porosity) and physical properties (density) of lead-free solder composite SAC305/SiC(Ni) were studied. The current research shows the successful application of electroless nickel (EN) plating method, and how nickel-coated SiC particles subsequently improve the mechanical properties and microstructure of lead-free solder.

Background: Recent studies suggest that clinically sound ventriculomegaly in dogs could be a preliminary form of the clinically significant hydrocephalus. We evaluated changes of ventricular volumes in awake functional magnetic resonance imaging (fMRI) trained dogs with indirectly assessed cognitive abilities over time (thus avoiding the use of anaesthetics, which can alter the pressure). Our research question was whether ventricular enlargement developing over time would have any detrimental effect on staying still while being scanned, which can be extrapolated to the ability to pay attention and to exert inhibition. Methods: Seven healthy dogs, 2&ndash, 8 years old at the baseline scan and 4 years older at rescan, participated in a rigorous and gradual training for staying motionless (&lt, 2 mm) in the magnetic resonance (MR) scanner without any sedation during 6 minute-long structural MR sequences. On T1 structural images, volumetric analyses of the lateral ventricles were completed by software guided semi-automated tissue-type segmentations performed with FMRIB Software Library (FSL, Analysis Group, Oxford, UK). Results and conclusion: We report significant enlargement for both ventricles (left: 47.46 %, right: 46.07 %) over time while dogs retained high levels of attention and inhibition. The results suggest that even considerable ventricular enlargement arising during normal aging does not necessarily reflect observable pathological changes in behavior.

Dogs live in 45% of households, integrated into various human groups in various societies. This is certainly not true for wolves. We suggest that dogs’ increased tractability (meant as individual dogs being easier to control, handle and direct by humans, in contrast to trainability defined as performance increase due to training) makes a crucial contribution to this fundamental difference. In this study, we assessed the development of tractability in hand-raised wolves and similarly raised dogs. We combined a variety of behavioural tests: fetching, calling, obeying a sit signal, hair brushing and walking in a muzzle. Wolf (N = 16) and dog (N = 11) pups were tested repeatedly, between the ages of 3–24 weeks. In addition to hand-raised wolves and dogs, we also tested mother-raised family dogs (N = 12) for fetching and calling. Our results show that despite intensive socialization, wolves remained less tractable than dogs, especially in contexts involving access to a resource. Dogs’ tractability appeared to be less context dependent, as they followed human initiation of action in more contexts than wolves. We found no evidence that different rearing conditions (i.e. intensive socialization vs. mother rearing) would affect tractability in dogs. This suggests that during domestication dogs might have been selected for increased tractability, although based on the current data we cannot exclude that the differential speed of development of dogs and wolves or the earlier relocation of wolves to live as a group explains some of the differences we found.

Generally, topically applied eye drops have low bioavailability due to short residence time and low penetration of the drug. The aim of the present study was to incorporate dexamethasone (DXM) into nano lipid carriers (NLC), which contain mucoadhesive polymer, in order to increase the bioavailability of the drug. A 23 factorial experimental design was applied, in which the three factors were the polymer, the DXM, and the emulsifier concentrations. The samples were analyzed for particle size, zeta potential, polydispersity index, and Span value. The significant factors were identified. The biocompatibility of the formulations was evaluated with human corneal toxicity tests and immunoassay analysis. The possible increase in bioavailability was analyzed by means of mucoadhesivity, in vitro drug diffusion, and different penetration tests, such as in vitro cornea PAMPA model, human corneal cell penetration, and ex vivo porcine corneal penetration using Raman mapping. The results indicated that DXM can be incorporated in stable mucoadhesive NLC systems, which are non-toxic and do not have any harmful effect on cell junctions. Mucoadhesive NLCs can create a depot on the surface of the cornea, which can predict improved bioavailability.

The domestic dog (Canis familiaris) is a promising animal model. Yet, the canine neuroscience literature is predominantly comprised of studies wherein (semi-)invasive methods and intensive training are used to study awake dog behavior. Given prior findings with humans and/or dogs, our goal was to assess, in 16 family dogs (1.5–7 years old; 10 males; 10 different breeds) the effects of pre-sleep activity and timing and location of sleep on sleep electrophysiology. All three factors had a main and/or interactive effect on sleep macrostructure. Following an active day, dogs slept more, were more likely to have an earlier drowsiness and NREM, and spent less time in drowsiness and more time in NREM and REM. Activity also had location- and time of day-specific effects. Time of day had main effects; at nighttime, dogs slept more and spent less time in drowsiness and awake after first drowsiness, and more time in NREM and in REM. Location had a main effect; when not at home, REM sleep following a first NREM was less likely. Findings are consistent with and extend prior human and dog data and have implications for the dog as an animal model and for informing future comparative research on sleep.

There is an ongoing need to improve animal models for investigating human behavior and its biological underpinnings. The domestic dog (Canis familiaris) is a promising model in cognitive neuroscience. However, before it can contribute to advances in this field in a comparative, reliable, and valid manner, several methodological issues warrant attention. We review recent non-invasive canine neuroscience studies, primarily focusing on (i) variability among dogs and between dogs and humans in cranial characteristics, and (ii) generalizability across dog and dog-human studies. We argue not for methodological uniformity but for functional comparability between methods, experimental designs, and neural responses. We conclude that the dog may become an innovative and unique model in comparative neuroscience, complementing more traditional models.

The dog rhinarium (naked and often moist skin on the nose-tip) is prominent and richly innervated, suggesting a sensory function. Compared to nose-tips of herbivorous artio- and perissodactyla, carnivoran rhinaria are considerably colder. We hypothesized that this coldness makes the dog rhinarium particularly sensitive to radiating heat. We trained three dogs to distinguish between two distant objects based on radiating heat; the neutral object was about ambient temperature, the warm object was about the same surface temperature as a furry mammal. In addition, we employed functional magnetic resonance imaging on 13 awake dogs, comparing the responses to heat stimuli of about the same temperatures as in the behavioural experiment. The warm stimulus elicited increased neural response in the left somatosensory association cortex. Our results demonstrate a hitherto undiscovered sensory modality in a carnivoran species.

Dogs are looking at and gaining information from human faces in a variety of contexts. Next to behavioral studies investigating the topic, recent fMRI studies reported face sensitive brain areas in dogs' temporal cortex. However, these studies used whole heads as stimuli which contain both internal (eyes, nose, mouth) and external facial features (hair, chin, face-outline). Behavioral studies reported that (1) recognition of human faces by dogs requires visibility of head contour and that (2) dogs are less successful in recognizing their owners from 2D pictures than from real human heads. In contrast, face perception in humans heavily depends on internal features and generalizes to 2D images. Whether putative face sensitive regions in dogs have comparable properties to those of humans has not been tested so far. In two fMRI experiments, we investigated (1) the location of putative face sensitive areas presenting only internal features of a real human face vs. a mono-colored control surface and (2) whether these regions show higher activity toward live human faces and/or static images of those faces compared to scrambled face images, all with the same outline. In Study 1 (n = 13) we found strong activity for faces in multiple regions, including the previously described temporo-parietal and occipital regions when the control was a mono-colored, homogeneous surface. These differences disappeared in Study 2 (n = 11) when we compared faces to scrambled faces, controlling for low-level visual cues. Our results do not support the assumption that dogs rely on a specialized brain region for processing internal facial characteristics, which is in line with the behavioral findings regarding dogs inability to recognize human faces based on these features.

Although a positive link between sleep spindle occurrence and measures of post-sleep recall (learning success) is often reported for humans and replicated across species, the test–retest reliability of the effect is sometimes questioned. The largest to date study could not confirm the association, however methods for automatic spindle detection diverge in their estimates and vary between studies. Here we report that in dogs using the same detection method across different learning tasks is associated with observing a positive association between sleep spindle density (spindles/minute) and learning success. Our results suggest that reducing measurement error by averaging across measurements of density and learning can increase the visibility of this effect, implying that trait density (estimated through averaged occurrence) is a more reliable predictor of cognitive performance than estimates based on single measures.

In the human speech signal, cues of speech sounds and voice identities are conflated, but they are processed separately in the human brain. The processing of speech sounds and voice identities is typically performed by non-primary auditory regions in humans and non-human primates. Additionally, these processes exhibit functional asymmetry in humans, indicating the involvement of distinct mechanisms. Behavioural studies indicate analogue side biases in dogs, but neural evidence for this functional dissociation is missing. In two experiments, using an fMRI adaptation paradigm, we presented awake dogs with natural human speech that either varied in segmental (change in speech sound) or suprasegmental (change in voice identity) content. In auditory regions, we found a repetition enhancement effect for voice identity processing in a secondary auditory region – the caudal ectosylvian gyrus. The same region did not show repetition effects for speech sounds, nor did the primary auditory cortex exhibit sensitivity to changes either in the segmental or in the suprasegmental content. Furthermore, we did not find evidence for functional asymmetry neither in the processing of speech sounds or voice identities. Our results in dogs corroborate former human and non-human primate evidence on the role of secondary auditory regions in the processing of suprasegmental cues, suggesting similar neural sensitivity to the identity of the vocalizer across the mammalian order.

The importance of dogs (Canis familiaris) in sleep research is primarily based on their comparability with humans. In spite of numerous differences, dogs' comparable sleep pattern, as well as several phenotypic similarities on both the behavioural and neural levels, make this species a most feasible model in many respects. Our aim was to investigate whether the so-called first-night effect, which in humans manifests as a marked macrostructure difference between the first and second sleep occasions, can be observed in family dogs. We used a non-invasive polysomnographic method to monitor and compare the characteristics of dogs' (N = 24) 3-hr-long afternoon naps on three occasions at the same location. We analysed how sleep macrostructure variables differed between the first, second and third occasions, considering also the effects of potential confounding variables such as the dogs' age and sleeping habits. Our findings indicate that first-night effect is present in dogs' sleep architecture, although its specifics somewhat deviate from the pattern observed in humans. Sleep macrostructure differences were mostly found between occasions 1 and 3; dogs slept more, had less wake after the first drowsiness episode, and reached drowsiness sleep earlier on occasion 3. Dogs, which had been reported to sleep rarely not at home, had an earlier non-rapid eye movement sleep, a shorter rapid eye movement sleep latency, and spent more time in rapid eye movement sleep on occasion 3, compared with occasion 1. Extending prior dog sleep data, these results help increase the validity of further sleep electroencephalography investigations in dogs.

Conspecific-preference in social perception is evident for multiple sensory modalities and in many species. There is also a dedicated neural network for face processing in primates. However, the evolutionary origin and the relative role of neural species sensitivity and face sensitivity in visuo-social processing are largely unknown., Conspecific-preference in social perception is evident for multiple sensory modalities and in many species. There is also a dedicated neural network for face processing in primates. However, the evolutionary origin and the relative role of neural species sensitivity and face sensitivity in visuo-social processing are largely unknown. In this comparative study, species sensitivity and face sensitivity to identical visual stimuli (videos of human and dog faces and occiputs) were examined using functional magnetic resonance imaging in dogs (n = 20; 45% female) and humans (n = 30; 50% female). In dogs, the bilateral mid suprasylvian gyrus showed conspecific-preference, no regions exhibited face-preference, and the majority of the visually-responsive cortex showed greater conspecific-preference than face-preference. In humans, conspecific-preferring regions (the right amygdala/hippocampus and the posterior superior temporal sulcus) also showed face-preference, and much of the visually-responsive cortex showed greater face-preference than conspecific-preference. Multivariate pattern analyses (MVPAs) identified species-sensitive regions in both species, but face-sensitive regions only in humans. Across-species representational similarity analyses (RSAs) revealed stronger correspondence between dog and human response patterns for distinguishing conspecific from heterospecific faces than other contrasts. Results unveil functional analogies in dog and human visuo-social processing of conspecificity but suggest that cortical specialization for face perception may not be ubiquitous across mammals. SIGNIFICANCE STATEMENT To explore the evolutionary origins of human face-preference and its relationship to conspecific-preference, we conducted the first comparative and noninvasive visual neuroimaging study of a non-primate and a primate species, dogs and humans. Conspecific-preferring brain regions were observed in both species, but face-preferring brain regions were observed only in humans. In dogs, an overwhelming majority of visually-responsive cortex exhibited greater conspecific-preference than face-preference, whereas in humans, much of the visually-responsive cortex showed greater face-preference than conspecific-preference. Together, these findings unveil functional analogies and differences in the organizing principles of visuo-social processing across two phylogenetically distant mammal species.

The sleeping activity of family dogs has been studied increasingly in the past years. Recently, a validated, non-invasive polysomnographic method has been developed for dogs, enabling the parallel recording of several neurophysiological signals on non-anesthetized family dogs, including brain activity (EEG), eye movements (EOG), cardiac (ECG), and respiratory activity (PNG). In this study, we examined the ECG (N = 30) and respiratory signals (N = 19) of dogs during a 3-h sleep period in the afternoon, under laboratory conditions. We calculated four time-domain heart rate variables [mean heart rate (HR), SDNN, RMSSD, and pNN50] from the ECG and the estimated average respiratory frequency from the respiratory signal. We analyzed how these variables are affected by the different sleep-wake phases (wakefulness, drowsiness, NREM, and REM) as well as the dogs’ sex, age and weight. We have found that the sleep-wake phase had a significant effect on all measured cardiac parameters. In the wake phase, the mean HR was higher than in all other phases, while SDNN, RMSSD, and pNN50 were lower than in all other sleep phases. In drowsiness, mean HR was higher compared to NREM and REM phases, while SDNN and RMSSD was lower compared to NREM and REM phases. In REM, SDNN, and RMSSD was higher than in NREM. However, the sleep-wake phase had no effect on the estimated average respiratory frequency of dogs. The dogs’ sex, age and weight had no effect on any of the investigated variables. This study represents a detailed analysis of the cardiac and respiratory activity of dogs during sleep. Since variations in these physiological signals reflect the dynamics of autonomic functions, a more detailed understanding of their changes may help us to gain a better understanding of the internal/emotional processes of dogs in response to different conditions of external stimuli. As such, our results are important since they are directly comparable to human findings and may also serve as a potential basis for future studies on dogs.

The aim of this research was to investigate the stability of a lidocaine-loaded nanostructured lipid carrier dispersion at different temperatures, formulate a nanostructured lipid carrier gel, and test the penetration profile of lidocaine from the nanostructured lipid carrier gel using different skin penetration modeling methods. The formulations were characterized by laser diffraction, rheological measurements and microscopic examinations. Various in vitro methods were used to study drug release, diffusion and penetration. Two types of vertical Franz diffusion cells with three different membranes, including cellulose, Strat-M&reg, and heat separated human epidermis were used and compared to the Skin-parallel artificial membrane permeability assay (PAMPA) method. Results indicated that the nanostructured lipid carrier dispersion had to be gelified as soon as possible for proper stability. Both the Skin-PAMPA model and Strat-M&reg, membranes correlated favorably with heat separated human epidermis in this research, with the Strat-M&reg, membranes sharing the most similar drug permeability profile to an ex vivo human skin model. Our experimental findings suggest that even when the best available in vitro experiment is selected for modeling human skin penetration to study nanostructured lipid carrier gel systems, relevant in vitro/in vivo correlation should be made to calculate the drug release/permeation in vivo. Future investigations in this field are still needed to demonstrate the influence of membranes and equipment from other classes on other drug candidates.

Cognitive biases, often used as indices of affective and emotional states, are associated with individual differences in personality in humans and have been observed in nonhuman animals, including dogs. Although dogs have complementary advantages over traditional animal models of human cognition, little is known about the relationship between dogs’ cognitive bias and personality. Here, we examined in 29 family dogs (representing 14 breeds and 12 mutts; Mage = 4.59 years, SD = 2.90), the association between naturally occurring – as opposed to experimentally induced – cognitive bias, indexed via active choice behavior in a Go/No-Go (GNG) paradigm reflecting positive/negative expectations about ambiguous stimuli, and owner-rated personality. In a subsample we additionally assessed whether prior inhibition, personality, and inattention (IA)/hyperactivity/impulsivity (H/I) results could be replicated in a modified paradigm. We also explored whether expanding the response time-window would increase GNG errors and whether dogs exhibited differences in their behavioral approach to uncertainty. Findings indicated dogs with higher conscientiousness and extraversion scores were more likely to exhibit a “go” response to ambiguous stimuli. Replicability across prior and current results was generally established, e.g., as previously, IA did not predict GNG performance but extraversion did, whereas H/I predicted different indices of GNG performance. Increased response time-window did not result in differential performance, except for less commission errors. No differences in behavioral response strategy to trained “no-go” and to ambiguous stimuli were apparent. Results evince the dog is a promising animal model of the association between an optimistic cognitive bias and personality.

Semisolid dosage forms are recommended for the dermal care of babies and children. If we look at the ingredients of these preparations, there are still many cases in which there are substances (occlusive agents, preservatives) that no longer meet certain requirements of the modern age, so it is timely to replace them with other substances. The aim of this work was to formulate a science-based formulation with new components that keep or improve its moisturizing properties, rheological parameters, and microbiological stability. Occlusive oils, like white petrolatum and liquid paraffin and the preservative parabens are traditional ingredients in oil in water creams, were replaced with white beeswax, sunflower oil, and phenoxyethanol, respectively. Cocoa butter, urea, and glycerol were added to improve long-lasting hydration and support the barrier function of the reformulated creams. The rheological properties of the formulations were determined. The effects of the preparations on skin hydration and on the barrier function of the skin were tested. Furthermore, microbiological stability was investigated. The result of the reformulation was an o/w cream that provided a good longer-lasting hydration effect, supported the barrier function of the baby skin without occlusion, and had adequate consistency, easy spreading, a pleasant skin feeling, proper pH, and good microbiological stability.

Background: Despite being a highly prevalent disease and a possible contributor to adult tooth loss, periodontitis possesses no well-established therapy. The aim of the recent study was the development and evaluation of a mucoadhesive monophase lipid formulation for the sustained local delivery of amoxicillin, metronidazole, and/or zinc hyaluronate or gluconate. Methods: To investigate our formulations, differential scanning calorimetry, X-ray diffraction, swelling, erosion, mucoadhesivity, drug release, and antimicrobial measurements were performed. Results: Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) results show that the loaded drugs are in a suspended form, the softening of the formulations starts at body temperature, but a part remains solid, providing sustained release. Swelling of the lipid compositions is affected by the hydrophilic components, their concentration, and the strength of the coherent lipid structure, while their erosion is impacted by the emulsification of melted lipid components. Conclusions: Results of drug release and antimicrobial effectiveness measurements show that a sustained release may be obtained. Amoxicillin had higher effectiveness against oral pathogens than metronidazole or zinc hyaluronate alone, but the combination of the two latter could provide similar effectiveness to amoxicillin. The applied mucoadhesive polymer may affect adhesivity, drug release through the swelling mechanism, and antimicrobial effect as well.

Purpose To design and stabilize Liraglutide loaded poly (lactic-co-glycolic acid) nanoparticles (PLGA NPs) proper for oral administration. Methods PLGA NPs were prepared by means of double emulsion solvent evaporation method and optimized by applying 7-factor 2-level Plackett-Burman screening design. Results Spherical shaped NPs with homogeneous distribution, 188.95 nm particle size and 51.81% encapsulation efficiency were obtained. Liraglutide was successfully entrapped in the NPs while maintaining its native amorphous nature, and its structural integrity as well. Conclusion Lira-PLGA NPs with the required Critical Quality Attributes (CQAs) were successfully designed by implementing a 7-factor 8-run Plackett Burman design into the extended Quality by Design (QbD) model, to elucidate the effect of formulation and process variables on the particle size, size-distribution, encapsulation efficiency and surface charge. As the developed nanoparticles maintained the native structure of the active pharmaceutical ingredient (API), they are promising compositions for the further development for the oral delivery of Lira. Graphical Abstract Electronic supplementary material The online version of this article (10.1007/s11095-019-2620-9) contains supplementary material, which is available to authorized users.

Resting-state networks are spatially distributed, functionally connected brain regions. Studying these networks gives us information about the large-scale functional organization of the brain and alternations in these networks are considered to play a role in a wide range of neurological conditions and aging. To describe resting-state networks in dogs, we measured 22 awake, unrestrained animals of either sex and carried out group-level spatial independent component analysis to explore whole-brain connectivity patterns. Using resting-state functional magnetic resonance imaging (rs-fMRI), in this exploratory study we found multiple resting-state networks in dogs, which resemble the pattern described in humans. We report the following dog resting-state networks: default mode network (DMN), visual network (VIS), sensorimotor network (SMN), combined auditory (AUD)-saliency (SAL) network and cerebellar network (CER). The DMN, similarly to Primates, but unlike previous studies in dogs, showed antero-posterior connectedness with involvement of hippocampal and lateral temporal regions. The results give us insight into the resting-state networks of awake animals from a taxon beyond rodents through a non-invasive method.

Szilvia Berkó,1 Stella Zsikó,1 Gábor Deák,2 Attila Gácsi,1 Anita Kovács,1 Mária Budai-Szűcs,1 László Pajor,2 Zoltán Bajory,2 Erzsébet Csányi1 1Institute of Pharmaceutical Technology and Regulatory Affairs, University of Szeged, Szeged, Hungary; 2Department of Urology, University of Szeged, Szeged, Hungary Purpose: Papaverine hydrochloride (PaHCl) is an old, well-known drug with spasmolytic activity but it has therapeutic effect in erectile dysfunction, too. As an intracavernous injection, it is not used in urologic clinics today because the side effects of the injection are pain, scarring or priapism. Our aim was to develop and test a topical semi-solid preparation containing PaHCl that would provide an alternative administration option by eliminating the undesirable side effects of the injection.Materials and methods: Lyotropic liquid crystal (LLC) systems were formulated as a semi-solid preparation with different concentrations of PaHCl. The characterization of the LLC structure was performed by polarization microscopy using a Leica image analyzer and rheological measurements. The drug diffusion and penetration tests were performed with in vitro synthetic membrane and an ex vivo human epidermis, using Franz diffusion cell to test the skin penetration of PaHCl. Human skin was investigated by Raman microscope to visualize the Active Pharmaceutical Ingredient (API) in different skin layers.Results: The results of diffusion and penetration showed reverse concentration dependency. The in vitro and ex vivo studies correlated with each other and the results of Raman microscopy. The LLC structure influenced the penetration results, the lower viscosity and lamellar structure increased penetration through the skin.Conclusion: Based on our results, a PaHCl containing topically used LLC formulation may be a suitable and effective alternative to the injectable formulation. Keywords: nanocarrier, dermal penetration, impotence, Raman microscopy

A special area of human-machine interaction, the expression of emotions gains importance with the continuous development of artificial agents such as social robots or interactive mobile applications. We developed a prototype version of an abstract emotion visualization agent to express five basic emotions and a neutral state. In contrast to well-known symbolic characters (e.g., smileys) these displays follow general biological and ethological rules. We conducted a multiple questionnaire study on the assessment of the displays with Hungarian and Japanese subjects. In most cases participants were successful in recognizing the displayed emotions. Fear and sadness were most easily confused with each other while both the Hungarian and Japanese participants recognized the anger display most correctly. We suggest that the implemented biological approach can be a viable complement to the emotion expressions of some artificial agents, for example mobile devices.

Knowledge of the mechanism of action of skin penetration enhancers is essential to formulators for optimizing formulations and to maximize the efficacy of enhancers. To obtain information about the effects of penetration enhancers as a fast initial screening, investigations have been performed to identify possible correlations of the biological effectiveness of penetration enhancers with their interaction with a well-defined model system consisting of skin mimic lipid bilayers, as determined by calcein release experiments using stratum corneum lipid liposomes (SCLLs). We aimed to investigate the enhancing effects of different concentrations of two chemical penetration enhancers, Kolliphor RH40 and Transcutol on SCLLs. The results obtained by SCLL-based techniques were compared with conventional ex vivo penetration studies in case of Kolliphor RH40 to evaluate the potential of SCLLs as an alternative tool for screening various types and concentrations of penetration enhancers. As a result, calcein leakage assay performed with SCLL was considered to be a good model for the skin penetration enhancing effect. This method could be used as a time-saving and sensitive alternative in vitro screening technique in the early stage of the development of dermal formulations.

The application of local anesthetics, usually administered by subcutaneous injection, is common in the course of diagnostic, therapeutic, and cosmetic dermatology procedures. The effective dermal delivery of lidocaine could offer a solution to many adverse effects caused by needle insertion, such as pain, local reactions or toxicity, and additionally, it avoids the disruption of anatomical landmarks. Therefore, novel dermal formulations of local anesthetics are needed to overcome the barrier function of the skin and provide sufficient and prolonged anesthesia. In our study, we aimed to investigate and compare the penetration profiles of four different lidocaine containing formulations (hydrogel, oleogel, lyotropic liquid crystal and nanostructured lipid carrier) by Raman microscopic mapping of the drug. The application of Raman spectroscopy provided information about the spatial distribution of lidocaine in the skin ex vivo. The penetration of lidocaine from lyotropic liquid crystal and nanostructured carrier reached deeper skin layers and a higher amount of the drug was diffused into the skin, compared with hydrogel and oleogel. This study confirmed that nanostructured carriers can improve skin penetration properties of lidocaine and proved the applicability of Raman spectroscopy in the research of dermatological preparations ex vivo as a nondestructive, relatively easy and fast technique.

Here we aim to lay the theoretical foundations of human-robot relationship drawing upon insights from disciplines that govern relevant human behaviors: ecology and ethology. We show how the paradox of the so called “uncanny valley hypothesis” can be solved by applying the “niche” concept to social robots, and relying on the natural behavior of humans. Instead of striving to build human-like social robots, engineers should construct robots that are able to maximize their performance in their niche (being optimal for some specific functions), and if they are endowed with appropriate form of social competence then humans will eventually interact with them independent of their embodiment. This new discipline, which we call ethorobotics, could change social robotics, giving a boost to new technical approaches and applications.

The aim of our research work was to develop dermally applicable, semisolid film-forming systems (FFSs) containing silicones, which form a film on the skin in situ, with suitable mechanical properties for skin application. FFSs were developed and investigated by means of the Quality by Design (QbD) methodology. With this QbD approach, the initial risk assessment defines the critical quality attributes (CQAs), the critical material attributes (CMAs) and the critical process parameters (CPPs) to ensure the required quality. Different semisolid systems were formed with or without silicones. During the initial risk assessment, three CQAs, namely skin adhesion, film flexibility and burst strength, were found to be critical attributes, while film appearance, film integrity and the drying time of the semisolid system, were found to be medium attributes. These parameters were investigated. The initial risk assessment also showed that there are three high CMAs: the type of silicones, film-forming excipients, drying excipients, and that there was one medium CMA: viscosity-enhancing excipients. Based on our results, the silicone content had a great effect on the film-forming systems. Different silicones affected the mechanical properties of the films in varying ways, decreased the drying time and showed promising results regarding the drying mechanism.

Dermal and transdermal drug therapy is increasing in importance nowadays in drug development. To completely utilize the potential of this administration route, it is necessary to optimize the drug release and skin penetration measurements. This review covers the most well-known and up-to-date methods for evaluating the cutaneous penetration of drugs in vitro as a supporting tool for pharmaceutical research scientists in the early stage of drug development. The aim of this article is to present various experimental models used in dermal/transdermal research and summarize the novel knowledge about the main in vitro methods available to study skin penetration. These techniques are: Diffusion cell, skin-PAMPA, tape stripping, two-photon microscopy, confocal laser scanning microscopy, and confocal Raman microscopic method.

In this study we aimed to investigate novel aspects of dogs' comprehension of human social behaviours by revealing potential differences in the responses of wolves and dogs when they interact with a human in socially ambiguous situations. In Experiment 1, pet dogs ( N =13) and hand-reared wolves ( N =13) encountered a stranger who approached them first in a friendly, then a threatening way, and finally switched back to friendliness again (Approaching stranger; AS) while the passive owner/caregiver was standing close to the subjects. In contrast to dogs, wolves avoided eye contact with both the caregiver and the stranger, however, only dogs showed aggressive displays towards the stranger. In Experiment 2, the same subjects were tested in an Object guarding (OG) situation. A familiar woman, communicating the playful nature of the encounter, pretended to aim at taking away her belt-bag from the subjects trying to make them respond with guarding behaviour. Finally, she tried to take away the object without using dominant/threatening behaviour. During the Game episode some dogs and wolves showed guarding displays, but only dogs switched their responses twice and finally allowed the human take hold of the object. All dogs but none of the wolves gazed at the owner/caregiver during the test. In Experiment 3, we tested trained Belgian shepherd dogs ( N =13) in AS, OG, and in a Food guarding (FG) situation. In FG a familiar woman challenged the subject to guard a bone by applying enticement but otherwise not communicating the playful/pretended nature of the encounter. Dogs displayed aggressive behaviours in all three situations as a response to the human's behaviour. In AS they adjusted their behaviour from passive/friendly to aggressive and then friendly again, according to the switch in the human partner's actions. In OG and FG situations, after showing aggressive guarding displays they allowed the human to take away the guarded object, both the bag and the food. A characteristic high-pitched vocalisation observed during both guarding situations, typically before the first aggressive display, could refer to the dogs' ambivalent emotions. This suggests that the human's challenging behaviour alone might be effective to evoke a simulated guarding behaviour. Our results support the view that dogs have advanced abilities and readiness to combine seemingly contradicting behaviour responses to respond to human behaviours or expectations, whilst even hand-reared and extensively socialised wolves tend to display less human centred behaviours and adjust their behaviours less to that of humans' in interspecific situations.

The active role of sleep in memory consolidation is still debated, and due to a large between-species variation, the investigation of a wide range of different animal species (besides humans and laboratory rodents) is necessary. The present study applied a fully non-invasive methodology to study sleep and memory in domestic dogs, a species proven to be a good model of human awake behaviours. Polysomnography recordings performed following a command learning task provide evidence that learning has an effect on dogs’ sleep EEG spectrum. Furthermore, spectral features of the EEG were related to post-sleep performance improvement. Testing an additional group of dogs in the command learning task revealed that sleep or awake activity during the retention interval has both short- and long-term effects. This is the first evidence to show that dogs’ human-analogue social learning skills might be related to sleep-dependent memory consolidation.

During speech processing, human listeners can separately analyze lexical and intonational cues to arrive at a unified representation of communicative content. The evolution of this capacity can be best investigated by comparative studies. Using functional magnetic resonance imaging, we explored whether and how dog brains segregate and integrate lexical and intonational information. We found a hemispheric bias for processing meaningful words, independently of intonation; an auditory brain region for distinguishing intonationally marked and unmarked words; and increased activity in primary reward regions only when both lexical and intonational information were consistent with praise. Neural mechanisms to separately analyze and integrate word meaning and intonation in dogs suggest that this capacity can evolve in the absence of language.

Recent studies have shown that the neuropeptide oxytocin is involved in the regulation of several complex human social behaviours. There is, however, little research on the effect of oxytocin on basic mechanisms underlying human sociality, such as the perception of biological motion. In the present study, we investigated the effect of oxytocin on biological motion perception in dogs (Canis familiaris), a species adapted to the human social environment and thus widely used to model many aspects of human social behaviour. In a within-subjects design, dogs (N = 39), after having received either oxytocin or placebo treatment, were presented with 2D projection of a moving point-light human figure and the inverted and scrambled version of the same movie. Heart rate (HR) and heart rate variability (HRV) were measured as physiological responses, and behavioural response was evaluated by observing dogs' looking time. Subjects were also rated on the personality traits of Neuroticism and Agreeableness by their owners. As expected, placebo-pretreated (control) dogs showed a spontaneous preference for the biological motion pattern; however, there was no such preference after oxytocin pretreatment. Furthermore, following the oxytocin pretreatment female subjects looked more at the moving point-light figure than males. The individual variations along the dimensions of Agreeableness and Neuroticism also modulated dogs' behaviour. Furthermore, HR and HRV measures were affected by oxytocin treatment and in turn played a role in subjects' looking behaviour. We discuss how these findings contribute to our understanding of the neurohormonal regulatory mechanisms of human (and non-human) social skills.

These studies are part of a project aiming to reveal relevant aspects of human-dog interactions, which could serve as a model to design successful human-robot interactions. Presently there are no successfully commercialised assistance robots, however, assistance dogs work efficiently as partners for persons with disabilities. In Study 1, we analysed the cooperation of 32 assistance dog-owner dyads performing a carrying task. We revealed typical behaviour sequences and also differences depending on the dyads’ experiences and on whether the owner was a wheelchair user. In Study 2, we investigated dogs’ responses to unforeseen difficulties during a retrieving task in two contexts. Dogs displayed specific communicative and displacement behaviours, and a strong commitment to execute the insoluble task. Questionnaire data from Study 3 confirmed that these behaviours could successfully attenuate owners’ disappointment. Although owners anticipated the technical competence of future assistance robots to be moderate/high, they could not imagine robots as emotional companions, which negatively affected their acceptance ratings of future robotic assistants. We propose that assistance dogs’ cooperative behaviours and problem solving strategies should inspire the development of the relevant functions and social behaviours of assistance robots with limited manual and verbal skills.

Many dog breeds are bred specifically for increased performance in scent-based tasks. Whether dogs bred for this purpose have higher olfactory capacities than other dogs, or even wolves with whom they share a common ancestor, has not yet been studied. Indeed, there is no standard test for assessing canine olfactory ability. This study aimed to create a simple procedure that requires no pre-training and to use it to measure differences in olfactory capacity across four groups of canines: (1) dog breeds that have been selected for their scenting ability; (2) dog breeds that have been bred for other purposes; (3) dog breeds with exaggerated short-nosed features; and (4) hand-reared grey wolves. The procedure involved baiting a container with raw turkey meat and placing it under one of four identical ceramic pots. Subjects were led along the row of pots and were tasked with determining by olfaction alone which of them contained the bait. There were five levels of increasing difficulty determined by the number of holes on the container's lid. A subsample of both dogs and wolves was retested to assess reliability. The results showed that breeds selected for scent work were better than both short-nosed and non-scent breeds. In the most difficult level, wolves and scenting breeds performed better than chance, while non-scenting and short-nosed breeds did not. In the retested samples wolves improved their success; however, dogs showed no change in their performances indicating that a single test may be reliable enough to assess their capacity. Overall, we revealed measurable differences between dog breeds in their olfactory abilities and suggest that the Natural Detection Task is a good foundation for developing an efficient way of quantifying them.

Social robotics is becoming a driving field in building artificial agents. The possibility to construct agents that can engage in meaningful social interaction with humans presents new challenges for the engineers. In general social robotics has been inspired dominantly by human psychology and aimed for building human-like robots. Only a small subcategory of “companion robots” (also referred to as robotic pets) was build to mimic animals. In the opinion essay we argue that all social robots should be seen as companions and more conceptual emphasis should be put on the inter-specific interaction between humans and social robots. This view is underlined by the means of an ethological analysis, and critical evaluation of present day companion robots. We suggest that human-animal interaction provides a rich source of knowledge for designing social robots that are able to interact with humans under a wide range of conditions.

Background: The comparison of human related communication skills of socialized canids may help to understand the evolution and the epigenesis of gesture comprehension in humans. To reconcile previously contradicting views on the origin of dogs’ outstanding performance in utilizing human gestures, we suggest that dog-wolf differences should be studied in a more complex way. Methodology/Principal Findings: We present data both on the performance and the behaviour of dogs and wolves of different ages in a two-way object choice test. Characteristic behavioural differences showed that for wolves it took longer to establish eye contact with the pointing experimenter, they struggled more with the handler, and pups also bit her more before focusing on the human’s signal. The performance of similarly hand-reared 8-week-old dogs and wolves did not differ in utilizing the simpler proximal momentary pointing. However, when tested with the distal momentary pointing, 4-monthold pet dogs outperformed the same aged hand reared wolves. Thus early and intensive socialisation does not diminish differences between young dogs and wolves in behaviour and performance. Socialised adult wolves performed similarly well as dogs in this task without pretraining. The success of adult wolves was accompanied with increased willingness to cooperate. Conclusion/Significance: Thus, we provide evidence for the first time that socialised adult wolves are as successful in relying on distal momentary pointing as adult pet dogs. However, the delayed emergence of utilising human distal momentary pointing in wolves shows that these wild canines react to a lesser degree to intensive socialisation in contrast to dogs, which are able to control agonistic behaviours and inhibition of actions in a food related task early in development. We suggest a ‘‘synergistic’’ hypothesis, claiming that positive feedback processes (both evolutionary and epigenetic) have increased the readiness of dogs to attend to humans, providing the basis for dog-human communication.