Recent work has nested the Alternative Model for Personality Disorders (AMPD) within several theoretical paradigms of personality and clinical psychology (e.g., multivariate, psychodynamic). This has both spurred on additional research and aided in practical application. Connecting the model to other theoretical heuristics may lead to further advances. One candidate for such a theory is that of evolutionary psychology, which attempts to provide explanations of human behavior (including personality traits) rooted in adaptation. In this article, we review and integrate the theoretical and empirical literature on the AMPD and evolutionary psychology, providing a synthesis of the two models in the hope of furthering the research and application of both.

Gallic acid (GA) has antioxidant, anti-inflammatory and antimicrobial properties, while ellagic acid (EA) demonstrates anticancer, antiviral and photoprotective activity. In this study, the combination of these substances incorporated into a poloxamer gel was tested to verify the individual effect of the substances, in addition to taking advantage of a probable complementary effect, aiming to provide additional therapeutic benefits. As a result of the incorporation, formulations containing GA, EA and GA + EA were obtained, which were evaluated for the effects of the Freeze-thaw cycle on pH, which revealed a significant decrease (p < 0.05) in most samples, including the vehicle (without drug) and the gel containing both drugs. No sample showed variation outside the normal pH range for the skin, with values ranging from 4.8 to 6.0. Regarding conductivity, the GA, EA and GA + EA formulations showed a reduction (p < 0.05) after the freeze-thaw cycle. The drug content in the formulations ranged from 95.86% to 101.35% initially to 91.30% to 101.51% after the freeze-thaw cycle. Regarding the drug release, the results revealed the following cumulative percentages: GA-3% - 92.58% after 1.5 h; AE-3% - 51.60% after 6 h; GA + EA (1.5% = 1.5%) - 99.91% after 2 h; GA + EA- (1.5% = 1.5%) released 57.06%, after 6 h. Regarding toxicity, it was observed that the group treated with GA showed a lower survival rate of the larvae (40%) at the dose 3000 mg/Kg in the formulation. Following the same trend, in the acute lethal concentration (ALC50) test performed using Zophobas morio larvae, an ALC50 of 2191.51 mg/Kg was observed for GA at 48 h. Melanin analysis showed a decrease in concentrations of 30 mg/Kg in the GA group, 3 mg/Kg of EA and 3, 300, 3000 mg/Kg of GA + EA, of the pure drugs. In the groups with the drugs incorporated into the gel, there was a significant decrease (P < 0.05) in melanin in the vehicle (gel), at concentrations of 300 and 3000 mg/Kg of GA and EA. On the other hand, in the combination of GA + EA, a reduction was observed at concentrations of 3 and 30 mg/Kg when compared to the control group. Thus, the gel showed good quality as a pharmaceutical formulation for topical use and low toxicity, making it promising for use in skin therapies.

BACKGROUND: The new coronavirus (SARS-CoV-2) pandemic emerged in 2019 causing millions of deaths. Vaccines were quickly developed and made available in 2021. Despite the availability of vaccines, some subjects refuse to take the immunizing or present comorbities, therefore developing serious cases of COVID-19, which makes necessary the development of antiviral drugs. Previous studies have demonstrated that ebselen, a selenium-containing molecule, can inhibit SARS-CoV-2 Mpro. In addition, selenium is a trace element that has antiviral and anti-inflammatory properties. Zidovudine (AZT) has been widely used against HIV infections and its action against SARS-CoV-2 may be altered by the structural modification with organochalcogen moieties, but this hypothesis still needs to be tested.
METHODS: In the present work we evaluated the Mpro inhibition capacity (in silico), the safety and antioxidant effect of six organochalcogen AZT-derivatives using the free-living nematode Caenorhabditis elegans, through acute (30 min) and chronic (48) exposure protocols.
RESULTS: We observed that the molecules were safe at a concentration range of 1-500 µM and did not alter any toxicological endpoint evaluated. Furthermore, the molecules are capable to decrease the ROS formation stimulated by hydrogen peroxide, to modulate the expression of important antioxidant enzymes such superoxide-dismutase-3 and glutathione S-transferese-4 and to stimulate the translocation of the DAF-16 to the cell nucleus. In addition, the molecules did not deplete thiol groups, which reinforces their safety and contribution to oxidative stress resistance.
CONCLUSIONS: We have found that compounds S116l (a Tellurium AZT-derivative) and S116h (a Selenium-AZT derivative) presented more promising effects both in silico and in vivo, being strong candidates for further in vivo studies.

Rhabdomyosarcoma (RMS) is the most common highly malignant pediatric soft tissue sarcoma. While recent multidisciplinary treatments have improved the 5‑year survival rate of low/intermediate‑risk patients to 70‑90%, there are various complications that arise due to treatment‑related toxicities. Immunodeficient mice‑derived xenograft models have been widely used in cancer drug research; however, these models have some limitations, including i) they are time‑consuming and expensive, ii) their use needs to be approved by animal experimental ethics committees, and iii) the inability to visualize where tumor cells or tissues were engrafted. The present study performed a chorioallantoic membrane (CAM) assay in fertilized chicken eggs, which is time‑saving, simple, and easy to standardize and handle because of the high vascularization and the immature immune system of the fertilized eggs. The present study aimed to examine the usability of the CAM assay as a novel therapeutic model for the development of precision medicine for pediatric cancer. A protocol was developed for constructing cell line‑derived xenograft (CDX) models using a CAM assay by transplanting RMS cells on the CAM. It was then examined as to whether these CDX models could be used as therapeutic drug evaluation models using vincristine (VCR) and human RMS cell lines. After grafting and culturing the RMS cell suspension on the CAM, three‑dimensional proliferation over time was observed visually and by comparing volumes. VCR reduced the size of the RMS tumor on the CAM in a dose‑dependent manner. Currently, treatment strategies based on patient‑specific oncogenic backgrounds have not been adequately developed in the field of pediatric cancer. The establishment of a CDX model with the CAM assay may lead to the advancement of precision medicine and help formulate novel therapeutic strategies for intractable pediatric cancer.

Deer mice (genus Peromyscus) are an emerging model for aging studies due to their longevity relative to rodents of similar size. Although Peromyscus species are well-represented in genetic, developmental, and behavioral studies, relatively few studies have investigated auditory sensitivity in this genus. Given the potential utility of Peromyscus for investigations of age-related changes to auditory function, we recorded auditory brainstem responses (ABRs) in two Peromyscus species, P. californicus, and P. leucopus, across the lifespan. We compared hearing sensitivity and ABR wave metrics measured in these species with measurements from Mus musculus (CBA/CaJ strain) to assess age-related effects on hearing across species. Recordings in young animals showed that all species had similar hearing ranges and thresholds with peak sensitivity ranging from 8 to 16 kHz; however, P. californicus and P. leucopus were more sensitive to frequencies below 8 kHz. Although M. musculus showed significant threshold shifts across a broad range of frequencies beginning at middle age and worsening among old individuals, older Peromyscus mice retained good sensitivity to sound across their lifespan. Middle-aged P. leucopus had comparable thresholds to young for frequencies below 24 kHz. P. leucopus also had notably large ABRs that were robust to age-related amplitude reductions, although response latencies increased with age. Old P. californicus were less sensitive to mid-range tones (8-16 kHz) than young individuals; however, there were no significant age-effects on ABR amplitudes or latencies in this species. These results indicate that longevity in Peromyscus mice may be correlated with delayed aging of the auditory system and highlight these species as promising candidates for longitudinal hearing research.

To discover new molecules or review the biological activity and toxicity of therapeutic substances, drug development, and research relies on robust biological systems to obtain reliable results. Phenotype-based screenings can transpose the organism\'s compensatory pathways by adopting multi-target strategies for treating complex diseases, and zebrafish emerged as an important model for biomedical research and drug screenings. Zebrafish\'s clear correlation between neuro-anatomical and physiological features and behavior is very similar to that verified in mammals, enabling the construction of reliable and relevant experimental models for neurological disorders research. Zebrafish presents highly conserved physiological pathways that are found in higher vertebrates, including mammals, along with a robust behavioral repertoire. Moreover, it is very sensitive to pharmacological/environmental manipulations, and these behavioral phenotypes are detected in both larvae and adults. These advantages align with the 3Rs concept and qualify the zebrafish as a powerful tool for drug screenings and pre-clinical trials. This review highlights important behavioral domains studied in zebrafish larvae and their neurotransmitter systems and summarizes currently used techniques to evaluate and quantify zebrafish larvae behavior in laboratory studies.

Exposing the immature nervous system to specific antiepileptic drugs (AEDs) during pregnancy is linked to neurodevelopmental disorders such as autism spectrum disorder (ASD). Newer AEDs like lamotrigine (LTG) are hailed as safer, but recent epidemiological data suggest that even LTG carries a risk, although much lower than that associated with valproic acid (VPA), an older AED, which is also known to cause morphological alterations in the developing brain. Increasing evidence highlights cerebellar abnormalities as important in ASD pathophysiology. Transcription factor PAX6 is a key activity-dependent mediator and regulates crucial processes during cerebellar development. The chicken cerebellum recapitulates important characteristics of human cerebellar development, and may thus be suitable for the assessment of interventions aiming to modify maturation and cerebellar development. In the present study, exposure of chicken on embryonic day 16 (E16) to LTG or VPA resulted in decreased cerebellar mass and level of proliferating nuclear cell antigen (PCNA) for clinically relevant concentrations of VPA. However, both AEDs reduced cerebellar protein levels of PAX6 and MMP-9 at E17. Furthermore, PAX6 immunohistochemical staining of coronal sections of chicken cerebellum showed a significant reduction in PAX6-positive cell density and changes in cerebellar cortex thickness, mostly caused by the change in IGL-layer thickness. In conclusion, prenatal exposure to LTG or VPA provoked differential maturational changes in the developing cerebellum that may reflect some of the underlying molecular mechanisms for the observed human ASD pathology after AEDs exposure during pregnancy.

In a previous in vitro study, dihydropyrimidinone-derived selenoesteres demonstrated antioxidant properties, metal chelators and inhibitory acetylcholinesterase (AChE) activity, making these compounds promising candidates for Alzheimer\'s Disease (AD) treatment. However, these effects have yet to be demonstrated in an in vivo animal model; therefore, this study aimed to evaluate the safety and efficacy of eight selenoester compounds in a Caenorhabditis elegans model using transgenic strains for amyloid-beta peptide (Aβ) aggregation. The L1 stage worms were acutely exposed (30 min) to the compounds at concentrations ranging from 5 to 200 μM and after 48 h the maintenance temperature was increased to 25 ° C for Aβ expression and aggregation. After 48 h, several parameters related to phenotypic manifestations of Aβ toxicity and mechanistic elucidation were analyzed. At the concentrations tested no significant toxicity of the compounds was found. The selenoester compound FA90 significantly reduced the rate of paralyzed worms and increased the number of swimming movements compared to the untreated worms. In addition, FA90 and FA130 improved egg-laying induced by levamisole and positively modulated HSP-6 and HSP-4 expression, thereby increasing reticular and mitochondrial protein folding response in C. elegans, which could attenuate Aβ aggregation in early exposure. Therefore, our initial screening using an alternative model demonstrated that FA90, among the eight selenoesters evaluated, was the most promising compound for AD evaluation screening in more complex animals.

Native human skin has been reported in the literature as being an important experimental model for studying skin biology. Studies performed by our group have shown that ex vivo skin, from elective plastic surgery, maintains the biological characteristics of native skin under specific culture conditions. As such, it might be a feasible model for the safety and efficacy testing of topical substances. While Brazil is at the forefront of global regulation implementation, Brazilian researchers are not always able to transfer certain widely used protocols to their laboratories, particularly protocols that involve the use of reconstructed tissues with limited viability, such as those for skin corrosion (OECD TG 431) and irritation testing (OECD TG 439). In this study, we investigated the applicability of the ex vivo skin model to the evaluation of irritation and corrosion potential of a number of proficiency substances described in TG 431 and TG 439. The skin fragments were standardised in size and diameter, and placed into cell culture inserts. The experimental protocol was conducted according to TG 431 and TG 439. The results obtained show that ex vivo skin could represent a promising tool for the evaluation of irritation and corrosion potential of substances (subject to inclusion and exclusion criteria), as recommended by OECD guidelines. While this is a proof-of-concept study, the use of ex vivo skin should be considered for such testing.

BACKGROUND: Rodent models are routinely used to assess the safety and developmental toxicity of pharmaceuticals, along with analysis of their distribution. These models require sacrifice of parent females, have challenges in the estimation of the number of embryos and stage of development, and are expensive and time-consuming. In this study, we used fertilized chicken eggs as an alternative model to address drug distribution to the developing brain of two antiepileptic drugs, valproic acid (VPA) and lamotrigine (LTG) at two developmental stages.
METHODS: VPA or LTG was injected into the allantois of the egg on embryonic day 13 (E13) or E16. Whole chicken brains were harvested at time-points of 5 min to 24 h and the concentrations of the drugs determined using GC/MS and LC-MS/MS, for VPA and LTG, respectively.
RESULTS: VPA and LTG had distinct absorption and elimination phases and were found in the brain as early as 5-15 min after injection. Both drugs reached the brain in clinically relevant concentrations, with Cmax 10-30% of the calculated concentration assuming uniform distribution throughout the egg. LTG concentrations were higher when injected at E13 compared to E16.
CONCLUSIONS: The chicken embryo model may be a suitable alternative animal model for preclinical drug distribution studies. It enables to easily approach antenatal development on an individual level, with a precise number of experimental animals, high reproducibility and low time and cost. Knowledge of the concentrations reaching the brain at different developmental stages with different drugs is important for the planning and interpretation of neurodevelopmental toxicity studies.