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A growing body of preclinical and clinical literature suggests that brain-gut-microbiota interactions may contribute to obesity pathogenesis. In this study, we use a machine learning approach to leverage the enormous amount of microstructural neuroimaging and fecal metabolomic data to better understand key drivers of the obese compared to overweight phenotype. Our findings reveal that although gut-derived factors play a role in this distinction, it is primarily brain-directed changes that differentiate obese from overweight individuals. Of the key gut metabolites that emerged from our model, many are likely at least in part derived or influenced by the gut-microbiota, including some amino-acid derivatives. Remarkably, key regions outside of the central nervous system extended reward network emerged as important differentiators, suggesting a role for previously unexplored neural pathways in the pathogenesis of obesity.

Abstract Indigenous Peoples’ advocacy and contributions to climate action have drawn international attention, including from the Intergovernmental Panel on Climate Change (IPCC). This article assesses to which degree the IPCC’s Sixth Assessment Report (AR6) recognises the role and knowledge systems of Indigenous Peoples. Through a content analysis of the Working Groups I, II, and III reports and the Synthesis Report, we found an increasing number of references related to Indigenous Peoples and their knowledge systems. However, the IPCC still perpetuates a reductionist approach that reinforces harmful stereotypes. Overcoming this weakness requires greater reflexivity and concrete actions, including consistent recognition of Indigenous Peoples’ rights, refraining from merely portraying Indigenous Peoples as vulnerable and adopting a strengths-based approach, ensuring ethical and equitable application of Indigenous Peoples’ knowledge systems, and involving Indigenous Peoples from the scoping process. By implementing these measures, the IPCC can improve its partnership with Indigenous Peoples in preparation for AR7.

A positive behavioral interventions and supports (PBIS) framework has been associated with a variety of positive student and school outcomes. However, additional research would be useful to further understand the relationship between school-wide (i.e., Tier 1) PBIS implementation level and student outcomes. This study examined whether there were differences in discipline and academic outcomes based on Tier 1 PBIS implementation fidelity level in 153 Ohio schools when accounting for key covariates. Schools with higher implementation fidelity were found to evidence a significantly lower number of out-of-school suspensions per 100 students than schools with lower implementation fidelity when accounting for demographic covariates. However, a significant trend was not evidenced for the academic achievement outcome variable. Limitations and implications of this study are discussed.

A motivating and engaging school environment has been associated with several positive student outcomes. Consequently, schools have an opportunity and responsibility to promote a culture that supports students in developing and maintaining their motivation, engagement, and self-improvement. Efforts to promote such a culture can be embedded within a Positive Behavioral Interventions and Supports (PBIS) framework. In this paper, we begin by describing motivation and engagement, and discussing the relevance of these concepts in schools. Next, we introduce the traditional PBIS framework, highlighting research and core features. Third, we propose how PBIS can be enhanced by incorporating a focus on relationships, engagement, and motivation in the school setting. Finally, we conclude with recommendations for school teams seeking to implement this approach.

Abstract A growing body of preclinical and clinical literature suggests that brain-gut-microbiota interactions may contribute to obesity pathogenesis. In this study, we use a machine learning approach to leverage the enormous amount of microstructural neuroimaging and fecal metabolomic data to better understand key drivers of the obese compared to overweight phenotype. Our findings reveal that although gut-derived factors play a role in this distinction, it is primarily brain-directed changes that differentiate obese from overweight individuals. Of the key gut metabolites that emerged from our model, many are likely at least in part derived or influenced by the gut-microbiota, including some amino-acid derivatives. Remarkably, key regions outside of the central nervous system extended reward network emerged as important differentiators, suggesting a role for previously unexplored neural pathways in the pathogenesis of obesity.

We designed a behavioral task called One-Trial Trace Escape Reaction (OTTER), in which rats incidentally associate two temporally discontinuous stimuli: a neutral acoustic cue (CS) with an aversive stimulus (US) which occurs two seconds later (CS-2s-US sequence). Rats are first habituated to two similar environmental contexts (A and B), each consisting of an interconnected dark and light chamber. Next, rats experience the CS-2s-US sequence in the dark chamber of one of the contexts (either A or B); the US is terminated immediately after a rat escapes into the light chamber. The CS-2s-US sequence is presented only once to ensure the incidental acquisition of the association. The recall is tested 24 h later when rats are presented with only the CS in the alternate context (B or A), and their behavioral response is observed. Our results show that 59% of the rats responded to the CS by escaping to the light chamber, although they experienced only one CS-2s-US pairing. The OTTER task offers a flexible high throughput tool to study memory acquired incidentally after a single experience. Incidental one-trial acquisition of association between temporally discontinuous events may be one of the essential components of episodic memory formation.

The amyloid cascade hypothesis, focusing on pathological proteins aggregation, has so far failed to uncover the root cause of Alzheimer's disease (AD), or to provide an effective therapy. This traditional paradigm essentially explains a mechanism involved in the development of sporadic AD rather than its cause. The failure of an overwhelming majority of clinical studies (99.6%) demonstrates that a breakthrough in therapy would be difficult if not impossible without understanding the etiology of AD. It becomes more and more apparent that the AD pathology might originate from brain infection. In this review, we discuss a potential role of bacteria, viruses, fungi, and eukaryotic parasites as triggers of AD pathology. We show evidence from the current literature that amyloid beta, traditionally viewed as pathological, actually acts as an antimicrobial peptide, protecting the brain against pathogens. However, in case of a prolonged or excessive activation of a senescent immune system, amyloid beta accumulation and aggregation becomes damaging and supports runaway neurodegenerative processes in AD. This is paralleled by the recent study by Alam and colleagues (2022) who showed that alpha-synuclein, the protein accumulating in synucleinopathies, also plays a critical physiological role in immune reactions and inflammation, showing an unforeseen link between the 2 unrelated classes of neurodegenerative disorders. The multiplication of the amyloid precursor protein gene, recently described by Lee and collegues (2018), and possible reactivation of human endogenous retroviruses by pathogens fits well into the same picture. We discuss these new findings from the viewpoint of the infection hypothesis of AD and offer suggestions for future research.

Introduction Autism spectrum disorders (ASD) are a group of neurodevelopmental disabilities causing major social, communication, and behavioural challenges. Although causative roles of altered genes and environment are recognized, the underlying mechanisms remain elusive. Objectives We carried out a longitudinal analysis of morphological correlates of synaptic plasticity in the cortex with an array of neuro-behavioural tests in Tsc2 loss-of-function ASD rats with persistent mTORC1 hyperactivity. Methods Dendritic spine density and morphology with astroglial response were analysed along with behavioural tests in 45 d.o., 90 d.o. and 12 m.o. age groups maintained under standard or enriched conditions. Results We report a higher density of spines, with a bigger proportion of thin spines in 90 d. o. Tsc2+/- rats, while under enrichment the spine density in 12 m.o groups was lower. In behavioural tests, rats under enrichment showed higher activity in open arms and anogenital contact tests in the second and third age groups. They also showed enhanced self-grooming. Total distance travelled in the open field by Tsc2+/- rats was less in the first and second age groups. Confocal imaging showed an increase in pS6 expression in second and third Tsc2+/- groups, implying mTORC1 hyperactivity. Conclusions Our results show that the environment may have differential neuro-behavioural impacts in rats with unleashed mTORC1, in agreement with the two-hit mechanisms of the underlying neuro-behavioural effects in this model. Although the results of the morphometric analysis suggest a causal link between behavioural changes with altered synaptic plasticity, the mechanisms and involved signalling remain to be defined. Disclosure No significant relationships.

Abstract Background Tuberous sclerosis complex (TSC), a multi-system genetic disorder often associated with autism spectrum disorder (ASD), is caused by mutations of TSC1 or TSC2, which lead to constitutive overactivation of mammalian target of rapamycin (mTOR). In several Tsc1+/- and Tsc2+/- animal models, cognitive and social behavior deficits were reversed by mTOR inhibitors. However, phase II studies have not shown amelioration of ASD and cognitive deficits in individuals with TSC during mTOR inhibitor therapy. We asked here if developmental epilepsy, common in the majority of individuals with TSC but absent in most animal models, could explain the discrepancy. Methods At postnatal day P12, developmental status epilepticus (DSE) was induced in male Tsc2+/- (Eker) and wild-type rats, establishing four experimental groups including controls. In adult animals (n = 36), the behavior was assessed in the paradigms of social interaction test, elevated plus-maze, light-dark test, Y-maze, and novel object recognition. The testing was carried out before medication (T1), during a 2-week treatment with the mTOR inhibitor everolimus (T2) and after an 8-week washing-out (T3). Electroencephalographic (EEG) activity was recorded in a separate set of animals (n = 18). Results Both Tsc2+/- mutation and DSE caused social behavior deficits and epileptiform EEG abnormalities (T1). Everolimus led to a persistent improvement of the social deficit induced by Tsc2+/-, while deficits related to DSE did not respond to everolimus (T2, T3). Conclusions These findings may contribute to an explanation why ASD symptoms in individuals with TSC, where comorbid early-onset epilepsy is common, were not reliably ameliorated by mTOR inhibitors in clinical studies.

This work deals with dielectric properties of lead-free ceramics from piezoelectric powders and focuses on the preparation and characterization of potassium-sodium niobate (K0.5Na0.5NbO₃, KNN) and barium titanate (BaTiO₃, BT) ceramics. Ceramic samples with different porosity were prepared from commercial KNN and BT powders by conventional firing in air or spark plasma sintering (SPS) at temperatures 600-1000 °C for KNN and 900-1300 °C for BT, resulting in partially or fully sintered microstructures. Bulk density, apparent density and open porosity were determined using the Archimedes method and closed and total porosities were calculated on the basis of theoretical densities. For both types of ceramics, the porosity decreases with increasing sintering temperature, and for identical temperatures the porosity of SPS samples is lower than for conventional firing, because the pressure applied during SPS promotes densification. For KNN the influence of SPS on the porosity is much larger than for BT. With increasing SPS temperature KNN exhibits a moderate decrease of the alkali content. The results of dielectric property measurements and their frequency dependence via impedance spectroscopy in the range from 10 or 100 Hz to 1 MHz show that the relative permittivity decreases in all cases with frequency and is usually higher for ceramics prepared via SPS than for conventional firing. This can be explained by the lower porosity and smaller grain size. The absolute values of the relative permittivity at 1 kHz are 134-532 (conventional firing) and 148-3780 (SPS) for KNN, and 753-1801 (conventional firing) and 923-10380 (SPS) for BT ceramics.

BACKGROUND:Indigenous peoples in Canada have higher prevalence of modifiable risk factors for Alzheimer's disease (AD). The relative importance of these risk factors on AD risk management is poorly understood. METHODS:Relative risks from literature and prevalence of risk factors from Statistics Canada or the First Nations Regional Health Survey were used to determine projected population attributable risk (PAR) associated with modifiable risk factors for AD (low education and vascular risk factors) among on- and off-reserve Indigenous and non-Indigenous people in Canada using the Levin formula. RESULTS:Physical inactivity had the highest PAR for AD among Indigenous and non-Indigenous peoples in Canada (32.5% [10.1%-51.1%] and 30.5% [9.2%-48.8%] respectively). The PAR for most modifiable risk factors was higher among Indigenous peoples in Canada, particularly among on-reserve groups. The greatest differences in PAR were for low educational attainment and smoking, which were approximately 10% higher among Indigenous peoples in Canada. The combined PAR for AD for all six modifiable risk factors was 79.6% among on-reserve Indigenous, 74.9% among off-reserve Indigenous, and 67.1% among non-Indigenous peoples in Canada. (All differences significant to p < .001.). CONCLUSIONS:Modifiable risk factors are responsible for the most AD cases among Indigenous peoples in Canada. Further research is necessary to determine the prevalence of AD and the impact of risk factor modification among Indigenous peoples in Canada.

With the increasing use of Positive Behavioral Interventions and Supports (PBIS) nationally, several states have developed systems to recognize exemplar schools that are implementing PBIS with fidelity. These systems serve the dual purpose of identifying model PBIS schools for other schools to emulate while also reinforcing schools' effective PBIS practice and outcomes. The authors (a) review the defining features of current statewide PBIS recognition systems; (b) provide a descriptive narrative on the development, implementation, initial outcomes, and refinement of Ohio's PBIS Recognition System and PBIS Showcase event; and (c) offer recommendations for practice based on this work to assist those interested in establishing a PBIS recognition system at the state or local level.

Excessive accumulation of lipids in the liver is crucial in the pathogenesis of alcoholic steatohepatitis and may be partly mediated by impaired degradation of lipid droplets by autophagy. The E3 ubiquitin ligase SMAD‐specific E3 ubiquitin protein ligase 1 (SMURF1) regulates selective autophagy by ubiquitinating proteins on cargo destined for autophagic delivery to the lysosome for degradation. Here, we evaluated the role of SMURF1 in the regulation of hepatic lipid degradation in alcoholic steatohepatitis. In patients with severe alcoholic hepatitis, SMURF1 colocalized with lipid droplet membranes in liver explants. In a mouse model of alcoholic steatohepatitis, Smurf1−/− mice fed an alcohol diet displayed increased hepatocyte accumulation of lipid droplets and triglycerides as well as more severe liver injury compared to wild‐type mice. The increased severity of liver steatosis in alcohol‐fed Smurf1−/− mice was rescued by adeno‐associated virus (AAV) serotype 8‐mediated hepatic expression of wild‐type Smurf1 protein but not by mutant Smurf1 proteins either lacking the catalytically active cysteine 699 required for ubiquitin transfer or the N‐terminal C2 phospholipid membrane‐binding domain. Conclusion: Smurf1 plays a protective role in the pathogenesis of alcoholic steatohepatitis through a mechanism that requires both its ubiquitin‐ligase activity and C2 phospholipid‐binding domains. These findings have implications for understanding the roles of ubiquitin ligases in fatty liver disease.

Bile acids (BAs) activate various dedicated receptors, including the farnesoid X receptor (FXR) and the Takeda G protein‐coupled receptor 5 (TGR5). The FXR agonist obeticholic acid (OCA) is licensed for the treatment of primary biliary cholangitis and has shown promising results in NASH patients, whereas TGR5 agonists target inflammation and metabolism. We hypothesized that FXR and/or TGR5 agonists may be therapeutic in early alcoholic liver disease (ALD) in mice, in which hepatic inflammation plays a major role. OCA, INT‐777, and INT‐767 are BA derivatives with selective agonist properties for FXR, TGR5, or both, respectively. These compounds were tested in two mouse models (3‐day binge model and prolonged Lieber DeCarli diet for 12 days) of early ALD. Serum alanine aminotransferase and liver histology were used to assess liver injury, Oil Red O staining of liver sections to assess steatosis, and real‐time polymerase chain reaction to assess changes in gene expression. In the ethanol binge model, treatment with OCA and INT‐777 decreased hepatic macrovesicular steatosis and protected from ethanol‐induced liver injury. After prolonged ethanol administration, mice treated with OCA, INT‐767, or INT‐777 showed decreased hepatic steatosis, associated with reduced liver fatty acid synthase protein expression, and protection from liver injury. Treatment with BA receptor agonists in both models of ethanol administration modulated lipogenic gene expression, and decreased liver interleukin‐1β mRNA expression associated with increased ubiquitination of NLRP3 inflammasome through cyclic adenosine monophosphate–induced activation of protein kinase A. Conclusion: OCA, INT‐767, or INT‐777 administration is effective in reducing acute and chronic ethanol‐induced steatosis and inflammation in mice, with varying degrees of efficacy depending on the duration of ethanol administration, indicating that both FXR and TGR5 activation can protect from liver injury in ALD models.

In this pilot study, a series of new 3,4-dihydroquinolin-2(1H)-one derivatives as potential dopamine receptor D2 (D2R) modulators were synthesized and evaluated in vitro. The preliminary structure–activity relationship disclosed that compound 5e exhibited the highest D2R affinity among the newly synthesized compounds. In addition, 5e showed a very low cytotoxic profile and a high probability to cross the blood–brain barrier, which is important considering the observed affinity. However, molecular modelling simulation revealed completely different binding mode of 5e compared to USC-D301, which might be the culprit of the reduced affinity of 5e toward D2R in comparison with USC-D301.

Chronic sensitization to serotonin 1A and 7 receptors agonist 8-OH-DPAT induces compulsive checking and perseverative behavior. As such, it has been used to model obsessive-compulsive disorder (OCD)-like behavior in mice and rats. In this study, we tested spatial learning in the 8-OH-DPAT model of OCD and the effect of co-administration of memantine and riluzole—glutamate-modulating agents that have been shown to be effective in several clinical trials. Rats were tested in the active place avoidance task in the Carousel maze, where they learned to avoid the visually imperceptible shock sector. All rats were subcutaneously injected with 8-OH-DPAT (0.25 mg/kg) or saline (control group) during habituation. During acquisition, they were pretreated with riluzole (1 mg/kg), memantine (1 mg/kg), or saline solution 30 min before each session and injected with 8-OH-DPAT (“OH” groups) or saline (“saline” groups) right before the experiment. We found that repeated application of 8-OH-DPAT during both habituation and acquisition significantly increased locomotion, but it impaired the ability to avoid the shock sector. However, the application of 8-OH-DPAT in habituation had no impact on the learning process if discontinued in acquisition. Similarly, memantine and riluzole did not affect the measured parameters in the “saline” groups, but in the “OH” groups, they significantly increased locomotion. In addition, riluzole increased the number of entrances and decreased the maximum time avoided of the shock sector. We conclude that monotherapy with glutamate-modulating agents does not reduce but exacerbates cognitive symptoms in the animal model of OCD.

The McGill-R-Thy1-APP transgenic rat is an animal model of the familial form of Alzheimer's disease (AD). This model mirrors several neuropathological hallmarks of the disease, including the accumulation of beta-amyloid and the formation of amyloid plaques (in homozygous animals only), neuroinflammation and the gradual deterioration of cognitive functions even prior to plaque formation, although it lacks the tauopathy observed in human victims of AD. The goal of the present study was a thorough characterization of the homozygous model with emphasis on its face validity in several domains of behavior known to be affected in AD patients, including cognitive functions, motor coordination, emotionality, sociability, and circadian activity patterns. On the behavioral level, we found normal locomotor activity in spontaneous exploration, but problems with balance and gait coordination, increased anxiety and severely impaired spatial cognition in 4–7 month old homozygous animals. The profile of social behavior and ultrasonic communication was altered in the McGill rats, without a general social withdrawal. McGill rats also exhibited changes in circadian profile, with a shorter free-running period and increased total activity during the subjective night, without signs of sleep disturbances during the inactive phase. Expression of circadian clock gene Bmal1 was found to be increased in the parietal cortex and cerebellum, while Nr1d1 expression was not changed. The clock-controlled gene Prok2 expression was found to be elevated in the parietal cortex and hippocampus, which might have contributed to the observed changes in circadian phenotype. We conclude that the phenotype in the McGill rat model is not restricted to the cognitive domain, but also includes gait problems, changes in emotionality, social behavior, and circadian profiles. Our findings show that the model should be useful for the development of new therapeutic approaches targeting not only memory decline but also other symptoms decreasing the quality of life of AD patients.

The role of NMDA receptors in learning, memory and hippocampal function has long been recognized. Post-mortem studies have indicated that the expression or subunit composition of the NMDA glutamate receptor subtype might be related to the impaired cognitive functions found in schizophrenia patients. NMDA receptor antagonists have been used to develop animal models of this disorder. There is accumulating evidence showing that not only the acute but also the chronic application of NMDA receptor antagonists may induce schizophrenia-like alterations in behavior and brain functions. However, limited evidence is available regarding the consequences of NMDA receptor blockage during periods of adolescence and early adulthood. This study tested the hypothesis that a 2-week treatment of male Long-Evans and Wistar rats with dizocilpine (MK-801; 0.5 mg/kg daily) starting at postnatal days (PD) 30 and 60 would cause a long-term cognitive deficit and changes in the levels of NMDA receptor subunits. The working memory version of the Morris water maze (MWM) and active place avoidance with reversal on a rotating arena (Carousel) requiring cognitive coordination and flexibility probed cognitive functions and an elevated-plus maze (EPM) was used to measure anxiety-like behavior. The western blot method was used to determine changes in NMDA receptor subunit levels in the hippocampus. Our results showed no significant changes in behaviors in Wistar rats. Slightly elevated anxiety-like behavior was observed in the EPM in Long-Evans rats with the onset of treatment on PD 30. Furthermore, Long-Evans rats treated from PD 60 displayed impaired working memory in the MWM. There were; however, no significant changes in the levels of NMDA receptor subunits because of MK-801 administration. These findings suggest that a 2-week treatment starting on PD 60 in Long-Evans rats leads to long-term changes in working memory, but this deficit is not paralleled by changes in NMDA receptor subunits. These results support the face validity, but not construct validity of this model. We suggest that chronic treatment of adolescent and adult rats does not constitute a plausible animal model of schizophrenia.

Objectives . To review the protective factors and causal mechanisms which promote and enhance Indigenous youth mental health in the Circumpolar North. Study design . A systematic literature review of peer-reviewed English-language research was conducted to systematically examine the protective factors and causal mechanisms which promote and enhance Indigenous youth mental health in the Circumpolar North. Methods . This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, with elements of a realist review. From 160 records identified in the initial search of 3 databases, 15 met the inclusion criteria and were retained for full review. Data were extracted using a codebook to organize and synthesize relevant information from the articles. Results . More than 40 protective factors at the individual, family, and community levels were identified as enhancing Indigenous youth mental health. These included practicing and holding traditional knowledge and skills, the desire to be useful and to contribute meaningfully to one's community, having positive role models, and believing in one's self. Broadly, protective factors at the family and community levels were identified as positively creating and impacting one's social environment, which interacts with factors at the individual level to enhance resilience. An emphasis on the roles of cultural and land-based activities, history, and language, as well as on the importance of social and family supports, also emerged throughout the literature. Conclusions . Healthy communities and families foster and support youth who are resilient to mental health challenges and able to adapt and cope with multiple stressors, be they social, economic, or environmental. Creating opportunities and environments where youth can successfully navigate challenges and enhance their resilience can in turn contribute to fostering healthy Circumpolar communities. Looking at the role of new social media in the way youth communicate and interact is one way of understanding how to create such opportunities. Youth perspectives of mental health programmes are crucial to developing appropriate mental health support and meaningful engagement of youth can inform locally appropriate and culturally relevant mental health resources, programmes and community resilience strategies.

Cell cortex remodeling during cell division is a result of myofilament-driven contractility of the cortical membrane-bound actin meshwork. Little is known about the interaction between individual myofilaments and membrane-bound actin filaments. Here we reconstituted a minimal actin cortex to directly visualize the action of individual myofilaments on membrane-bound actin filaments using TIRF microscopy. We show that synthetic myofilaments fragment and compact membrane-bound actin while processively moving along actin filaments. We propose a mechanism by which tension builds up between the ends of myofilaments, resulting in compressive stress exerted to single actin filaments, causing their buckling and breakage. Modeling of this mechanism revealed that sufficient force (∼20 pN) can be generated by single myofilaments to buckle and break actin filaments. This mechanism of filament fragmentation and compaction may contribute to actin turnover and cortex reorganization during cytokinesis.

In the multifactorial pathophysiology of alcoholic liver disease (ALD), inflammatory cascade activation plays a central role. Recent studies demonstrated that Toll-like Receptors, the sensors of microbial and endogenous danger signals, are expressed and activated in innate immune cells as well as in parenchymal cells in the liver and thereby contribute to ALD. In this paper, we discuss the importance of gut-derived endotoxin and its recognition by TLR4. The significance of TLR-induced intracellular signaling pathways and cytokine production as well as the contribution of reactive oxygen radicals is evaluated. The contribution of TLR signaling to induction of liver fibrosis and hepatocellular cancer is reviewed in the context of alcohol-induced liver disease.