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Light microscopy methods have continued to advance allowing for unprecedented analysis of various cell types in tissues including the brain. Although the functional state of some cell types such as microglia can be determined by morphometric analysis, techniques to perform robust, quick, and accurate measurements have not kept pace with the amount of imaging data that can now be generated. Most of these image segmentation tools are further burdened by an inability to assess structures in three-dimensions. Despite the rise of machine learning techniques, the nature of some biological structures prevents the training of several current day implementations. Here we present PrestoCell, a novel use of persistence-based clustering to segment cells in light microscopy images, as a customized Python-based tool that leverages the free multidimensional image viewer Napari. In evaluating and comparing PrestoCell to several existing tools, including 3DMorph, Omipose, and Imaris, we demonstrate that PrestoCell produces image segmentations that rival these solutions. In particular, our use of cell nuclei information resulted in the ability to correctly segment individual cells that were interacting with one another to increase accuracy. These benefits are in addition to the simplified graphically based user refinement of cell masks that does not require expensive commercial software licenses. We further demonstrate that PrestoCell can complete image segmentation in large samples from light sheet microscopy, allowing quantitative analysis of these large datasets. As an open-source program that leverages freely available visualization software, with minimum computer requirements, we believe that PrestoCell can significantly increase the ability of users without data or computer science expertise to perform complex image analysis.

This exploratory study analyzes the advocacy practices and outputs of three national associations representing libraries and organizations of various types: the Canadian Association of Research Libraries (CARL), the Canadian Urban Libraries Council (CULC), and the Canadian Federation of Library Associations-Fédération canadienne des associations de bibliothèques (CFLA-FCAB). Data was collected from a variety of sources, including the associations’ websites, records of federal government consultations and lobbying activities. A thematic analysis was conducted using open coding and visual theme mapping, and the results analyzed using Schein’s model for understanding organizational culture. The results provide important insights into publicly available advocacy work by these associations since 2016. By providing the first step of quantifying advocacy work by Canadian library associations, this study lays the groundwork for further investigation to explore the impact of library association advocacy and to identify successful patterns and strategies for advocacy initiatives in the future.

Introduction : Les unités de soins intensifs (USI) accueillent les personnes dont la condition de santé est critique. Au congé, celles-ci peuvent conserver plusieurs séquelles incapacitantes. Cet ensemble de symptômes physiques, cognitifs et psychologiques constitue le syndrome post soins intensifs (Post Intensive Care Syndrome [PICS]). Les proches peuvent également souffrir d’une forme du PICS (Post Intensive Care Syndrome – Family [PICS-F]). Le journal de bord permettrait de réduire les symptômes de santé mentale du PICS ou du PICS-F. Ce document, qui contient des informations narratives sur le séjour de la personne hospitalisée à l’USI, vise à combler les trous dans sa mémoire et à contextualiser les souvenirs perturbants qui seraient à l’origine de la souffrance psychologique. Or, cette intervention préventive demeure peu utilisée et étudiée en contexte québécois (Canada).Objectifs : Cette étude vise à évaluer l’acceptabilité prospective du journal de bord dans 2 USI québécoises par les personnes recevant des soins de santé, les proches significatifs, le personnel soignant et les membres de l’équipe multidisciplinaire. Un second objectif sera d’explorer les recommandations de ces acteurs clés entourant les modalités de l’intervention.Méthodes : Cette étude mixte se déroulera dans 2 USI d’un hôpital quaternaire situé dans la ville de Québec. Des entretiens semi-dirigés seront conduits auprès de 4 groupes de 6 à 8 participants représentant les acteurs clés de l’intervention. L’entretien individuel pourra également être appliqué. Par la suite, les participants répondront à un questionnaire d’acceptabilité.Discussion et retombées anticipées : Cette étude guidera l’adaptation de cette intervention de façon à optimiser son adoption par les acteurs clés concernés et promouvoir leur implication dans le développement de l’intervention.

A large subset of patients with Angelman syndrome (AS) suffer from concurrent gastrointestinal (GI) issues, including constipation, poor feeding, and reflux. AS is caused by the loss of ubiquitin ligase E3A (UBE3A) gene expression in the brain. Clinical features of AS, which include developmental delays, intellectual disability, microcephaly, and seizures, are primarily due to the deficient expression or function of the maternally inherited UBE3A allele. The association between neurodevelopmental delay and GI disorders is part of the increasing evidence suggesting a link between the brain and the gut microbiome via the microbiota-gut-brain axis. To investigate the associations between colonization of the gut microbiota in AS, we characterized the fecal microbiome in three animal models of AS involving maternal deletions of Ube3A, including mouse, rat, and pig, using 16S rRNA amplicon sequencing. Overall, we identified changes in bacterial abundance across all three animal models of AS. Specific bacterial groups were significantly increased across all animal models, including Lachnospiraceae Incertae sedis, Desulfovibrios sp., and Odoribacter, which have been correlated with neuropsychiatric disorders. Taken together, these findings suggest that specific changes to the local environment in the gut are driven by a Ube3a maternal deletion, unaffected by varying housing conditions, and are prominent and detectable across multiple small and large animal model species. These findings begin to uncover the underlying mechanistic causes of GI disorders in AS patients and provide future therapeutic options for AS patients. IMPORTANCE Angelman syndrome (AS)-associated gastrointestinal (GI) symptoms significantly impact quality of life in patients. In AS models in mouse, rat, and pig, AS animals showed impaired colonization of the gut microbiota compared to wild-type (healthy) control animals. Common changes in AS microbiomes across all three animal models may play a causal effect for GI symptoms and may help to identify ways to treat these comorbidities in patients in the future.

Author(s): Camille Guérin-Marion [sup.1] , Jean-François Bureau [sup.1] , Alexandre Gareau [sup.2] , Marie-France Lafontaine [sup.1] , Patrick Gaudreau [sup.1] Author Affiliations: (1) https://ror.org/03c4mmv16, grid.28046.38, 0000 0001 2182 2255, School [...], Non-suicidal self-injury (NSSI) is prevalent among university students, yet risk models for NSSI are rarely contextualized to the experiences of university students. The current study explored a risk model for NSSI among university students, with a focus on parent-child relational risk factors and intrapersonal vulnerabilities likely to be heightened by the achievement-focused context of the university years. A sample of 2,579 students (75.2% female) reported on experiences relating to perceived mother and father pressure, emotion dysregulation, academic coping, perfectionism (self-oriented, socially-prescribed), and past-year NSSI. Analyses involved structural equation modeling using a combined linear and zero-inflated negative binomial regression approach. Structural equation models revealed that higher perceived mother and father pressure were associated with greater past-year NSSI likelihood amongst university students. Perceived mother and father pressure were also positively associated with four intrapersonal markers of risk (self-oriented perfectionism, socially-prescribed perfectionism, academic disengagement coping, emotion dysregulation). Among these, only emotion dysregulation was linked with higher NSSI likelihood and frequency. In contrast, students higher in self-oriented perfectionism appeared less likely to engage in NSSI. Gender differences were also examined as an exploratory goal. Findings provide further insights into patterns of NSSI vulnerability among university students.

Background. Biomarkers that predict posttransplant alloimmunity could lead to improved long-term graft survival. Evaluation of the number of mismatched epitopes between donor and recipient HLA proteins, termed molecular mismatch analysis, has emerged as an approach to classify transplant recipients as having high, intermediate, or low risk of graft rejection. When high-resolution genotypes are unavailable, molecular mismatch analysis requires algorithmic assignment, or imputation, of a high-resolution genotyping. Although imputation introduces inaccuracies in molecular mismatch analyses, it is unclear whether these inaccuracies would impact the clinical risk assessment for graft rejection. Methods. Using renal transplant patients and donors from our center, we constructed cohorts of surrogate donor-recipient pairs with high-resolution and low-resolution HLA genotyping that were racially concordant or discordant. We systemically assessed the impact of imputation on molecular mismatch analysis for cohorts of 180–200 donor-recipient pairs for each of 4 major racial groups. We also evaluated the effect of imputation for a racially diverse validation cohort of 35 real-world renal transplant pairs. Results. In the surrogate donor-recipient cohorts, imputation preserved the molecular mismatch risk category for 90.5%–99.6% of racially concordant donor-recipient pairs and 92.5%–100% of racially discordant pairs. In the validation cohort, which comprised 72% racially discordant pairs, we found that imputation preserved the molecular mismatch risk category for 97.1% of pairs. Conclusions. Overall, these data demonstrate that imputation preserves the molecular mismatch risk assessment in the vast majority of cases and provides evidence supporting imputation in the performance of molecular mismatch analysis for clinical assessment.

The gut microbiota is increasingly being found to contribute to the etiology and severity of multiple diseases, including within the central nervous system (CNS). This microbiota-gut-brain (MGB) axis facilitates communication between gut microbes and the brain to regulate behavior. Communication along the axis occurs via multiple routes, including the vagus nerve, gut-derived neurohormones, and immune cells, and more recently, a role for microbial metabolites has been uncovered. This commentary highlights the recent findings by H. Fang, Y. Wang, J. Deng, H. Zhang, et al. (mSystems 7:e01399-21, 2022, https://doi.org/10.1128/msystems.01399-21) on the role of gut microbiota and bacterial metabolites in mediating sepsis-associated encephalopathy in a mouse model of cecal puncture and ligation.

Diarrheal diseases are a leading cause of death in children under the age of 5 years worldwide. Repeated early-life exposures to diarrheal pathogens can result in comorbidities including stunted growth and cognitive deficits, suggesting an impairment in the microbiota-gut-brain (MGB) axis. Neonatal C57BL/6 mice were infected with enteropathogenic Escherichia coli (EPEC) (strain e2348/69; ΔescV [type III secretion system {T3SS} mutant]) or the vehicle (Luria-Bertani [LB] broth) via orogastric gavage at postnatal day 7 (P7). Behavior (novel-object recognition [NOR] task, light/dark [L/D] box, and open-field test [OFT]), intestinal physiology (Ussing chambers), and the gut microbiota (16S Illumina sequencing) were assessed in adulthood (6 to 8 weeks of age). Neonatal infection of mice with EPEC, but not the T3SS mutant, caused ileal inflammation in neonates and impaired recognition memory (NOR task) in adulthood. Cognitive impairments were coupled with increased neurogenesis (Ki67 and doublecortin immunostaining) and neuroinflammation (increased microglia activation [Iba1]) in adulthood. Intestinal pathophysiology in adult mice was characterized by increased secretory state (short-circuit current [Isc]) and permeability (conductance) (fluorescein isothiocyanate [FITC]-dextran flux) in the ileum and colon of neonatally EPEC-infected mice, along with increased expression of proinflammatory cytokines (Tnfα, Il12, and Il6) and pattern recognition receptors (Nod1/2 and Tlr2/4). Finally, neonatal EPEC infection caused significant dysbiosis of the gut microbiota, including decreased Firmicutes, in adulthood. Together, these findings demonstrate that infection in early life can significantly impair the MGB axis in adulthood.

N-glycosylation is a ubiquitous posttranslational modification that affects protein structure and function, including those of the central nervous system. N-glycans attached to cell membrane proteins play crucial roles in all aspects of biology, including embryogenesis, development, cell-cell recognition and adhesion, and cell signaling and communication. Although brain function and behavior are known to be regulated by the N-glycosylation state of numerous cell surface glycoproteins, our current understanding of brain glycosylation is limited, and glycan variations associated with functional brain regions remain largely unknown. In this work, we used a well-established cell surface glycomic nanoLC-Chip-Q-TOF platform developed in our laboratory to characterize the N-glycome of membrane fractions enriched in cell surface glycoproteins obtained from specific functional brain areas. We report the cell membrane N-glycome of two major developmental divisions of mice brain with specific and distinctive functions, namely the forebrain and hindbrain. Region-specific glycan maps were obtained with ∼120 N-glycan compositions in each region, revealing significant differences in "brain-type" glycans involving high mannose, bisecting, and core and antenna fucosylated species. Additionally, the cell membrane N-glycome of three functional regions of the forebrain and hindbrain, the cerebral cortex, hippocampus, and cerebellum, was characterized. In total, 125 N-glycan compositions were identified, and their region-specific expression profiles were characterized. Over 70 N-glycans contributed to the differentiation of the cerebral cortex, hippocampus, and cerebellum N-glycome, including bisecting and branched glycans with varying degrees of core and antenna fucosylation and sialylation. This study presents a comprehensive spatial distribution of the cell-membrane enriched N-glycomes associated with five discrete anatomical and functional brain areas, providing evidence for the presence of a previously unknown brain glyco-architecture. The region-specific molecular glyco fingerprints identified here will enable a better understanding of the critical biological roles that N-glycans play in the specialized functional brain areas in health and disease.

Patients with chronic wounds often have associated cognitive dysfunction and depression with an as yet unknown mechanism for this association. To address the possible causality of skin wounding inducing these changes, behavior and cognitive functions of female C57BL/6 mice with an excisional skin wound were compared to unwounded animals. At six days post wounding, animals exhibited anxiety-like behaviors, impaired recognition memory, and impaired coping behavior. Wounded animals also had concomitant increased hippocampal expression of Tnfa, the pattern recognition receptor (PRR) Nod2, the glucocorticoid receptors GR/Nr3c1 and Nr3c2. Prefrontal cortex serotonin and dopamine turnover were increased on day six post-wounding. In contrast to the central nervous system (CNS) findings, day six post -wounding serum catecholamines did not differ between wounded and unwounded animals, nor did levels of the stress hormone corticosterone, TNFα, or TGFβ. Serum IL6 levels were, however elevated in the wounded animals. These findings provide evidence of skin-to-brain signaling, mediated either by elevated serum IL6 or a direct neuronal signaling from the periphery to the CNS, independent of systemic mediators. Wounding in the periphery is associated with an altered expression of inflammatory mediators and PRR genes in the hippocampus, which may be responsible for the observed behavioral deficits.

BackgroundEnteropathogenic Escherichia coli (EPEC) infection causes prolonged, watery diarrhea leading to morbidity and mortality. Although EPEC infection impacts nutrient transporter function and expression in intestinal epithelial cells, the effects of EPEC infection on intestinal absorption of ascorbic acid (AA) have not yet been investigated.AimsTo investigate the effect of EPEC infection on intestinal AA uptake process and expression of both AA transporters.MethodsWe used two experimental models: human-derived intestinal epithelial Caco-2 cells and mice. 14C-AA uptake assay, Western blot, RT-qPCR, and promoter assay were performed.ResultsEPEC (WT) as well as ΔespF and ΔespG/G2 mutant-infected Caco-2 cells showed markedly inhibited AA uptake, while other mutants (ΔescN, ΔespA, ΔespB, and ΔespD) did not affect AA uptake. Infection also reduced protein and mRNA expression levels for both hSVCT1 and hSVCT2. EPEC-infected mice showed marked inhibitory effect on AA uptake and decreased protein and mRNA expression levels for both mSVCT1 and mSVCT2 in jejunum and colon. MicroRNA regulators of SVCT1 and SVCT2 (miR103a, miR141, and miR200a) were upregulated significantly upon EPEC infection in both Caco-2 and mouse jejunum and colon. In addition, expression of the accessory protein glyoxalate reductase/hydroxypyruvate reductase (GRHPR), which regulates SVCT1 function, was markedly decreased by EPEC infection in both models.ConclusionsThese findings suggest that EPEC infection causes inhibition in AA uptake through a multifactorial dysregulation of SVCT1 and SVCT2 expression in intestinal epithelial cells.

Low-frequency 1q21.1 distal deletion and duplication copy number variant (CNV) carriers are predisposed to multiple neurodevelopmental disorders, including schizophrenia, autism and intellectual disability. Human carriers display a high prevalence of micro- and macrocephaly in deletion and duplication carriers, respectively. The underlying brain structural diversity remains largely unknown. We systematically called CNVs in 38 cohorts from the large-scale ENIGMA-CNV collaboration and the UK Biobank and identified 28 1q21.1 distal deletion and 22 duplication carriers and 37,088 non-carriers (48% male) derived from 15 distinct magnetic resonance imaging scanner sites. With standardized methods, we compared subcortical and cortical brain measures (all) and cognitive performance (UK Biobank only) between carrier groups also testing for mediation of brain structure on cognition. We identified positive dosage effects of copy number on intracranial volume (ICV) and total cortical surface area, with the largest effects in frontal and cingulate cortices, and negative dosage effects on caudate and hippocampal volumes. The carriers displayed distinct cognitive deficit profiles in cognitive tasks from the UK Biobank with intermediate decreases in duplication carriers and somewhat larger in deletion carriers-the latter potentially mediated by ICV or cortical surface area. These results shed light on pathobiological mechanisms of neurodevelopmental disorders, by demonstrating gene dose effect on specific brain structures and effect on cognitive function.

Physician rating of cutaneous erythema is central to clinical dermatological assessment as well as quantification of outcome measures in clinical trials in a number of dermatologic conditions. However, issues with inter-rater reliability and variability in the setting of higher Fitzpatrick skin types make visual erythema assessment unreliable. We developed and validated a computer-assisted image-processing algorithm (EQscore) to reliably quantify erythema (across a range of skin types) in the dermatology clinical setting. Our image processing algorithm evaluated erythema based upon green light suppression differentials between affected and unaffected skin. A group of four dermatologists used a 4-point Likert scale as a human evaluation of similar erythematous patch tests. The algorithm and dermatologist scores were compared across 164 positive patch test reactions. The intra-class correlation coefficient of groups and the correlation coefficient between groups were calculated. The EQscore was validated on and independent image set of psoriasis, minimal erythema dose testing and steroid-induced blanching images. The reliability of the erythema quantification method produced an intra-class correlation coefficient of 0.84 for the algorithm and 0.67 for dermatologists. The correlation coefficient between groups was 0.85. The EQscore demonstrated high agreement with clinical scoring and superior reliability compared with clinical scoring, avoiding the pitfalls of erythema underrating in the setting of pigmentation. The EQscore is easily accessible (http://lab.rockefeller.edu/krueger/EQscore), user-friendly, and may allow dermatologists to more readily and accurately rate the severity of dermatological conditions and the response to therapeutic treatments.

In recent years, the gut microbiota has been increasingly implicated in the development of many extraintestinal disorders, including neurodevelopmental and neurodegenerative disorders. Despite this growing connection, our understanding of the precise mechanisms behind these effects is currently lacking. Pattern recognition receptors (PRRs) are important innate immune proteins expressed on the surface and within the cytoplasm of a multitude of cells, both immune and otherwise, including epithelial, endothelial and neuronal. PRRs comprise four major subfamilies: the Toll-like receptors (TLRs), the nucleotide-binding oligomerization domain leucine rich repeats-containing receptors (NLRs), the retinoic acid inducible gene 1-like receptors and the C-type lectin receptors. Recognition of commensal bacteria by PRRs is critical for maintaining host-microbe interactions and homeostasis, including behaviour. The expression of PRRs on multiple cell types makes them a highly interesting and novel target for regulation of host-microbe signalling, which may lead to gut-brain signalling. Emerging evidence indicates that two of the four known families of PRRs (the NLRs and the TLRs) are involved in the pathogenesis of neurodevelopmental and neurodegenerative disorders via the gut-brain axis. Taken together, increasing evidence supports a role for these PRRs in the development of neurological disorders, including Alzheimer's disease, Parkinson's disease and multiple sclerosis, via the microbiota-gut-brain axis.

Background: Cheating at the post-secondary level is a skewed phenomenon. While personality and environmental factors are associated with cheating, few studies account for the zero inflation when predicting cheating behaviour. Aim: In this study, we explore a person-situation interaction hypothesis where teacher autonomy support (AS) could modify the relation between students' honesty trait and premeditated cheating. Sample: Participants were 710 college students and 31 teachers. Methods: Teacher and student reports of teacher AS were collected and students also completed self-reports of honesty and premeditated cheating. Results: Given that cheating had a zero-inflated negative binomial distribution, we can investigate two separate outcomes--likelihood of cheating and magnitude of cheating. Predictably, student honesty trait predicted lower likelihood and magnitude of cheating. AS, whether student- or teacher-reported, moderated the relation between honesty and likelihood of cheating. In low perceived AS teaching environments, student honesty was associated with cheating likelihood. However, there was no such relation in high perceived AS teaching environments. Conclusions: Students' honesty generally predicts lower cheating. However, the educational environment provided by the teacher influences the strength of this association. The less autonomy-supportive students perceive the educational environment, the more their personality is important in predicting the likelihood of cheating.

Light microscopy methods have continued to advance allowing for unprecedented analysis of various cell types in tissues including the brain. Although the functional state of some cell types such as microglia can be determined by morphometric analysis, techniques to perform robust, quick, and accurate measurements have not kept pace with the amount of imaging data that can now be generated. Most of these image segmentation tools are further burdened by an inability to assess structures in three-dimensions. Despite the rise of machine learning techniques, the nature of some biological structures prevents the training of several current day implementations. Here we present PrestoCell, a novel use of persistence-based clustering to segment cells in light microscopy images, as a customized Python-based tool that leverages the free multidimensional image viewer Napari. In evaluating and comparing PrestoCell to several existing tools, including 3DMorph, Omipose, and Imaris, we demonstrate that PrestoCell produces image segmentations that rival these solutions. In particular, our use of cell nuclei information resulted in the ability to correctly segment individual cells that were interacting with one another to increase accuracy. These benefits are in addition to the simplified graphically based user refinement of cell masks that does not require expensive commercial software licenses. We further demonstrate that PrestoCell can complete image segmentation in large samples from light sheet microscopy, allowing quantitative analysis of these large datasets. As an open-source program that leverages freely available visualization software, with minimum computer requirements, we believe that PrestoCell can significantly increase the ability of users without data or computer science expertise to perform complex image analysis.

ABSTRACTObjective Changes in couples’ relationship quality are common post-cardiac event but it is unclear how relationship quality is linked to patients’ and spouses’ quality of life (QoL). The purpose of the present study was to examine the association between relationship quality on QoL in patient-spouse dyads within six months of a cardiac event.Methods Participants (N = 181 dyads; 25.9% female patients), recruited from a large cardiac hospital, completed validated questionnaires measuring demographic, relationship (Dyadic Adjustment Scale; DAS) and QoL variables (Heart-QoL & Quality of life of Cardiac Spouses Questionnaire). An Actor-Partner Interdependence Model was used to investigate actor (i.e. responses influencing their own outcome) and partner effects (responses influencing their partner’s outcome) of relationship quality and QoL.Results Patients’ and spouses’ perceptions of relationship quality were in the satisfied range (DAS > 108; 65% of sample) and, as expected, patients reported lower general physical QoL than did their spouse (t(180) = −10.635, p

Myelination in the peripheral and central nervous systems is critical in regulating motor, sensory, and cognitive functions. As myelination occurs rapidly during early life, neonatal gut dysbiosis during early colonization can potentially alter proper myelination by dysregulating immune responses and neuronal differentiation. Despite common usage of antibiotics (Abx) in children, the impact of neonatal Abx-induced dysbiosis on the development of microbiota, gut, brain (MGB) axis, including myelination and behavior, is unknown. We hypothesized that neonatal Abx-induced dysbiosis dysregulates host-microbe interactions, impairing myelination in the brain, and altering the MGB axis. Neonatal C57BL/6 mice were orally gavaged daily with an Abx cocktail (neomycin, vancomycin, ampicillin) or water (vehicle) from postnatal day 7 (P7) until weaning (P23) to induce gut dysbiosis. Behavior (cognition; anxiety-like behavior), microbiota sequencing, and qPCR (ileum, colon, hippocampus and pre-frontal cortex [PFC]) were performed in adult mice (6-8 weeks). Neonatal Abx administration led to intestinal dysbiosis in adulthood, impaired intestinal physiology, coupled with perturbations of bacterial metabolites and behavioral alterations (cognitive deficits and anxiolytic behavior). Expression of myelin-related genes (Mag, Mog, Mbp, Mobp, Plp) and transcription factors (Sox10, Myrf) important for oligodendrocytes were significantly increased in the PFC region of Abx-treated mice. Increased myelination was confirmed by immunofluorescence imaging and western blot analysis, demonstrating increased expression of MBP, SOX10 and MYRF in neonatally Abx-treated mice compared to sham controls in adulthood. Finally, administration of the short chain fatty acid butyrate following completion of the Abx treatment restored intestinal physiology, behavior, and myelination impairments, suggesting a critical role for the gut microbiota in mediating these effects. Taken together, we identified a long-lasting impact of neonatal Abx administration on the MGB axis, specifically on myelin regulation in the PFC region, potentially contributing to impaired cognitive function and bacterial metabolites are effective in reversing this altered phenotype.

BackgroundNeurons are an integral component of the immune system that functions to coordinate responses to bacterial pathogens. Sensory nociceptive neurons that can detect bacterial pathogens are found throughout the body with dense innervation of the intestinal tract.MethodsIn this study, we assessed the role of these nerves in the coordination of host defenses to Citrobacter rodentium. Selective ablation of nociceptive neurons significantly increased bacterial burden 10 days postinfection and delayed pathogen clearance.ResultsBecause the sensory neuropeptide CGRP (calcitonin gene-related peptide) regulates host responses during infection of the skin, lung, and small intestine, we assessed the role of CGRP receptor signaling during C rodentium infection. Although CGRP receptor blockade reduced certain proinflammatory gene expression, bacterial burden and Il-22 expression was unaffected.ConclusionsOur data highlight that sensory nociceptive neurons exert a significant host protective role during C rodentium infection, independent of CGRP receptor signaling.

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P

Prior to and following the publication of this article the authors noted that the complete list of authors was not included in the main article and was only present in Supplementary Table 1. The author list in the original article has now been updated to include all authors, and Supplementary Table 1 has been removed. All other supplementary files have now been updated accordingly. Furthermore, in Table 1 of this Article, the replication cohort for the row Close relative in data set, n (%) was incorrect. All values have now been corrected to 0(0%). The publishers would like to apologise for this error and the inconvenience it may have caused.

A series of complex physiological processes underlie the development of the microbiota, gut, and brain in early life, which together communicate via the microbiota-gut-brain axis to maintain health and homeostasis. Disruption of these processes can lead to dysbiosis of the microbiota, pathophysiology of the gut and behavioral deficits including depression, anxiety and cognitive deficits. Environmental exposures, particularly in early life, can interfere with development and impact these pathways. This review will focus on the role of the microbiome and the gut in neurodevelopment and neurodegeneration as well as the impacts of environmental exposures, particularly to the neurotoxicant polychlorinated biphenyls (PCBs), given that the gut serves as the primary exposure route. There exists extensive research on the importance of the microbiome in the developing brain and connections with autism spectrum disorder (ASD) and increasing links being established between the microbiome and development of Alzheimer's disease (AD) in the elderly. Finally, we will speculate on the mechanisms through which PCBs can induce dysbiosis and dysregulate physiology of the gut and brain.

Key points•Nucleotide binding oligomerization domain (Nod)-like receptors regulate cognition, anxiety and hypothalamic-pituitary-adrenal axis activation. •Nod-like receptors regulate central and peripheral serotonergic biology. •Nod-like receptors are important for maintenance of gastrointestinal physiology. •Intestinal epithelial cell expression of Nod1 receptors regulate behaviour.AbstractGut-brain axis signalling is critical for maintaining health and homeostasis. Stressful life events can impact gut-brain signalling, leading to altered mood, cognition and intestinal dysfunction. In the present study, we identified nucleotide binding oligomerization domain (Nod)-like receptors (NLR), Nod1 and Nod2, as novel regulators for gut-brain signalling. NLR are innate immune pattern recognition receptors expressed in the gut and brain, and are important in the regulation of gastrointestinal physiology. We found that mice deficient in both Nod1 and Nod2 (NodDKO) demonstrate signs of stress-induced anxiety, cognitive impairment and depression in the context of a hyperactive hypothalamic-pituitary-adrenal axis. These deficits were coupled with impairments in the serotonergic pathway in the brain, decreased hippocampal cell proliferation and immature neurons, as well as reduced neural activation. In addition, NodDKO mice had increased gastrointestinal permeability and altered serotonin signalling in the gut following exposure to acute stress. Administration of the selective serotonin reuptake inhibitor, fluoxetine, abrogated behavioural impairments and restored serotonin signalling. We also identified that intestinal epithelial cell-specific deletion of Nod1 (VilCre+ Nod1f/f ), but not Nod2, increased susceptibility to stress-induced anxiety-like behaviour and cognitive impairment following exposure to stress. Together, these data suggest that intestinal epithelial NLR are novel modulators of gut-brain communication and may serve as potential novel therapeutic targets for the treatment of gut-brain disorders.

The gut microbiome (GM) contributes to host development, metabolism, and disease. Perturbations in GM composition, elicited through chronic administration of oral antibiotics (Abx) or studied using germ-free environments, alter bone mass, and microarchitecture. However, studies primarily involved chronic Abx exposure to adult mice prior to evaluating the skeletal phenotype. Children are more prone to infection with bacterial pathogens than adults and are thus treated more frequently with broad-spectrum Abx; consequently, Abx treatment disproportionately occurs during periods of greatest skeletal plasticity to anabolic cues. Because early-life exposures may exert long-lasting effects on adult health, we hypothesized that acute Abx administration during a developmentally sensitive period would elicit lasting effects on the skeletal phenotype. To test this hypothesis, neonatal mice were treated with Abx (P7-P23; oral gavage) or vehicle (water); GM composition, gut physiology, and bone structural and material properties were assessed in adulthood (8 weeks). We found sexually dimorphic effects of neonatal Abx administration on GM composition, gut barrier permeability, and the skeleton, indicating a negative role for neonatal Abx on bone mass and quality. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2122-2129, 2019.

The gut microbiota is important for maintaining homeostasis of the host. Gut microbes represent the initial site for toxicant processing following dietary exposures to environmental contaminants. The diet is the primary route of exposure to polychlorinated biphenyls (PCBs), which are absorbed via the gut, and subsequently interfere with neurodevelopment and behavior. Developmental exposures to PCBs have been linked to increased risk of neurodevelopmental disorders (NDD), including autism spectrum disorder (ASD), which are also associated with a high prevalence of gastrointestinal (GI) distress and intestinal dysbiosis. We hypothesized that developmental PCB exposure impacts colonization of the gut microbiota, resulting in GI pathophysiology, in a genetically susceptible host. Mouse dams expressing two heritable human mutations (double mutants [DM]) that result in abnormal Ca2+ dynamics and produce behavioral deficits (gain of function mutation in the ryanodine receptor 1 [T4826I-RYR1] and a human CGG repeat expansion [170-200 CGG repeats] in the fragile X mental retardation gene 1 [FMR1 premutation]). DM and congenic wild type (WT) controls were exposed to PCBs (0-6 mg/kg/d) in the diet starting 2 weeks before gestation and continuing through postnatal day 21 (P21). Intestinal physiology (Ussing chambers), inflammation (qPCR) and gut microbiome (16S sequencing) studies were performed in offspring mice (P28-P30). Developmental exposure to PCBs in the maternal diet caused significant mucosal barrier defects in ileum and colon (increased secretory state and tight junction permeability) of juvenile DM mice. Furthermore, PCB exposure increased the intestinal inflammatory profile (Il6, Il1β, and Il22), and resulted in dysbiosis of the gut microbiota, including altered β-diversity, in juvenile DM mice developmentally exposed to 1 mg/kg/d PCBs when compared to WT controls. Collectively, these findings demonstrate a novel interaction between PCB exposure and the gut microbiota in a genetically susceptible host that provide novel insight into environmental risk factors for neurodevelopmental disorders.