A tryptophan metabolite made by a gut microbiome eukaryote induces pro-inflammatory T cells.

The large intestine harbors microorganisms playing unique roles in host physiology. The beneficial or detrimental outcome of host-microbiome coexistence depends largely on the balance between regulators and responder intestinal CD4+ T cells. We found that ulcerative colitis-like changes in the large intestine after infection with the protist Blastocystis ST7 in a mouse model are associated with reduction of anti-inflammatory Treg cells and simultaneous expansion of pro-inflammatory Th17 responders. These alterations in CD4+ T cells depended on the tryptophan metabolite indole-3-acetaldehyde (I3AA) produced by this single-cell eukaryote. I3AA reduced the Treg subset in vivo and iTreg development in vitro by modifying their sensing of TGFß, concomitantly affecting recognition of self-flora antigens by conventional CD4+ T cells. Parasite-derived I3AA also induces over-exuberant TCR signaling, manifested by increased CD69 expression and downregulation of co-inhibitor PD-1. We have thus identified a new mechanism dictating CD4+ fate decisions. The findings thus shine a new light on the ability of the protist microbiome and tryptophan metabolites, derived from them or other sources, to modulate the adaptive immune compartment, particularly in the context of gut inflammatory disorders.

New insights into the interactions between Blastocystis, the gut microbiota, and host immunity.

The human gut microbiota is a diverse and complex ecosystem that is involved in beneficial physiological functions as well as disease pathogenesis. Blastocystis is a common protistan parasite and is increasingly recognized as an important component of the gut microbiota. The correlations between Blastocystis and other communities of intestinal microbiota have been investigated, and, to a lesser extent, the role of this parasite in maintaining the host immunological homeostasis. Despite recent studies suggesting that Blastocystis decreases the abundance of beneficial bacteria, most reports indicate that Blastocystis is a common component of the healthy gut microbiome. This review covers recent finding on the potential interactions between Blastocystis and the gut microbiota communities and its roles in regulating host immune responses.

Experimental colonization with Blastocystis ST4 is associated with protective immune responses and modulation of gut microbiome in a DSS-induced colitis mouse model.

BACKGROUND: Blastocystis is a common gut protistan parasite in humans and animals worldwide, but its interrelationship with the host gut microbiota and mucosal immune responses remains poorly understood. Different murine models of Blastocystis colonization were used to examine the effect of a common Blastocystis subtype (ST4) on host gut microbial community and adaptive immune system. RESULTS: Blastocystis ST4-colonized normal healthy mice and Rag1-/- mice asymptomatically and was able to alter the microbial community composition, mainly leading to increases in the proportion of Clostridia vadinBB60 group and Lachnospiraceae NK4A136 group, respectively. Blastocystis ST4 colonization promoted T helper 2 (Th2) response defined by interleukin (IL)-5 and IL-13 cytokine production, and T regulatory (Treg) induction from colonic lamina propria in normal healthy mice. Additionally, we observed that Blastocystis ST4 colonization can maintain the stability of bacterial community composition and induce Th2 and Treg immune responses to promote faster recovery from experimentally induced colitis. Furthermore, fecal microbiota transplantation of Blastocystis ST4-altered gut microbiome to colitis mice reduced the severity of colitis, which was associated with increased production of short-chain fat acids (SCFAs) and anti-inflammatory cytokine IL-10. CONCLUSIONS: The data confirm our hypothesis that Blastocystis ST4 is a beneficial commensal, and the beneficial effects of Blastocystis ST4 colonization is mediated through modulating of the host gut bacterial composition, SCFAs production, and Th2 and Treg responses in different murine colonization models.

Lck bound to coreceptor is less active than free Lck.

Src family kinase Lck plays critical roles during T cell development and activation, as it phosphorylates the TCR/CD3 complex to initiate TCR signaling. Lck is present either in coreceptor-bound or coreceptor-unbound (free) forms, and we here present evidence that the two pools of Lck have different molecular properties. We discovered that the free Lck fraction exhibited higher mobility than CD8α-bound Lck in OT-I T hybridoma cells. The free Lck pool showed more activating Y394 phosphorylation than the coreceptor-bound Lck pool. Consistent with this, free Lck also had higher kinase activity, and free Lck mediated higher T cell activation as compared to coreceptor-bound Lck. Furthermore, the coreceptor-Lck coupling was independent of TCR activation. These findings give insights into the initiation of TCR signaling, suggesting that changes in coreceptor-Lck coupling constitute a mechanism for regulation of T cell sensitivity.

Misophonia in Children and Adolescents: Age Differences, Risk Factors, Psychiatric and Psychological Correlates. A Pilot Study with Mothers' Involvement.

Misophonia is a type of disorder characterized by decreased sound tolerance. While it typically begins in childhood, research on its characteristics in this population is limited. We assessed 90 children aged 7-18 with and without misophonia, along with their mothers, using interviews, questionnaires, and performance-based tests. Younger children with misophonia were more likely to use aggression in response to triggers than older, while adolescents largely reported self-harm during triggers. Children with misophonia did not differ from their peers in terms of ADHD, ODD, ASD, dyslexia, social and emotional competencies, head injuries, epilepsy, tinnitus, being prematurely born, or delivered via cesarean sections. However, they had significantly higher symptoms of anxiety and depression, more frequent occurrences of OCD, migraines, and psychosomatic complaints. Their mothers self-reported postpartum depression significantly more frequently than mothers in the control group. There is a need for further research on pediatric misophonia, with the involvement and assessment of parents.

Taming the Sentinels: Microbiome-Derived Metabolites and Polarization of T Cells.

A global increase in the prevalence of metabolic syndromes and digestive tract disorders, like food allergy or inflammatory bowel disease (IBD), has become a severe problem in the modern world. Recent decades have brought a growing body of evidence that links the gut microbiome's complexity with host physiology. Hence, understanding the mechanistic aspects underlying the synergy between the host and its associated gut microbiome are among the most crucial questions. The functionally diversified adaptive immune system plays a central role in maintaining gut and systemic immune homeostasis. The character of the reciprocal interactions between immune components and host-dwelling microbes or microbial consortia determines the outcome of the organisms' coexistence within the holobiont structure. It has become apparent that metabolic by-products of the microbiome constitute crucial multimodal transmitters within the host-microbiome interactome and, as such, contribute to immune homeostasis by fine-tuning of the adaptive arm of immune system. In this review, we will present recent insights and discoveries regarding the broad landscape of microbiome-derived metabolites, highlighting the role of these small compounds in the context of the balance between pro- and anti-inflammatory mechanisms orchestrated by the host T cell compartment.

From twins to genetic polymorphisms: behavioral genetic research in Poland.

Behavioral genetic research has been conducted at the University of Warsaw for the past 20 years. The work done at the University focuses primarily on the origins of individual differences in temperament and other personality traits. In particular, research is directed toward the traits postulated in the Regulative Theory of Temperament. We also focused on the heritability of socio-political attitudes, risk factors for human health, and post-traumatic stress disorder. The majority of the research that has been carried out is grounded in twin and family studies, although recent work based on molecular techniques has also been developed. This article reviews the most important directions and findings of behavioral genetics research at the University of Warsaw.

Beyond sound irritation: cross-cultural evidence on the robustness of the five aspects of misophonic experience measured by the S-Five in a Polish sample.

Misophonia is commonly associated with negative emotional or physiological responses to specific sounds. However, the consensus definition emphasizes that misophonia entails much more than that. Even in cases of subclinical misophonia, where individuals do not meet the disorder criteria, the experience can still be burdensome, despite not currently causing significant distress or impairment. The S-Five is a psychometric tool for comprehensive assessment of five aspects of misophonic experience: internalizing, externalizing, impact, threat, and outburst, and includes S-Five-T section to evaluate feelings evoked by triggering sounds and their intensity. We examined whether the five-factor structure developed in the UK could be replicated in a Polish sample, including individuals with and without self-identified misophonia. The Polish version of the S-Five was translated and tested on 288 Polish-speaking individuals. Comprehensive psychometric evaluation, including factor structure, measurement invariance, test-retest reliability, internal consistency, and concurrent validity evaluations, was conducted on the translated scale. Exploratory factor analysis suggested similar structure to the original English study, while bootstrap exploratory graph analysis showed the factor structure to be reproducible in other samples. The scale was found to be bias free with respect to gender, internally consistent and stable in time, and evidence of validity was provided using MisoQuest and Misophonia Questionnaire. These results offer support for the cross-cultural stability of the five factors and provide preliminary evidence for the suitability of the Polish version for clinical and research purposes. The study also investigated five facets of misophonia, triggering sounds, emotional responses, and their associations with symptoms of psychopathology across various cultures. It underscores the central role of anger, distress, and panic, while also highlighting the mixed role of irritation and disgust in misophonia across different cultural contexts. Mouth sounds evoked the most pronounced reactions compared to other repetitive sounds, although there were discernible cultural differences in the nature and intensity of reactions to various trigger sounds. These findings hold significant implications for future research and underscore the importance of considering cultural nuances in both research and the clinical management of misophonia.

Colonization with two different Blastocystis subtypes in DSS-induced colitis mice is associated with strikingly different microbiome and pathological features.

Rationale: The gut microbiota plays a significant role in the pathogenesis of inflammatory bowel disease (IBD). However, the role of Blastocystis infection and Blastocystis-altered gut microbiota in the development of inflammatory diseases and their underlying mechanisms are not well understood. Methods: We investigated the effect of Blastocystis ST4 and ST7 infection on the intestinal microbiota, metabolism, and host immune responses, and then explored the role of Blastocystis-altered gut microbiome in the development of dextran sulfate sodium (DSS)-induced colitis in mice. Results: This study showed that prior colonization with ST4 conferred protection from DSS-induced colitis through elevating the abundance of beneficial bacteria, short-chain fatty acid (SCFA) production and the proportion of Foxp3+ and IL-10-producing CD4+ T cells. Conversely, prior ST7 infection exacerbated the severity of colitis by increasing the proportion of pathogenic bacteria and inducing pro-inflammatory IL-17A and TNF-α-producing CD4+ T cells. Furthermore, transplantation of ST4- and ST7-altered microbiota resulted in similar phenotypes. Conclusions: Our data showed that ST4 and ST7 infection exert strikingly differential effects on the gut microbiota, and these could influence the susceptibility to colitis. ST4 colonization prevented DSS-induced colitis in mice and may be considered as a novel therapeutic strategy against immunological diseases in the future, while ST7 infection is a potential risk factor for the development of experimentally induced colitis that warrants attention.

Colonization with ubiquitous protist Blastocystis ST1 ameliorates DSS-induced colitis and promotes beneficial microbiota and immune outcomes.

Blastocystis is a species complex that exhibits extensive genetic diversity, evidenced by its classification into several genetically distinct subtypes (ST). Although several studies have shown the relationships between a specific subtype and gut microbiota, there is no study to show the effect of the ubiquitous Blastocystis ST1 on the gut microbiota and host health. Here, we show that Blastocystis ST1 colonization increased the proportion of beneficial bacteria Alloprevotella and Akkermansia, and induced Th2 and Treg cell responses in normal healthy mice. ST1-colonized mice showed decreases in the severity of DSS-induced colitis when compared to non-colonized mice. Furthermore, mice transplanted with ST1-altered gut microbiota were refractory to dextran sulfate sodium (DSS)-induced colitis via induction of Treg cells and elevated short-chain fat acid (SCFA) production. Our results suggest that colonization with Blastocystis ST1, one of the most common subtypes in humans, exerts beneficial effects on host health through modulating the gut microbiota and adaptive immune responses.

Themis controls T cell activation, effector functions, and metabolism of peripheral CD8+ T cells.

Themis is important in regulating positive selection of thymocytes during T cell development, but its role in peripheral T cells is less understood. Here, we investigated T cell activation and its sequelae using a tamoxifen-mediated, acute Themis deletion mouse model. We find that proliferation, effector functions including anti-tumor killing, and up-regulation of energy metabolism are severely compromised. This study reveals the phenomenon of peripheral adaptation to loss of Themis, by demonstrating direct TCR-induced defects after acute deletion of Themis that were not evident in peripheral T cells chronically deprived of Themis in dLck-Cre deletion model. Peripheral adaptation to long-term loss was compared using chronic versus acute tamoxifen-mediated deletion and with the (chronic) dLck-Cre deletion model. We found that upon chronic tamoxifen-mediated Themis deletion, there was modulation in the gene expression profile for both TCR and cytokine signaling pathways. This profile overlapped with (chronic) dLck-Cre deletion model. Hence, we found that peripheral adaptation induced changes to both TCR and cytokine signaling modules. Our data highlight the importance of Themis in the activation of CD8+ T cells.

MUC1 in human and murine mammary carcinoma cells decreases the expression of core 2 ß1,6-N-acetylglucosaminyltransferase and ß-galactoside α2,3-sialyltransferase.

A good correlation between the expression of mucin1 (MUC1) and T antigen was found in breast cancer tumors and breast cancer cell lines, especially after treatment with neuraminidase. The association between the appearance of T antigen and the overexpression of MUC1 was further confirmed by transfecting MDA-MB-231 cells and murine 4T1 mammary carcinoma cells with cDNA for MUC1 and using an RNAi approach to inhibit the expression of MUC1 gene in T47D cells. Furthermore, we discovered that in 4T1 cells which express the sialyl Le(X) antigen, overexpression of MUC1 caused not only appearance of T antigen, but also loss of the sialyl Le(X) structure. As the observed changes in O-glycan synthesis can be associated with changes in the expression of specific glycosyltransferases, core 1 ß1,3-galactosyltransferase, core 2 ß1,6-N-acetylglucosaminyltransferase (C2GnT1) and ß-galactoside α2,3-sialyltransferase (ST3Gal I), we studied their expression in parental, vector-transfected and MUC1-transfected MDA-MB-231 and 4T1 cells as well as T47D cells transduced with small hairpin RNA targeted MUC1 mRNA. It was found that the expression of C2GnT1 and ST3Gal I is highly decreased in MUC1-expressing MDA-MB-231 and 4T1 cells and increased in T47D cells with suppressed expression of MUC1. Therefore, we found that changes in the structure of O-linked oligosaccharides, resulting in the occurrence of T antigen, are at least partially associated with MUC1 overexpression which down-regulates the expression of C2GnT1 and ST3Gal I. We showed also that the overexpression of MUC1 in 4T1 cells changes their adhesive properties, as MUC1-expressing cells do not adhere to E-selectin, but bind galectin-3.

The Influence of the Accelerated Aging Process on the Compressive Strength of Wood Treated with Components of a Salt Fire Retardant.

This paper presents the results of research on the influence of the components of salt flame retardants on the compressive strength of wood depending on the time of accelerated aging. The effect of the agent was assessed on the basis of the change in the strength of treated wood compared to that of untreated wood. In addition, a statistical analysis of the obtained results was used to determine which of the components most significantly affect the changes in the compressive strength of wood along the fibers, and to what extent. It was found that extending the aging process time in the case of control and boric acid-protected samples did not significantly change the strength properties. It has also been found that some compounds contained in fire retardant have an antagonistic effect related to the compressive strength of wood.

New data on the validity of the Fazio Laterality Inventory.

The Fazio Laterality Inventory (FLI) is a recent measure of handedness. Although initially validated, there is still a lack of studies assessing its psychometric properties in samples outside the USA. The present study explores the validity of the Polish adaptation of the FLI. We used data gathered from a convenience sample of 727 participants. They completed the FLI and the Edinburgh Handedness Inventory to establish concurrent validity. Confirmatory factor analysis was used to investigate the factor structure of the FLI. In addition, an Item Response Theory (IRT) model for continuous item scores was also used to identify the discrimination and difficulty parameters of the FLI items. The Polish version of the FLI was characterized by good reliability indices and has high concurrent validity with the Edinburgh Handedness Inventory. We identified a bi-factorial structure for the questionnaire. The IRT analyses showed that the FLI items have good discrimination and difficulty parameters. Our study provides new insights into the properties of the Fazio Laterality Inventory.

Does context matter in misophonia? A multi-method experimental investigation.

Introduction: Misophonia is a recently defined disorder in which certain aversive repetitive sounds and associated stimuli elicit distressing and impairing affective, behavioral, and physiological responses. The responses in misophonia may be stronger when the sound is produced by close friends and family, suggesting that the context in which a triggering cue occurs may have an important role in misophonia. As such, the goal of this study was to test experimentally whether the context of the sound source influences affective and psychophysiological responses to triggering stimuli in misophonia. Methods: Sixty one adults with misophonia and 45 controls listened to audio recordings (8 s) of human eating, animals eating, and human mouth smacking sounds (without eating). After a break, the same audio recordings were presented embedded within videos of human eating (congruent stimuli), animals eating (congruent stimuli), and, in the mouth smacking condition, with visually incongruent stimuli (hands playing in mud or in a bowl with a watery dough). Psychophysiological responses-skin conductance response (SCR) and heart rate (HR), and self-reported affective responses (valence, arousal, dominance) were gathered during the experiment in a laboratory. Results: Participants with misophonia assessed all the stimuli as more negative and arousing than the controls, and reported feeling less dominant with respect to the sounds. Animal and mouth smacking sounds were assessed by all the participants as less negative and arousing than human eating sounds, but only in the audio-video conditions. SCR data partially confirmed increased psychophysiological arousal in misophonia participants during an exposure to mouth sounds, but did not reflect the self-report changes in response to different contexts. Misophonia participants had deeper deceleration of HR than controls during human eating sound with congruent video stimuli, while there was no group difference during human mouth smacking with incongruent video stimuli. Conclusion: Results suggest that the context of mouth sounds influences affective experiences in adults with misophonia, but also in participants without misophonia. Presentation of animal eating sounds with congruent visual stimuli, or human mouth smacking sounds with incongruent stimuli, decreased self-report reaction to common misophonic triggers.

Expansion of an Unusual Virtual Memory CD8+ Subpopulation Bearing Vα3.2 TCR in Themis-Deficient Mice.

Deletion of the gene for Themis affects T cell selection in the thymus, which would be expected to affect the TCR repertoire. We found an increased proportion of cells expressing Vα3.2 (TRAV9N-3) in the peripheral CD8+ T cell population in mice with germline Themis deficiency. Analysis of the TCRα repertoire indicated it was generally reduced in diversity in the absence of Themis, whereas the diversity of sequences using the TRAV9N-3 V-region element was increased. In wild type mice, Vα3.2+ cells showed higher CD5, CD6 and CD44 expression than non-Vα3-expressing cells, and this was more marked in cells from Themis-deficient mice. This suggested a virtual memory phenotype, as well as a stronger response to self-pMHC. The Vα3.2+ cells responded more strongly to IL-15, as well as showing bystander effector capability in a Listeria infection. Thus, the unusually large population of Vα3.2+ CD8+ T cells found in the periphery of Themis-deficient mice reflects not only altered thymic selection, but also allowed identification of a subset of bystander-competent cells that are also present in wild-type mice.

Canonical T cell receptor docking on peptide-MHC is essential for T cell signaling.

T cell receptor (TCR) recognition of peptide-major histocompatibility complexes (pMHCs) is characterized by a highly conserved docking polarity. Whether this polarity is driven by recognition or signaling constraints remains unclear. Using "reversed-docking" TCRß-variable (TRBV) 17+ TCRs from the naïve mouse CD8+ T cell repertoire that recognizes the H-2Db-NP366 epitope, we demonstrate that their inability to support T cell activation and in vivo recruitment is a direct consequence of reversed docking polarity and not TCR-pMHCI binding or clustering characteristics. Canonical TCR-pMHCI docking optimally localizes CD8/Lck to the CD3 complex, which is prevented by reversed TCR-pMHCI polarity. The requirement for canonical docking was circumvented by dissociating Lck from CD8. Thus, the consensus TCR-pMHC docking topology is mandated by T cell signaling constraints.

Prevalence of Misophonia and Correlates of Its Symptoms among Inpatients with Depression.

Misophonia is an underexplored condition that significantly decreases the quality of life of those who suffer from it. It has neurological and physiological correlates and is associated with a variety of psychiatric symptoms; however, a growing body of data suggests that it is a discrete disorder. While comorbid diagnoses among people with misophonia have been a matter of research interest for many years there is no data on the frequency of misophonia among people with psychiatric disorders. This could be the next step to reveal additional mechanisms underlying misophonia. Until recently, the use of a variety of non-validated questionnaires and the dominance of internet-based studies have been also a major obstacles to a proper definition of misophonia. A total of 94 inpatients diagnosed with depression were assessed for misophonia with face-to-face interviews as well as with MisoQuest-a validated misophonia questionnaire. The prevalence of misophonia among these patients and the congruence of MisoQuest with face-to-face interviews were evaluated. Additionally, the patients filled in a series of questionnaires that measured a variety of psychiatric symptoms and psychological traits. Anxiety, depression, impulsivity, somatic pain, vegetative symptoms, post-traumatic stress disorder (PTSD) symptoms, gender, and age were analyzed in relation to the severity of symptoms of misophonia. Between 8.5 to 12.76% of inpatients with depression were diagnosed with misophonia (depending on measurement and inclusion criteria). MisoQuest accuracy was equal to 92.55%, sensitivity-66.67% and specificity-96.34%. Severity of misophonia symptoms was positively correlated to the greatest extent with anxiety. Moderate positive correlation was also found between severity of misophonia symptoms and depressive symptoms, intrusions, and somatic pain; a weak positive correlation was found between severity of misophonia and non-planning impulsivity, motor impulsivity, avoidance, and vegetative symptoms. There was no relationship between the severity of misophonia symptoms and attentional impulsivity or the age of participants.

Sex-Specific Relationship of Childhood Adversity With Gray Matter Volume and Temperament.

Background: To date, many studies have attempted to show a relationship between potentially harmful experiences in childhood and gray matter volume (GMV) in specific brain areas. These studies managed to identify several affected regions, yet most of them neglected the influence of sex or the occurrence of mental health problems. Furthermore, little is known about mechanisms linking childhood adversity (CA) and temperamental traits as plausible endophenotypes of psychopathology. Objective: The present study addresses these two issues by trying to identify sex-specific relationships between CA and brain volumes as well as to show the role of the latter in predicting temperament scores. Method: Forty-eight people (23 women) without anxiety or affective disorders participated in this study. CA was measured using the Childhood Questionnaire (CQ) and temperament was measured with the use of the behavioral inhibition system-behavioral activation system (BIS-BAS) Scales. Whole-brain MR imaging was performed to identify GMV differences. Results: In women, we identified negative relationships between CA and GMV in the left inferior parietal lobule (IPL), right cerebellum, and right precentral gyrus. In men, we found a negative correlation between CA and GMV in the right fusiform gyrus. We also identified sex-specific relationships between CA and temperament traits. Conclusions: The results of our study suggest a sex-specific pattern in the relationship between early adverse experiences and brain structure. The results can also help explain the role that temperament plays in the relationship between CA and the risk of psychopathology.