Inappropriate Responses Research Articles

FTY720 attenuates acute colitis via colonic T cells reduction and inhibition of M1 macrophages polarization independent of CCR2-mediated monocytes input

Ulcerative colitis (UC) is a complex multifactorial disease, of which the exact etiology is not fully understood. The inappropriate aggressive inflammatory response is closely related to the disease progression of UC. FTY720 is a sphingosine-1-phosphate receptor agonist and acts as a key immunomodulator in inflammation. This study aims to investigate the protective influence of FTY720 on inflammation in the DSS-induced colitis model. In the present study, the C57BL/6 mice and the CCR2−/− mice were exposed to 5% Dextran Sodium Sulfate (DSS) drinking water for 6 days followed by an injection of FTY720 (1 mg/kg/d) or vehicle (PBS) 6 times starting on the next day. The body weight, stool consistency, and occult blood were assessed daily. The inflammatory cytokines level in colon tissues and serum were assessed. Leukocyte subsets of bone marrow (BM), spleen, and colon were analyzed by flow cytometry. Our results demonstrated that FTY720 ameliorated the aberrant immune responses by trapping T cells and inhibiting the polarization of M1 macrophages in colitis mice. The effect of FTY720 on the increased number of colonic macrophages did not dependent on CCR2-mediated monocyte influx, despite most monocytes being reduced after DSS administration in the inflamed colon of CCR2−/− mice. Rather, depletion of CCR2 did not impact the protective influence of FTY720 on colonic injury in acute colitis. All these findings unravel a beneficial function of FTY720 in the inflammatory response to DSS-induced acute colitis, provided further insights into monocyte migration and might provide potential opportunities for UC therapeutic intervention.

Spontaneous episodic inflammation in the intestines of mice lacking HNF4A is driven by microbiota and associated with early life microbiota alterations.

The inflammatory bowel diseases (IBD) occur in genetically susceptible individuals who mount inappropriate immune responses to their microbiota leading to chronic intestinal inflammation. Whereas IBD clinical presentation is well described, how interactions between microbiota and host genotype impact early subclinical stages of the disease remains unclear. The transcription factor hepatocyte nuclear factor 4 alpha (HNF4A) has been associated with human IBD, and deletion of Hnf4a in intestinal epithelial cells (IECs) in mice (Hnf4aΔIEC) leads to spontaneous colonic inflammation by 6-12 mo of age. Here, we tested if pathology in Hnf4aΔIEC mice begins earlier in life and if microbiota contribute to that process. Longitudinal analysis revealed that Hnf4aΔIEC mice reared in specific pathogen-free (SPF) conditions develop episodic elevated fecal lipocalin 2 (Lcn2) and loose stools beginning by 4-5 wk of age. Lifetime cumulative Lcn2 levels correlated with histopathological features of colitis at 12 mo. Antibiotic and gnotobiotic tests showed that these phenotypes in Hnf4aΔIEC mice were dependent on microbiota. Fecal 16S rRNA gene sequencing in SPF Hnf4aΔIEC and control mice disclosed that genotype significantly contributed to differences in microbiota composition by 12 mo, and longitudinal analysis of the Hnf4aΔIEC mice with the highest lifetime cumulative Lcn2 revealed that microbial community differences emerged early in life when elevated fecal Lcn2 was first detected. These microbiota differences included enrichment of a novel phylogroup of Akkermansia muciniphila in Hnf4aΔIEC mice. We conclude that HNF4A functions in IEC to shape composition of the gut microbiota and protect against episodic inflammation induced by microbiota throughout the lifespan. IMPORTANCE The inflammatory bowel diseases (IBD), characterized by chronic inflammation of the intestine, affect millions of people around the world. Although significant advances have been made in the clinical management of IBD, the early subclinical stages of IBD are not well defined and are difficult to study in humans. This work explores the subclinical stages of disease in mice lacking the IBD-associated transcription factor HNF4A in the intestinal epithelium. Whereas these mice do not develop overt disease until late in adulthood, we find that they display episodic intestinal inflammation, loose stools, and microbiota changes beginning in very early life stages. Using germ-free and antibiotic-treatment experiments, we reveal that intestinal inflammation in these mice was dependent on the presence of microbiota. These results suggest that interactions between host genotype and microbiota can drive early subclinical pathologies that precede the overt onset of IBD and describe a mouse model to explore those important processes.

KRP-DS: A Knowledge Graph-Based Dialogue System with Inference-Aided Prediction.

With the popularity of ChatGPT, there has been increasing attention towards dialogue systems. Researchers are dedicated to designing a knowledgeable model that can engage in conversations like humans. Traditional seq2seq dialogue models often suffer from limited performance and the issue of generating safe responses. In recent years, large-scale pretrained language models have demonstrated their powerful capabilities across various domains. Many studies have leveraged these pretrained models for dialogue tasks to address concerns such as safe response generation. Pretrained models can enhance responses by carrying certain knowledge information after being pre-trained on large-scale data. However, when specific knowledge is required in a particular domain, the model may still generate bland or inappropriate responses, and the interpretability of such models is poor. Therefore, in this paper, we propose the KRP-DS model. We design a knowledge module that incorporates a knowledge graph as external knowledge in the dialogue system. The module utilizes contextual information for path reasoning and guides knowledge prediction. Finally, the predicted knowledge is used to enhance response generation. Experimental results show that our proposed model can effectively improve the quality and diversity of responses while having better interpretability, and outperforms baseline models in both automatic and human evaluations.

Behavioural Response Patterns on the Government Incentives Influencing Compliance Behaviour of Business Zakat among SMEs

Government incentives and compliance behaviour of business zakat have a significant relationship as revealed by a few studies. However, the lack of study focused on respondents' response on the government incentives in influencing compliance behaviour of business zakat. Hence, this article examines the usage of Rasch Wright map in evaluating the behavioural response patterns on the government incentives and compliance behaviour of business zakat among SMEs. A total of 276 questionnaires were collected from SMEs entrepreneurs in Selangor. The Rasch Measurement Model was employed to analyze the data. Out of the 276 questionnaires collected, only 247 responses were consistent with the Rasch Measurement Model. Among the respondents, 107 individuals (43.3%) who complied with business zakat payment were influenced by government incentives, while 140 individuals (56.7%) who did not comply with business zakat payment were likely not influenced by government incentives. This study's results highlight the importance of the Rasch Measurement Model in elucidating the response patterns of participants, demonstrating its ability to explain how government incentives impact compliance behavior regarding business zakat among SMEs. This study has illustrated that this method of analysis is expedient in identifying the unusual and inappropriate response patterns and items based on fit statistics and misfit response series compared others. This shows that the Rasch Measurement analysis is an alternative tool to investigate the behavioural response patterns since analyze items and respondents of the study. This study suggests that future research regarding compliance and zakat employ the Rasch Measurement Model analysis as an alternative method to identify ability of respondents and the response behavior patterns among respondents.

Parenting toddlers: Evidences of parental needs from South India.

Quality of childcare can predict a child's emotional and behavioural adjustment throughout the life span. Furthermore, this has major implications for child development and mental health in the long-term. Parents often face major challenges while providing childcare especially during the early years of a child. This paper describes specific parental concerns in raising a toddler from a mental health developmental perspective. The study was conducted in urban Bengaluru, India under an exploratory research design using semi-structured interviews. Ten parents participated in the study. Data was analysed using thematic analysis. Four major themes emerged. The first theme was related to the formation of parental beliefs about parenting which identified several sources such as parenting practices witnessed during childhood, childhood experiences and influence of culture, mass or social media. The second theme to emerge was on concerns related to toddlers which parents had difficulties in understanding as well as managing, specially navigating through sleep and feed pattern, identifying developmental needs and making a meaning of toddlers' communication styles and content. The third theme showed parental concerns which consisted of areas such as parental stress, physical exhaustion, lack of time for each other or toddler, lack of information about handling toddlers and absence of validation of parental efforts. The final theme was on their current parenting practices with their toddlers which showcased controlling styles, play time but low on quality, inappropriate responses to toddlers' emotions or behaviours and several culturally practiced measures which were not validated scientifically. The pre-existing belief among parents about parenting and toddlers' specific behaviours influence parenting practices. The understanding of the parental challenges is beneficial in developing an appropriate parenting programme focussing on strengthening psychological capacities of toddlers.

Multiheaded deep learning chatbot for increasing production and marketing

Some businesses on product development prefer to use a chatbot for judging the customer's view. Today, the ability of a chatbot to consider the context is challenging due to its technical nature. Sometimes, it may misjudge the context, making the wrong decision in predicting the product's originality in the market. This task of chatbot helps the enterprise make huge profits from accurate predictions. However, chatbots may commit errors in dialogs and bring inappropriate responses to users, reducing the confidentiality of product and marketing information. This, in turn, reduces the enterprise gain and imposes cost complications on businesses. To improve the performance of chatbots, AI models are used based on deep learning concepts. This research proposes a multi-headed deep neural network (MH-DNN) model for addressing the logical and fuzzy errors caused by retrieval chatbot models. This model cuts down on the error raised from the information loss. Our experiments extensively trained the model on a large Ubuntu dialog corpus. The recall evaluation scores showed that the MH-DNN approach slightly outperformed selected state-of-the-art retrieval-based chatbot approaches. The results obtained from the MHDNN augmentation approach were pretty impressive. In our proposed work, the MHDNN algorithm exhibited accuracy rates of 94% and 92%, respectively, with and without the help of the Seq2Seq technique.

The dual roles of fungi: allergens and pathogens

Fungal infections and hypersensitivity represent two distinct yet interconnected host immune responses. While infection primarily activates innate immune pathways to combat pathogens and opportunists, hypersensitivity arises from exaggerated immune responses to fungal allergens. This duality highlights the complex balance between immune defence against infection and the risk of an inappropriate hypersensitivity response to fungal antigens. Allergens elicit allergic reactions in the respiratory system, skin, and gastrointestinal tract. Inhalation of airborne propagules from e.g., Aspergillus, Alternaria, and Penicillium species frequently leads to respiratory disorders like allergic rhinitis, allergic fungal rhinosinusitis, allergic asthma, or allergic bronchopulmonary aspergillosis / mycosis. Cutaneous exposure to allergens such as Trichophyton may provoke Id reactions, and Malassezia and Candida exacerbate atopic dermatitis or induce urticaria. Furthermore, fungal antigens may interact with the gut-associated immune system, potentially triggering or aggravating food allergies. Antibody- and T-cell-mediated hypersensitivity responses are central to these pathophysiological processes, with environmental influences and genetic predispositions modulating the intensity of allergic manifestations, especially in predisposed individuals. Despite the high prevalence of fungus-induced allergic diseases, precise diagnosis remains challenging due to the vast heterogeneity of extant species and antigenic cross-reactivity. Conventional diagnostic tools, such as skin prick tests and serum total or specific IgE assays are limited by the lack of standardized extracts and variability in antigenic specificity. The dual role of fungal exposure in infection and hypersensitivity underscores the need to deepen our understanding of the immunopathological mechanisms underlying microbial sensitization, identify specific allergens, and elucidate the molecular pathways involved. These areas are essential for enhancing diagnostic accuracy and developing standardized allergen extracts, thereby facilitating the management and treatment of allergic conditions.

Potential applications of ChatGPT in endoscopy: Opportunities and limitations

ChatGPT is an artificial intelligence model that has the potential to revolutionize the field of endoscopy. It can rapidly summarize medical records, assist with diagnosis, provide patient communication support, and even understand endoscopic images. However, there are limitations, including the risk of inaccurate or inappropriate responses, privacy and security issues, and the potential to limit doctors' thinking. Further research and improvements are needed to ensure ChatGPT's safe use in the medical field. Overall, the potential benefits of ChatGPT in endoscopy are vast, and it has the ability to greatly improve the efficiency of diagnosis and treatment.

Identification and Validation of the Diagnostic Markers for Inflammatory Bowel Disease by Bioinformatics Analysis and Machine Learning.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract which is mediated by the inappropriate immune responses. This study was aimed to identify novel diagnostic biomarkers for diagnosis of IBD and explore the relationship between the diagnostic biomarkers and infiltrated immune cells. GSE38713, GSE53306, and GSE75214 downloaded from the Gene Expression Omnibus (GEO) database were split into training and testing sets. Differentially expressed genes (DEGs) were screened using the "limma" package. Gene Ontology (GO) and KEGG pathway enrichment analysis of DEGs were performed by clusterProfiler package. The LASSO regression and support vector machine recursive feature elimination (SVM-RFE) algorithms were conducted to identify novel diagnostic biomarkers. The receiver operating characteristic (ROC) curve was applied to evaluate the diagnostic value of the candidate biomarkers. The relationship of the candidate biomarkers and infiltrating immune cells in IBD were evaluated by CIBERSOTR. Quantitative Real-Time PCR (qRT-PCR) was applied to measure the expression level of the biomarkers in IBD. A total of 289 dysregulated genes were identified as DEGs in IBD. These DEGs were significantly enriched in chemokine signaling pathway and cytokine-cytokine receptor interaction. RHOU was identified as a critical diagnostic gene in IBD, which was confirmed using ROC curve and qRT-PCR assays. Immune cell infiltration analysis showed that RHOU was correlated with macrophages M2, dendritic cells resting, mast cells resting, T cells CD4 memory resting, macrophages M0, and mast cells activated. Our results imply that RHOU may be a potential diagnostic biomarker for IBD.

Autistic adults' perspectives on appropriate empathic responses to others' emotions.

Although the ability of autistic adults to recognize others' emotions has been extensively studied, less attention has been given to how they respond to these emotions. We examined two aspects of autistic and non-autistic adults' responsiveness to the emotional expressions of non-autistic actors: their perspectives on the appropriate way of responding to others' emotions and their awareness of others' perceptions of the likely appropriateness of such responses. Autistic (N = 63) and non-autistic (N = 67) adult samples viewed videos of 74 dyadic social interactions displaying different examples of 12 emotions expressed by one actor in response to the behavior of the other. After each video, participants (a) nominated the emotion expressed by the first actor, (b) offered their perspective on what would constitute an appropriate empathic response by the second actor, and (c) indicated their confidence in that response. Although the autistic group provided fewer appropriate empathic responses-operationalized via a panel's interpretations of normative responses-than the non-autistic group, within-group variability was marked, and the effect was weak and largely confined to basic emotions. Autistic individuals were, however, considerably less confident in their responses. Examination of the relationships between confidence in and the appropriateness of empathic responses provided no indication in either group of reliable discrimination of appropriate from inappropriate empathic responses or finely tuned metacognitive awareness of variations in appropriateness. In sum, autistic adults' perspectives on the appropriate empathic reactions to non-autistic adults' emotions were not unilaterally or markedly different to those of non-autistic adults.

Mutant FUS induces chromatin reorganization in the hippocampus and alters memory processes

Cytoplasmic mislocalization of the nuclear Fused in Sarcoma (FUS) protein is associated to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS accumulation is recapitulated in the frontal cortex and spinal cord of heterozygous Fus∆NLS/+ mice. Yet, the mechanisms linking FUS mislocalization to hippocampal function and memory formation are still not characterized. Herein, we show that in these mice, the hippocampus paradoxically displays nuclear FUS accumulation. Multi-omic analyses showed that FUS binds to a set of genes characterized by the presence of an ETS/ELK-binding motifs, and involved in RNA metabolism, transcription, ribosome/mitochondria and chromatin organization. Importantly, hippocampal nuclei showed a decompaction of the neuronal chromatin at highly expressed genes and an inappropriate transcriptomic response was observed after spatial training of Fus∆NLS/+ mice. Furthermore, these mice lacked precision in a hippocampal-dependent spatial memory task and displayed decreased dendritic spine density. These studies shows that mutated FUS affects epigenetic regulation of the chromatin landscape in hippocampal neurons, which could participate in FTD/ALS pathogenic events. These data call for further investigation in the neurological phenotype of FUS-related diseases and open therapeutic strategies towards epigenetic drugs.

Investigation of Crohn's Disease by Immunohistochemistry Technique in Iraqi Patients

Crohn's disease (CD) is one of the most common IBD types. CD necessitates an erratic immune response. Previous research has shown that inflammation of the intestines is elevated or continues due to inappropriate immune responses that result from the relationships between environmental factors, intestinal microbiota, and genetic factors. Induces intense transmural inflammation. This study aimed to investigate (i) CD detection by Histopathology and Immunohistochemistry (IHC) Markers that are Mycobacterium avium subspecies paratuberculosis MAP antibody and TWEAK/Fn14 antibody and their association with CD. (ii) Prove or disprove the hypothesis of MAP as a potential cause of CD. Tissue biopsies of 30 cases with a recognized diagnosis of CD and 20 cases as control presented without disease symptoms were collected. They are 20 males and 10 females for patients, and 13 males and 7 females for control with ages ranging from 9-55(±34.78) years. From 2019 - 2020, Biopsies were collected from Medical City Hospitals in Baghdad. One tissue section has been stained by the Hematoxylin & Eosin (H&E) for histopathology examinations. IHC stained the other two sections to the markers mentioned earlier in the IHC technique. The results of IHC for MAP showed a highly significant relationship in the ileal tissues of patients with disease CD with varying degrees according to the intensity of the immune reaction, which represents the intensity of the color, which is distributed between weak, moderate and strong, according to the (Aperio image Scope) program. Where it was 10% weak, 43.33% medium, and 46.67% strong. The P-value for patients vs. control was 0.0052 and 0.0001, respectively (P-value 0 ≤ 0.01). The result of IHC proves the hypothesis of MAP as a potential cause of CD. The other effects of IHC staining for TWEAK/Fn14 marker showed a highly significant relationship in the ileal tissues of patients with Crohn's Disease with varying degrees according to the intensity of the immune reaction, according to the Aperio image Scope program. It was 10% weak, 36.67% medium, and 53.33% strong. P-value for patients vs control were 0.0003 and 0.0001, respectively (P-value 0 ≤ 0.01).

Inflammasomes during SARS-CoV-2 infection and development of their corresponding inhibitors.

Corona Virus Disease 2019 (COVID-19) continues to be a burden for human health since its outbreak in Wuhan, China in December 2019. Recently, the emergence of new variants of concerns (VOCs) is challenging for vaccines and drugs efficiency. In severe cases, SARS-CoV-2 provokes inappropriate hyperinflammatory immune responses leading to acute respiratory distress syndrome (ARDS) and even death. This process is regulated by inflammasomes which are activated after binding of the viral spike (S) protein to cellular angiotensin-converting enzyme 2 (ACE2) receptor and triggers innate immune responses. Therefore, the formation of "cytokines storm" leads to tissue damage and organ failure. NOD-like receptor family pyrin domain containing 3 (NLRP3) is the best studied inflammasome known to be activated during SARS-CoV-2 infection. However, some studies suggest that SARS-CoV-2 infection is associated with other inflammasomes as well; such as NLRP1, absent in melanoma-2 (AIM-2), caspase-4 and -8 which were mostly found during dsRNA virus or bacteria infection. Multiple inflammasome inhibitors that exist for other non-infectious diseases have the potential to be used to treat severe SARS-CoV-2 complications. Some of them have showed quite encouraging results during pre- and clinical trials. Nevertheless, further studies are in need for the understanding and targeting of SARS-Cov-2-induced inflammasomes; mostly an update of its role during the new VOCs infection is necessary. Hence, this review highlights all reported inflammasomes involved in SARS-CoV-2 infection and their potential inhibitors including NLRP3- and Gasdermin D (GSDMD)-inhibitors. Further strategies such as immunomodulators and siRNA are also discussed. As highly related to COVID-19 severe cases, developing inflammasome inhibitors holds a promise to treat severe COVID-19 syndrome effectively and reduce mortality.

Institutional Barriers to Healthcare Services Among Transgender Individuals in the Rural Midwest

ABSTRACT Often the barriers that arise in healthcare are due to healthcare professionals lack of education, exposure, and transphobia. Another potential barrier is due to geographical location of living in a rural area where there is a lack of healthcare services. This phenomenological study investigated barriers faced by transgender individuals who were transitioning in a rural area, focusing particularly on institutional barriers present in the healthcare system. Transgender individuals were recruited using convenience and snowball sampling. Data were collected via in-depth, face-to-face interviews in a rural area of the Midwest in the United States (n = 8). Transgender participants discussed themes of discrimination among healthcare providers based on gender. Participants reported gender markers as a barrier for healthcare services, such as inappropriate or incomplete response options on billing and medical forms. Participants perceived discrimination among gynecology, psychiatry, and medical emergency staff, and pharmacists. Overall, transgender individuals experienced mistreatment while transitioning in a rural area which created issues with participants’ progress in transitioning. This study shows that education for all types of healthcare providers is needed regarding transgender health. Particularly in rural areas—many of which continue to lack essential healthcare services for the general population—the transgender population might not receive the culturally sensitive and appropriate attention they require.

The Secondary Motor Cortex-striatum Circuit Contributes to Suppressing Inappropriate Responses in Perceptual Decision Behavior

The secondary motor cortex (M2) encodes choice-related information and plays an important role in cue-guided actions. M2 neurons innervate the dorsal striatum (DS), which also contributes to decision-making behavior, yet how M2 modulates signals in the DS to influence perceptual decision-making is unclear. Using mice performing a visual Go/No-Go task, we showed that inactivating M2 projections to the DS impaired performance by increasing the false alarm (FA) rate to the reward-irrelevant No-Go stimulus. The choice signal of M2 neurons correlated with behavioral performance, and the inactivation of M2 neurons projecting to the DS reduced the choice signal in the DS. By measuring and manipulating the responses of direct or indirect pathway striatal neurons defined by M2 inputs, we found that the indirect pathway neurons exhibited a shorter response latency to the No-Go stimulus, and inactivating their early responses increased the FA rate. These results demonstrate that the M2-to-DS pathway is crucial for suppressing inappropriate responses in perceptual decision behavior.

Rosmarinic acid ameliorates autoimmune responses through suppression of intracellular nucleic acid-mediated type I interferon expression

Recognition of intracellular nucleic acids is a vital step for host to mount prompt immune responses against microbial pathogens. However, inappropriate response to self-nucleic acids leads to sustained type I interferon (IFN) production, which is implicated in the development of several autoimmune diseases, such as Aicardi–Goutières syndrome (AGS). Therefore, effective confinement of intracellular nucleic acid-induced IFN expression is a potential strategy for the treatment of such autoimmune diseases. In this study, we found that rosmarinic acid (RA), a natural compound isolated from rosemary, inhibits intracellular nucleic acid-stimulated IFN expression. Mechanistic investigation revealed that RA binds to both G3BP1 and cGAS, and impairs cGAS activation through disrupting the binding of DNA with cGAS. More importantly, we showed that RA could effectively attenuate the expression of IFN-stimulated genes (ISGs) in the well-established cell models for AGS. Thus, our study provides a promising compound for the treatment of autoimmune responses induced by aberrant nucleic acid-sensing.

Dietary protein shapes the profile and repertoire of intestinal CD4+ T cells.

The intestinal immune system must tolerate food antigens to avoid allergy, a process requiring CD4+ T cells. Combining antigenically defined diets with gnotobiotic models, we show that food and microbiota distinctly influence the profile and T cell receptor repertoire of intestinal CD4+ T cells. Independent of the microbiota, dietary proteins contributed to accumulation and clonal selection of antigen-experienced CD4+ T cells at the intestinal epithelium, imprinting a tissue-specialized transcriptional program including cytotoxic genes on both conventional and regulatory CD4+ T cells (Tregs). This steady state CD4+ T cell response to food was disrupted by inflammatory challenge, and protection against food allergy in this context was associated with Treg clonal expansion and decreased proinflammatory gene expression. Finally, we identified both steady-state epithelium-adapted CD4+ T cells and tolerance-induced Tregs that recognize dietary antigens, suggesting that both cell types may be critical for preventing inappropriate immune responses to food.

New Insights into the Mechanism of Ulva pertusa on Colitis in Mice: Modulation of the Pain and Immune System

Inflammatory bowel diseases (IBDs) involving Crohn's disease (CD) and ulcerative colitis (UC) are gastrointestinal (GI) disorders in which abdominal pain, discomfort, and diarrhea are the major symptoms. The immune system plays an important role in the pathogenesis of IBD and, as indicated by several clinical studies, both innate and adaptative immune response has the faculty to induce gut inflammation in UC patients. An inappropriate mucosal immune response to normal intestinal constituents is a main feature of UC, thus leading to an imbalance in local pro- and anti-inflammatory species. Ulva pertusa, a marine green alga, is known for its important biological properties, which could represent a source of beneficial effects in various human pathologies. We have already demonstrated the anti-inflammatory, antioxidant, and antiapoptotic effects of an Ulva pertusa extract in a murine model of colitis. In this study, we aimed to examine thoroughly Ulva pertusa immunomodulatory and pain-relieving properties. Colitis was induced by using the DNBS model (4 mg in 100 μL of 50% ethanol), whereas Ulva pertusa was administered daily at the dosage of 50 and 100 mg/kg by oral gavage. Ulva pertusa treatments have been shown to relieve abdominal pain while modulating innate and adaptative immune-inflammatory responses. This powerful immunomodulatory activity was specifically linked with TLR4 and NLRP3 inflammasome modulation. In conclusion, our data suggest Ulva pertusa as a valid approach to counteract immune dysregulation and abdominal discomfort in IBD.

Towards molecular mechanisms for pathogenic Th17 cell differentiation in ocular autoimmunity

Abstract CD4+ T helper (Th) cells play critical roles in coordinating proper immune responses by differentiating into effector subtypes specialized against different types of pathogens, while dysregulated Th cells can drive autoimmune disease by triggering inappropriate immune responses. Pathogenic Th17 (pTh17) cells, which combine behaviors of classic Th1 and Th17 effector cells by producing both interferon-gamma (IFNg) and interleukin-17A (IL17A), have been implicated in autoimmune diseases. Our goal is to map regulatory networks and identify novel regulators underlying pTh17 differentiation and activation using the murine model experimental autoimmune uveitis (EAU), in which ocular autoimmunity is driven by pTh17 cells. To track pTh17 differentiation, we bred a double reporter mouse with IL17A-cre/tdTomato-flox tracer and IFNg-YFP. We sorted both Tomato+YFP+ and Tomato+YFP- CD4+ T cells from eyes and spleens after EAU induction for single-cell RNA-seq. Clustering of single-cell transcriptomes revealed distinct transcriptomes between eyes and spleen. In the eye, we identified clusters similar to pTh17 and non-pathogenic (np)Th17 populations defined in a myelin autoimmunity model. The pTh17 cluster contained both double positive and Tomato single positive cells, suggesting a heterogeneous pathogenic population. In contrast, the npTh17 cluster only contained single positives. Differential gene expression analysis showed that pathogenic and non-pathogenic clusters utilize distinct sets of transcription factors. We are further characterizing epigenetic differences between pTh17 and npTh17 to better understand how distinct regulatory networks shape pTh17 differentiation. Supported by the NEI Intramural Research Program fund (ZIAEY000569-01)

Two Case Reports of Newly Diagnosed Crohn’s Disease after COVID-19 in Pediatric Patients

Since the coronavirus disease 2019 (COVID-19) outbreak caused by the severe acute respiratory syndrome-coronavirus-2 virus (SARS-CoV-2), various complications have been reported. Although most COVID-19 cases exhibited flu-like symptoms, COVID-19 may dysregulate the immune response and promote overwhelming levels of inflammation in some patients. Inflammatory bowel disease (IBD) is caused by dysregulated or inappropriate immune responses to environmental factors in a genetically susceptible host, and a SARS-CoV-2 infection may act as a possible cause of IBD. This paper describes two pediatric patients who developed Crohn's disease following a SARS-CoV-2 infection. They were previously healthy before the SARS-CoV-2 infection. On the other hand, they started to develop fever and gastrointestinal symptoms several weeks after recovery from the infection. They were diagnosed with Crohn's disease by imaging and endoscopic studies, and their symptoms improved after treatment with steroids and azathioprine. This paper suggests that a SARS-CoV-2 infection may trigger IBD in predisposed patients.