Identification of a unique subset of tissue-resident memory CD4+ T cells in Crohn's disease.

T cells differentiate into highly diverse subsets and display plasticity depending on the environment. Although lymphocytes are key mediators of inflammation, functional specialization of T cells in inflammatory bowel disease (IBD) has not been effectively described. Here, we performed deep profiling of T cells in the intestinal mucosa of IBD and identified a CD4+ tissue-resident memory T cell (Trm) subset that is increased in Crohn's disease (CD) showing unique inflammatory properties. Functionally and transcriptionally distinct CD4+ Trm subsets are observed in the inflamed gut mucosa, among which a CD-specific CD4+ Trm subset, expressing CD161 and CCR5 along with CD103, displays previously unrecognized pleiotropic signatures of innate and effector activities. These inflammatory features are further enhanced by their spatial proximity to gut epithelial cells. Furthermore, the CD-specific CD4+ Trm subset is the most predominant producer of type 1 inflammatory cytokines upon various stimulations among all CD4+ T cells, suggesting that the accumulation of this T cell subset is a pathological hallmark of CD. Our results provide comprehensive insights into the pathogenesis of IBD, paving the way for decoding of the molecular mechanisms underlying this disease.

Epithelial miR-215 negatively modulates Th17-dominant inflammation by inhibiting CXCL12 production in the small intestine.

MicroRNAs are a class of non-coding short-chained RNAs that control cellular functions by downregulating their target genes. Recent research indicates that microRNAs play a role in the maintenance of gut homeostasis. miR-215 was found to be highly expressed in epithelial cells of the small intestine; however, the involvement of miR-215 in gut immunity remains unknown. Here, we show that miR-215 negatively regulates inflammation in the small intestine by inhibiting CXCL12 production. Mice lacking miR-215 showed high susceptibility to inflammation induced by indomethacin, accompanied by an increased number of Th17 cells in the lamina propria of the small intestine. Our findings provide a rationale for targeting miR-215 as a therapeutic intervention for inflammatory conditions in the small intestine.

Genomic repertoires linked with pathogenic potency of arthritogenic Prevotella copri isolated from the gut of patients with rheumatoid arthritis.

OBJECTIVES: Prevotella copri is considered to be a contributing factor in rheumatoid arthritis (RA). However, in some non-Westernised countries, healthy individuals also harbour an abundance of P. copri in the intestine. This study investigated the pathogenicity of RA patient-derived P. copri (P. copri RA) compared with healthy control-derived P. copri (P. copri HC). METHODS: We obtained 13 P. copri strains from the faeces of patients with RA and healthy controls. Following whole genome sequencing, the sequences of P. copri RA and P. copri HC were compared. To analyse the arthritis-inducing ability of P. copri, we examined two arthritis models (1) a collagen-induced arthritis model harbouring P. copri under specific-pathogen-free conditions and (2) an SKG mouse arthritis model under P. copri-monocolonised conditions. Finally, to evaluate the ability of P. copri to activate innate immune cells, we performed in vitro stimulation of bone marrow-derived dendritic cells (BMDCs) by P. copri RA and P. copri HC. RESULTS: Comparative genomic analysis revealed no apparent differences in the core gene contents between P. copri RA and P. copri HC, but pangenome analysis revealed the high genome plasticity of P. copri. We identified a P. copri RA-specific genomic region as a conjugative transposon. In both arthritis models, P. copri RA-induced more severe arthritis than P. copri HC. In vitro BMDC stimulation experiments revealed the upregulation of IL-17 and Th17-related cytokines (IL-6, IL-23) by P. copri RA. CONCLUSION: Our findings reveal the genetic diversity of P. copri, and the genomic signatures associated with strong arthritis-inducing ability of P. copri RA. Our study contributes towards elucidation of the complex pathogenesis of RA.

Midwifery scale to support shared decision-making for unplanned pregnancies: A cross-sectional study.

Midwives significantly support women with unplanned pregnancies-promoting a shared perspective on the decision-making process. This study aimed to develop a scale to support midwives to self-assess their practice of this vital role. Following the derivation of scale items and pilot testing, the final version of the scale was administered to 531 midwives to establish internal consistency and construct criterion-related validity. Through exploratory factor analysis, 35 items with a five-factor structure were retained to form the midwifery practice self-assessment scale to promote shared decision-making in women with unplanned pregnancies. These factors illustrate midwives' general aptitude and competencies in understanding environmental factors, collaborating with significant others and the interprofessional group, forming rapport and problem sharing, focusing on consultation content, and promoting autonomous decision-making. There were high and low scores on the scales after attendance of the workshops to support the decision-making of women with unplanned pregnancies. The reliability analysis showed acceptable Cronbach's alpha values for the five factors, from 0.85 to 0.87. The scale was demonstrated to be a reliable and valid measure that would help improve the quality of midwives' practice.

Total synthesis of pyrrolo[2,3-c]quinoline alkaloid: trigonoine B.

The first total synthesis of the pyrrolo[2,3-c]quinoline alkaloid trigonoine B (1) was accomplished via a six-step sequence involving the construction of an N-substituted 4-aminopyrrolo[2,3-c]quinoline framework via electrocyclization of 2-(pyrrol-3-yl)benzene containing a carbodiimide moiety as a 2-azahexatriene system. The employed six-step sequence afforded trigonoine B (1) in 9.2% overall yield. The described route could be employed for the preparation of various N-substituted 4-aminopyrroloquinolines with various biological activities.

[Early Detection of and Initial Response to Oxaliplatin-Related Hypersensitivity Reactions].

Oxaliplatin(L-OHP)-related hypersensitivity reactions(HSRs)may be fatal due to bronchospasm, dyspnea, and hypotension. Therefore, management of HSRs is extremely important, and a prompt and appropriate response is required when HSRs develop. To clarify the importance of early detection and an appropriate initial response to HSRs, we retrospectively investigated the expression of HSRs and subsequent response in patients using L-OHP from April 2016 to December 2017 at the outpatient chemotherapy center of Nagasaki Medical Center. HSRs were observed in 14/155 cases(one case of Grade 1 HSRs and 13 cases of Grade 2 HSRs). No significant risk factors were identified in individuals with and without HSRs. HSRs devel- oped following a median of 7.9(2-11)courses of chemotherapy and a median 687.8(75.4-960.2)mg/m2 cumulative dose. Half of the patients were able to recognize the hypersensitivity early by themselves. Furthermore, nurses were able to implement an appropriate initial response. Early detection and an appropriate early response to HSRs can possibly prevent the severity of symptoms.

Gut microbiota directs PPARγ-driven reprogramming of the liver circadian clock by nutritional challenge.

The liver circadian clock is reprogrammed by nutritional challenge through the rewiring of specific transcriptional pathways. As the gut microbiota is tightly connected to host metabolism, whose coordination is governed by the circadian clock, we explored whether gut microbes influence circadian homeostasis and how they distally control the peripheral clock in the liver. Using fecal transplant procedures we reveal that, in response to high-fat diet, the gut microbiota drives PPARγ-mediated activation of newly oscillatory transcriptional programs in the liver. Moreover, antibiotics treatment prevents PPARγ-driven transcription in the liver, underscoring the essential role of gut microbes in clock reprogramming and hepatic circadian homeostasis. Thus, a specific molecular signature characterizes the influence of the gut microbiome in the liver, leading to the transcriptional rewiring of hepatic metabolism.

Ingestion of eicosapentaenoic acid in the early stage of social isolation reduces a fibroblast growth factor 21 resistant state independently of body weight in KKA(y) mice.

Fibroblast growth factor (FGF) 21 is a mediator of glucose and lipid metabolism. Although exogenous administration of FGF21 exerts beneficial effects on glucose and lipid metabolism, circulating FGF21 levels are elevated in ob/ob and db/db mice, diet-induced obese mice and obese human. Here we show that ingestion of eicosapentaenoic acid (EPA) for 6 days after individually-housing significantly suppressed the hyperglycemia and hypertriglyceridemia associated with decreases in plasma insulin and FGF21 levels in KKA(y) mice while having no effects on food intake, body weight or plasma active GLP-1 levels. The ingestion of EPA had no significant effects on the expression of FGF21 in the liver, epididymal white adipose tissue and skeletal muscle. Moreover, the ingestion of EPA significantly decreased the expression of hepatic peroxisome sterol regulatory element-binding protein (SREBP1c), carbohydrate response element-binding protein (ChREBP), stearoyl-CoA deaturase and periostin, which are involved in hepatic lipogenesis and hepatosteaotosis, in KKA(y) mice. On the other hand, the ingestion of EPA had no significant effects on expression of hepatic gp78, Notch, forkhead box protein O1 or glucose-6-phosphatase. These findings suggest that EPA ingestion in the early stage of social isolation suppresses hyperglycemia and hypertriglyceridemia associated with reduced FGF21 and insulin resistance without altering food intake and body weight, and that the EPA ingestion suppresses hepatic lipogenesis by suppressing Notch- and gp78-independent SEREBP1c and ChREBP pathways in KKA(y) mice.

Tissue-resident memory T cells: decoding intra-organ diversity with a gut perspective.

Tissue-resident memory T cells (TRM) serve as the frontline of host defense, playing a critical role in protection against invading pathogens. This emphasizes their role in providing rapid on-site immune responses across various organs. The physiological significance of TRM is not just confined to infection control; accumulating evidence has revealed that TRM also determine the pathology of diseases such as autoimmune disorders, inflammatory bowel disease, and cancer. Intensive studies on the origin, mechanisms of formation and maintenance, and physiological significance of TRM have elucidated the transcriptional and functional diversity of these cells, which are often affected by local cues associated with their presence. These were further confirmed by the recent remarkable advancements of next-generation sequencing and single-cell technologies, which allow the transcriptional and phenotypic characterization of each TRM subset induced in different microenvironments. This review first overviews the current knowledge of the cell fate, molecular features, transcriptional and metabolic regulation, and biological importance of TRM in health and disease. Finally, this article presents a variety of recent studies on disease-associated TRM, particularly focusing and elaborating on the TRM in the gut, which constitute the largest and most intricate immune network in the body, and their pathological relevance to gut inflammation in humans.

Distress of Educators Teaching Nursing Students with Potential Learning Disabilities: A Qualitative Analysis.

Clinical training at Japanese nursing universities has an increasing need for individualized learning support for students with potential learning disabilities. Despite a high interest in student support, educators' difficulties are neglected. This study clarified the difficulties encountered by practical training instructors in delivering clinical training to nursing students with potential learning disabilities. In this descriptive, qualitative study, online focus group interviews were conducted. Participants were nine Japanese nursing university graduates with over five years of clinical education experience. A total of five categories were extracted: searching for measures tailored to students in a short period of time during training; resistance to individualized responses that significantly differ from traditional Japanese collectivist education; conflict over support being perceived as favoring a particular student; hesitation to identify students' limits; and barriers in the process of supporting difficulties due to the nature of learning disabilities. Practical training instructors experience difficulties and hesitation when teaching students with potential learning disabilities. The practical training instructors need support and educational opportunities as well as students who need help. To overcome these difficulties, university educational staff, as well as students and families, must be educated on the existence and value of support tailored to the characteristics of an individual's learning disability.