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.

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.

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.

Molecular Mechanisms Underlying the Bioactive Properties of a Ketogenic Diet.

The consumption of a high-fat, low-carbohydrate diet (ketogenic diet) has diverse effects on health and is expected to have therapeutic value in neurological disorders, metabolic syndrome, and cancer. Recent studies have shown that a ketogenic diet not only pronouncedly shifts the cellular metabolism to pseudo-starvation, but also exerts a variety of physiological functions on various organs through metabolites that act as energy substrates, signaling molecules, and epigenetic modifiers. In this review, we highlight the latest findings on the molecular mechanisms of a ketogenic diet and speculate on the significance of these functions in the context of the epigenome and microbiome. Unraveling the molecular basis of the bioactive effects of a ketogenic diet should provide solid evidence for its clinical application in a variety of diseases including cancer.

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.

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.

TRPM5 Negatively Regulates Calcium-Dependent Responses in Lipopolysaccharide-Stimulated B Lymphocytes.

B cells produce high amounts of cytokines and immunoglobulins in response to lipopolysaccharide (LPS) stimulation. Calcium signaling cascades are critically involved in cytokine production of T cells, and the cytosolic calcium concentration is regulated by calcium-activated monovalent cation channels (CAMs). Calcium signaling is also implicated in B cell activation; however, its involvement in the cytokine production of LPS-stimulated B cells remains less well characterized. Here, we show that the transient receptor potential melastatin 5 channel (TRPM5), which is one of the CAMs, negatively modulates calcium signaling, thereby regulating LPS-induced proliferative and inflammatory responses by B cells. LPS-stimulated B cells of Trpm5-deficient mice exhibit an increased cytosolic calcium concentration, leading to enhanced proliferation and the production of the inflammatory cytokines interleukin-6 and CXCL10. Furthermore, Trpm5-deficient mice show an exacerbation of endotoxic shock with high mortality. Our findings demonstrate the importance of TRPM5-dependent regulatory mechanisms in LPS-induced calcium signaling of splenic B cells.

[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.

The Circadian Clock as an Essential Molecular Link Between Host Physiology and Microorganisms.

Advances in high-throughput sequencing technologies in the past decade has led to a tremendous growth in knowledge about the role played by microorganisms on our body health. Trillions of microbes live in close symbiosis with their host, and have impacts on various aspects of host physiology as well as predisposition to disease. This is a consequence of the direct interaction between host cells and microbes or their signaling molecules, such as metabolites, which can reach and exert their effects in distal tissues. Among the essential factors modulating the human body's ecosystem of symbionts, the circadian clock might be one of the key regulators. The endogenous clock is a highly conserved timekeeper able to align organismal physiology to the daily cycle, thus maximizing survival and fitness. Circadian rhythms coordinate whole-body biological processes synchronizing cellular biochemical reactions, tissue function and finally controlling systemic homeostasis. Intriguingly, growing body of evidence has demonstrated that the host circadian cycle governs the structure of the gut microbiota community and its diurnal rhythmicity, whereas the microbes contribute to maintenance of clock function. In this review, we will give an overview of the multisystem aspects of microbiome-host interactions in the context of circadian rhythmicity. In particular, the effect of the interaction clock-microbial communities on immune system function and metabolic homeostasis will be discussed. Finally, the possible implication of daily rhythm on the gut-microbiome-brain axis will be analyzed, focusing on the reciprocal effects of clock disruption and microbiota alterations on brain function and behavior.

Low-frequency and low-intensity ultrasound increases cardiac parasympathetic neural activity and decreases clinic hypertension in elderly hypertensive subjects with type 2 diabetes.

BACKGROUND: The aims of the present study were to determine the effects of an ultrasound irradiation on clinic hypertension and the heart rate variability in elderly hypertensive subjects with type 2 diabetes. METHODS: We examined the effects of ultrasound (800 kHz, 25 mW/cm2) applied to the forearm for 10 min on the autonomic nerve activity and the difference between BP at home and at a clinic visit in Japanese subjects with type 2 diabetes and hypertension. RESULTS: In 108 subjects who displayed systolic BP (SBP) >140 mm Hg at a clinic visit, 75 subjects (69%) had a mean SBP <135 mm Hg at home and 33 subjects (31%) had a mean SBP >135 mm Hg at home in the morning for 14 days. SBP, pulse rate, and pulse pressure in the ultrasound treatment group were significantly lower than the baseline values in these hypertensive subjects with type 2 diabetes, and lower than those of placebo controls independently of SBP at home. In 31 subjects who displayed systolic BP >140 mm Hg at a clinic, standard deviation of all RR intervals and the root mean square of successive differences were significantly higher in the ultrasound treatment group than the baseline values in these hypertensive subjects with type 2 diabetes, and lower than those of placebo controls. CONCLUSIONS: The ultrasound treatment increases the cardiac parasympathetic neural activity and decreases the differences between SBP at home and at a clinic visit in elderly hypertensive subjects with type 2 diabetes.

Interplay between Microbes and the Circadian Clock.

Circadian rhythms influence virtually all life forms on our planet, a notion that opens the question on how the circadian cycles of individual organisms may interplay with each other. In mammals, a potentially dangerous environmental stress is represented by encounters with infectious agents. Microbial attack is a major risk for organismal homeostasis and therefore needs to be efficiently counteracted by mechanisms implemented by the host immune system. Accumulating evidence shows that the immune system may anticipate an emerging pathogenic exposure through an enhanced inflammatory state. Notably, the circadian clock orchestrates these anticipatory responses to fluctuating conditions in the external world. In this article, we review the current knowledge about the relationship between the circadian clock and pathogenic infections. We discuss the role of the circadian clock against infection and specific pathogens, the core clock proteins involved in the defense mechanisms, and the specific tissue or cell type in which they function to counteract the infection. Finally, circadian oscillations in the gut microbiome composition and its possible role in protecting against foodborne pathogen colonization are presented.

Slc3a2 Mediates Branched-Chain Amino-Acid-Dependent Maintenance of Regulatory T Cells.

Foxp3+ regulatory T (Treg) cells, which suppress immune responses, are highly proliferative in vivo. However, it remains unclear how the active replication of Treg cells is maintained in vivo. Here, we show that branched-chain amino acids (BCAAs), including isoleucine, are required for maintenance of the proliferative state of Treg cells via the amino acid transporter Slc3a2-dependent metabolic reprogramming. Mice fed BCAA-reduced diets showed decreased numbers of Foxp3+ Treg cells with defective in vivo proliferative capacity. Mice lacking Slc3a2 specifically in Foxp3+ Treg cells showed impaired in vivo replication and decreased numbers of Treg cells. Slc3a2-deficient Treg cells showed impaired isoleucine-induced activation of the mTORC1 pathway and an altered metabolic state. Slc3a2 mutant mice did not show an isoleucine-induced increase of Treg cells in vivo and exhibited multi-organ inflammation. Taken together, these findings demonstrate that BCAA controls Treg cell maintenance via Slc3a2-dependent metabolic regulation.

Low-frequency and low-intensity ultrasound irradiation to the forearm improves an index of arterial stiffness in subjects with type 2 diabetes and hypertension.

OBJECTIVES: The arterial pressure-volume index (API) is a non-invasive assessment of arterial stiffness, and is suggested as a useful predictor of future cardiovascular events. The aim of the present study was to determine the effects of low-frequency and low-intensity ultrasound applied to the forearm for 10 min on the API in Japanese subjects with type 2 diabetes and hypertension. METHODS: We examined the effects of low-frequency and low-intensity ultrasound (800 kHz, 25 mW/cm2) applied to the forearm for 10 min on the API, blood pressure (BP) and pulse rate in 40 Japanese subjects (13 men and 27 women; mean age ± SE, 70 ± 2 years) with type 2 diabetes and hypertension, who had the API > 30 and systolic BP > 140 mmHg at a clinic visit. We also examined the effects of the ultrasound irradiation for 10 min on the API, BP and pulse rate in 33 Japanese subjects (11 men and 22 women; mean age ± SE, 65 ± 2 years) with type 2 diabetes and hypertension, who had the API > 30 and systolic BP (SBP) < 140 mmHg. RESULTS: The API, systolic BP and pulse rate in the ultrasound treatment group was significantly lower than the baseline values in the subjects who had the API > 30 and either the baseline of systolic BP > 140 mmHg or systolic BP < 140 mmHg. CONCLUSIONS: The low-frequency and low-intensity ultrasound irradiation to the forearm for 10 min might be useful as a preventive application for arterial stiffness in subjects with type 2 diabetes and hypertension.

Distinct Circadian Signatures in Liver and Gut Clocks Revealed by Ketogenic Diet.

The circadian clock orchestrates rhythms in physiology and behavior, allowing organismal adaptation to daily environmental changes. While food intake profoundly influences diurnal rhythms in the liver, how nutritional challenges are differentially interpreted by distinct tissue-specific clocks remains poorly explored. Ketogenic diet (KD) is considered to have metabolic and therapeutic value, though its impact on circadian homeostasis is virtually unknown. We show that KD has profound and differential effects on liver and intestine clocks. Specifically, the amplitude of clock-controlled genes and BMAL1 chromatin recruitment are drastically altered by KD in the liver, but not in the intestine. KD induces nuclear accumulation of PPARα in both tissues but with different circadian phase. Also, gut and liver clocks respond differently to carbohydrate supplementation to KD. Importantly, KD induces serum and intestinal ß-hydroxyl-butyrate levels to robustly oscillate in a circadian manner, an event coupled to tissue-specific cyclic histone deacetylase (HDAC) activity and histone acetylation.

Treatment with FGFR2-IIIc monoclonal antibody suppresses weight gain and adiposity in KKAy mice.

Expression of ß-Kotho, fibroblast growth factor receptor (FGFR)-1c and 2c, which bind FGF21, is decreased in the white adipose tissue of obese mice. The aim of the present study was to determine the role of FGFR2c in the development of obesity and diabetes in KKAy mice. Treatment with mouse monoclonal FGFR2-IIIc antibody (0.5 mg kg-1) significantly suppressed body weight gain and epididymal white adipose tissue weight in individually housed KKAy mice while having no effect on daily food intake. In addition, treatment with FGFR2-IIIc antibody significantly increased plasma-free fatty acid levels while having no effect on blood glucose or plasma FGF21 levels. Moreover, treatment with FGFR2-IIIc antibody had no significant effect on the expression of uncoupling protein-1, uncoupling protein-2 or peroxisome proliferator-activated receptor-γ coactivator 1α in the epididymal white adipose tissue. The treatment with FGFR2-IIIc antibody had no significant effects on daily food intake and body weight gain in individually housed KK mice. These findings suggest that FGFR2-IIIc upregulates the adiposity induced by social isolation in KKAy mice, and that decreased expression and/or function of FGFR2c might be a compensatory response to enhanced adiposity. Inhibition of FGFR2-IIIc function might be a novel therapeutic approach for obesity.

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.

Low-frequency and very low-intensity ultrasound decreases blood pressure in hypertensive subjects with type 2 diabetes.

BACKGROUND: Despite lifestyle interventions and various types of anti-hypertension agents, hypertension remains difficult to control in some patients with type 2 diabetes. As a noninvasive device-based approach for the treatment of clinic hypertension, we examined the effects of low-frequency and low-intensity ultrasound (500 or 800kHz, 25mW/cm(2)) applied to the forearm on blood pressure (BP) and pulse rate in Japanese subjects with type 2 diabetes and hypertension. METHODS: We examined the effects of low-frequency and low-intensity ultrasound (500 or 800kHz, 25mW/cm(2)) applied to the forearm on BP, pulse rate, and pulse pressure in 212 Japanese subjects (82 men and 130 women; mean age±SE, 65±1years) with type 2 diabetes and hypertension (systolic BP>140mmHg). The subjects were treated with anti-hypertension agents. RESULTS: Systolic and diastolic BP, pulse rate, pulse pressure in the 800-kHz ultrasound treatment group were significantly lower than the baseline values in hypertensive subjects with type 2 diabetes, and lower than those of placebo controls. In addition, systolic and diastolic BP, pulse rate, and pulse pressure in the 500-kHz ultrasound treatment group were significantly lower than the baseline values in hypertensive subjects with type 2 diabetes, and systolic BP, pulse rate, and pulse pressure were significantly lower than those of placebo controls. CONCLUSIONS: Low-frequency (800kHz or 500kHz) and low-intensity (25mW/cm(2)) ultrasound irradiation to the forearm might have potential usefulness as a therapeutic application for clinic hypertension in subjects with type 2 diabetes.

The Circadian Clock in the Ventromedial Hypothalamus Controls Cyclic Energy Expenditure.

Organismal homeostasis relies on coherent interactions among tissues, specifically between brain-driven functions and peripheral metabolic organs. Hypothalamic circuits compute metabolic information to optimize energetic resources, but the role of the circadian clock in these pathways remains unclear. We have generated mice with targeted ablation of the core-clock gene Bmal1 within Sf1-neurons of the ventromedial hypothalamus (VMH). While this mutation does not affect the central clock in the suprachiasmatic nucleus (SCN), the VMH clock controls cyclic thermogenesis in brown adipose tissue (BAT), a tissue that governs energy balance by dissipating chemical energy as heat. VMH-driven control is exerted through increased adrenergic signaling within the sympathetic nervous system, without affecting the BAT's endogenous clock. Moreover, we show that the VMH circadian clock computes light and feeding inputs to modulate basal energy expenditure. Thus, we reveal a previously unsuspected circuit where an SCN-independent, hypothalamic circadian clock controls BAT function, energy expenditure, and thermogenesis.