Comparable clinical advantages identification of three formulae on rheumatic disease using a modular-based network proximity approach.

ETHNOPHARMACOLOGICAL RELEVANCE: Herbal formulae have been used in China for thousands of years but have unclear clinical positioning and unknown characteristic indications make it difficult to determine their specific application in various diseases, which seriously hamper their clinical value. Identifying the precise clinical positioning and clinical advantages of similar formulae for related diseases is a critical issue. AIM OF THIS STUDY: To develop a methodology based on modular pharmacology to determine the clinical advantages and precise clinical position of similar formulae. MATERIALS AND METHODS: In this study, we proposed a modular-based network proximity approach to explore drug repositioning and clinical advantages of three formulae, Shirebi tablets (SRB), Yuxuebi capsules (YXB), and Wangbifukang granules (WBFK), for rheumatic disease. First, we constructed a rheumatology target network, and modules were obtained using the cluster tool molecular complex detection (MCODE). Based on the modular interaction map established by a quantitative approach for inter-module coordination and its transition (IMCC), using a targeting rate (TR) matrix to identify targeted modules of three formulae. Moreover, the network proximity Z-score and Jaccard similarity coefficient were used to identify potential optimal symptomatic indications and related diseases using three formulae. At the same time, the driver genes for SRB and gouty arthritis were identified by flow centrality and shortest distance, and the epresentative driver genes were validated by in vivo experiments. RESULTS: 32 modules were obtained using the MCODE method. 4, 4, and 14 characteristic targeted modules of SRB, YXB, and WBFK, respectively, were identified using a targeting rate (TR) matrix. Module 2, 16, and 19 were targeted by both SRB and WBFK. The common effects of SRB and WBFK focused on inflammatory response and innate immune response, YXB was found to be involved in the collagen catabolic process, transmembrane receptor protein serine/threonine kinase signaling pathway. Moreover, potential optimal symptomatic indications and representative related diseases were identified for three formulae: SRB was significantly associated with GA (Z = -20.26); YXB was significantly associated with AS (Z = -4.532), MI (Z = -29.11), RhFv (Z = -6.945), OA (Z = -39.97), and GA (Z = -13.03); and WBFK was significantly associated with MI (Z = -205.5), SLE (Z = -37.65), RhFv (Z = -42.45), and GA (Z = -17.24). Finally, 8 driver genes for SRB and gouty arthritis were identified,the representative driver genes TRAF6 and NFE2L1 were validated by in vivo experiments. CONCLUSIONS: The modular-based network proximity approach proposed in this study may provide a new perspective for the precise drug repositioning and clinical advantages of similar formulae in disease treatment.

Association of electronic screen exposure with depression among women in early pregnancy: a cross-sectional study.

BACKGROUND: Previous studies indicated that excessive engagement in digital devices could lead to negative psychological impacts in general population. We aimed to determine the association of electronic screen exposure with depression among women in early pregnancy. METHODS: A cross-sectional study was conducted from June 2021 to June 2022. A total of 665 women in early pregnancy were recruited and the information included socio-demographic characteristics, screen exposure and Patient Health Questionnaire - 9 depression scale. RESULTS: Among the women in early pregnancy, the total daily smartphone viewing time was the longest (median [P25-P75], 5 [3-6] hours/day) in the three types of electronic screen exposure. The total daily smartphone viewing time (P = 0.015, OR[95%CI] = 1.09[1.11-1.18]), smartphone (P = 0.016, OR[95%CI] = 1.24[1.04-1.47]) and television viewing time (P = 0.006, OR[95%CI] = 1.35[1.09-1.67]) before nocturnal sleep were significantly associated with depression among women in early pregnancy. The thresholds calculated by receiver operator characteristic curves were 7.5 h/day, 1.5 h/day and 1.5 h/day, respectively. In addition, women with higher scores of smartphone addiction were more susceptible to depression (P<0.001, OR[95%CI] = 1.11[1.07-1.16]). The top three smartphone usages in women with depression were watching videos (22.0%), listening to music (20.9%) and playing games (16.7%). CONCLUSIONS: In conclusion, electronic screen exposure, including screen viewing time, smartphone addiction and problematic smartphone use was associated with depression among women in early pregnancy. Further studies are warranted to verify the conclusions.

Exploration of undergraduate nursing students' perspectives on conducting specialized nursing education during internship: A phenomenological research study.

AIM: To comprehend the perspectives of undergraduate nursing students on conducting specialized nursing education during the internship phase, providing a basis for colleges to formulate plans for specialized nursing education. BACKGROUND: Nursing specialty in China was included in the national controlled specialty in 2024, which means signifying an effort to decrease the enrollment of junior college degree nurses, thereby increasing the number of high-quality undergraduate nurses. While the higher the education level of nursing students, the higher their expectations for themselves. However, after entering clinical practice, their social status and job nature are significantly different from those of doctors, which creates a psychological imbalance. In addition, employers lack a reasonable employment mechanism and undergraduate nursing students are used equally with vocational and technical nursing students, making them feel that their self-worth is difficult to realize. Therefore, their professional attitude becomes more negative (Meng Wei, 2018). In the process of forming professional identity among undergraduate nursing students, the professional role models and clinical experience of specialized nurses can serve as important promoting factors. By increasing interaction with specialized nurses and learning specialized nursing, undergraduate nursing students can better understand the professional role and values of nurses and form positive professional ethics and attitudes (Huang et al., 2023). To better adapt to the national health needs and assist undergraduates in transitioning to clinical practice, deepening the understanding of the profession and career, the integration of professional education during the internship phase can enable students to recognize their strengths, cultivate an awareness of suitable professions and facilitate a targeted adaptation from academic studies to clinical practice. DESIGN: The researcher initially drafted the interview outline through a literature review and intra-group discussions. To ensure the research content's richness, a semi-structured interview method was adopted. The Colaizzi seven-step analysis method was applied in the analysis. METHODS: Employing phenomenological study and purposive sampling, with data saturation as the guiding principle, 24 undergraduate nursing students undergoing internship at a tertiary hospital in China were selected for focus group interviews. RESULTS: Four main themes were extracted from the perspectives of undergraduate nursing students. These themes encompass awareness of specialized nursing and specialized nurses, recognition of specialized nursing education during the internship phase, demands for specialized nursing education during the internship phase and career expectations. CONCLUSION: Nursing administrators in hospitals and educational managers in colleges should prioritize align education with clinical needs, address the requirements of nursing students, strengthen collaboration between institutions，and advance the further development of specialized nursing.

A core competency evaluation index system for the graded use of clinical nurse specialists: A Delphi study.

AIMS AND OBJECTIVES: To describe a grading system that can be used to evaluate core competency of clinical nurse specialists (CNSs) at different levels. BACKGROUND: Evaluate core competence of CNSs at different levels reflects the quality of nursing and the development of the nursing profession. DESIGN: This research employed the Delphi method. METHODS: The STROBE checklist for observational cross-sectional studies was followed to report this research study. This study consisted of two main phases: a literature review and semistructured interviews. Individual semistructured interviews were conducted with 11 healthcare experts and two patients. Two rounds of questionnaire surveys were administered to 21 nursing experts using the Delphi method. The CNSs were classified as primary, intermediate or advanced based on their years of work, professional titles and educational qualifications. RESULTS: The graded competency evaluation system consisted of five first-level indicators (clinical practice, consulting guidance and teaching, scientific research innovation, management and discipline development, and ethical decision-making), 15 second level indicators, and 40 third-level indicators. The authority coefficients (Cr) of the experts were .865 and .901. The Kendall's concordance coefficients of the three-level indicators were .417, .289 and .316 for primary CNSs; .384, .294 and .337 for intermediate CNSs; and .489, .289 and .239 for advanced CNSs. CONCLUSION: The graded use evaluation system in clinical practice initially involves a comprehensive evaluation of the core abilities of CNSs. This is a tool for cultivating and grading the abilities of specialised nurses that can promote a practical upwards spiral. RELEVANCE TO CLINICAL PRACTICE: The evaluation system can promote the scientific management and continuous improvement of CNSs in clinical nursing and can serve as a practical and objective reference for the effective management and development of CNSs. PATIENT OR PUBLIC CONTRIBUTION: Patients participated in the data collection process, during which they shared their health-seeking experience with our research team.

Ex vivo intestinal permeability assay (X-IPA) for tracking barrier function dynamics.

The intestinal epithelial barrier facilitates homeostatic host-microbiota interactions and immunological tolerance. However, mechanistic dissections of barrier dynamics following luminal stimulation pose a substantial challenge. Here, we describe an ex vivo intestinal permeability assay, X-IPA, for quantitative analysis of gut permeability dynamics at the whole-tissue level. We demonstrate that specific gut microbes and metabolites induce rapid, dose-dependent increases to gut permeability, thus providing a powerful approach for precise investigation of barrier functions.

A Novel Serum Metabolomic Panel for the Diagnosis of Crohn's Disease.

BACKGROUND: A distinctive metabolic phenotype provides the opportunity to discover noninvasive biomarkers for the diagnosis of Crohn's disease (CD) and for differentiating it from other intestinal inflammatory diseases. The study sought to identify new biomarkers for CD diagnosis. METHODS: Serum metabolites from 68 newly diagnosed and treatment-naïve patients with CD and 56 healthy control (HC) subjects were profiled using targeted liquid chromatography-mass spectrometry. Five metabolic biomarkers were identified to distinguish patients with CD from the HC subjects and validated in a separate cohort consisting of 110 patients with CD and 90 HC subjects using a combination of univariate analysis, orthogonal partial least-squares discriminant analysis, and receiver-operating characteristic curve analysis. Differences in the 5 metabolites were evaluated among patients with CD and patients with ulcerative colitis (n = 62), intestinal tuberculosis (n = 48), and Behçet's disease (n = 31). RESULTS: Among the 185 quantified metabolites, a panel of 5 (pyruvate, phenylacetylglutamine, isolithocholic acid, taurodeoxycholic acid, and glycolithocholic acid) were found to distinguish patients with CD with high accuracy from HC subjects, with an area under the curve of 0.861 (P < .001). The performance of the model in assessing clinical disease activity was comparable to that of the present biomarkers: C-reactive protein and erythrocyte sedimentation rate. The 5 metabolites were significantly different among the patients and were valuable in the differentiation between CD and other chronic intestinal inflammatory diseases. CONCLUSIONS: The combination of 5 serum metabolite biomarkers for the diagnosis of CD has the potential to provide an accurate, noninvasive, and inexpensive alternative to conventional tests and might be valuable for the differentiation from other diagnostically challenging intestinal inflammatory diseases.

Serum metabolomic analysis was performed on patients with Crohn's disease and healthy control subjects, which discovered 5 metabolites as a novel serum metabolomic panel. These metabolites were further validated in a second patient cohort and a third differentiation cohort. The data showed that these metabolites were valuable in diagnosis of Crohn's disease and for differentiating it from other intestinal inflammatory diseases.

Epithelial Nlrp10 inflammasome mediates protection against intestinal autoinflammation.

Unlike other nucleotide oligomerization domain-like receptors, Nlrp10 lacks a canonical leucine-rich repeat domain, suggesting that it is incapable of signal sensing and inflammasome formation. Here we show that mouse Nlrp10 is expressed in distal colonic intestinal epithelial cells (IECs) and modulated by the intestinal microbiome. In vitro, Nlrp10 forms an Apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)-dependent, m-3M3FBS-activated, polyinosinic:polycytidylic acid-modulated inflammasome driving interleukin-1ß and interleukin-18 secretion. In vivo, Nlrp10 signaling is dispensable during steady state but becomes functional during autoinflammation in antagonizing mucosal damage. Importantly, whole-body or conditional IEC Nlrp10 depletion leads to reduced IEC caspase-1 activation, coupled with enhanced susceptibility to dextran sodium sulfate-induced colitis, mediated by altered inflammatory and healing programs. Collectively, understanding Nlrp10 inflammasome-dependent and independent activity, regulation and possible human relevance might facilitate the development of new innate immune anti-inflammatory interventions.

Immunomodulatory Activity and Its Mechanisms of Two Polysaccharides from Poria cocos.

Polyporaceae is an important fungal family that has been a source of natural products with a range of pharmaceutical activities in China. In our previous study, two polysaccharides, PCWPW and PCWPS, with significant antioxidant and antidepressant activity were obtained from Poria cocos. In this study, we evaluated their potential molecular mechanisms in the immunomodulation of macrophages. PCWPW and PCWPS were characterized by GC-MS analysis to contain 1,3-linked Glcp. ELISA assays results demonstrated that the secretion of TNF-α was significantly enhanced by PCWPW/PCWPS. RNA-seq data demonstrated that PCWPS treatment modulated the expression of immune-related genes in macrophages, which was further confirmed by RT-qPCR assays. The activation of TNF-α secretion was found to be mannose receptor (MR) dependent and suppressed by MR inhibitor pretreatment. Moreover, the amount of TNF-α cytokine secretion in PCWPW/PCWPS-induced RAW264.7 cells was decreased when pretreated with NF-κB or MAPK signaling pathway inhibitors. Collectively, our results suggested that PCWPW and PCWPS possessed immunomodulatory activity that regulates TNF-α expression through the NF-κB/MAPK signaling pathway by binding to mannose receptors. Therefore, PCWPW and PCWPS isolated from Poria cocos have potential as drug candidates for immune-related disease treatment.

Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation.

Human gut commensals are increasingly suggested to impact non-communicable diseases, such as inflammatory bowel diseases (IBD), yet their targeted suppression remains a daunting unmet challenge. In four geographically distinct IBD cohorts (n = 537), we identify a clade of Klebsiella pneumoniae (Kp) strains, featuring a unique antibiotics resistance and mobilome signature, to be strongly associated with disease exacerbation and severity. Transfer of clinical IBD-associated Kp strains into colitis-prone, germ-free, and colonized mice enhances intestinal inflammation. Stepwise generation of a lytic five-phage combination, targeting sensitive and resistant IBD-associated Kp clade members through distinct mechanisms, enables effective Kp suppression in colitis-prone mice, driving an attenuated inflammation and disease severity. Proof-of-concept assessment of Kp-targeting phages in an artificial human gut and in healthy volunteers demonstrates gastric acid-dependent phage resilience, safety, and viability in the lower gut. Collectively, we demonstrate the feasibility of orally administered combination phage therapy in avoiding resistance, while effectively inhibiting non-communicable disease-contributing pathobionts.

Identifying unmet non-COVID-19 health needs during the COVID-19 outbreak based on social media data: a proof-of-concept study in Wuhan city.

BACKGROUND: The occupancy of healthcare resources by the COVID-19 outbreak had led to the unmet health needs of non-COVID-19 diseases. We aimed to explore whether the social media information could help surveil and understand the characteristics of unmet non-COVID-19 health needs during the COVID-19 outbreak in Wuhan city. METHODS: This was an observational study based on social media data. The study period was set during the 3 months of the COVID-19 outbreak. Non-COVID-19 urgent and emergent health needs in Wuhan city were derived from Sina Weibo-one of China's largest social media platforms. Lag Spearman correlation was used to investigate the epidemiological relationship between the COVID-19 outbreak and non-COVID-19 health needs. Patient's primary diseases and needed care were annotated and categorized according to the International Classification of Diseases 11th Revision. The delay time in seeking help was calculated and compared. RESULTS: After screening 114,795 Weibo posts, a total of 229 patients with non-COVID-19 health needs were included in our study. There were significant correlations between the daily number of COVID-19 cases at a 10-day lag, deaths at a 5-day lag, and non-COVID-19 Weibo. The actual number of non-COVID-19 patients with urgent and emergent health needs was estimated to be about 6,966. Patients with non-COVID-19 health needs were skewed to those aged 50 to 70 years. The non-COVID-19 diseases were diverse, with 46.3% as non-neoplastic diseases and 53.7% as neoplasms. The most needed cares were palliative cancer care (22.7%), chemotherapy (18.8%), and critical care (17.0%). The median delay in seeking help was 3 days [interquartile range (IQR), 1 to 15 days] for acute care, and 18.5 days (IQR, 6 to 30 days) for cancer care. CONCLUSIONS: Our preliminary findings in Wuhan city indicated that the social media data might provide a viable option to surveil and understand the unmet health needs during an outbreak. Those heterogeneous health needs derived from the social media data might inspire a more resilient healthcare system to address the unmet needs promptly.

The NLRP6 inflammasome.

The NOD-like receptor family pyrin domain containing 6 (NLRP6), a member of the NOD-like receptor (NLR) family, acts as a cytosolic innate immune sensor that recognizes microbe-associated molecular patterns. In some circumstances upon activation, NLRP6 recruits the adaptor apoptosis-associated speck-like protein (ASC) and the inflammatory caspase-1 or caspase-11 to form an inflammasome, which mediates the maturation and secretion of the pro-inflammatory cytokines IL-18 and IL-1ß. In other contexts, NLRP6 can exert its function in an inflammasome-independent manner. Tight regulation of the NLRP6 inflammasome is critical in maintaining tissue homeostasis, while improper inflammasome activation may contribute to the development of multiple diseases. In intestinal epithelial cells, the NLRP6 inflammasome is suggested to play a role in regulating gut microbiome composition, goblet cell function and related susceptibility to gastrointestinal inflammatory, infectious and neoplastic diseases. Additionally, NLRP6 may regulate extra-intestinal diseases. In this review, we summarize current knowledge on the NLRP6 inflammasome and its activation and regulation patterns, as well as its effector functions contributing to disease modulation. We discuss current challenges in NLRP6 research and future prospects in harnessing its function into potential human interventions.

High expression of Notch2 drives tongue squamous cell carcinoma carcinogenesis.

Tongue squamous cell carcinoma (TSCC) is one of the most common cancers in the oral cavity. Notch signaling is frequently dysregulated in cancer. However, the role of Notch2 in TSCC is not well understood. The aim of this study was to investigate the effect of abnormal expression of Notch2 in TSCC. The expression of Notch2 was tested in 47 pairs of tissues from tongue cancer and normal samples by using immunohistochemical staining. Tongue cancer cells were transfected with siRNA or plasmid. The proliferation of the cells was tested by the CCK8 assay and colony formation assay. Subcutaneous tumor model was established to observe tumor growth. Transwell assay was used to detect the changes of cell migration and invasion ability. A humanized anti-Notch2 antibody was used to TSCC cells. We found that Notch2 was upregulated in tongue carcinoma tissues. Knocking down the expression of Notch2 by siRNA in the TSCC cell lines decreased proliferation ability both in vitro and in vivo. In addition, migration and invasion abilities were inhibited by knockdown of Notch2 in the TSCC cells. However, overexpression of Notch2 increased tongue cancer cell proliferation, invasion and migration. The humanized anti-Notch2 antibody inhibited TSCC cell growth. The results indicated that Notch2 is an oncogene in tongue squamous cell carcinoma and may become the target of a new approach for treating TSCC.

Classifying Crohn's disease into colon-involving versus non-colon-involving groups is a better predictor of clinical outcomes than the Montreal classification.

BACKGROUND: A suitable disease classification is essential for individualized therapy in patients with Crohn's disease (CD). Although a potential mechanistic classification of colon-involving and non-colon-involving disease was suggested by recent genetic and microbiota studies, the clinical implication has seldom been investigated. We aimed to explore the association of this colonic-based classification with clinical outcomes in patients with CD compared with the Montreal classification. METHODS: This was a retrospective study of CD patients from a tertiary referral center. Patients were categorized into colon-involving and non-colon-involving disease, and according to the Montreal classification. Clinico-demographic data, medications, and surgeries were compared between the two classifications. The primary outcome was the need for major abdominal surgery. RESULTS: Of 934 patients, those with colonic involvement had an earlier median (interquartile range) age of onset [23.0 (17.0-30.0) versus 26.0 (19.0-35.0) years, p = 0.001], higher frequency of perianal lesions (31.2% versus 14.5%, p < 0.001) and extraintestinal manifestations (21.8% versus 14.5%, p = 0.010), but lower frequency of stricture (B2) (16.3% versus 24.0%, p = 0.005), than those with non-colon-involving disease. Colon-involving disease was a protective factor against major abdominal surgery [hazard ratio, 0.689; 95% confidence interval (CI), 0.481-0.985; p = 0.041]. However, patients with colon-involving CD were more prone to steroids [odds ratio (OR), 1.793; 95% CI, 1.206-2.666; p = 0.004] and azathioprine/6-mercaptopurine (AZA/6-MP) treatment (OR, 1.732; 95% CI, 1.103-2.719; p = 0.017) than were patients with non-colon-involving disease. The Montreal classification was not predictive of surgery or steroids and AZA/6-MP treatment. CONCLUSION: This study supports the rationale for disease classification based on the involvement of colon. This new classification of CD is a better predictor of clinical outcomes than the Montreal classification.

High-Throughput Screen Identifies Host and Microbiota Regulators of Intestinal Barrier Function.

BACKGROUND & AIMS: The intestinal barrier protects intestinal cells from microbes and antigens in the lumen-breaches can alter the composition of the intestinal microbiota, the enteric immune system, and metabolism. We performed a screen to identify molecules that disrupt and support the intestinal epithelial barrier and tested their effects in mice. METHODS: We performed an imaging-based, quantitative, high-throughput screen (using CaCo-2 and T84 cells incubated with lipopolysaccharide; tumor necrosis factor; histamine; receptor antagonists; and libraries of secreted proteins, microbial metabolites, and drugs) to identify molecules that altered epithelial tight junction (TJ) and focal adhesion morphology. We then tested the effects of TJ stabilizers on these changes. Molecules we found to disrupt or stabilize TJs were administered mice with dextran sodium sulfate-induced colitis or Citrobacter rodentium-induced intestinal inflammation. Colon tissues were collected and analyzed by histology, fluorescence microscopy, and RNA sequencing. RESULTS: The screen identified numerous compounds that disrupted or stabilized (after disruption) TJs and monolayers of epithelial cells. We associated distinct morphologic alterations with changes in barrier function, and identified a variety of cytokines, metabolites, and drugs (including inhibitors of actomyosin contractility) that prevent disruption of TJs and restore TJ integrity. One of these disruptors (putrescine) disrupted TJ integrity in ex vivo mouse colon tissues; administration to mice exacerbated colon inflammation, increased gut permeability, reduced colon transepithelial electrical resistance, increased pattern recognition receptor ligands in mesenteric lymph nodes, and decreased colon length and survival times. Putrescine also increased intestine levels and fecal shedding of viable C rodentium, increased bacterial attachment to the colonic epithelium, and increased levels of inflammatory cytokines in colon tissues. Colonic epithelial cells from mice given putrescine increased expression of genes that regulate metal binding, oxidative stress, and cytoskeletal organization and contractility. Co-administration of taurine with putrescine blocked disruption of TJs and the exacerbated inflammation. CONCLUSIONS: We identified molecules that disrupt and stabilize intestinal epithelial TJs and barrier function and affect development of colon inflammation in mice. These agents might be developed for treatment of barrier intestinal impairment-associated and inflammatory disorders in patients, or avoided to prevent inflammation.

The microbiome and cytosolic innate immune receptors.

The discovery of innate immune sensors (pattern recognition receptors, PRRs) has profoundly transformed the notion of innate immunity, in providing a mechanistic basis for host immune interactions with a wealth of environmental signals, leading to a variety of immune-mediated outcomes including instruction and activation of the adaptive immune arm. As part of this growing understanding of host-environmental cross talk, an intimate connection has been unveiled between innate immune sensors and signals perceived from the commensal microbiota, which may be regarded as a hub integrating a variety of environmental cues. Among cytosolic PRRs impacting on host homeostasis by interacting with the commensal microbiota are nucleotide-binding domain, leucine-rich repeat-containing protein receptors (NLRs), together with a number of cytosolic DNA sensors and the family of absent in melanoma (AIM)-like receptors (ALRs). NLR sensors have been a particular focus of research, and some NLRs have emerged as key orchestrators of inflammatory responses and host homeostasis. Some NLRs achieve this through the formation of cytoplasmic multiprotein complexes termed inflammasomes. More recently discovered PRRs include retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), cyclic GMP-AMP synthase (cGAS), and STING. In the present review, they summarize recent advancements in knowledge on structure and function of cytosolic PRRs and their roles in host-microbiota cross talk and immune surveillance. In addition, we discuss their relevance for human health and disease and future therapeutic applications involving modulation of their activation and signaling.

Inflammasome activation and regulation: toward a better understanding of complex mechanisms.

Inflammasomes are cytoplasmic multiprotein complexes comprising a sensor protein, inflammatory caspases, and in some but not all cases an adapter protein connecting the two. They can be activated by a repertoire of endogenous and exogenous stimuli, leading to enzymatic activation of canonical caspase-1, noncanonical caspase-11 (or the equivalent caspase-4 and caspase-5 in humans) or caspase-8, resulting in secretion of IL-1ß and IL-18, as well as apoptotic and pyroptotic cell death. Appropriate inflammasome activation is vital for the host to cope with foreign pathogens or tissue damage, while aberrant inflammasome activation can cause uncontrolled tissue responses that may contribute to various diseases, including autoinflammatory disorders, cardiometabolic diseases, cancer and neurodegenerative diseases. Therefore, it is imperative to maintain a fine balance between inflammasome activation and inhibition, which requires a fine-tuned regulation of inflammasome assembly and effector function. Recently, a growing body of studies have been focusing on delineating the structural and molecular mechanisms underlying the regulation of inflammasome signaling. In the present review, we summarize the most recent advances and remaining challenges in understanding the ordered inflammasome assembly and activation upon sensing of diverse stimuli, as well as the tight regulations of these processes. Furthermore, we review recent progress and challenges in translating inflammasome research into therapeutic tools, aimed at modifying inflammasome-regulated human diseases.

Interaction between microbiota and immunity in health and disease.

The interplay between the commensal microbiota and the mammalian immune system development and function includes multifold interactions in homeostasis and disease. The microbiome plays critical roles in the training and development of major components of the host's innate and adaptive immune system, while the immune system orchestrates the maintenance of key features of host-microbe symbiosis. In a genetically susceptible host, imbalances in microbiota-immunity interactions under defined environmental contexts are believed to contribute to the pathogenesis of a multitude of immune-mediated disorders. Here, we review features of microbiome-immunity crosstalk and their roles in health and disease, while providing examples of molecular mechanisms orchestrating these interactions in the intestine and extra-intestinal organs. We highlight aspects of the current knowledge, challenges and limitations in achieving causal understanding of host immune-microbiome interactions, as well as their impact on immune-mediated diseases, and discuss how these insights may translate towards future development of microbiome-targeted therapeutic interventions.

Circadian Influences of Diet on the Microbiome and Immunity.

Host circadian rhythmicity and the timing of feeding are increasingly recognized to cross-regulate and entrain each other, and may play crucial roles in regulating multiple physiological functions including host immunity and metabolic health. Of relevance, these circadian diet-immune interactions may be modulated by the gut microbiota. We review current knowledge linking the circadian clock and dietary timing to host immune-microbiota interactions, exemplifying how this axis may impact on host immunity in health and in a variety of immune-mediated diseases. We also discuss current challenges in reaching mechanistic insights regarding the functions of the diurnally shifting diet-microbiome-host immune axis. We highlight the possible implications of circadian reprogramming by dietary timing patterns as a future intervention to modulate a variety of immune-related diseases.

Diet-microbiota interactions and personalized nutrition.

Conceptual scientific and medical advances have led to a recent realization that there may be no single, one-size-fits-all diet and that differential human responses to dietary inputs may rather be driven by unique and quantifiable host and microbiome features. Integration of these person-specific host and microbiome readouts into actionable modules may complement traditional food measurement approaches in devising diets that are of benefit to the individual. Although many host-derived factors are hardwired and difficult to modulate, the microbiome may be more readily reshaped by environmental factors such as dietary exposures and is increasingly recognized to potentially impact human physiology by participating in digestion, the absorption of nutrients, shaping of the mucosal immune response and the synthesis or modulation of a plethora of potentially bioactive compounds. Thus, diet-induced microbiota alterations may be harnessed in order to induce changes in host physiology, including disease development and progression. However, major limitations in 'big-data' processing and analysis still limit our interpretive and translational capabilities concerning these person-specific host, microbiome and diet interactions. In this Review, we describe the latest advances in understanding diet-microbiota interactions, the individuality of gut microbiota composition and how this knowledge could be harnessed for personalized nutrition strategies to improve human health.