Search

African swine fever (ASF), a viral disease affecting both domestic pigs and wild boars, is caused by the African swine fever virus (ASFV). Currently, an effective vaccine is lacking. The structural protein p49, encoded by the B438L gene, is vital for the virus's capsid structure and architecture. Research indicates its potential as a vaccine target. In this study, mAbs against ASFV p49 were generated using the hybridoma technique. The full-length B438L sequence was divided into 5 segments (B1 ∼ B5) via the overlapping polypeptide method, and an expression vector was constructed for expression and purification. Three hybridoma cell lines recognized epitope regions, with 3B12 and 6F1 recognizing the B4 (aa 234-362) fragment, and 3B12, 6F1, and 7C5 reacting with the B5 (aa 312-438) segment. The amino acid sequence (aa 333-438) was further divided into three segments (B6 ∼ B8) for verification. Results from Dot-ELISA and peptide ELISA confirmed that 333-YQTHYMENIVTLVPR-347 and 383-NNYIPKYTGGIGDSK-397 were the major B cell antigenic, highly conserved across ASFV strains. Interestingly, the motif 333-YQTHYMENIVTLVPR-347 was highly conserved, except for a single substitution (T → S) in three residues. This study identifies the B cell epitope of p49 protein, providing insights into ASFV p49 protein structure and function and supporting the development of ASFV-related vaccine products., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Microbial signatures have emerged as promising biomarkers for disease diagnostics and prognostics, yet their variability across different studies calls for a standardized approach to biomarker research. Therefore, we introduce xMarkerFinder, a four-stage computational framework for microbial biomarker identification with comprehensive validations from cross-cohort datasets, including differential signature identification, model construction, model validation and biomarker interpretation. xMarkerFinder enables the identification and validation of reproducible biomarkers for cross-cohort studies, along with the establishment of classification models and potential microbiome-induced mechanisms. Originally developed for gut microbiome research, xMarkerFinder's adaptable design makes it applicable to various microbial habitats and data types. Distinct from existing biomarker research tools that typically concentrate on a singular aspect, xMarkerFinder uniquely incorporates a sophisticated feature selection process, specifically designed to address the heterogeneity between different cohorts, extensive internal and external validations, and detailed specificity assessments. Execution time varies depending on the sample size, selected algorithm and computational resource. Accessible via GitHub ( https://github.com/tjcadd2020/xMarkerFinder ), xMarkerFinder supports users with diverse expertise levels through different execution options, including step-to-step scripts with detailed tutorials and frequently asked questions, a single-command execution script, a ready-to-use Docker image and a user-friendly web server ( https://www.biosino.org/xmarkerfinder )., (© 2024. Springer Nature Limited.)

Introducing sacrificial bonds is a common method for increasing the toughness of hydrogels. Many sacrificial bonds have been extensively investigated, but the sacrifice efficiency has never been studied. In this study, polyacrylamide hydrogels with highly entangled polymer chains containing carboxyl-zirconium (-COO - -Zr 4+ ) sacrificial bonds are prepared to study the effect of polymer chain entanglement on the sacrificial bond efficiency. Unlike chemical crosslinking points, the dense physical entanglements do not affect the toughness (∼43 MJ/m 3 ) of hydrogels but significantly improve the tensile strength (by two times) and Young's modulus (by six times). Physical entanglements enable the chains to slide and adjust the network structure under stress, which enables more polymer chains and sacrificial bonds to participate in the deformation process. Therefore, dense entanglements will greatly improve the sacrifice efficiency. However, a high density of chemical crosslinking points will limit the improvement in the sacrifice efficiency, which is attributed to the sliding limitations because of physical entanglement. The highly entangled polyacrylamide hydrogels toughened by -COO - -Zr 4+ have an excellent load-bearing capacity. This study provides a novel strategy for designing hydrogels with ultra-high strength and toughness, which paves the way for the development of many hydrogels used in engineering materials., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: The current early warning model for organ damage in critically ill patients has certain limitations. Based on the pathological mechanism, the establishment of an early warning system for organ damage in critically ill children using cytokines profile has not been explored. The aim of this study is to explore the predicting value of cytokines in critically ill patients., Methods: There were 200 critically pediatric patients and 49 general patients between August 22, 2018 and April 28, 2023 from Children's Hospital of Soochow University enrolled in this study. The clinical information was retrospectively collected and analyzed. The cytokine profiles of these patients were detected by flow cytometry. Receiver operating characteristic (ROC) curves were plotted to determine the association between the cytokines and organ injury., Results: There were no statistically significant differences in gender, age and underlying disease between critically ill patients and general patients. The interleukin (IL)-6 (P<0.001), IL-10 (P<0.001), IL-17A (P=0.001), tumor necrosis factor-α (TNF-α) (P=0.02) and interferon-γ (IFN-γ) (P=0.02) level in the critically patients were significantly higher than those in the general patients. The results showed that the incidence of acute gastrointestinal injury (AGI) and acute kidney injury (AKI) in critically ill patients was 39% and 23.5%, respectively. Moreover, there were 4% and 3.5% patients with the occurrence of cardiac arrest and acute live injury. The IFN-γ level was increased in these patients with acute liver injury compared to those without these organ injuries, but reduced in the patients with AGI compared to those without. The patients with AKI showed a significant increase in IL-10 in contrast to those without. The IL-2, IL-4, IL-6, IL-10 and IL-17A were higher in patients with acute liver failure (ALF), but TNF-α was reduced, compared to those without. The IL-2, IL-4, IL-6 and IL-10 were significantly increased in the patients with cardiac arrest compared to those without. When IL-10 was higher than 279.45 pg/mL, the sensitivity and specificity for predicting cardiac arrest were 0.875 and 0.927, respectively. While the sensitivity and specificity of IL-6 (more than 1,425.6 pg/mL) were 0.625 and 0.844, respectively. However, no synergistic effect of IL-6 and IL-10 was observed for predicting cardiac arrest. Additionally, the IL-17A (more than 21.6 pg/mL) was a good predictor for the incidence of ALF (sensitivity =0.714, specificity =0.876)., Conclusions: The cytokines profile was different between critically ill patients with organ injury and those without organ injury. The IL-6 and IL-10 levels were good predictors for cardiac arrest in critically ill patients. Additionally, higher IL-17A predicted the incidence of ALF of the critically ill patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-95/coif). The authors have no conflicts of interest to declare., (2024 Translational Pediatrics. All rights reserved.)

Prior studies indicate no correlation between the gut microbes of healthy first-degree relatives (HFDRs) of patients with Crohn's disease (CD) and the development of CD. Here, we utilize HFDRs as controls to examine the microbiota and metabolome in individuals with active (CD-A) and quiescent (CD-R) CD, thereby minimizing the influence of genetic and environmental factors. When compared to non-relative controls, the use of HFDR controls identifies fewer differential taxa. Faecalibacterium, Dorea, and Fusicatenibacter are decreased in CD-R, independent of inflammation, and correlated with fecal short-chain fatty acids (SCFAs). Validation with a large multi-center cohort confirms decreased Faecalibacterium and other SCFA-producing genera in CD-R. Classification models based on these genera distinguish CD from healthy individuals and demonstrate superior diagnostic power than models constructed with markers identified using unrelated controls. Furthermore, these markers exhibited limited discriminatory capabilities for other diseases. Finally, our results are validated across multiple cohorts, underscoring their robustness and potential for diagnostic and therapeutic applications., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease with a broad spectrum of histologic manifestations. The rapidly growing prevalence and the complex pathologic mechanisms of NAFLD pose great challenges for treatment development. Despite tremendous efforts devoted to drug development, there are no FDA-approved medicines yet. Here, we present NAFLDkb, a specialized knowledge base and platform for computer-aided drug design against NAFLD. With multiperspective information curated from diverse source materials and public databases, NAFLDkb presents the associations of drug-related entities as individual knowledge graphs. Practical drug discovery tools that facilitate the utilization and expansion of NAFLDkb have also been implemented in the web interface, including chemical structure search, drug-likeness screening, knowledge-based repositioning, and research article annotation. Moreover, case studies of a knowledge graph repositioning model and a generative neural network model are presented herein, where three repositioning drug candidates and 137 novel lead-like compounds were newly established as NAFLD pharmacotherapy options reusing data records and machine learning tools in NAFLDkb, suggesting its clinical reliability and great potential in identifying novel drug-disease associations of NAFLD and generating new insights to accelerate NAFLD drug development. NAFLDkb is freely accessible at https://www.biosino.org/nafldkb and will be updated periodically with the latest findings.

Cyclic peptides offer a range of notable advantages, including potent antibacterial properties, high binding affinity and specificity to target molecules, and minimal toxicity, making them highly promising candidates for drug development. However, a comprehensive database that consolidates both synthetically derived and naturally occurring cyclic peptides is conspicuously absent. To address this void, we introduce CyclicPepedia (https://www.biosino.org/iMAC/cyclicpepedia/), a pioneering database that encompasses 8744 known cyclic peptides. This repository, structured as a composite knowledge network, offers a wealth of information encompassing various aspects of cyclic peptides, such as cyclic peptides' sources, categorizations, structural characteristics, pharmacokinetic profiles, physicochemical properties, patented drug applications, and a collection of crucial publications. Supported by a user-friendly knowledge retrieval system and calculation tools specifically designed for cyclic peptides, CyclicPepedia will be able to facilitate advancements in cyclic peptide drug development., (© The Author(s) 2024. Published by Oxford University Press.)

Most tough hydrogels are reinforced by introducing energy dissipation mechanisms, but simultaneously realizing a high toughness and low hysteresis is challenging because the energy dissipation structure cannot recover rapidly. In this work, high mechanical performance highly entangled double network hydrogels without energy dissipation structure are fabricated, in which physical entanglements act as the primary effective crosslinking in the first network. This sliding entanglement structure allows the hydrogel network to form a highly uniform oriented structure during stretching, resulting in a high tensile strength of ~3 MPa, a fracture energy of 8340 J m -2 and a strain-stiffening capability of 47.5 in 90% water content. Moreover, almost 100% reversibility is obtained in this hydrogel via energy storage based on entropy loss. The highly entangled double network structure not only overcomes the typical trade-off between the high toughness and low hysteresis of hydrogels, but more importantly, it provides an insight into the application of entanglement structures in high-performance hydrogels., (© 2024. The Author(s).)

Colorectal cancer (CRC) exhibits pronounced heterogeneity and is categorized into four widely accepted consensus molecular subtypes (CMSs) with unique tumor microenvironments (TMEs). However, the intricate landscape of the microbiota and host-microbiota interactions within these TMEs remains elusive. Using RNA-sequencing data from The Cancer Genome Atlas, we analyzed the host transcriptomes and intratumoral microbiome profiles of CRC samples. Distinct host genes and microbial genera were identified among the CMSs. Immune microenvironments were evaluated using CIBERSORTx and ESTIMATE, and microbial coabundance patterns were assessed with FastSpar. Through LASSO penalized regression, we explored host-microbiota associations for each CMS. Our analysis revealed distinct host gene signatures within the CMSs, which encompassed ferroptosis-related genes and specific immune microenvironments. Moreover, we identified 293, 153, 66, and 109 intratumoral microbial genera with differential abundance, and host-microbiota associations contributed to distinct TMEs, characterized by 829, 1,270, 634, and 1,882 robust gene-microbe associations for each CMS in CMS1-CMS4, respectively. CMS1 featured inflammation-related HSF1 activation and gene interactions within the endothelin pathway and Flammeovirga . Integrin-related genes displayed positive correlations with Sutterella in CMS2, whereas CMS3 spotlighted microbial associations with biosynthetic and metabolic pathways. In CMS4, genes involved in collagen biosynthesis showed positive associations with Sutterella , contributing to disruptions in homeostasis. Notably, immune-rich subtypes exhibited pronounced ferroptosis dysregulation, potentially linked to tissue microbial colonization. This comprehensive investigation delineates the diverse landscapes of the TME within each CMS, incorporating host genes, intratumoral microbiota, and their complex interactions. These findings shed light on previously uncharted mechanisms underpinning CRC heterogeneity and suggest potential therapeutic targets. NEW & NOTEWORTHY This study determined the following: 1 ) providing a comprehensive landscape of consensus molecular subtype (CMS)-specific tumor microenvironments (TMEs); 2 ) constructing CMS-specific networks, including host genes, intratumoral microbiota, and enriched pathways, analyzing their associations to uncover unique patterns that demonstrate the intricate interplay within the TME; and 3 ) revealing a connection between immune-rich subtypes and ferroptosis activation, suggesting a potential regulatory role of the microbiota in ferroptosis dysregulation of the colorectal cancer TME.

Excess body weight (EBW) increases the risk of colorectal cancer (CRC) and is linked to lower colonoscopy compliance. Here, we extensively analyzed 981 metagenome samples from multiple cohorts to pinpoint the specific microbial signatures and their potential capability distinguishing EBW patients with CRC. The gut microbiome displayed considerable variations between EBW and lean CRC. We identify 44 and 37 distinct multi-kingdom microbial species differentiating CRC and controls in EBW and lean populations, respectively. Unique bacterial-fungal associations are also observed between EBW-CRC and lean-CRC. Our analysis revealed specific microbial functions in EBW-CRC, including D-Arginine and D-ornithine metabolism, and lipopolysaccharide biosynthesis. The best-performing classifier for EBW-CRC, comprising 12 bacterial and three fungal species, achieved an AUROC of 0.90, which was robustly validated across three independent cohorts (AUROC = 0.96, 0.94, and 0.80). Pathogenic microbial species, Anaerobutyricum hallii, Clostridioides difficile and Fusobacterium nucleatum, are EBW-CRC specific signatures. This work unearths the specific multi-kingdom microbial signatures for EBW-CRC and lean CRC, which may contribute to precision diagnosis and treatment of CRC., (© 2024. The Author(s).)

Achieving adhesion of hydrogels to universal materials with desirable strength remains a challenge despite emerging application of hydrogels. Herein we present a mussel foot protein (Mfp) inspired polyelectrolyte hydrogel of poly(ethylenimine)/poly(acrylic acid)-dopamine (PEI/PAADA) developed for universal tough adhesion. The highly-concentrated electrostatic and hydrogen-bonding interactions in PEI/PAADA hydrogel resulted in a tensile strength, strain at break, and toughness of 0.297 MPa, 2784 % and 5.440 MJ m -3 , respectively. Moreover, the hydrogel can heal itself from physical damages, even can be recycled after totally dried via rehydration because of the high flexibility and reversibility of its dynamic bonds. Combining the strategies of topological stitching and direct bonding, Mfp-derived catechol and PEI/PAA backbone in PEI/PAADA corporately facilitated robust adhesion of universal materials with shear strength of up to 4.4 MPa and peeling strength of 870 J m -2 , which is over 10 times greater than that of commercial fibrin gel. The adhesive also exhibited self-healing capability for at least 5 cycles, good stability in 1 M NaCl solution and characteristic debonding catalyzed by calcium. Moreover, in vitro cell behavior and in vivo wound healing assays suggested the potential of PEI/PAADA as wound dressing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Microbial signatures show remarkable potentials in predicting colorectal cancer (CRC). This study aimed to evaluate the diagnostic powers of multimodal microbial signatures, multi-kingdom species, genes, and single-nucleotide variants (SNVs) for detecting precancerous adenomas. We performed cross-cohort analyses on whole metagenome sequencing data of 750 samples via xMarkerFinder to identify adenoma-associated microbial multimodal signatures. Our data revealed that fungal species outperformed species from other kingdoms with an area under the ROC curve (AUC) of 0.71 in distinguishing adenomas from controls. The microbial SNVs, including dark SNVs with synonymous mutations, displayed the strongest diagnostic capability with an AUC value of 0.89, sensitivity of 0.79, specificity of 0.85, and Matthews correlation coefficient (MCC) of 0.74. SNV biomarkers also exhibited outstanding performances in three independent validation cohorts (AUCs = 0.83, 0.82, 0.76; sensitivity = 1.0, 0.72, 0.93; specificity = 0.67, 0.81, 0.67, MCCs = 0.69, 0.83, 0.72) with high disease specificity for adenoma. In further support of the above results, functional analyses revealed more frequent inter-kingdom associations between bacteria and fungi, and abnormalities in quorum sensing, purine and butanoate metabolism in adenoma, which were validated in a newly recruited cohort via qRT-PCR. Therefore, these data extend our understanding of adenoma-associated multimodal alterations in the gut microbiome and provide a rationale of microbial SNVs for the early detection of CRC.

Competing Interests: None declared.

Background/objectives: Some individuals with overweight/obesity may be relatively metabolically healthy (MHO) and have a lower risk of cardiovascular disease than those with metabolically unhealthy overweight/obesity (MUO). We aimed to compare changes in body weight and cardiometabolic risk factors and type 2 diabetes incidence during a lifestyle intervention between individuals with MHO vs MUO., Methods: This post-hoc analysis included 1012 participants with MHO and 1153 participants with MUO at baseline in the randomized trial PREVIEW. Participants underwent an eight-week low-energy diet phase followed by a 148-week lifestyle-based weight-maintenance intervention. Adjusted linear mixed models and Cox proportional hazards regression models were used., Results: There were no statistically significant differences in weight loss (%) between participants with MHO vs MUO over 156 weeks. At the end of the study, weight loss was 2.7% (95% CI, 1.7%-3.6%) in participants with MHO and 3.0% (2.1%-4.0%) in those with MUO. After the low-energy diet phase, participants with MHO had smaller decreases in triglyceride (mean difference between MHO vs MUO 0.08 mmol·L -1 [95% CI, 0.04-0.12]; P < 0.001) but similar reductions in fasting glucose and HOMA-IR than those with MUO. However, at the end of weight maintenance, those with MHO had greater reductions in triglyceride (mean difference -0.08 mmol·L -1 [-0.12--0.04]; P < 0.001), fasting glucose, 2-hour glucose (difference -0.28 mmol·L -1 [-0.41--0.16]; P < 0.001), and HOMA-IR than those with MUO. Participants with MHO had smaller decreases in diastolic blood pressure and HbA 1c and greater decreases in HDL cholesterol after weight loss than those with MUO, whereas the statistically significant differences disappeared at the end of weight maintenance. Participants with MHO had lower 3-year type 2 diabetes incidence than those with MUO (adjusted hazard ratio 0.37 [0.20-0.66]; P < 0.001)., Conclusions: Individuals with MUO had greater improvements in some cardiometabolic risk factors during the low-energy diet phase, but had smaller improvements during long-term lifestyle intervention than those with MHO., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Dysregulated host-microbial interactions play critical roles in initiation and perpetuation of gut inflammation in Crohn's disease (CD). However, the spatial distribution and interaction network across the intestine and its accessory tissues are still elusive. Here, we profile the host proteins and tissue microbes in 540 samples from the intestinal mucosa, submucosa-muscularis-serosa, mesenteric adipose tissues, mesentery, and mesenteric lymph nodes of 30 CD patients and spatially decipher the host-microbial interactions. We observe aberrant antimicrobial immunity and metabolic processes across multi-tissues during CD and determine bacterial transmission along with altered microbial communities and ecological patterns. Moreover, we identify several candidate interaction pairs between host proteins and microbes associated with perpetuation of gut inflammation and bacterial transmigration across multi-tissues in CD. Signature alterations in host proteins (e.g., SAA2 and GOLM1) and microbes (e.g., Alistipes and Streptococcus) are further imprinted in serum and fecal samples as potential diagnostic biomarkers, thus providing a rationale for precision diagnosis., Competing Interests: Declaration of interests T.G. is a shareholder of Westlake Omics Inc., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

The use of non- and low-caloric sweetener(s) (NCS and LCS) as a means to prevent overweight and obesity is highly debated, as both NCS and LCS have been proposed to have a negative impact on energy homeostasis. This systematic review aimed to assess the impact of NCS and LCS on fasting and postprandial substrate oxidation, energy expenditure, and catecholamines, compared to caloric sweeteners or water, across different doses and types of NCS and LCS, acutely and in the longer-term. A total of 20 studies were eligible: 16 studies for substrate oxidation and energy expenditure and four studies for catecholamines. Most studies compared the acute effects of NCS or LCS with caloric sweeteners under non-isoenergetic conditions. These studies generally found higher fat oxidation and lower carbohydrate oxidation with NCS or LCS than with caloric sweeteners. Findings for energy expenditure were inconsistent. With the limited number of studies, no convincing pattern for the remaining outcomes and comparisons could be seen. In conclusion, drinks or meals with NCS or LCS resulted in higher fat and lower carbohydrate oxidation compared to caloric sweeteners. No other conclusions could be drawn due to insufficient or inconsistent results. Further studies in this research field are warranted.

Objective: Monocyte chemotactic protein-1-induced protein 1 (MCPIP1) is highly expressed in inflamed mucosa of inflammatory bowel disease (IBD) and negatively regulates immune response, while the underlying mechanisms regulating mucosal macrophage functions remain unknown. Here, we investigated the roles of MCPIP1 in modulating the differentiation and functions of intestinal macrophages in the pathogenesis of IBD., Design: ScRNA-seq was used to cluster the monocyte/macrophage lineage from macrophage-specific Mcpip1 -deficient ( Mcpip1 ∆Mye ) mice and Mcpip1 fl/fl littermates. The differentially expressed genes were confirmed by RNA-seq, luciferase assay, CUT&Tag assay and Western blotting. Effects of MCPIP1 and the activating transcription factor 3 (ATF3)-AP1S2 axis were assessed in patients with IBD., Results: Mcpip1 ∆Mye mice developed more severe dextran sulfate sodium (DSS)-induced colitis characterised by an increase in macrophage migratory capacity and M1 macrophage polarisation but a decrease in the monocyte-to-macrophage maturation in gut mucosa compared with their littermates. ScRNA-seq unravelled a proinflammatory population (Ccr2 + Il-1β + Tlr2 + Cx3cr1 - Cd163 - Mrc1 - Ly6c + ) of the monocyte/macrophage lineage from lamina propria CD11b + cells and an arrest of Mcpip1 ∆Mye monocyte-to-macrophage maturation in an Atf3-Ap1s2 axis-dependent manner. Silencing of Ap1s2 or Atf3 markedly suppressed Mcpip1 ∆Mye macrophage migration, M1-like polarisation, and production of proinflammatory cytokines and chemokines. Notably, in vivo blockage of Ap1s2 ameliorated DSS-induced colitis in Mcpip1 ΔMye mice through enhancing intestinal macrophage maturation. Furthermore, MCPIP1, ATF3 and AP1S2 were highly expressed in inflamed mucosa of active patients with IBD and blockage of ATF3 or AP1S2 significantly suppressed IBD CD14 + -derived M1-like macrophage polarisation and proinflammatory cytokine production., Conclusions: Macrophage-specific Mcpip1 deficiency polarises macrophages towards M1-like phenotype, arrests macrophage maturation and exacerbates intestinal inflammation in an Atf3-Ap1s2-dependent manner, thus providing novel mechanistic insight into intestinal macrophage functions during IBD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: To examine the differences between HbA 1c and glucose related variables in predicting weight loss and glycaemic changes following 8 weeks of low energy diet (LED) in individuals with overweight and hyperglycaemia., Research Design and Methods: 2178 individuals with ADA-defined pre-diabetes - impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) - who started an 8 week LED weight loss diet, were included in this analysis. Participants were enrolled in the PREVIEW (PREVention of diabetes through lifestyle interventions and population studies In Europe and around the World) clinical trial. Multivariable linear mixed effects regression models and generalised additive mixed effect logistic models were used., Results: Only 1 in 3 participants (33%) had HbA 1c levels defined as pre-diabetes. Neither baseline HbA 1c , IFG or IGT were associated with body weight change at 8 weeks. Higher baseline body weight, baseline fasting insulin and weight loss predicted normalisation of fasting plasma glucose (FPG), whilst higher baseline fasting insulin, C-reactive protein (hsCRP) and older age predicted normalisation of HbA 1c . Additionally, male sex and higher baseline BMI, body fat and energy intake were positively associated with weight loss, whereas greater age and higher HDL-cholesterol predicted less weight loss., Conclusions: Whilst neither HbA 1c nor fasting glucose predicts short-term weight loss success, both may impact the metabolic response to rapid weight loss. We propose a role of inflammation versus total body adiposity since these variables are independent predictors of the normalisation of HbA 1c and fasting glucose, respectively., Competing Interests: Declaration of competing interests AR has received honorariums from the International Sweeteners Association and Unilever. IAM was a member of the UK Government Scientific Advisory Committee on Nutrition, Treasurer of the Federation of European Nutrition Societies, Treasurer of the World Obesity Federation, member of the Mars Scientific Advisory Council, member of the Mars Europe Nutrition Advisory Board, and Scientific Adviser to the Waltham Centre for Pet Nutrition. He was also a member of the Nestle Research Scientific Advisory Board, and of the Novozymes Scientific Advisory Board. He withdrew from all of these roles in 2020 and on August 1 2020 became Professor Emeritus at the University of Nottingham and took up the post of Scientific Director of the Nestle Institute of Health Sciences in Lausanne, Switzerland. JB-M is President and Director of the Glycemic Index Foundation, oversees of a glycemic index testing service at the University of Sydney and is a co-author of books about diet and diabetes. She is also a member of the Scientific Advisory Board of the Novo Foundation and of ZOE Global. SDP was the Fonterra Chair in Human Nutrition during the PREVIEW intervention. TL is employed by NetUnion sarl, who contributed to the data collection process in the absence of commercial or financial conflict of interest with the study analysis., (Copyright © 2023 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

A modified new method for microbial enrichment analysis, reporter score was incorrectly used in many articles due to a lack of comprehensive and systematic understanding of the original method by the researchers, leading to a serious snowball effect. Here we describe the reasons for the misuse of reporter score and its negative impact on microbial research and hope this comment will facilitate community discussion on the importance of statistical rigor, informing future efforts to enhance reliable and reproducible research., Competing Interests: The authors declared no conflict of interest., (© 2023 The Authors. iMeta published by John Wiley & Sons Australia, Ltd on behalf of iMeta Science.)

Dysbiosis of gut microbial community is associated with the pathogenesis of CD and may serve as a promising noninvasive diagnostic tool. We aimed to compare the performances of the microbial markers of different biological levels by conducting a multidimensional analysis on the microbial metagenomes of CD. We collected fecal metagenomic datasets generated from eight cohorts that altogether include 870 CD patients and 548 healthy controls. Microbial alterations in CD patients were assessed at multidimensional levels including species, gene, and SNV level, and then diagnostic models were constructed using artificial intelligence algorithm. A total of 227 species, 1047 microbial genes, and 21,877 microbial SNVs were identified that differed between CD and controls. The species, gene, and SNV models achieved an average AUC of 0.97, 0.95, and 0.77, respectively. Notably, the gene model exhibited superior diagnostic capability, achieving an average AUC of 0.89 and 0.91 for internal and external validations, respectively. Moreover, the gene model was specific for CD against other microbiome-related diseases. Furthermore, we found that phosphotransferase system (PTS) contributed substantially to the diagnostic capability of the gene model. The outstanding performance of PTS was mainly explained by genes celB and manY, which demonstrated high predictabilities for CD with metagenomic datasets and was validated in an independent cohort by qRT-PCR analysis. Our global metagenomic analysis unravels the multidimensional alterations of the microbial communities in CD and identifies microbial genes as robust diagnostic biomarkers across geographically and culturally distinct cohorts.

Monocyte chemotactic protein-1-induced protein-1 (MCPIP-1) is highly expressed in activated immune cells and negatively regulates immune responses, while the mechanisms underlying the immunoregulation of neutrophils in acute bacterial infection and liver injury remain elusive. Here, we examined the role of MCPIP-1 in regulating neutrophil functions during acute bacterial peritonitis and liver injury. Mice with myeloid cell-specific overexpression (McpipMye-tg) or knockout (McpipΔMye) of MCPIP-1 were generated. We found that reactive oxygen species and myeloperoxidase production, formation of neutrophil extracellular traps, and migratory capacity were deficient in McpipMye-tg neutrophils but enhanced in McpipΔMye neutrophils. The recruitment of neutrophils and pathogen clearance were markedly suppressed in McpipMye-tg mice following intraperitoneal infection with Salmonella typhimurium while intensified in McpipΔMye mice. Severe acute S. typhimurium-infected peritonitis and liver injury occurred in McpipMye-tg mice but were alleviated in McpipΔMye mice. RNA sequencing, RNA-binding protein immunoprecipitation and qPCR analysis revealed that MCPIP-1 downregulated the protective functions of neutrophils via degrading the mRNA of cold inducible RNA-binding protein. Consistently, MCPIP-1 was highly expressed in neutrophils of patients with acute infectious diseases, especially in those with liver injury. Collectively, we uncover that MCPIP-1 negatively regulates the antibacterial capacities of neutrophils, leading to exacerbating severe acute bacterial peritonitis and liver injury. It may serve as a candidate target for maintaining neutrophil homeostasis to control acute infectious diseases., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Neutrophils synergize with intestinal resident intraepithelial lymphocytes (IELs) to serve as the first-line defense and maintain intestinal homeostasis. However, the underlying mechanisms whereby neutrophils regulate IELs to inhibit intestinal inflammation are still not completely understood. Here, we found that depletion of neutrophils (especially CD177 + subset) caused expansion of colitogenic TCRγδ + CD8αα + IELs, increased intestinal inflammation, and dysbiosis after dextran sulfate sodium exposure or Citrobacter rodentium infection in mice. scRNA-seq analysis revealed a pyroptosis-related gene signature and hyperresponsiveness to microbiota in TCRγδ + CD8αα + IELs from colitic Cd177 -/- mice. Microbiota-derived fumarate and its derivative dimethyl fumarate (DMF), as well as fumarate-producing microbiotas, decreased in the feces of colitic Cd177 -/- mice. Elimination of dysbiosis by antibiotics treatment or co-housing procedure and DMF supplementation restrained TCRγδ + CD8αα + IEL activation. Consistently, DMF significantly alleviated intestinal mucosal inflammation in mice through restricting gasdermin D (GSDMD)-induced pyroptosis of TCRγδ + CD8αα + IELs. Therefore, our data reveal that neutrophils inhibit intestinal inflammation by promoting microbiota-derived DMF to regulate TCRγδ + CD8αα + IEL activation in a GSDMD-mediated pyroptosis-dependent manner, and that DMF may serve as a therapeutic target for the management of intestinal inflammation.

Growing evidence indicates an association between gut dysbiosis and coronary artery disease (CAD). However, the underlying mechanisms relevant to stable CAD (SCAD) pathogenesis, based on microbe-host metabolism interactions, are poorly explored. Here, we constructed a quasi-paired cohort based on the metabolic background of metagenomic samples by the propensity score matching (PSM) principle. Compared to healthy controls (HCs), gut microbiome disturbances were observed in SCAD patients, accompanied by differences in serum metabolome, mainly including elevated acylcarnitine and decreased unsaturated fatty acids in SCAD patients, which implicated the reduced cardiac fatty acid oxidation. Moreover, we identified Ralstonia pickettii as the core strain responsible for impaired microbial homeostasis in SCAD patientsm and may be partly responsible for the decrease of host unsaturated fatty acid levels. These findings highlight the importance of unsaturated fatty acids, R. pickettii, and their interaction in the pathogenesis of SCAD. IMPORTANCE Stable coronary artery disease (SCAD) is an early stage of CAD development. It is important to understand the pathogenesis of SCAD and find out the possible prevention and control targets for delaying the progression of CAD. We observed reduced levels of unsaturated fatty acids (USFAs) in SCAD patients. However, the reduced USFAs may be related to Ralstonia Pickettii, which was the core strain responsible for the impaired gut microbial function in SCAD patients, and further affected the host's cardiovascular health by altering amino acids, vitamin B metabolism, and LPS biosynthesis. These findings not only emphasized the importance of USFAs for cardiovascular health, but also R. Pickettii for maintaining microbial function homeostasis. More importantly, our study revealed, for the first time, that enriched R. Pickettii might be responsible for the reduced USFAs in SCAD patients, which adds new evidence on the role of altered gut microbiota for SCAD formation.

The dysbiosis of the gut microbiome is one of the pathogenic factors of nonalcoholic fatty liver disease (NAFLD) and also affects the treatment and intervention of NAFLD. Among gut microbiomes, keystone species that regulate the integrity and stability of an ecological community have become the potential intervention targets for NAFLD. Here, we collected stool samples from 22 patients with nonalcoholic steatohepatitis (NASH), 25 obese patients, and 16 healthy individuals from New York for 16S rRNA gene sequencing. An algorithm was implemented to identify keystone species based on causal inference theories and dynamic intervention simulation. External validation was performed in an independent cohort from California. Eight keystone species in the gut of NAFLD, represented by Porphyromonas loveana, Alistipes indistinctus , and Dialister pneumosintes , were identified, which could efficiently restore the microbial composition of the NAFLD toward a normal gut microbiome with 92.3% recovery. These keystone species regulate intestinal amino acid metabolism and acid-base environment to promote the growth of the butyrate-producing Lachnospiraceae and Ruminococcaceae species that are significantly reduced in NAFLD patients. Our findings demonstrate the importance of keystone species in restoring the microbial composition toward a normal gut microbiome, suggesting a novel potential microbial treatment for NAFLD., Competing Interests: The authors have declared no competing interest., (© 2022 The Authors. iMeta published by John Wiley & Sons Australia, Ltd on behalf of iMeta Science.)

Objective: To examine whether the effect of a 3-year lifestyle intervention on body weight and cardiometabolic risk factors differs by prediabetes metabolic phenotype., Research Design and Methods: This post hoc analysis of the multicenter, randomized trial, PREVention of diabetes through lifestyle interventions and population studies In Europe and around the World (PREVIEW), included 1,510 participants with prediabetes (BMI ≥25 kg ⋅ m-2; defined using oral glucose tolerance tests). Of these, 58% had isolated impaired fasting glucose (iIFG), 6% had isolated impaired glucose tolerance (iIGT), and 36% had IFG+IGT; 73% had normal hemoglobin A1c (HbA1c; <39 mmol ⋅ mol-1) and 25% had intermediate HbA1c (39-47 mmol ⋅ mol-1). Participants underwent an 8-week diet-induced rapid weight loss, followed by a 148-week lifestyle-based weight maintenance intervention. Linear mixed models adjusted for intervention arm and other confounders were used., Results: In the available-case and complete-case analyses, participants with IFG+IGT had greater sustained weight loss after lifestyle intervention (adjusted mean at 156 weeks -3.5% [95% CI, -4.7%, -2.3%]) than those with iIFG (mean -2.5% [-3.6%, -1.3%]) relative to baseline (P = 0.011). Participants with IFG+IGT and iIFG had similar cardiometabolic benefits from the lifestyle intervention. The differences in cardiometabolic benefits between those with iIGT and IFG+IGT were minor or inconsistent in different analyses. Participants with normal versus intermediate HbA1c had similar weight loss over 3 years and minor differences in cardiometabolic benefits during weight loss, whereas those with normal HbA1c had greater improvements in fasting glucose, 2-h glucose (adjusted between-group difference at 156 weeks -0.54 mmol ⋅ L-1 [95% CI -0.70, -0.39], P < 0.001), and triglycerides (difference -0.07 mmol ⋅ L-1 [-0.11, -0.03], P < 0.001) during the lifestyle intervention., Conclusions: Individuals with iIFG and IFG+IGT had similar improvements in cardiometabolic health from a lifestyle intervention. Those with normal HbA1c had greater improvements than those with intermediate HbA1c., (© 2022 by the American Diabetes Association.)

Aims/hypothesis: Lifestyle interventions are the first-line treatment option for body weight and cardiometabolic health management. However, whether age groups or women and men respond differently to lifestyle interventions is under debate. We aimed to examine age- and sex-specific effects of a low-energy diet (LED) followed by a long-term lifestyle intervention on body weight, body composition and cardiometabolic health markers in adults with prediabetes (i.e. impaired fasting glucose and/or impaired glucose tolerance)., Methods: This observational study used longitudinal data from 2223 overweight participants with prediabetes in the multicentre diabetes prevention study PREVIEW. The participants underwent a LED-induced rapid weight loss (WL) period followed by a 3 year lifestyle-based weight maintenance (WM) intervention. Changes in outcomes of interest in prespecified age (younger: 25-45 years; middle-aged: 46-54 years; older: 55-70 years) or sex (women and men) groups were compared., Results: In total, 783 younger, 319 middle-aged and 1121 older adults and 1503 women and 720 men were included in the analysis. In the available case and complete case analyses, multivariable-adjusted linear mixed models showed that younger and older adults had similar weight loss after the LED, whereas older adults had greater sustained weight loss after the WM intervention (adjusted difference for older vs younger adults -1.25% [95% CI -1.92, -0.58], p<0.001). After the WM intervention, older adults lost more fat-free mass and bone mass and had smaller improvements in 2 h plasma glucose (adjusted difference for older vs younger adults 0.65 mmol/l [95% CI 0.50, 0.80], p<0.001) and systolic blood pressure (adjusted difference for older vs younger adults 2.57 mmHg [95% CI 1.37, 3.77], p<0.001) than younger adults. Older adults had smaller decreases in fasting and 2 h glucose, HbA 1c and systolic blood pressure after the WM intervention than middle-aged adults. In the complete case analysis, the above-mentioned differences between middle-aged and older adults disappeared, but the direction of the effect size did not change. After the WL period, compared with men, women had less weight loss (adjusted difference for women vs men 1.78% [95% CI 1.12, 2.43], p<0.001) with greater fat-free mass and bone mass loss and smaller improvements in HbA 1c , LDL-cholesterol and diastolic blood pressure. After the WM intervention, women had greater fat-free mass and bone mass loss and smaller improvements in HbA 1c and LDL-cholesterol, while they had greater improvements in fasting glucose, triacylglycerol (adjusted difference for women vs men -0.08 mmol/l [-0.11, -0.04], p<0.001) and HDL-cholesterol., Conclusions/interpretation: Older adults benefited less from a lifestyle intervention in relation to body composition and cardiometabolic health markers than younger adults, despite greater sustained weight loss. Women benefited less from a LED followed by a lifestyle intervention in relation to body weight and body composition than men. Future interventions targeting older adults or women should take prevention of fat-free mass and bone mass loss into consideration., Clinical Trial Registration Number: ClinicalTrials.gov NCT01777893., (© 2022. The Author(s).)

Hexavalent chromium [Cr (VI)] is a common environmental pollutant. Although selenium (Se) can antagonize the toxicity of Cr (VI), the specific underlying mechanism has not been identified. To investigate this mechanism, we used potassium dichromate (K 2 Cr 2 O 7 ) and selenium-rich yeast (SeY) to construct single Cr (VI)- and combined Se/Cr (VI)-exposed broiler models during a 42-day period. Broilers were randomly assigned to the control (C), SeY (Se), SeY + Cr (VI) (Se/Cr), and Cr (VI) (Cr) groups. The antagonistic mechanisms of Se and Cr (VI) were evaluated using histopathological evaluation, serum and tissue biochemical tests, real-time fluorescence quantitative polymerase chain reaction, and western blotting. The results suggested that Se alleviated the morphological and structural damage to renal tubules and glomeruli, while reducing the organ index, creatinine levels, and blood urea nitrogen levels in the kidneys of Cr (VI)-exposed broilers. Furthermore, Cr (VI) reduced the levels of superoxide dismutase and glutathione, and increased the levels of malondialdehyde, in broiler kidney tissues. However, Se alleviated Cr (VI)-induced oxidative stress by increasing the levels of superoxide dismutase and glutathione, and decreasing the levels of malondialdehyde, within a certain range. Compared to the C group, the levels of p38, JNK, p-p38, p-JNK, p-p38/p38, and p-JNK/JNK significantly increased, whereas those of ERK, p-ERK, and p-ERK/ERK decreased, in the Cr group. Compared to the Cr group, the levels of p38, JNK, p-p38, p-JNK, p-p38/p38, and p-JNK/JNK significantly decreased, whereas those of ERK, p-ERK, and p-ERK/ERK increased, in the Se/Cr group. Furthermore, the levels of p53, c-Myc, Bax, Cyt-c, caspase-9, and caspase-3 significantly increased, and those of Bcl-2 and Bcl-2/Bax significantly decreased, following Cr (VI) exposure, while Se restored the expression of these genes. In conclusion, our findings suggest that SeY can protect against Cr (VI)-induced dysfunction and apoptosis by regulating the mitogen-activated protein kinase pathway activated by oxidative stress in broiler kidney tissues., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The pathological differences between Crohn's disease (CD) and ulcerative colitis (UC) are substantial and unexplained yet. Here, we aimed to identify potential regulators that drive different pathogenesis of CD and UC by causal inference analysis of transcriptome data. Methods: Kruskal-Wallis and Dunnett's tests were performed to identify differentially expressed genes (DEGs) among CD patients, UC patients, and controls. Subsequently, differentially expressed pathways (DEPs) between CD and UC were identified and used to construct the interaction network of DEPs. Causal inference was performed to identify IBD subtype-regulators. The expression of the subtype-regulators and their downstream genes was validated by qRT-PCR with an independent cohort. Results: Compared with the control group, we identified 1,352 and 2,081 DEGs in CD and UC groups, respectively. Multiple DEPs between CD and UC were closely related to inflammation-related pathways, such as NOD-like receptor signaling, IL-17 signaling, and chemokine signaling pathways. Based on the priori interaction network of DEPs, causal inference analysis identified IFNG and GBP5 as IBD subtype-regulators. The results with the discovery cohort showed that the expression level of IFNG , GBP5 , and NLRP3 was significantly higher in the CD group than that in the UC group. The regulation relationships among IFNG , GBP5 , and NLRP3 were confirmed with transcriptome data from an independent cohort and validated by qRT-PCR. Conclusion: Our study suggests that IFNG and GBP5 were IBD subtype-regulators that trigger more intense innate immunity and inflammatory responses in CD than those in UC. Our findings reveal pathomechanical differences between CD and UC that may contribute to personalized treatment for CD and UC., Competing Interests: Author RxZ serves as an advisory board member for Research Institute, GloriousMed Clinical Laboratory, GloriousMed Technology Co., Ltd., China. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gao, Li, Wu, Jiao, Yang, Zhao, Xu, Chen, Lin, Cheng, Zhu, Lan and Zhu.)

The internal modification of natural hierarchical materials can largely improve their inherent properties and afford them new functions. However, conventional methods using small-molecule agents often encounter poor uniformity and low efficiency. By comparing the penetration of small molecules and nanoparticles into hierarchical collagen fibers, we propose a general strategy, namely modular penetration and controlled release (MP-CR), for the internal modification of 3D biomass materials. We demonstrate that nano-sized aluminum-loaded particles can penetrate into collagen networks more effectively and evenly than small-molecule crosslinkers. After the on-demand pH-triggered release of interactive aluminum ions, enhanced internal crosslinking is achieved. Importantly, we elucidate the mechanism in depth and show that the MP-CR strategy can comprehensively improve the overall performance of natural hierarchical materials. The MP-CR strategy represents a significant step forward for the internal modification of hierarchical materials, which will find broad applications in biomedicine, catalysis, water treatment, soft electronics, and energy storage.

Background & Aims: Low-energy diet replacement is an effective tool to induce large and rapid weight loss and improve metabolic health, but in the long-term individuals often experience significant weight regain. Little is known about the role of animal-based foods in weight maintenance and metabolic health. We aimed to examine longitudinal associations of animal-based foods with weight maintenance and glycaemic and cardiometabolic risk factors. We also modelled replacement of processed meat with other high-protein foods., Methods: In this secondary analysis, longitudinal data were analysed from 688 adults (26-70 years) with overweight and prediabetes after 8-week low-energy diet-induced weight loss (≥8% of initial body weight) in a 3-year, multi-centre, diabetes prevention study (PREVIEW). Animal-based food consumption, including unprocessed red meat, processed red meat, poultry, dairy products, fish and seafood, and eggs, was repeatedly assessed using 4-day food records. Multi-adjusted linear mixed models and isoenergetic substitution models were used to examine the potential associations., Results: The available-case analysis showed that each 10-g increment in processed meat, but not total meat, unprocessed red meat, poultry, dairy products, or eggs, was positively associated with weight regain (0.17 kg⋅year -1 , 95% CI 0.10, 0.25, P < 0.001) and increments in waist circumference, HbA 1c , and triacylglycerols. The associations of processed meat with HbA 1c or triacylglycerols disappeared when adjusted for weight change. Fish and seafood consumption was inversely associated with triacylglycerols and triacylglycerol-glucose index, independent of weight change. Modelled replacement of processed meat with isoenergetic (250-300 kJ·day -1 or 60-72 kcal·day -1 ) dairy, poultry, fish and seafood, grains, or nuts was associated with -0.59 (95% CI -0.77, -0.41), -0.66 (95% CI -0.93, -0.40), -0.58 (95% CI -0.88, -0.27), and -0.69 (95% CI -0.96, -0.41) kg·year -1 of weight regain, respectively (all P < 0.001) and significant improvements in HbA 1c , and triacylglycerols., Conclusions: Higher intake of processed meat, but not total or unprocessed red meat, poultry, dairy products, or eggs may be associated with greater weight regain and more adverse glycaemic and cardiometabolic risk factors. Replacing processed meat with a wide variety of high-protein foods, including unprocessed red meat, poultry, dairy products, fish, eggs, grains, and nuts, could improve weight maintenance and metabolic health after rapid weight loss. This study was registered as ClinicalTrials.gov, NCT01777893., Competing Interests: Conflicts of interest AR has received honorariums from the International Sweeteners Association and Unilever. JB-M is President and Director of the Glycemic Index Foundation, oversees of a glycemic index testing service at the University of Sydney and is a co-author of books about diet and diabetes. She is also a member of the Scientific Advisory Board of the Novo Foundation and of ZOE Global. IAM was a member of the UK Government Scientific Advisory Committee on Nutrition, Treasurer of the Federation of European Nutrition Societies, Treasurer of the World Obesity Federation, member of the Mars Scientific Advisory Council, member of the Mars Europe Nutrition Advisory Board, and Scientific Adviser to the Waltham Centre for Pet Nutrition. He was also a member of the Nestle Research Scientific Advisory Board, and of the Novozymes Scientific Advisory Board. He withdrew from all of these roles in 2020 and on August 1 2020 became Professor Emeritus at the University of Nottingham and took up the post of Scientific Director of the Nestle Institute of Health Sciences in Lausanne, Switzerland. SDP was the Fonterra Chair in Human Nutrition during the PREVIEW intervention. The rest of the authors declare that they have no potential conflicts of interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Despite recent progress in our understanding of the association between the gut microbiome and colorectal cancer (CRC), multi-kingdom gut microbiome dysbiosis in CRC across cohorts is unexplored. We investigated four-kingdom microbiota alterations using CRC metagenomic datasets of 1,368 samples from 8 distinct geographical cohorts. Integrated analysis identified 20 archaeal, 27 bacterial, 20 fungal and 21 viral species for each single-kingdom diagnostic model. However, our data revealed superior diagnostic accuracy for models constructed with multi-kingdom markers, in particular the addition of fungal species. Specifically, 16 multi-kingdom markers including 11 bacterial, 4 fungal and 1 archaeal feature, achieved good performance in diagnosing patients with CRC (area under the receiver operating characteristic curve (AUROC) = 0.83) and maintained accuracy across 3 independent cohorts. Coabundance analysis of the ecological network revealed associations between bacterial and fungal species, such as Talaromyces islandicus and Clostridium saccharobutylicum. Using metagenome shotgun sequencing data, the predictive power of the microbial functional potential was explored and elevated D-amino acid metabolism and butanoate metabolism were observed in CRC. Interestingly, the diagnostic model based on functional EggNOG genes achieved high accuracy (AUROC = 0.86). Collectively, our findings uncovered CRC-associated microbiota common across cohorts and demonstrate the applicability of multi-kingdom and functional markers as CRC diagnostic tools and, potentially, as therapeutic targets for the treatment of CRC., (© 2022. The Author(s).)

Background & Aims: TOB1 is an anti-proliferative protein of Tob/BTG family and typically involved in the tumorigenesis and T cell activation. Although TOB1 is associated with T helper 17 cell-related autoimmunity, its role in modulating T cell-mediated immune responses in IBD remains poorly understood. Here, we explored its expression and the underlying mechanisms involved in the pathogenesis of inflammatory bowel disease (IBD)., Methods: TOB1 and ID2 expression in IBD patients was examined by quantitative real time polymerase chain reaction and immunohistochemistry. IBD CD4 + T cells were transfected with lentivirus expressing TOB1, ID2, TOB1 short hairpin RNA and ID2 short hairpin RNA, respectively, and Tob1 -/- CD4 + T cells were transfected with lentivirus expressing Id2. Experimental colitis was established in Tob1 -/- mice by trinitrobenzene sulfonic acid enema and in Rag1 -/- mice reconstituted with Tob1 -/- CD45RB high CD4 + T cells to further explore the role of Tob1 in intestinal mucosal inflammation. Splenic CD4 + T cells of Tob1 -/- mice were sorted to determine transcriptome differences by RNA sequencing., Results: TOB1 expression was decreased in inflamed mucosa and peripheral blood CD4 + T cells of IBD patients compared with healthy subjects. Overexpression of TOB1 downregulated IBD CD4 + T cells to differentiate into Th1/Th17 cells compared with control subjects. Severe colitis was observed in Tob1 -/- mice through trinitrobenzene sulfonic acid enema or in Rag1 -/- mice reconstituted with Tob1 -/- CD45RB high CD4 + T cells, compared with control animals. RNA sequencing analysis revealed ID2 as functional target of TOB1 to inhibit IBD CD4 + T cell differentiation into Th1/Th17 cells. Mechanistically, TOB1 was associated with Smad4/5 to induce ID2 expression and restrain Th1/Th17 cell differentiation., Conclusions: TOB1 restrains intestinal mucosal inflammation through suppressing Th1/Th17 cell-mediated immune responses via the Smad4/5-ID2 pathway. It may serve as a novel therapeutic target for treatment of human IBD., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: The association of quantity and quality of carbohydrate sources with appetite during long-term weight-loss maintenance (WLM) after intentional weight loss (WL) is unclear. We aimed to investigate longitudinal associations of quantity and quality of carbohydrate sources with changes in subjective appetite sensations during WLM., Methods: This secondary analysis evaluated longitudinal data from the 3-year WLM phase of the PREVIEW study, a 2 × 2 factorial (diet-physical activity arms), multi-center, randomized trial. 1279 individuals with overweight or obesity and prediabetes (25-70 years; BMI≥25 kg m -2 ) were included. Individuals were merged into 1 group to assess longitudinal associations of yearly changes in appetite sensations. Quantity and quality of carbohydrate sources including total carbohydrate, glycemic index (GI), glycemic load (GL), and total dietary fiber were assessed via 4-day food diaries at 4 timepoints (26, 52, 104, and 156 weeks) during WLM. Visual analog scales were used to assess appetite sensations in the previous week., Results: During WLM, participants consumed on average 160.6 (25th, 75th percentiles 131.1, 195.8) g·day -1 of total carbohydrate, with GI 53.8 (48.7, 58.8) and GL 85.3 (67.2, 108.9) g day -1 , and 22.3 (17.6, 27.3) g·day -1 of dietary fiber. In the available-case analysis, multivariable-adjusted linear mixed models with repeated measures showed that each 30-g increment in total carbohydrate was associated with increases in hunger (1.36 mm year -1 , 95% CI 0.77, 1.95, P < 0.001), desire to eat (1.10 mm year -1 , 0.59, 1.60, P < 0.001), desire to eat something sweet (0.99 mm year -1 , 0.30, 1.68, P = 0.005), and weight regain (0.20%·year -1 , 0.03, 0.36, P = 0.022). Increasing GI was associated with weight regain, but not associated with increases in appetite sensations. Each 20-unit increment in GL was associated with increases in hunger (0.92 mm year -1 , 0.33, 1.51, P = 0.002), desire to eat (1.12 mm year -1 , 0.62, 1.62, P < 0.001), desire to eat something sweet (1.13 mm year -1 , 0.44, 1.81, P < 0.001), and weight regain (0.35%·year -1 , 0.18, 0.52, P < 0.001). Surprisingly, dietary fiber was also associated with increases in desire to eat, after adjustment for carbohydrate or GL., Conclusions: In participants with moderate carbohydrate and dietary fiber intake, and low to moderate GI, we found that higher total carbohydrate, GL, and total fiber, but not GI, were associated with increases in subjective desire to eat or hunger over 3 years. This study was registered as ClinicalTrials.gov, NCT01777893., Competing Interests: Conflicts of interest AR has received honorariums from the International Sweeteners Association and Unilever. JB-M is President and Director of the Glycemic Index Foundation, oversees of a glycemic index testing service at the University of Sydney and is a co-author of books about diet and diabetes. She is also a member of the Scientific Advisory Board of the Novo Foundation and of ZOE Global. SDP was the Fonterra Chair in Human Nutrition during the PREVIEW intervention. TML is advisor for “Sense” diet programme. TL is employed by NetUnion sarl, who contributed to the data collection process in the absence of commercial or financial conflict of interest with the study analysis. The rest of the authors declare that they have no potential conflicts of interests., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Owing to their significant impact on children's long-term health, familial factors in the microbiomes of children have attracted increasing attention. However, the mechanism underlying microbiome transmission across generations remains unclear. A significantly lower alpha diversity was observed in the gut flora of children than in the gut flora of parents and grandparents; the alpha diversity of oral and skin microbiota was relatively higher in children than in their predecessors. Gut, oral, and skin microbiome was more similar between family members than between unrelated individuals. Meanwhile, 55.05%, 61.09%, and 76.73% of amplicon sequence variants (ASVs) in children's gut, oral, and skin microbiomes, respectively, were transmitted from all family members. Among these, the most transmissible ASVs belonged to Methylophilaceae , Solimonadaceae , Neisseriaceae , and Burkholderiaceae , which were defined as "putative familial transmissible bacteria." Furthermore, we found that the time spent with parents/grandparents and children's dietary preferences were important factors that influenced the proportion of the transmissible microbiome. Moreover, the majority of transmissible ASVs (85.06%), especially those of Ruminococcaceae and Lachnospiraceae , were significantly associated with the immune indices, such as CD3 + , CD4 + , CD8 + , IgG, and IgA. IMPORTANCE Our study revealed that the children's microbiota was partially transmitted from their family members and specific putative transmissible ASVs were associated with the immune system of children. These findings suggest that home life plays a key role in the shaping of young children's microbiomes and has long-term health benefits.

Plant-based diets are recommended by dietary guidelines. This secondary analysis aimed to assess longitudinal associations of an overall plant-based diet and specific plant foods with weight-loss maintenance and cardiometabolic risk factors. Longitudinal data on 710 participants (aged 26-70 years) with overweight or obesity and pre-diabetes from the 3-year weight-loss maintenance phase of the PREVIEW intervention were analyzed. Adherence to an overall plant-based diet was evaluated using a novel plant-based diet index, where all plant-based foods received positive scores and all animal-based foods received negative scores. After adjustment for potential confounders, linear mixed models with repeated measures showed that the plant-based diet index was inversely associated with weight regain, but not with cardiometabolic risk factors. Nut intake was inversely associated with regain of weight and fat mass and increments in total cholesterol and LDL cholesterol. Fruit intake was inversely associated with increments in diastolic blood pressure, total cholesterol, and LDL cholesterol. Vegetable intake was inversely associated with an increment in diastolic blood pressure and triglycerides and was positively associated with an increase in HDL cholesterol. All reported associations with cardiometabolic risk factors were independent of weight change. Long-term consumption of nuts, fruits, and vegetables may be beneficial for weight management and cardiometabolic health, whereas an overall plant-based diet may improve weight management only.

Background/purpose: Previous studies have suggested that there is a mutual antagonism between caries and periodontitis. This research aimed to investigate the ecological connection and bacterial interaction of these two diseases., Materials and Methods: We profiled and analyzed the salivary microbiota from 124 individuals (including 38 caries patients, 34 periodontitis patients, 15 comorbid diseases patients, and 37 healthy controls) by using 16 S rRNA gene sequencing and bioinformatics approaches, and also quantified their salivary bacteria loads via quantitative real-time PCR. The putative biological functions of the salivary microbiome of the different groups were predicted by PICRUSt., Results: We observed that both the total bacteria loads and the overall microbial richness in the saliva of the periodontitis group were higher than that in the healthy group. The principal coordinate analysis (PCoA) showed that the caries, periodontitis and healthy groups were separated from each other, and that the samples from comorbid diseases were located at the overlap of caries and periodontitis groups. Using LEfSe analysis, 20 differentially abundant genera were identified as potential biomarkers. These genera also performed complicated interactions among the four groups. Additionally, the PICRUSt analysis indicated caries-related and periodontitis-related functions (e.g., carbohydrate metabolism and bacteria proliferation) respectively., Conclusion: We disclosed the significant differences in the salivary bacterial community under caries, periodontitis and comorbid diseases. The periodontitis group was marked by the increased complexity of the salivary microbiota. The result may have vital clinical significance to the screening and early treatment of caries-active and periodontitis-active individuals., Competing Interests: The authors declare that they have no conflicts of interest relevant to this article., (© 2020 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Mature microfiltration (MF) membrane is a low-cost, effective, and promising technology to provide affordable purified water for people living in developing countries. However, the lack of disinfection ability and inherent membrane fouling problems have seriously restricted the large-scale application of conventional MF treatment system in producing safe drinking water. In this work, zwitterionic silver nanoparticles (AgNPs) with surface modification of poly(carboxybetaine acrylate-co-dopamine methacryamide) (PCBDA) copolymers were robustly immobilized onto commercial polyamide MF membrane via mussel-inspired chemistry for water disinfection. The designed microfiltration membrane, named as PCBDA@AgNPs-MF, exhibited integrated properties of high and stable payload of AgNPs, broad-spectrum anti-adhesive and antimicrobial activities, and easy removal of inactivated microbial cells from membrane surface. Ascribing to the synergetic effect of anti-adhesive and antimicrobial features brought by zwitterionic PCBDA@AgNPs, the biofilms growth on polyamide membrane surface was significantly inhibited, which showed potential access to achieve long-term biofouling resistance and maintain water flux for conventional MF membrane. As water disinfection device, these attributes enabled PCBDA@AgNPs-MF to effectively disinfect the model and natural bacteria-contaminated water., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Multiple mechanisms for the gut microbiome contributing to the pathogenesis of nonalcoholic fatty liver disease (NAFLD) have been implicated. Here, we aim to investigate the contribution and potential application for altered bile acids (BA) metabolizing microbes in NAFLD by post hoc analysis of whole metagenome sequencing (WMS) data. The discovery cohort consisted of 86 well-characterized patients with biopsy-proven NAFLD and 38 healthy controls. Assembly-based analysis was performed to identify BA-metabolizing microbes. Statistical tests, feature selection, and microbial coabundance analysis were integrated to identify microbial alterations and markers in NAFLD. An independent validation cohort was subjected to similar analyses. NAFLD microbiota exhibited decreased diversity and microbial associations. We established a classifier model with 53 differential species exhibiting a robust diagnostic accuracy [area under the receiver-operator curve (AUC) = 0.97] for detecting NAFLD. Next, eight important differential pathway markers including secondary BA biosynthesis were identified. Specifically, increased abundance of 7α-hydroxysteroid dehydrogenase (7α-HSDH), 3α-hydroxysteroid dehydrogenase (baiA), and bile acid-coenzyme A ligase (baiB) was detected in NAFLD. Furthermore, 10 of 50 BA-metabolizing metagenome-assembled genomes (MAGs) from Bacteroides ovatus and Eubacterium biforme were dominant in NAFLD and interplayed as a synergetic ecological guild. Importantly, two subtypes of patients with NAFLD were observed according to secondary BA metabolism potentials. Elevated capability for secondary BA biosynthesis was also observed in the validation cohort. These bacterial BA-metabolizing genes and microbes identified in this study may serve as disease markers. Microbial differences in BA-metabolism and strain-specific differences among patients highlight the potential for precision medicine in NAFLD treatment.

This study aimed to investigate the impact of fruit preloads on the acute postprandial glycemic response (PGR) and satiety response of a rice meal in healthy female subjects based on iso-carbohydrate (IC) and hyper-carbohydrate (HC) contents, respectively. The IC test meals including (1) rice preload (R + 35R), (2) orange preload (O + 35R), (3) apple preload (A + 35R) and (4) pear preload (P + 35R), contained 50.0 g available carbohydrates (AC) where the preload contributed 15.0 g and rice provided 35.0 g. The HC meals included (1) orange preload (O + 50R), (2) apple preload (A+50R) and (3) pear preload (P + 50R), each containing 65.0 g AC, where the fruits contributed 15.0 g and rice provided 50.0 g. Drinking water 30 min before the rice meal was taken as reference (W + 50R). All the preload treatments, irrespective of IC or HC meals, resulted in remarkable reduction ( p < 0.001) in terms of incremental peak glucose (IPG) and the maximum amplitude of glycemic excursion in 180 min (MAGE 0-180 ), also a significant decrease ( p < 0.05) in the area of PGR contributed by per gram of AC (AAC), compared with the W + 50R. Apple elicited the lowest PGR among all test meals, as the A + 35R halved the IPG and slashed the incremental area under the curve in 180 min (iAUC 0-180 ) by 45.7%, while the A + 50R reduced the IPG by 29.7%, compared with the W + 50R. All the preload meals and the reference meal showed comparable self-reported satiety in spite of the difference in AC. In conclusion, pre-meal consumption of three fruits effectively curbed post-meal glycemia even in the case of a 30% extra carbohydrate load.

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disease. Although visceral hypersensitivity (VH) and disturbed gastrointestinal motility are typical pathophysiological features of IBS, the pathological mechanisms underlying this disease remain unclear. Serotonin system abnormalities are considered to play an important role in the pathomechanisms of IBS. Here, we hypothesize that similar alterations, including VH and colonic motility, induced by serotonin transporter (SERT) knockout result from altered serotonin signaling. We sought to determine the molecular mechanism underlying VH and colonic dysmotility induced by SERT knockout. We found that female SERT (slc6a4)-knockout (KO; ie, slc6a4 -/- ) rats exhibited lower pain pressure thresholds (PPTs) than wild-type (WT; ie, slc6a4 +/+ ) rats in response to colorectal distension (CRD). Significantly increased fecal pellet output and reduced concentration of serum tryptophan were observed in the female SERT KO rats. The concentrations of 5-hydroxytryptamine (5-HT) in platelet-rich plasma (PRP) and serum in SERT KO rats were lower than those in WT rats, but the numbers of enterochromaffin cells (ECs) and the concentrations of 5-HT in colon of SERT KO rats were higher than those of WT rats. Finally, increased expression levels of 5-HT 1B receptors, 5-HT 2C receptors, 5-HT 3A receptors, 5-HT 3B receptors, 5-HT 6 receptors, 5-HT 7 receptors, and glycosylated dopamine transporters (DATs) were found in the female SERT KO rats. We concluded that alterations in the serotonin system induced by the knockout of slc6a4 might result in VH and accelerated gastrointestinal motility in female SERT KO rats, which can be used as an animal model of IBS., (© 2021 Federation of American Societies for Experimental Biology.)

Objective: To examine longitudinal and dose-dependent associations of dietary glycemic index (GI), glycemic load (GL), and fiber with body weight and glycemic status during 3-year weight loss maintenance (WLM) in adults at high risk of type 2 diabetes., Research Design and Methods: In this secondary analysis we used pooled data from the PREVention of diabetes through lifestyle Intervention and population studies in Europe and around the World (PREVIEW) randomized controlled trial, which was designed to test the effects of four diet and physical activity interventions. A total of 1,279 participants with overweight or obesity (age 25-70 years and BMI ≥25 kg ⋅ m -2 ) and prediabetes at baseline were included. We used multiadjusted linear mixed models with repeated measurements to assess longitudinal and dose-dependent associations by merging the participants into one group and dividing them into GI, GL, and fiber tertiles, respectively., Results: In the available-case analysis, each 10-unit increment in GI was associated with a greater regain of weight (0.46 kg ⋅ year -1 ; 95% CI 0.23, 0.68; P < 0.001) and increase in HbA 1c . Each 20-unit increment in GL was associated with a greater regain of weight (0.49 kg ⋅ year -1 ; 0.24, 0.75; P < 0.001) and increase in HbA 1c . The associations of GI and GL with HbA 1c were independent of weight change. Compared with those in the lowest tertiles, participants in the highest GI and GL tertiles had significantly greater weight regain and increases in HbA 1c . Fiber was inversely associated with increases in waist circumference, but the associations with weight regain and glycemic status did not remain robust in different analyses., Conclusions: Dietary GI and GL were positively associated with weight regain and deteriorating glycemic status. Stronger evidence on the role of fiber is needed., (© 2021 by the American Diabetes Association.)