Exosomes secreted by Fusobacterium nucleatum-infected colon cancer cells transmit resistance to oxaliplatin and 5-FU by delivering hsa_circ_0004085.

BACKGROUND: A large number of Fusobacterium nucleatum (Fn) are present in colorectal cancer (CRC) tissues of patients who relapse after chemotherapy, and Fn has been reported to promote oxaliplatin and 5-FU chemoresistance in CRC. Pathogens such as bacteria and parasites stimulate exosome production in tumor cells, and the regulatory mechanism of exosomal circRNA in the transmission of oxaliplatin and 5-FU chemotherapy resistance in Fn-infected CRC remains unclear. METHODS: Hsa_circ_0004085 was screened by second-generation sequencing of CRC tissues. The correlation between hsa_circ_0004085 and patient clinical response to oxaliplatin/5-FU was analyzed. Exosome tracing experiments and live imaging systems were used to test the effect of Fn infection in CRC on the distribution of hsa_circ_0004085. Colony formation, ER tracking analysis and immunofluorescence were carried out to verify the regulatory effect of exosomes produced by Fn-infected CRC cells on chemotherapeutic resistance and ER stress. RNA pulldown, LC-MS/MS analysis and RIP were used to explore the regulatory mechanism of downstream target genes by hsa_circ_0004085. RESULTS: First, we screened out hsa_circ_0004085 with abnormally high expression in CRC clinical samples infected with Fn and found that patients with high expression of hsa_circ_0004085 in plasma had a poor clinical response to oxaliplatin/5-FU. Subsequently, the circular structure of hsa_circ_0004085 was identified. Fn infection promoted hsa_circ_0004085 formation by hnRNP L and packaged hsa_circ_0004085 into exosomes by hnRNP A1. Exosomes produced by Fn-infected CRC cells transferred hsa_circ_0004085 between cells and delivered oxaliplatin/5-FU resistance to recipient cells by relieving ER stress. Hsa_circ_0004085 enhanced the stability of GRP78 mRNA by binding to RRBP1 and promoted the nuclear translocation of ATF6p50 to relieve ER stress. CONCLUSIONS: Plasma levels of hsa_circ_0004085 are increased in colon cancer patients with intracellular Fn and are associated with a poor response to oxaliplatin/5-FU. Fn infection promoted hsa_circ_0004085 formation by hnRNP L and packaged hsa_circ_0004085 into exosomes by hnRNP A1. Exosomes secreted by Fn-infected CRC cells deliver hsa_circ_0004085 between cells. Hsa_circ_0004085 relieves ER stress in recipient cells by regulating GRP78 and ATF6p50, thereby delivering resistance to oxaliplatin and 5-FU.

Novel Insight Into Nutritional Regulation in Enhancement of Immune Status and Mediation of Inflammation Dynamics Integrated Study In Vivo and In Vitro of Teleost Grass Carp (Ctenopharyngodon idella): Administration of Threonine.

This study aims to investigate the effects of threonine (Thr) on immunoregulation in vivo and in vitro of teleost grass carp (Ctenopharyngodon idella). Juveniles (9.53 ± 0.02 g) were reared for 8 weeks with respective Thr diet (3.99, 7.70, 10.72, 14.10, 17.96, and 21.66 g/kg) and then challenged with Aeromonas hydrophila for in vivo study. Macrophages isolated from head kidney were treated in vitro for 48 h with L-Thr (0, 0.5, 1.0, 2.0, 4.0, and 8.0 mM) after 6 h of lipopolysaccharide induction. The results showed that, compared with Thr deficiency (3.99 g/kg), the optimal dietary Thr (14.10g/kg) affected the immunocyte activation in the head kidney (HK) and spleen (SP) by downregulating the mRNA expressions of MHC-II and upregulating CD4 (not CD8), and it mediated the innate immune by enhancing the activities of lysozyme (LZ), acid phosphatase content of complement 3 (C3) and C4, increasing the mRNA abundances of hepcidin, liver expressed antimicrobial peptide-2A (LEAP-2A), LEAP-2B, ß-defensin1, downregulating tumor necrosis factor α (TNF-α), IL-6, IL-1ß, IL-12p35, IL-12p40, IL-17AF1, and IL-17D partly by attenuating RORγ1 transcriptional factor and nuclear factor kappa B p65 (NF-κBp65) signaling cascades [IKKß/IκBα/NF-κBp65] and upregulating transforming growth factor ß1 (TGF-ß1), IL-4/13A, -4/13B, IL-10, and IL-22 partly by GATA-3. Besides these, the optimal dietary Thr regulated the adaptive immune by upregulating the mRNAs of immunoglobulin M (IgM) and IgZ (not IgD). Moreover, 2 mM Thr downregulated in vitro the mRNA abundances of colony stimulating factor-1, inducible nitric oxide synthase, mannose receptor 1, matrix metalloproteinase2 (MMP-2), and MMP-9 significantly (P < 0.05), indicating that Thr could attenuate the M1-type macrophages' activation. Moreover, L-Thr downregulated the mRNA transcripts of TNF-α, IL-6, and IL-1ß associated with impairing the SOCS1/STAT1 signaling and upregulated IL-10 and TGF-ß1 partly by accentuating the SOCS3/STAT3 pathway. The above-mentioned observations suggested that Thr improved the immune status in the immune organs of fish by enhancing the immune defense and mediating the inflammation process. Finally, based on the immune indices of LZ activity in HK and C3 content in SP, the optimal Thr for immune enhancement in juvenile grass carp (9.53-53.43 g) was determined to be 15.70 g/kg diet (4.85 g/100 g protein) and 14.49 g/kg diet (4.47 g/100 g protein), respectively.

Optimizing Behavioral Interventions to Regulate Gestational Weight Gain With Sequential Decision Policies Using Hybrid Model Predictive Control.

Excessive gestational weight gain is a significant public health concern that has been the recent focus of control systems-based interventions. Healthy Mom Zone (HMZ) is an intervention study that aims to develop and validate an individually-tailored and "intensively adaptive" intervention to manage weight gain for pregnant women with overweight or obesity using control engineering approaches. This paper presents how Hybrid Model Predictive Control (HMPC) can be used to assign intervention dosages and consequently generate a prescribed intervention with dosages unique to each individuals needs. A Mixed Logical Dynamical (MLD) model enforces the requirements for categorical (discrete-level) doses of intervention components and their sequential assignment into mixed-integer linear constraints. A comprehensive system model that integrates energy balance and behavior change theory, using data from one HMZ participant, is used to illustrate the workings of the HMPC-based control system for the HMZ intervention. Simulations demonstrate the utility of HMPC as a means for enabling optimized complex interventions in behavioral medicine, and the benefits of a HMPC framework in contrast to conventional interventions relying on "IF-THEN" decision rules.

Dietary threonine deficiency depressed the disease resistance, immune and physical barriers in the gills of juvenile grass carp (Ctenopharyngodon idella) under infection of Flavobacterium columnare.

This study was conducted to investigate the effects of dietary threonine on the disease resistance, gill immune and physical barriers function of juvenile grass carp (Ctenopharyngodon idella). A total of 1080 juveniles were fed six iso-nitrogenous diets containing graded levels of threonine (3.99-21.66 g kg-1 diet) for 8 weeks, and then challenged with Flavobacterium columnare. Results showed that threonine deficiency (3.99 g kg-1 diet): (1) increased the gill rot morbidity after exposure to F. columnare; (2) attenuated the gill immune barrier function by decreasing antimicrobial substances production, up-regulating the mRNA levels of pro-inflammatory cytokines (except IL-12p40), and down-regulating the anti-inflammatory cytokines partly due to the modulation of NF-κB and TOR signaling. (3) disrupt the gill tight junction complexes by down-regulating TJs (claudin-3, -b, -c, 12, occludin, ZO-1 and ZO-2) and up-regulating TJs (claudin-7a, -7b) as well as related signaling molecule myosin light chain kinase mRNA levels (P < 0.05). (4) exacerbated the gill apoptosis by up-regulating cysteinyl aspartic acid-protease-3, 8, 9, c-Jun N-terminal kinases and mediating apoptosis related factors mRNA levels (P < 0.05); (5) exacerbated oxidative injury with increased reactive oxygen species, malondialdehyde and protein carbonyl contents (P < 0.05), decreased the antioxidant related enzymes activities and corresponding mRNA levels (except glutathione peroxidase-1b and glutathione-S-transferase-omega 2) as well as glutathione contents (P < 0.05) partly ascribe to the abridgement of NF-E2-related factor 2 signaling [Nrf2/Keap1a (not Keap1b)] in fish gill. Overall, threonine deficiency depressed the disease resistance, and impaired immune and physical barriers in fish gill. Finally, based on the gill rot morbidity and biochemical indices (immune indices LA activity and antioxidant indices MDA content), threonine requirements for juvenile grass carp (9.53-53.43 g) were estimated to be 15.32 g kg-1 diet (4.73 g 100 g-1 protein), 15.52 g kg-1 diet (4.79 g 100 g-1 protein), 15.46 g kg-1 diet (4.77 g 100 g-1 protein), respectively.

Threonine deficiency decreased intestinal immunity and aggravated inflammation associated with NF-κB and target of rapamycin signalling pathways in juvenile grass carp (Ctenopharyngodon idella) after infection with Aeromonas hydrophila.

This study aimed to investigate the impacts of dietary threonine on intestinal immunity and inflammation in juvenile grass carp. Six iso-nitrogenous semi-purified diets containing graded levels of threonine (3·99-21·66 g threonine/kg) were formulated and fed to fishes for 8 weeks, and then challenged with Aeromonas hydrophila for 14 d. Results showed that, compared with optimum threonine supplementation, threonine deficiency (1) decreased the ability of fish against enteritis, intestinal lysozyme activities (except in the distal intestine), acid phosphatase activities, complement 3 (C3) and C4 contents and IgM contents (except in the proximal intestine (PI)), and it down-regulated the transcript abundances of liver-expressed antimicrobial peptide (LEAP)-2A, LEAP-2B, hepcidin, IgZ, IgM and ß-defensin1 (except in the PI) (P<0·05); (2) could up-regulate intestinal pro-inflammatory cytokines TNF-α, IL-1ß, IL-6, IL-8 and IL-17D mRNA levels partly related to NF-κB signalling; (3) could down-regulate intestinal anti-inflammatory cytokine transforming growth factor (TGF)-ß1, TGF-ß2, IL-4/13A (not IL-4/13B) and IL-10 mRNA levels partly by target of rapamycin signalling. Finally, on the basis of the specific growth rate, against the enteritis morbidity and IgM contents, the optimum threonine requirements were estimated to be 14·53 g threonine/kg diet (4·48 g threonine/100 g protein), 15.05 g threonine/kg diet (4·64 g threonine/100 g protein) and 15·17 g threonine/kg diet (4·68 g threonine/100 g protein), respectively.

Control systems engineering for optimizing a prenatal weight gain intervention to regulate infant birth weight.

OBJECTIVES: We used dynamical systems modeling to describe how a prenatal behavioral intervention that adapts to the needs of each pregnant woman may help manage gestational weight gain and alter the obesogenic intrauterine environment to regulate infant birth weight. METHODS: This approach relies on integrating mechanistic energy balance, theory of planned behavior, and self-regulation models to describe how internal processes can be impacted by intervention dosages, and reinforce positive outcomes (e.g., healthy eating and physical activity) to moderate gestational weight gain and affect birth weight. RESULTS: A simulated hypothetical case study from MATLAB with Simulink showed how, in response to our adaptive intervention, self-regulation helps adjust perceived behavioral control. This, in turn, changes the woman's intention and behavior with respect to healthy eating and physical activity during pregnancy, affecting gestational weight gain and infant birth weight. CONCLUSIONS: This article demonstrates the potential for real-world applications of an adaptive intervention to manage gestational weight gain and moderate infant birth weight. This model could be expanded to examine the long-term sustainable impacts of an intervention that varies according to the participant's needs on maternal postpartum weight retention and child postnatal eating behavior.

Hybrid Model Predictive Control for Sequential Decision Policies in Adaptive Behavioral Interventions.

Control engineering offers a systematic and efficient method to optimize the effectiveness of individually tailored treatment and prevention policies known as adaptive or "just-in-time" behavioral interventions. The nature of these interventions requires assigning dosages at categorical levels, which has been addressed in prior work using Mixed Logical Dynamical (MLD)-based hybrid model predictive control (HMPC) schemes. However, certain requirements of adaptive behavioral interventions that involve sequential decision making have not been comprehensively explored in the literature. This paper presents an extension of the traditional MLD framework for HMPC by representing the requirements of sequential decision policies as mixed-integer linear constraints. This is accomplished with user-specified dosage sequence tables, manipulation of one input at a time, and a switching time strategy for assigning dosages at time intervals less frequent than the measurement sampling interval. A model developed for a gestational weight gain (GWG) intervention is used to illustrate the generation of these sequential decision policies and their effectiveness for implementing adaptive behavioral interventions involving multiple components.

Hybrid Model Predictive Control for Optimizing Gestational Weight Gain Behavioral Interventions.

Excessive gestational weight gain (GWG) represents a major public health issue. In this paper, we pursue a control engineering approach to the problem by applying model predictive control (MPC) algorithms to act as decision policies in the intervention for assigning optimal intervention dosages. The intervention components consist of education, behavioral modification and active learning. The categorical nature of the intervention dosage assignment problem dictates the need for hybrid model predictive control (HMPC) schemes, ultimately leading to improved outcomes. The goal is to design a controller that generates an intervention dosage sequence which improves a participant's healthy eating behavior and physical activity to better control GWG. An improved formulation of self-regulation is also presented through the use of Internal Model Control (IMC), allowing greater flexibility in describing self-regulatory behavior. Simulation results illustrate the basic workings of the model and demonstrate the benefits of hybrid predictive control for optimized GWG adaptive interventions.

A Dynamical Systems Model for Improving Gestational Weight Gain Behavioral Interventions.

Excessive gestational weight gain (GWG) represents a major public health concern. In this paper, we present a dynamical systems model that describes how a behavioral intervention can influence weight gain during pregnancy. The model relies on the integration of a mechanistic energy balance with a dynamical behavioral model. The behavioral model incorporates some well-accepted concepts from psychology: the Theory of Planned Behavior (TPB) and the principle of self-regulation which describes how internal processes within the individual can serve to reinforce the positive outcomes of an intervention. A hypothetical case study is presented to illustrate the basic workings of the model and demonstrate how the proper design of the intervention can counteract natural trends towards declines in healthy eating and reduced physical activity during the course of pregnancy. The model can be used by behavioral scientists to evaluate decision rules for adaptive time-varying behavioral interventions, or as the open-loop model for hybrid model predictive control algorithms acting as decision frameworks for such interventions.