Amyloid-ß Causes NMDA Receptor Dysfunction and Dendritic Spine Loss through mGluR1 and AKAP150-Anchored Calcineurin Signaling.

Neuronal excitatory synapses are primarily located on small dendritic protrusions called spines. During synaptic plasticity underlying learning and memory, Ca2+ influx through postsynaptic NMDA-type glutamate receptors (NMDARs) initiates signaling pathways that coordinate changes in dendritic spine structure and synaptic function. During long-term potentiation (LTP), high levels of NMDAR Ca2+ influx promote increases in both synaptic strength and dendritic spine size through activation of Ca2+-dependent protein kinases. In contrast, during long-term depression (LTD), low levels of NMDAR Ca2+ influx promote decreased synaptic strength and spine shrinkage and elimination through activation of the Ca2+-dependent protein phosphatase calcineurin (CaN), which is anchored at synapses via the scaffold protein A-kinase anchoring protein (AKAP)150. In Alzheimer's disease (AD), the pathological agent amyloid-ß (Aß) may impair learning and memory through biasing NMDAR Ca2+ signaling pathways toward LTD and spine elimination. By employing AKAP150 knock-in mice of both sexes with a mutation that disrupts CaN anchoring to AKAP150, we revealed that local, postsynaptic AKAP-CaN-LTD signaling was required for Aß-mediated impairment of NMDAR synaptic Ca2+ influx, inhibition of LTP, and dendritic spine loss. Additionally, we found that Aß acutely engages AKAP-CaN signaling through activation of G-protein-coupled metabotropic glutamate receptor 1 (mGluR1) leading to dephosphorylation of NMDAR GluN2B subunits, which decreases Ca2+ influx to favor LTD over LTP, and cofilin, which promotes F-actin severing to destabilize dendritic spines. These findings reveal a novel interplay between NMDAR and mGluR1 signaling that converges on AKAP-anchored CaN to coordinate dephosphorylation of postsynaptic substrates linked to multiple aspects of Aß-mediated synaptic dysfunction.

Viral airway injury promotes cell engraftment in an in vitro model of cystic fibrosis cell therapy.

Cell therapy is a potential treatment for cystic fibrosis (CF). However, cell engraftment into the airway epithelium is challenging. Here, we model cell engraftment in vitro using the air-liquid interface (ALI) culture system by injuring well-differentiated CF ALI cultures and delivering non-CF cells at the time of peak injury. Engraftment efficiency was quantified by measuring chimerism by droplet digital PCR and functional ion transport in Ussing chambers. Using this model, we found that human bronchial epithelial cells (HBECs) engraft more efficiently when they are cultured by conditionally reprogrammed cell (CRC) culture methods. Cell engraftment into the airway epithelium requires airway injury, but the extent of injury needed is unknown. We compared three injury models and determined that severe injury with partial epithelial denudation facilitates long-term cell engraftment and functional CFTR recovery up to 20% of wildtype function. The airway epithelium promptly regenerates in response to injury, creating competition for space and posing a barrier to effective engraftment. We examined competition dynamics by time-lapse confocal imaging and found that delivered cells accelerate airway regeneration by incorporating into the epithelium. Irradiating the repairing epithelium granted engrafting cells a competitive advantage by diminishing resident stem cell proliferation. Intentionally, causing severe injury to the lungs of people with CF would be dangerous. However, naturally occurring events like viral infection can induce similar epithelial damage with patches of denuded epithelium. We found that viral preconditioning promoted effective engraftment of cells primed for viral resistance.NEW & NOTEWORTHY Cell therapy is a potential treatment for cystic fibrosis (CF). Here, we model cell engraftment by injuring CF air-liquid interface cultures and delivering non-CF cells. Successful engraftment required severe epithelial injury. Intentionally injuring the lungs to this extent would be dangerous. However, naturally occurring events like viral infection induce similar epithelial damage. We found that viral preconditioning promoted the engraftment of cells primed for viral resistance leading to CFTR functional recovery to 20% of the wildtype.

A Quality Improvement Project to Reduce Rapid Response System Inequities for Patients with Limited English Proficiency at a Quaternary Academic Medical Center.

BACKGROUND: Recognition of clinically deteriorating hospitalized patients with activation of rapid response (RR) systems can prevent patient harm. Patients with limited English proficiency (LEP), however, experience less benefit from RR systems than do their English-speaking counterparts. OBJECTIVE: To improve outcomes among hospitalized LEP patients experiencing clinical deteriorations. DESIGN: Quasi-experimental pre-post design using quality improvement (QI) statistics. PARTICIPANTS: All adult hospitalized non-intensive care patients with LEP who were admitted to a large academic medical center from May 2021 through March 2023 and experienced RR system activation were included in the evaluation. All patients included after May 2022 were exposed to the intervention. INTERVENTIONS: Implementation of a modified RR system for LEP patients in May 2022 that included electronic dashboard monitoring of early warning scores (EWSs) based on electronic medical record data; RR nurse initiation of consults or full RR system activation; and systematic engagement of interpreters. MAIN MEASURES: Process of care measures included monthly rates of RR system activation, critical response nurse consultations, and disease severity scores prior to activation. Main outcomes included average post-RR system activation length of stay, escalation of care, and in-hospital mortality. Analyses used QI statistics to identify special cause variation in pre-post control charts based on monthly data aggregates. KEY RESULTS: In total, 222 patients experienced at least one RR system activation during the study period. We saw no special cause variation for process measures, or for length of hospitalization or escalation of care. There was, however, special cause variation in mortality rates with an overall pre-post decrease in average monthly mortality from 7.42% (n = 8/107) to 6.09% (n = 7/115). CONCLUSIONS: In this pilot study, prioritized tracking, utilization of EWS-triggered evaluations, and interpreter integration into the RR system for LEP patients were feasible to implement and showed promise for reducing post-RR system activation mortality.

Prediction of cardiac surgery associated acute kidney injury using response to loop diuretic and urine neutrophil gelatinase associated lipocalin.

BACKGROUND: Cardiac surgery associated acute kidney injury (CS-AKI) is common. Urine response to loop diuretic and urine neutrophil gelatinase associated lipocalin (uNGAL) are separately associated with CS-AKI. We aimed to determine whether urine response to loop diuretic and uNGAL together were associated with postoperative day 2-4 CS-AKI. METHODS: Two-center prospective observational study (ages 0-18 years). uNGAL (8-12 h after admission) (ng/mL) and urine response to loop diuretic (6 h for bolus furosemide and 12 h for infusion bumetanide) (mL/kg/hr) were measured. All diuretic doses were converted to furosemide equivalents. The primary outcome was day 2-4 CS-AKI. Patients were sub-phenotyped using a priori cutoffs (uNGAL + ≥ 100 ng/mL and UOP + < 1.5 mL/kg/hr) and optimal cutoffs (uNGAL + ≥ 127 ng/mL and UOP + ≤ 0.79 mL/kg/hr): 1) uNGAL-/UOP-, 2) uNGAL-/UOP + , 3) uNGAL + /UOP-, and 4) uNGAL + /UOP + . Multivariable regression was used to assess the association of uNGAL, UOP and each sub-phenotype with outcomes. RESULTS: 476 patients were included. CS-AKI occurred in 52 (10.9%). uNGAL was associated with 2.59-fold greater odds (95%CI: 1.52-4.41) of CS-AKI. UOP was not associated with CS-AKI. Compared with uNGAL + alone, uNGAL + /UOP + improved prediction of CS-AKI using a priori and optimal cutoffs respectively (AUC 0.70 vs. 0.75). Both uNGAL + /UOP + (IQR OR:4.63, 95%CI: 1.74-12.32) and uNGAL + /UOP- (IQR OR:5.94, 95%CI: 2.09-16.84) were associated with CS-AKI when compared with uNGAL-/UOP-. CONCLUSIONS: uNGAL is associated with CS-AKI. The sub-phenotype association was largely driven by uNGAL. Future studies standardizing diuretic dose and timing may be needed to refine the combined performance for clinical decision making.

Biomarker-based acute kidney injury sub-phenotypes refine risk assessment in children undergoing cardiac surgery.

BACKGROUND: Pediatric cardiac surgery-associated acute kidney injury (CS-AKI) is common with variable association with outcomes, possibly because transient serum creatinine (SCr) elevations are unrelated to kidney disease. Sub-phenotypes of CS-AKI with biomarker integration may provide prognostic enrichment. This study aims to determine if combining early postoperative urine neutrophil gelatinase-associated lipocalin (uNGAL) and SCr into sub-phenotypes strengthens associations with AKI and outcomes. We hypothesized that patients with early subclinical (uNGAL + , SCr -) or damage (uNGAL + , SCr +) CS-AKI would have more postoperative day 2-4 KDIGO-defined AKI and worse clinical outcomes than patients with early functional AKI (uNGAL - , SCr +). METHODS: Two-center prospective observational study evaluating combinations of early uNGAL (8-12 h from ICU admission, ≥ 150 ng/mL) and early postoperative (≤ 8 h of admission) KDIGO SCr-defined AKI to predict CS-AKI on postoperative days (POD) 2-4. Four CS-AKI phenotypes were derived (uNGAL - /SCr - ; uNGAL + /SCr - ; uNGAL - /SCr + and uNGAL + /SCr +). The primary outcome was POD2-4 KDIGO SCr-defined CS-AKI. Secondary outcomes included ventilator and intensive care unit-free days (maximum 28). RESULTS: Four hundred seventy-six patients (median age 4.8 [IQR 1.4-30.4] months, 39% female) were included. POD2-4 AKI occurred in 44 (9.2%). 27% were uNGAL + /SCr - and 0.4% (n = 2) uNGAL + /SCr + . The adjusted odds of POD2-4 AKI was ninefold higher (aOR: 9.09, 95%CI: 3.84-21.53) in uNGAL + /SCr - when compared to uNGAL - /SCr - . uNGAL + /SCr - was associated with fewer ventilator-free (aOR: 0.30, 95%CI: 0.19-0.48) and ICU-free days (aOR: 0.41, 95%CI: 0.26-0.66) when compared to uNGAL - /SCr - . CONCLUSION: Early postoperative uNGAL, regardless of SCr elevation, refines risk assessment for pediatric POD2-4 CS-AKI and associated morbidity, enabling earlier AKI identification and prognostics.

Multicolor Light-Induced Immune Activation via Polymer Photocaged Cytokines.

Cytokines act as potent, extracellular signals of the human immune system and can elicit striking treatment responses in patients with autoimmune disease, tissue damage, and cancer. Yet, despite their therapeutic potential, recombinant cytokine-mediated immune responses remain difficult to control as their administration is often systemic, whereas their intended sites of action are localized. To address the challenge of spatially and temporally constraining cytokine signals, we recently devised a strategy whereby recombinant cytokines are reversibly inactivated via chemical modification with photo-labile polymers that respond to visible LED light. Extending this approach to enable both in vivo and multicolor immune activation, here we describe a strategy whereby cytokines appended with heptamethine cyanine-polyethylene glycol are selectively re-activated ex vivo using tissue-penetrating near-infrared (NIR) light. We show that NIR LED light illumination of caged, pro-inflammatory cytokines restores cognate receptor signaling and potentiates the activity of T cell-engager cancer immunotherapies ex vivo. Using combinations of visible- and NIR-responsive cytokines, we further demonstrate multiwavelength optical control of T cell cytolysis ex vivo, as well as the ability to perform Boolean logic using multicolored light and orthogonally photocaged cytokine pairs as inputs and T cell activity as outputs. Together, this work demonstrates a novel approach to control extracellular immune cell signals using light, a strategy that in the future may improve our understanding of and ability to treat cancer and other diseases.

Intestinal Microbial and Metabolic Alterations Following Successful Fecal Microbiota Transplant for D-Lactic Acidosis.

Fecal microbiota transplantation (FMT) involves the transfer of stool from a healthy individual into the intestinal tract of a diseased recipient. Although used primarily for recurrent Clostridium difficile infection, FMT is increasingly being attempted as an experimental therapy for other illnesses, including metabolic disorders. D-lactic acidosis (D-LA) is a metabolic disorder that may occur in individuals with short bowel syndrome when lactate-producing bacteria in the colon overproduce D-lactate. This results in elevated systemic levels of D-lactate, metabolic acidosis, and encephalopathy. In this study, we report the successful use of FMT for the treatment of recurrent D-LA in a child who was unresponsive to conventional therapies. Importantly, we also present profiles of the enteric microbiota, as well as fecal D-/L-lactic acid metabolites, before and longitudinally after FMT. These data provide valuable insight into the putative mechanisms of D-LA pathogenesis and its treatment.

I: INTRODUCTION.

The majority of the world's children grow up learning two or more languages. The study of early bilingualism is central to current psycholinguistics, offering insights into issues such as transfer and interference in development. From an applied perspective, it poses a universal challenge to language assessment practices throughout childhood, as typically developing bilingual children usually underperform relative to monolingual norms when assessed in one language only. We measured vocabulary with Communicative Development Inventories for 372 24-month-old toddlers learning British English and one Additional Language out of a diverse set of 13 (Bengali, Cantonese, Dutch, French, German, Greek, Hindi-Urdu, Italian, Mandarin, Polish, Portuguese, Spanish, and Welsh). We furthered theoretical understanding of bilingual development by showing, for the first time, that linguistic distance between the child's two languages predicts vocabulary outcome, with phonological overlap related to expressive vocabulary, and word order typology and morphological complexity related to receptive vocabulary, in the Additional Language. Our study also has crucial clinical implications: we have developed the first bilingual norms for expressive and receptive vocabulary for 24-month-olds learning British English and an Additional Language. These norms were derived from factors identified as uniquely predicting CDI vocabulary measures: the relative amount of English versus the Additional Language in child-directed input and parental overheard speech, and infant gender. The resulting UKBTAT tool was able to accurately predict the English vocabulary of an additional group of 58 bilinguals learning an Additional Language outside our target range. This offers a pragmatic method for the assessment of children in the majority language when no tool exists in the Additional Language. Our findings also suggest that the effect of linguistic distance might extend beyond bilinguals' acquisition of early vocabulary to encompass broader cognitive processes, and could constitute a key factor in the study of the debated bilingual advantage.

38.8 million additional modern contraceptive users: this, in fact, is "a never-before opportunity to strengthen investment and action on adolescent contraception".

BACKGROUND: We thank Bijlmakers et al. for their interest in our article, "A never-before opportunity to strengthen investment and action on adolescent contraception, and what we must do to make full use of it", and are grateful for the opportunity to respond to their four key assertions. RESPONSE: First, we fully agree that sexual rights are controversial, which we discussed in depth in our original article. However, we reaffirm that there is global consensus on adolescent contraception as evidenced in part by recent data emerging from FP2020 on 38.8 million additional modern contraceptive users, the Global Goods and commitments emanating from the 2017 FP2020 summit, and their translated actions at the country level. Additionally, we clarify WHO's working definitions of sex, sexual health, and sexuality, and introduce WHO's newly released Operational Framework on Sexual Health and its Linkages to Reproductive Health. We welcome and agree with Bijlmakers et al.'s second point, which elaborates on the barrier of restrictive laws and policies. To address this barrier, we describe examples of resources that can help programmes understand the political/social context that drives these laws and policies at national and subnational levels, and identify programmatic gaps and best practices to address them within specific political/social contexts. We also welcome and agree with Bijlmakers et al.'s third point, which reiterates that discomfort around adolescent sexuality is a major barrier for sexuality education. In response, we point to four relevant reviews of CSE policies and their implementation, our original article's description of three programmes that have successfully addressed inadequate teacher skills, and our ongoing work on documenting strategies to build an enabling environment for CSE and deal with resistance. Lastly, we wholeheartedly agree that the harmful policies noted by Bijlmakers et al. are damaging to international efforts to improve adolescent SRH and rights. We argue, though, that these policies alone will not undermine efforts by countless other stakeholders around the world who are working in defence and promotion of adolescents' SRH and rights. CONCLUSION: Despite the many valid obstacles noted by Bijlmakers et al., we truly believe that this is "a never-before opportunity to strengthen investment and action on adolescent contraception".

Eating Disorders and the Intestinal Microbiota: Mechanisms of Energy Homeostasis and Behavioral Influence.

PURPOSE OF REVIEW: We reviewed and evaluated recently published scientific studies that explored the role of the intestinal microbiota in eating disorders. RECENT FINDINGS: Studies have demonstrated that the intestinal microbiota is a contributing factor to both host energy homeostasis and behavior-two traits commonly disrupted in patients with eating disorders. To date, intestinal microbiota research in eating disorders has focused solely on anorexia nervosa (AN). Initial studies have reported an atypical intestinal microbial composition in patients with AN compared to healthy controls. However, the impact of these AN-associated microbial communities on host metabolism and behavior remains unknown. The intriguing pattern of findings in patients with AN encourages further investigation of the intestinal microbiota in eating disorders. Elucidating the specific role(s) of these microbial communities may yield novel ideas for augmenting current clinical therapies to promote weight gain, decrease gastrointestinal distress, and even reduce psychological symptomatology.

A never-before opportunity to strengthen investment and action on adolescent contraception, and what we must do to make full use of it.

BACKGROUND: Increasingly, the health and rights of adolescents are being recognized and prioritized on the global agenda. This presents us with a "never-before" opportunity to address adolescent contraception. This is timely, as there are enormous numbers of adolescents who are currently unable to obtain and use contraceptives. From research evidence and programmatic experience, it is clear that we need to do things differently to meet their needs/fulfil their rights. MAIN BODY: In this commentary, we call for action in several key areas to address adolescents' persistent inability to obtain and use contraceptives. We must move away from one-size-fits-all approaches, from a 'condoms-only' mind set, from separate services for adolescents, from ignoring the appeal of pharmacies and shops, and from one-off-training to make health workers adolescent friendly. Our efforts to expand access to quality contraceptive services to adolescents must be combined with efforts to build their desire and ability to use them, and to do so consistently. In order for these changes to be made, action must be taken on several levels. This includes the formulation of sound national policies and strategies, robust programme implementation with monitoring, regular programmatic reviews, and implementation research. Further, high-quality collection, analysis, and dissemination of data must underlie all of our efforts. As we move ahead, we must also recognize and draw lessons from positive examples of large scale and sustained programmes in countries that have led the way in increasing contraceptive use by adolescents. CONCLUSION: This unprecedented moment in history gives us a real opportunity to bring about transformational change, particularly when there is so much at stake.

Daily Changes in Composition and Diversity of the Intestinal Microbiota in Patients with Anorexia Nervosa: A Series of Three Cases.

Anorexia nervosa, a severe psychiatric illness, is associated with an intestinal microbial dysbiosis. Individual microbial signatures dominate in healthy samples, even over time and under controlled conditions, but whether microbial markers of the disorder overcome inter-individual variation during the acute stage of illness or renourishment is unknown. We characterized daily changes in the intestinal microbiota in three acutely ill patients with anorexia nervosa over the entire course of hospital-based renourishment and found significant, patient-specific changes in microbial composition and diversity. This preliminary case series suggests that even in a state of pathology, individual microbial signatures persist in accounting for the majority of intestinal microbial variation. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

The Science Behind the Academy for Eating Disorders' Nine Truths About Eating Disorders.

OBJECTIVE: In 2015, the Academy for Eating Disorders collaborated with international patient, advocacy, and parent organizations to craft the 'Nine Truths About Eating Disorders'. This document has been translated into over 30 languages and has been distributed globally to replace outdated and erroneous stereotypes about eating disorders with factual information. In this paper, we review the state of the science supporting the 'Nine Truths'. METHODS: The literature supporting each of the 'Nine Truths' was reviewed, summarized and richly annotated. RESULTS: Most of the 'Nine Truths' arise from well-established foundations in the scientific literature. Additional evidence is required to further substantiate some of the assertions in the document. Future investigations are needed in all areas to deepen our understanding of eating disorders, their causes and their treatments. CONCLUSIONS: The 'Nine Truths About Eating Disorders' is a guiding document to accelerate global dissemination of accurate and evidence-informed information about eating disorders. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

Cooperation of C/EBP family proteins and chromatin remodeling proteins is essential for termination of liver regeneration.

UNLABELLED: Liver cancer is the fifth most common cancer. A highly invasive surgical resection of the liver tumor is the main approach used to eliminate the tumor. Mechanisms that terminate liver regeneration when the liver reaches the original size are not known. The aims of this work were to generate an animal model that fails to stop liver regeneration after surgical resections and elucidate mechanisms that are involved in termination of liver regeneration. Because epigenetic control of liver function has been previously implicated in the regulation of liver proliferation, we generated C/EBPα-S193A knockin mice, which have alterations in formation of complexes of C/EBP family proteins with chromatin remodeling proteins. The C/EBPα-S193A mice have altered liver morphology and altered liver function leading to changes of glucose metabolism and blood parameters. Examination of the proliferative capacity of C/EBPα-S193A livers showed that livers of S193A mice have a higher rate of proliferation after birth, but stop proliferation at the age of 2 months. These animals have increased liver proliferation in response to liver surgery as well as carbon tetrachloride (CCl4 )-mediated injury. Importantly, livers of C/EBPα-S193A mice fail to stop liver regeneration after surgery when livers reach the original, preresection, size. The failure of S193A livers to stop regeneration correlates with the epigenetic repression of key regulators of liver proliferation C/EBPα, p53, FXR, SIRT1, PGC1α, and TERT by C/EBPß-HDAC1 complexes. The C/EBPß-HDAC1 complexes also repress promoters of enzymes of glucose synthesis PEPCK and G6Pase. CONCLUSION: Proper cooperation of C/EBP and chromatin remodeling proteins is essential for the termination of liver regeneration after surgery and for maintenance of liver functions.

Age-associated change of C/EBP family proteins causes severe liver injury and acceleration of liver proliferation after CCl4 treatments.

The aged liver is more sensitive to the drug treatments and has a high probability of developing liver disorders such as fibrosis, cirrhosis, and cancer. Here we present mechanisms underlying age-associated severe liver injury and acceleration of liver proliferation after CCl4 treatments. We have examined liver response to CCl4 treatments using old WT mice and young C/EBPα-S193D knockin mice, which express an aged-like isoform of C/EBPα. Both animal models have altered chromatin structure as well as increased liver injury and proliferation after acute CCl4 treatments. We found that these age-related changes are associated with the repression of key regulators of liver biology: C/EBPα, Farnesoid X Receptor (FXR) and telomere reverse transcriptase (TERT). In quiescent livers of old WT and young S193D mice, the inhibition of TERT is mediated by HDAC1-C/EBPα complexes. After CCl4 treatments, TERT, C/EBPα and FXR are repressed by different mechanisms. These mechanisms include the increase of a dominant negative isoform, C/EBPß-LIP, and subsequent repression of C/EBPα, FXR, and TERT promoters. C/EBPß-LIP also disrupts Rb-E2F1 complexes in C/EBPα-S193D mice after CCl4 treatments. To examine if these alterations are involved in drug-mediated liver diseases, we performed chronic treatments of mice with CCl4. We found that C/EBPα-S193D mice developed fibrosis much more rapidly than WT mice. Thus, our data show that the age-associated alterations of C/EBP proteins create favorable conditions for the increased liver proliferation after CCl4 treatments and for development of drug-mediated liver diseases.

The Intestinal Microbiota in Acute Anorexia Nervosa and During Renourishment: Relationship to Depression, Anxiety, and Eating Disorder Psychopathology.

OBJECTIVE: The relevance of the microbe-gut-brain axis to psychopathology is of interest in anorexia nervosa (AN), as the intestinal microbiota plays a critical role in metabolic function and weight regulation. METHODS: We characterized the composition and diversity of the intestinal microbiota in AN, using stool samples collected at inpatient admission (T1; n = 16) and discharge (T2; n = 10). At T1, participants completed the Beck Depression and Anxiety Inventories and the Eating Disorder Examination-Questionnaire. Patients with AN were compared with healthy individuals who participated in a previous study (healthy comparison group; HCG). Genomic DNA was isolated from stool samples, and bacterial composition was characterized by 454 pyrosequencing of the 16S rRNA gene. Sequencing results were processed by the Quantitative Insights Into Microbial Ecology pipeline. We compared T1 versus T2 samples, samples from both points were compared with HCG (n = 12), and associations between psychopathology and T1 samples were explored. RESULTS: In patients with AN, significant changes emerged between T1 and T2 in taxa abundance and beta (between-sample) diversity. Patients with AN had significantly lower alpha (within-sample) diversity than did HCG at both T1 (p = .0001) and T2 (p = .016), and differences in taxa abundance were found between AN patients and HCG. Levels of depression, anxiety, and eating disorder psychopathology at T1 were associated with composition and diversity of the intestinal microbiota. CONCLUSIONS: We provide evidence of an intestinal dysbiosis in AN and an association between mood and the enteric microbiota in this patient population. Future directions include mechanistic investigations of the microbe-gut-brain axis in animal models and association of microbial measures with metabolic changes and recovery indices.

Transcriptional and translational regulation of C/EBPß-HDAC1 protein complexes controls different levels of p53, SIRT1, and PGC1α proteins at the early and late stages of liver cancer.

Cancer changes biological processes in the liver by altering gene expression at the levels of transcription, translation, and protein modification. The RNA binding protein CUGBP1 is a key regulator of translation of CCAAT enhancer binding protein ß and histone deacetylase 1 (HDAC1). These proteins form complexes that are involved in the regulation of liver biology. Here we show a critical role of the translational activation of CCAAT/enhancer binding protein ß-HDAC1 complexes in the development of liver cancer mediated by diethylnitrosamine. We found that diethylnitrosamine increases the levels of CUGBP1 and activates CUGBP1 by phosphorylation, leading to the formation of the CUGBP1-eIF2 complex, which is an activator of translation of CUGBP1-dependent mRNAs. The elevation of the CUGBP1-eIF2 complex increases translation of C/EBPß and HDAC1, resulting in an increase of C/EBPß-HDAC1 complexes at later stages of liver cancer. We found that C/EBPß-HDAC1 complexes repress promoters of three key regulators of liver functions: p53, SIRT1, and PGC1α. As the result of this suppression, the p53-, SIRT1-, and PGC1α-dependent downstream pathways are reduced, leading to increased liver proliferation. We also found that the proper regulation of C/EBPß-HDAC1 complexes is required for the maintenance of biological levels of p53, SIRT1, and PGC1α in quiescent livers and at early stages of liver cancer. Taken together, these studies showed that the development of liver cancer includes a tight regulation of levels of C/EBPß-HDAC1 complexes on the levels of transcription, translation, and posttranslational modifications.

Farnesoid X receptor inhibits gankyrin in mouse livers and prevents development of liver cancer.

UNLABELLED: One of the early events in the development of liver cancer is a neutralization of tumor suppressor proteins Rb, p53, hepatocyte nuclear factor 4α (HNF4α), and CCAAT/enhancer binding protein (C/EBP) α. The elimination of these proteins is mediated by a small subunit of proteasome, gankyrin, which is activated by cancer. The aim of this study was to determine the mechanisms that repress gankyrin in quiescent livers and mechanisms of activation of gankyrin in liver cancer. We found that farnesoid X receptor (FXR) inhibits expression of gankyrin in quiescent livers by silencing the gankyrin promoter through HDAC1-C/EBPß complexes. C/EBPß is a key transcription factor that delivers HDAC1 to gankyrin promoter and causes epigenetic silencing of the promoter. We show that down-regulation of C/EBPß in mouse hepatoma cells and in mouse livers reduces C/EBPß-HDAC1 complexes and activates the gankyrin promoter. Deletion of FXR signaling in mice leads to de-repression of the gankyrin promoter and to spontaneous development of liver cancer at 12 months of age. Diethylnitrosoamine (DEN)-mediated liver cancer in wild-type mice also involves the reduction of FXR and activation of gankyrin. Examination of liver cancer in old mice and liver cancer in human patients revealed that FXR is reduced, while gankyrin is elevated during spontaneous development of liver cancer. Searching for animal models with altered levels of FXR, we found that long-lived Little mice have high levels of FXR and do not develop liver cancer with age and after DEN injections due to failure to activate gankyrin and eliminate Rb, p53, HNF4α and C/EBPα proteins. CONCLUSION: FXR prevents liver cancer by inhibiting the gankyrin promoter via C/EBPß-HDAC1 complexes, leading to subsequent protection of tumor suppressor proteins from degradation.

JK1 (FAM134B) represses cell migration in colon cancer: a functional study of a novel gene.

BACKGROUND: JK1 is a novel cancer-related gene with unknown functional role in carcinogenesis. The aim of this study is to investigate the role of JK1 gene in carcinogenesis in an in vitro cell proliferation and migration analysis model. METHODS: Small hairpin RNAs (shRNA) were designed to knock-down JK1 expression in colon cancer cell line (SW480) using transduction ready lentiviral particles. Cell proliferation and cell migration assays were performed on multiple extracellular matrices to investigate the cellular effects of JK1 in colon cancer cells. A non-cancer colonic epithelial cell line (FHC) was used to compare the expression of JK1 in cancer cell line. RESULTS: JK1 knock-down did not affect cellular proliferation or survival in colon cancer. However, the manipulation increased cancer cell migration rates on collagen and fibronectin substrates. CONCLUSIONS: JK1 was shown for the first time to have a functional role in the pathogenesis of colon cancer. The results imply that JK1 represses the capacity of cancer cells to migrate within their tissue. They also concurred with the previous findings of JK1 activity correlations with clinical and pathological features in colon cancer. The capacity may have utility as a means to prevent cancer cells forming metastases.