An extended transcription factor regulatory network controls hepatocyte identity.

Cell identity is specified by a core transcriptional regulatory circuitry (CoRC), typically limited to a small set of interconnected cell-specific transcription factors (TFs). By mining global hepatic TF regulons, we reveal a more complex organization of the transcriptional regulatory network controlling hepatocyte identity. We show that tight functional interconnections controlling hepatocyte identity extend to non-cell-specific TFs beyond the CoRC, which we call hepatocyte identity (Hep-ID)CONNECT TFs. Besides controlling identity effector genes, Hep-IDCONNECT TFs also engage in reciprocal transcriptional regulation with TFs of the CoRC. In homeostatic basal conditions, this translates into Hep-IDCONNECT TFs being involved in fine tuning CoRC TF expression including their rhythmic expression patterns. Moreover, a role for Hep-IDCONNECT TFs in the control of hepatocyte identity is revealed in dedifferentiated hepatocytes where Hep-IDCONNECT TFs are able to reset CoRC TF expression. This is observed upon activation of NR1H3 or THRB in hepatocarcinoma or in hepatocytes subjected to inflammation-induced loss of identity. Our study establishes that hepatocyte identity is controlled by an extended array of TFs beyond the CoRC.

Nuclear receptors: pathophysiological mechanisms and drug targets in liver disease.

Nuclear receptors (NRs) are ligand-dependent transcription factors required for liver development and function. As a consequence, NRs have emerged as attractive drug targets in a wide range of liver diseases. However, liver dysfunction and failure are linked to loss of hepatocyte identity characterised by deficient NR expression and activities. This might at least partly explain why several pharmacological NR modulators have proven insufficiently efficient to improve liver functionality in advanced stages of diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD). In this perspective, we review the most recent advances in the hepatic NR field and discuss the contribution of multiomic approaches to our understanding of their role in the molecular organisation of an intricated transcriptional regulatory network, as well as in liver intercellular dialogues and interorgan cross-talks. We discuss the potential benefit of novel therapeutic approaches simultaneously targeting multiple NRs, which would not only reactivate the hepatic NR network and restore hepatocyte identity but also impact intercellular and interorgan interplays whose importance to control liver functions is further defined. Finally, we highlight the need of considering individual parameters such as sex and disease stage in the development of NR-based clinical strategies.

Decreased circulating IPA levels identify subjects with metabolic comorbidities: A multi-omics study.

In recent years several experimental observations demonstrated that the gut microbiome plays a role in regulating positively or negatively metabolic homeostasis. Indole-3-propionic acid (IPA), a Tryptophan catabolic product mainly produced by C. Sporogenes, has been recently shown to exert either favorable or unfavorable effects in the context of metabolic and cardiovascular diseases. We performed a study to delineate clinical and multiomics characteristics of human subjects characterized by low and high IPA levels. Subjects with low IPA blood levels showed insulin resistance, overweight, low-grade inflammation, and features of metabolic syndrome compared to those with high IPA. Metabolomics analysis revealed that IPA was negatively correlated with leucine, isoleucine, and valine metabolism. Transcriptomics analysis in colon tissue revealed the enrichment of several signaling, regulatory, and metabolic processes. Metagenomics revealed several OTU of ruminococcus, alistipes, blautia, butyrivibrio and akkermansia were significantly enriched in highIPA group while in lowIPA group Escherichia-Shigella, megasphera, and Desulfovibrio genus were more abundant. Next, we tested the hypothesis that treatment with IPA in a mouse model may recapitulate the observations of human subjects, at least in part. We found that a short treatment with IPA (4 days at 20/mg/kg) improved glucose tolerance and Akt phosphorylation in the skeletal muscle level, while regulating blood BCAA levels and gene expression in colon tissue, all consistent with results observed in human subjects stratified for IPA levels. Our results suggest that treatment with IPA may be considered a potential strategy to improve insulin resistance in subjects with dysbiosis.

Factors Predictive of Binaural Hearing Restoration by Cochlear Implant in Single-Sided Deafness.

INTRODUCTION: Cochlear implants (CIs) can restore binaural hearing in cases of single-sided deafness (SSD). However, studies with a high level of evidence in support of this phenomenon are lacking. The aim of this study is to analyze the effectiveness of CIs using several spatialized speech-in-noise tests and to identify potential predictors of successful surgery. METHODS: Ten cases underwent standard CI surgery (MEDEL-Flex24). The speech-in-noise test was used in three different spatial configurations. The noise was presented from the front (N0), toward the CI (NCI), and toward the ear (Near), while the speech was always from the front (S0). For each test, the speech-to-noise ratio at 50% intelligibility (SNR50) was evaluated. Seven different effects were assessed (summation, head shadow [HS], speech released of masking [SRM], and squelch for the CI and for the ear). RESULTS: A significant summation effect of 1.5 dB was observed. Contralateral PTA was positively correlated with S0N0-B and S0NCI-B (CIon and unplugged ear). S0N0-B results were positively correlated with S0N0-CIoff (p < 0.0001) and with S0Near-CIoff results (p = 0.004). A significant positive correlation was found between delay post-activation and HS gain for the CI (p = 0.005). Finally, the HS was negatively correlated with the squelch effect for the ear. CONCLUSION: CI benefits patients with SSD in noise and can improve the threshold for detecting low-level noise. Contralateral PTA could predict good postoperative results. Simple tests performed preoperatively can predict the likelihood of surgical success in reversing SSD.

Cochlear Implant: Analysis of the Frequency-to-Place Mismatch with the Table-Based Software OTOPLAN® and Its Influence on Hearing Performance.

OBJECTIVE: The purpose of this study was to compare the originally applied frequency allocation of cochlear implant electrodes assigned by default at the time of activation with a more recent frequency allocation that is anatomy-based by a software called OTOPLAN®. Based on a computed tomography scan of the temporal bone, this software calculates the position of each electrode in the cochlea and its corresponding tonotopic frequency. We also evaluated whether patients with a significant mismatch between these two allocations present poorer speech intelligibility. MATERIALS AND METHODS: Patients who underwent cochlear implantation from 2016 to 2021 at the University Hospital of Liege were included in this retrospective study. We used OTOPLAN® to calculate the tonotopic frequency allocation of each electrode according to its exact position in the cochlear duct. This anatomical frequency mapping was compared with the default frequency mapping at the time of cochlear implant activation. Finally, we compared the mismatch with the patients' auditory performance, represented by the Auditory Capacity Index (ACI). RESULTS: Thirteen patients were included in the study. All patients had a mismatch between the two frequency maps, to a variable extent (200 Hz-1,100 Hz). Frequency shift was significantly inversely correlated with ACI and with the time needed to improve speech intelligibility. CONCLUSION: Our primary results show that patients with a larger mismatch between default frequency mapping and anatomically assigned frequency mapping experience poorer hearing performance and slower adaptation to a cochlear implant.

Roux-en-Y gastric bypass induces hepatic transcriptomic signatures and plasma metabolite changes indicative of improved cholesterol homeostasis.

BACKGROUND & AIMS: Roux-en-Y gastric bypass (RYGB), the most effective surgical procedure for weight loss, decreases obesity and ameliorates comorbidities, such as non-alcoholic fatty liver (NAFLD) and cardiovascular (CVD) diseases. Cholesterol is a major CVD risk factor and modulator of NAFLD development, and the liver tightly controls its metabolism. How RYGB surgery modulates systemic and hepatic cholesterol metabolism is still unclear. METHODS: We studied the hepatic transcriptome of 26 patients with obesity but not diabetes before and 1 year after undergoing RYGB. In parallel, we measured quantitative changes in plasma cholesterol metabolites and bile acids (BAs). RESULTS: RYGB surgery improved systemic cholesterol metabolism and increased plasma total and primary BA levels. Transcriptomic analysis revealed specific alterations in the liver after RYGB, with the downregulation of a module of genes implicated in inflammation and the upregulation of three modules, one associated with BA metabolism. A dedicated analysis of hepatic genes related to cholesterol homeostasis pointed towards increased biliary cholesterol elimination after RYGB, associated with enhancement of the alternate, but not the classical, BA synthesis pathway. In parallel, alterations in the expression of genes involved in cholesterol uptake and intracellular trafficking indicate improved hepatic free cholesterol handling. Finally, RYGB decreased plasma markers of cholesterol synthesis, which correlated with an improvement in liver disease status after surgery. CONCLUSIONS: Our results identify specific regulatory effects of RYGB on inflammation and cholesterol metabolism. RYGB alters the hepatic transcriptome signature, likely improving liver cholesterol homeostasis. These gene regulatory effects are reflected by systemic post-surgery changes of cholesterol-related metabolites, corroborating the beneficial effects of RYGB on both hepatic and systemic cholesterol homeostasis. IMPACT AND IMPLICATIONS: Roux-en-Y gastric bypass (RYGB) is a widely used bariatric surgery procedure with proven efficacy in body weight management, combatting cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). RYGB exerts many beneficial metabolic effects, by lowering plasma cholesterol and improving atherogenic dyslipidemia. Using a cohort of patients undergoing RYGB, studied before and 1 year after surgery, we analyzed how RYGB modulates hepatic and systemic cholesterol and bile acid metabolism. The results of our study provide important insights on the regulation of cholesterol homeostasis after RYGB and open avenues that could guide future monitoring and treatment strategies targeting CVD and NAFLD in obesity.

[Globus pharyngeus : etiologies, diagnosis and management. A narrative review]. / Globus pharyngé : étiologies, diagnostic et prise en charge. Revue narrative de la littérature.

Globus pharyngeus is a very common symptom in the general population. It is defined as a sensation of lump or foreign body in the throat, generally not accompanied by pain and relieved by eating. This last notion makes the differential diagnosis with dysphagia, which requires a different management. Its possible etiologies are complex and multiple, both organic and psychological, and many of them are still debated. Therefore, there is no consensus on the management and the treatment of globus pharyngeus. The purpose of this narrative review of the literature is to synthesize the current evidence regarding the causes, diagnostic strategy, and therapeutic management of globus pharyngeus.

Le globus pharyngé est un symptôme très fréquent dans la population générale. Il est défini comme une sensation de boule ou de corps étranger dans la gorge généralement, non accompagnée de douleurs et soulagée par l'alimentation. Cette dernière notion fait le diagnostic différentiel avec la dysphagie qui relève d'une mise au point et de traitements différents. Ses étiologies possibles sont complexes et multiples, aussi bien organiques que psychologiques et nombre d'entre elles restent débattues. Par conséquent, il n'existe aucun consensus sur la mise au point du globus pharyngé ni sur son traitement. Cette revue narrative de la littérature a pour objectif de synthétiser les données actuelles concernant les causes, la mise au point et la prise en charge thérapeutique du globus pharyngé.

Hepatic Molecular Signatures Highlight the Sexual Dimorphism of Nonalcoholic Steatohepatitis (NASH).

BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) is considered as a pivotal stage in nonalcoholic fatty liver disease (NAFLD) progression, given that it paves the way for severe liver injuries such as fibrosis and cirrhosis. The etiology of human NASH is multifactorial, and identifying reliable molecular players and/or biomarkers has proven difficult. Together with the inappropriate consideration of risk factors revealed by epidemiological studies (altered glucose homeostasis, obesity, ethnicity, sex, etc.), the limited availability of representative NASH cohorts with associated liver biopsies, the gold standard for NASH diagnosis, probably explains the poor overlap between published "omics"-defined NASH signatures. APPROACH AND RESULTS: Here, we have explored transcriptomic profiles of livers starting from a 910-obese-patient cohort, which was further stratified based on stringent histological characterization, to define "NoNASH" and "NASH" patients. Sex was identified as the main factor for data heterogeneity in this cohort. Using powerful bootstrapping and random forest (RF) approaches, we identified reliably differentially expressed genes participating in distinct biological processes in NASH as a function of sex. RF-calculated gene signatures identified NASH patients in independent cohorts with high accuracy. CONCLUSIONS: This large-scale analysis of transcriptomic profiles from human livers emphasized the sexually dimorphic nature of NASH and its link with fibrosis, calling for the integration of sex as a major determinant of liver responses to NASH progression and responses to drugs.

CDKN2A/p16INK4a suppresses hepatic fatty acid oxidation through the AMPKα2-SIRT1-PPARα signaling pathway.

In addition to their well-known role in the control of cellular proliferation and cancer, cell cycle regulators are increasingly identified as important metabolic modulators. Several GWAS have identified SNPs near CDKN2A, the locus encoding for p16INK4a (p16), associated with elevated risk for cardiovascular diseases and type-2 diabetes development, two pathologies associated with impaired hepatic lipid metabolism. Although p16 was recently shown to control hepatic glucose homeostasis, it is unknown whether p16 also controls hepatic lipid metabolism. Using a combination of in vivo and in vitro approaches, we found that p16 modulates fasting-induced hepatic fatty acid oxidation (FAO) and lipid droplet accumulation. In primary hepatocytes, p16-deficiency was associated with elevated expression of genes involved in fatty acid catabolism. These transcriptional changes led to increased FAO and were associated with enhanced activation of PPARα through a mechanism requiring the catalytic AMPKα2 subunit and SIRT1, two known activators of PPARα. By contrast, p16 overexpression was associated with triglyceride accumulation and increased lipid droplet numbers in vitro, and decreased ketogenesis and hepatic mitochondrial activity in vivo Finally, gene expression analysis of liver samples from obese patients revealed a negative correlation between CDKN2A expression and PPARA and its target genes. Our findings demonstrate that p16 represses hepatic lipid catabolism during fasting and may thus participate in the preservation of metabolic flexibility.

Endoplasmic reticulum stress actively suppresses hepatic molecular identity in damaged liver.

Liver injury triggers adaptive remodeling of the hepatic transcriptome for repair/regeneration. We demonstrate that this involves particularly profound transcriptomic alterations where acute induction of genes involved in handling of endoplasmic reticulum stress (ERS) is accompanied by partial hepatic dedifferentiation. Importantly, widespread hepatic gene downregulation could not simply be ascribed to cofactor squelching secondary to ERS gene induction, but rather involves a combination of active repressive mechanisms. ERS acts through inhibition of the liver-identity (LIVER-ID) transcription factor (TF) network, initiated by rapid LIVER-ID TF protein loss. In addition, induction of the transcriptional repressor NFIL3 further contributes to LIVER-ID gene repression. Alteration to the liver TF repertoire translates into compromised activity of regulatory regions characterized by the densest co-recruitment of LIVER-ID TFs and decommissioning of BRD4 super-enhancers driving hepatic identity. While transient repression of the hepatic molecular identity is an intrinsic part of liver repair, sustained disequilibrium between the ERS and LIVER-ID transcriptional programs is linked to liver dysfunction as shown using mouse models of acute liver injury and livers from deceased human septic patients.

The Use of a Robot to Insert an Electrode Array of Cochlear Implants in the Cochlea: A Feasibility Study and Preliminary Results.

INTRODUCTION: Cochlear implants (CIs) are commonly used for the rehabilitation of profound bilateral hearing loss. However, patients with substantial residual acoustic hearing are potential CI candidates. Because of both improvements in technology and advancements in surgical techniques, it may be possible to preserve hearing to some extent. For more than a decade, it has been suggested that robots are used to perform middle ear surgery. We evaluated the use of the RobOtol® otologic robot specifically to insert CI electrodes into the inner ear. METHODS: CI surgery with the conventional approach was performed under general anesthesia. The MED-El Flex 24-electrode array was inserted using RobOtol®. Video recordings were used to calculate the speed of insertion. The positions of the electrodes were evaluated using a cone beam CT. All subjects underwent pure-tone audiometry tests before and after surgery, and the pure-tone average (PTA) was calculated from 250 to 4,000 Hz. RESULTS: The robot inserted implants in 5 patients, and complete insertion of the electrode array was achieved. The speed of insertion of the electrode array was 0.88 ± 0.12 mm/s. The mean loss of the PTA for 5 frequencies (250, 500, 1,000, 2,000, and 4,000 Hz) was 13.60 ± 7.70 dB. Only 1 patient showed a loss of the PTA by >20 dB. For these 5 patients, the cone beam CT findings showed that all the electrode arrays were in the tympanic ramp and had a grade of 0. The results were compared with those obtained from a cohort of 17 patients who underwent manual implantation of a MED-El Flex 24-electrode array. CONCLUSION: To minimize disturbance to the cochlea while atraumatic electrode arrays are inserted, electrodes can be inserted at a constant, slow speed in the inner ear with the assistance of the RobOtol® robot in a normal clinical surgical setting.

Auditory function and dysfunction: estrogen makes a difference.

Estrogen is the major female hormone involved in reproductive functions, but it also exerts a variety of additional roles in non-reproductive organs. In this review, we highlight the preclinical and clinical studies that have pointed out sex differences and estrogenic influence on audition. We also describe the experimental evidences supporting a protective role of estrogen towards acquired forms of hearing loss. Although a high level of endogenous estrogen is associated with a better hearing function, hormonal treatments at menopause have provided contradictory outcomes. The various factors that are likely to explain these discrepancies include the treatment regimen as well as the hormonal status and responsiveness of the patients. The complexity of estrogen signaling is being untangled and many downstream effectors of its genomic and non-genomic actions have been identified in other systems. Based on these advances and on the common physio-pathological events that underlie age-related, drug or noise-induced hearing loss, we discuss potential mechanisms for their protective actions in the cochlea.

Combinatorial regulation of hepatic cytoplasmic signaling and nuclear transcriptional events by the OGT/REV-ERBα complex.

The nuclear receptor REV-ERBα integrates the circadian clock with hepatic glucose and lipid metabolism by nucleating transcriptional comodulators at genomic regulatory regions. An interactomic approach identified O-GlcNAc transferase (OGT) as a REV-ERBα-interacting protein. By shielding cytoplasmic OGT from proteasomal degradation and favoring OGT activity in the nucleus, REV-ERBα cyclically increased O-GlcNAcylation of multiple cytoplasmic and nuclear proteins as a function of its rhythmically regulated expression, while REV-ERBα ligands mostly affected cytoplasmic OGT activity. We illustrate this finding by showing that REV-ERBα controls OGT-dependent activities of the cytoplasmic protein kinase AKT, an essential relay in insulin signaling, and of ten-of-eleven translocation (TET) enzymes in the nucleus. AKT phosphorylation was inversely correlated to REV-ERBα expression. REV-ERBα enhanced TET activity and DNA hydroxymethylated cytosine (5hmC) levels in the vicinity of REV-ERBα genomic binding sites. As an example, we show that the REV-ERBα/OGT complex modulates SREBP-1c gene expression throughout the fasting/feeding periods by first repressing AKT phosphorylation and by epigenomically priming the Srebf1 promoter for a further rapid response to insulin. Conclusion: REV-ERBα regulates cytoplasmic and nuclear OGT-controlled processes that integrate at the hepatic SREBF1 locus to control basal and insulin-induced expression of the temporally and nutritionally regulated lipogenic SREBP-1c transcript.

The logic of transcriptional regulator recruitment architecture at cis-regulatory modules controlling liver functions.

Control of gene transcription relies on concomitant regulation by multiple transcriptional regulators (TRs). However, how recruitment of a myriad of TRs is orchestrated at cis-regulatory modules (CRMs) to account for coregulation of specific biological pathways is only partially understood. Here, we have used mouse liver CRMs involved in regulatory activities of the hepatic TR, NR1H4 (FXR; farnesoid X receptor), as our model system to tackle this question. Using integrative cistromic, epigenomic, transcriptomic, and interactomic analyses, we reveal a logical organization where trans-regulatory modules (TRMs), which consist of subsets of preferentially and coordinately corecruited TRs, assemble into hierarchical combinations at hepatic CRMs. Different combinations of TRMs add to a core TRM, broadly found across the whole landscape of CRMs, to discriminate promoters from enhancers. These combinations also specify distinct sets of CRM differentially organized along the genome and involved in regulation of either housekeeping/cellular maintenance genes or liver-specific functions. In addition to these TRMs which we define as obligatory, we show that facultative TRMs, such as one comprising core circadian TRs, are further recruited to selective subsets of CRMs to modulate their activities. TRMs transcend TR classification into ubiquitous versus liver-identity factors, as well as TR grouping into functional families. Hence, hierarchical superimpositions of obligatory and facultative TRMs bring about independent transcriptional regulatory inputs defining different sets of CRMs with logical connection to regulation of specific gene sets and biological pathways. Altogether, our study reveals novel principles of concerted transcriptional regulation by multiple TRs at CRMs.

Daytime variation of perioperative myocardial injury in cardiac surgery and its prevention by Rev-Erbα antagonism: a single-centre propensity-matched cohort study and a randomised study.

BACKGROUND: On-pump cardiac surgery provokes a predictable perioperative myocardial ischaemia-reperfusion injury which is associated with poor clinical outcomes. We determined the occurrence of time-of-the-day variation in perioperative myocardial injury in patients undergoing aortic valve replacement and its molecular mechanisms. METHODS: We studied the incidence of major adverse cardiac events in a prospective observational single-centre cohort study of patients with severe aortic stenosis and preserved left ventricular ejection fraction (>50%) who were referred to our cardiovascular surgery department at Lille University Hospital (Lille, France) for aortic valve replacement and underwent surgery in the morning or afternoon. Patients were matched into pairs by propensity score. We also did a randomised study, in which we evaluated perioperative myocardial injury and myocardial samples of patients randomly assigned (1:1) via permuted block randomisation (block size of eight) to undergo isolated aortic valve replacement surgery either in the morning or afternoon. We also evaluated human and rodent myocardium in ex-vivo hypoxia-reoxygenation models and did a transcriptomic analysis in myocardial samples from the randomised patients to identify the signalling pathway(s) involved. The primary objective of the study was to assess whether myocardial tolerance of ischaemia-reperfusion differed depending on the timing of aortic valve replacement surgery (morning vs afternoon), as measured by the occurrence of major adverse cardiovascular events (cardiovascular death, myocardial infarction, and admission to hospital for acute heart failure). The randomised study is registered with ClinicalTrials.gov, number NCT02812901. FINDINGS: In the cohort study (n=596 patients in matched pairs who underwent either morning surgery [n=298] or afternoon surgery [n=298]), during the 500 days following aortic valve replacement, the incidence of major adverse cardiac events was lower in the afternoon surgery group than in the morning group: hazard ratio 0·50 (95% CI 0·32-0·77; p=0·0021). In the randomised study, 88 patients were randomly assigned to undergo surgery in the morning (n=44) or afternoon (n=44); perioperative myocardial injury assessed with the geometric mean of perioperative cardiac troponin T release was significantly lower in the afternoon group than in the morning group (estimated ratio of geometric means for afternoon to morning of 0·79 [95% CI 0·68-0·93; p=0·0045]). Ex-vivo analysis of human myocardium revealed an intrinsic morning-afternoon variation in hypoxia-reoxygenation tolerance, concomitant with transcriptional alterations in circadian gene expression with the nuclear receptor Rev-Erbα being highest in the morning. In a mouse Langendorff model of hypoxia-reoxygenation myocardial injury, Rev-Erbα gene deletion or antagonist treatment reduced injury at the time of sleep-to-wake transition, through an increase in the expression of the ischaemia-reperfusion injury modulator CDKN1a/p21. INTERPRETATION: Perioperative myocardial injury is transcriptionally orchestrated by the circadian clock in patients undergoing aortic valve replacement, and Rev-Erbα antagonism seems to be a pharmacological strategy for cardioprotection. Afternoon surgery might provide perioperative myocardial protection and lead to improved patient outcomes compared with morning surgery. FUNDING: Fondation de France, Fédération Française de Cardiologie, EU-FP7-Eurhythdia, Agence Nationale pour la Recherche ANR-10-LABX-46, and CPER-Centre Transdisciplinaire de Recherche sur la Longévité.

The BEACH protein LRBA is required for hair bundle maintenance in cochlear hair cells and for hearing.

Lipopolysaccharide-responsive beige-like anchor protein (LRBA) belongs to the enigmatic class of BEACH domain-containing proteins, which have been attributed various cellular functions, typically involving intracellular protein and membrane transport processes. Here, we show that LRBA deficiency in mice leads to progressive sensorineural hearing loss. In LRBA knockout mice, inner and outer hair cell stereociliary bundles initially develop normally, but then partially degenerate during the second postnatal week. LRBA deficiency is associated with a reduced abundance of radixin and Nherf2, two adaptor proteins, which are important for the mechanical stability of the basal taper region of stereocilia. Our data suggest that due to the loss of structural integrity of the central parts of the hair bundle, the hair cell receptor potential is reduced, resulting in a loss of cochlear sensitivity and functional loss of the fraction of spiral ganglion neurons with low spontaneous firing rates. Clinical data obtained from two human patients with protein-truncating nonsense or frameshift mutations suggest that LRBA deficiency may likewise cause syndromic sensorineural hearing impairment in humans, albeit less severe than in our mouse model.

Responsiveness of acoustic rhinometry to septorhinoplasty by comparison with rhinomanometry and subjective instruments.

OBJECTIVES: Nose patency measures and instruments assessing subjective health are increasingly being used in rhinology. However, there is very little evidence of comparing existing methods' responsiveness to change. We evaluated the responsiveness of acoustic rhinometry to nasal valve surgery by comparison with rhinomanometry and patient-reported outcome instruments. DESIGN: Prospective case-control study. SETTING: Tertiary referral University Hospital. PARTICIPANTS: Sixty consecutive patients with internal nasal valve dysfunction and 20 healthy volunteers as control group were enrolled. Prospectively collected data included acoustic rhinometry, rhinomanometry, NOSE scale, SNOT-23 questionnaire, visual analogue scale and demographics. MAIN OUTCOME MEASURES: Primary endpoint was the responsiveness of acoustic rhinometry to functional septorhinoplasty surgery at 3 months. Secondary endpoints were ability of acoustic rhinometry to reflect "known group" differences and correlation to subjective symptoms. RESULTS: Acoustic rhinometry was highly responsive to septorhinoplasty (P < 0.0001) while anterior rhinomanometry was not (P = 0.08). Based on the quartiles of the postoperative change in NOSE score, patients were classified as, respectively, non-responders, mild, moderate and good responders to surgery. Logistic regression model showed that acoustic rhinometry was able to discriminate non-responders to responders to surgery (P = 0.019), while anterior rhinomanometry failed (P = 0.611). Sensitivity and specificity of acoustic rhinometry were significantly higher (ROC area = 0.76) than rhinomanometry (ROC area = 0.48). Acoustic rhinometry was also superior than rhinomanometry to discriminate patients from control subjects and agreed better with patients-based subjective questionnaires. CONCLUSIONS: Our study confirms and quantifies the responsiveness of acoustic rhinometry to nasal valve surgery, with a higher sensitivity and specificity than rhinomanometry.

The nuclear bile acid receptor FXR is a PKA- and FOXA2-sensitive activator of fasting hepatic gluconeogenesis.

BACKGROUND & AIMS: Embedded into a complex signaling network that coordinates glucose uptake, usage and production, the nuclear bile acid receptor FXR is expressed in several glucose-processing organs including the liver. Hepatic gluconeogenesis is controlled through allosteric regulation of gluconeogenic enzymes and by glucagon/cAMP-dependent transcriptional regulatory pathways. We aimed to elucidate the role of FXR in the regulation of fasting hepatic gluconeogenesis. METHODS: The role of FXR in hepatic gluconeogenesis was assessed in vivo and in mouse primary hepatocytes. Gene expression patterns in response to glucagon and FXR agonists were characterized by quantitative reverse transcription PCR and microarray analysis. FXR phosphorylation by protein kinase A was determined by mass spectrometry. The interaction of FOXA2 with FXR was identified by cistromic approaches and in vitro protein-protein interaction assays. The functional impact of the crosstalk between FXR, the PKA and FOXA2 signaling pathways was assessed by site-directed mutagenesis, transactivation assays and restoration of FXR expression in FXR-deficient hepatocytes in which gene expression and glucose production were assessed. RESULTS: FXR positively regulates hepatic glucose production through two regulatory arms, the first one involving protein kinase A-mediated phosphorylation of FXR, which allowed for the synergistic activation of gluconeogenic genes by glucagon, agonist-activated FXR and CREB. The second arm involves the inhibition of FXR's ability to induce the anti-gluconeogenic nuclear receptor SHP by the glucagon-activated FOXA2 transcription factor, which physically interacts with FXR. Additionally, knockdown of Foxa2 did not alter glucagon-induced and FXR agonist enhanced expression of gluconeogenic genes, suggesting that the PKA and FOXA2 pathways regulate distinct subsets of FXR responsive genes. CONCLUSIONS: Thus, hepatic glucose production is regulated during physiological fasting by FXR, which integrates the glucagon/cAMP signal and the FOXA2 signal, by being post-translationally modified, and by engaging in protein-protein interactions, respectively. LAY SUMMARY: Activation of the nuclear bile acid receptor FXR regulates gene expression networks, controlling lipid, cholesterol and glucose metabolism, which are mostly effective after eating. Whether FXR exerts critical functions during fasting is unknown. The results of this study show that FXR transcriptional activity is regulated by the glucagon/protein kinase A and the FOXA2 signaling pathways, which act on FXR through phosphorylation and protein-protein interactions, respectively, to increase hepatic glucose synthesis.

Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease.

Bile acids are signaling molecules that coordinately regulate metabolism and inflammation via the nuclear farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5). These receptors activate transcriptional networks and signaling cascades controlling the expression and activity of genes involved in bile acid, lipid and carbohydrate metabolism, energy expenditure, and inflammation by acting predominantly in enterohepatic tissues, but also in peripheral organs. In this review, we discuss the most recent findings on the inter-organ signaling and interplay with the gut microbiota of bile acids and their receptors in meta-inflammation, with a focus on their pathophysiologic roles in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic steatohepatitis, and their potential therapeutic applications.

Stapes Surgery for Otosclerosis in Patients Presenting with Mixed Hearing Loss.

OBJECTIVES: To evaluate the efficacy of stapes surgery in patients presenting with a preoperative mixed hearing loss (bone conduction thresholds ≥40 dB; 40 < air conduction thresholds (AC) < 85 dB). PATIENTS AND METHODS: A total of 30 patients (32 ears) with mixed hearing loss who underwent primary stapedotomy were evaluated. Audiometric parameters were assessed before and after surgery. Contralateral thresholds were also reported. The need for a hearing aid (HA) after surgery and its impact on quality of life were also measured. RESULTS: AC and word recognition at 40, 55 and 70 dB were significantly improved after stapes surgery. Only 16.6% of the patients needed an HA after surgery and reported being satisfied with the aid. CONCLUSION: Stapes surgery improved auditory function in patients with mixed hearing loss, allowing most patients to delay the need for an HA without worsening their quality of life.