Atlas of Circadian Metabolism Reveals System-wide Coordination and Communication between Clocks.

Metabolic diseases are often characterized by circadian misalignment in different tissues, yet how altered coordination and communication among tissue clocks relate to specific pathogenic mechanisms remains largely unknown. Applying an integrated systems biology approach, we performed 24-hr metabolomics profiling of eight mouse tissues simultaneously. We present a temporal and spatial atlas of circadian metabolism in the context of systemic energy balance and under chronic nutrient stress (high-fat diet [HFD]). Comparative analysis reveals how the repertoires of tissue metabolism are linked and gated to specific temporal windows and how this highly specialized communication and coherence among tissue clocks is rewired by nutrient challenge. Overall, we illustrate how dynamic metabolic relationships can be reconstructed across time and space and how integration of circadian metabolomics data from multiple tissues can improve our understanding of health and disease.

CD4+ T cell-derived IFN-γ and LIGHT synergistically upregulate chemokine production from airway smooth muscle cells.

Airway smooth muscle (ASM) remodeling in asthmatic airways may contribute to persistent airflow limitation and airway hyperresponsiveness. CD4+ T cells infiltrate the ASM layer where they may induce a proliferative and secretory ASM cell phenotype. We studied the interaction between activated CD4+ T cells and ASM cells in co-culture in vitro and investigated the effects of CD4+ T cells on chemokine production by ASM cells. CD4+ T cells induced marked upregulation of C-X-C motif chemokine ligands (CXCL) 9, 10, and 11 in ASM cells. Blockade of the IFN-γ receptor on ASM cells prevented this upregulation. Furthermore, T cell-derived IFN-γ and LIGHT (lymphotoxin, exhibits inducible expression and competes with HSV glycoprotein D for binding to herpesvirus entry mediator, a receptor expressed on T lymphocytes) synergize in a dose-dependent manner to coordinately enhance CXCL9, 10, and 11 expression. The synergistic property of LIGHT was mediated exclusively through the lymphotoxin-ß receptor (LTBR), but not herpes virus entry mediator (HVEM). Disruption of LTBR signaling in ASM cells reduced CXCL9, 10, and 11 production and ASM cell-mediated CD4+ T cell chemotaxis. We conclude that the LIGHT-LTBR signaling axis acts together with IFN-γ to regulate chemokines that mediate lymphocyte infiltration in asthmatics.

Risk for diagnosis or treatment of mood or anxiety disorders in adults after SARS-CoV-2 infection, 2020-2022.

COVID-19 is associated with increased risks for mood or anxiety disorders, but it remains uncertain how the association evolves over time or which patient groups are most affected. We conducted a retrospective cohort study using a nationwide database of electronic health records to determine the risk of depressive or anxiety disorder diagnoses after SARS-CoV-2 infection by 3-month blocks from January 2020 to April 2022. The study population comprised 822,756 patients (51.8% female; mean age 42.8 years) with COVID-19 and 2,034,353 patients with other respiratory tract infections (RTIs) (53.5% female, mean age 30.6 years). First time diagnoses of depressive or anxiety disorders 14 days to 3 months after infection, as well as new or new plus recurrent prescriptions of antidepressants or anxiolytics, were compared between propensity score matched cohorts using Kaplan-Meier survival analysis, including hazard ratio (HR) and 95% confidence interval (CI). Risk of a new diagnosis or prescription was also stratified by age, sex, and race to better characterize which groups were most affected. In the first three months of the pandemic, patients infected with SARS-CoV-2 had significantly increased risk of depression or anxiety disorder diagnosis (HR 1.65 [95% CI, 1.30-2.08]). October 2021 to January 2022 (HR, 1.12 [95% CI, 1.06-1.18]) and January to April 2022 (HR, 1.08 [95% CI, 1.01-1.14]). Similar temporal patterns were observed for antidepressant and anxiolytic prescriptions, when the control group was patients with bone fracture, when anxiety and depressive disorders were considered separately, when recurrent depressive disorder was tested, and when the test period was extended to 6 months. COVID-19 patients ≥65 years old demonstrated greatest absolute risk at the start of the pandemic (6.8%), which remained consistently higher throughout the study period (HR, 1.20 [95% CI, 1.13-1.27]), and overall, women with COVID-19 had greater risk than men (HR 1.35 [95% CI 1.30-1.40]).

First Results from a Broadband Search for Dark Photon Dark Matter in the 44 to 52 µeV Range with a Coaxial Dish Antenna.

We present first results from a dark photon dark matter search in the mass range from 44 to 52 µeV (10.7-12.5 GHz) using a room-temperature dish antenna setup called GigaBREAD. Dark photon dark matter converts to ordinary photons on a cylindrical metallic emission surface with area 0.5 m^{2} and is focused by a novel parabolic reflector onto a horn antenna. Signals are read out with a low-noise receiver system. A first data taking run with 24 days of data does not show evidence for dark photon dark matter in this mass range, excluding dark photon photon mixing parameters χ≳10^{-12} in this range at 90% confidence level. This surpasses existing constraints by about 2 orders of magnitude and is the most stringent bound on dark photons in this range below 49 µeV.

Fixed prosthodontic rehabilitation of a patient after bariatric surgery using a facially driven fully digital workflow: A clinical report with a 3-year follow-up.

Patients who have received bariatric surgery have specific and complex dental needs. After surgery, nutrient deficiencies, osteoporosis, gastroesophageal reflux, and changes to the oral cavity may be seen, and erosion, caries, wear, xerostomia, hypersensitivity, and changes to the salivary buffering capacity may occur. In addition, patients are advised to ingest smaller, more frequent, meals throughout the day, and the oral condition may decline rapidly after surgery. Without oversight, this accelerated decline may even necessitate complete mouth rehabilitation postoperatively. Dental providers should be an integral part of the multidisciplinary management team of these patients. This clinical report describes a patient with a terminal dentition following bariatric surgery who underwent prosthodontic rehabilitation with a facially driven fully digital workflow.

Geographic Variation in Colorectal Cancer Incidence Among Asian Americans: A Population-Based Analysis 2006-2016.

Among Asian Americans, cancer is the leading cause of death and colorectal cancer (CRC) is the second most common cancer.1 The uptake of CRC screening influences incidence and mortality trends; however, the most recent American Cancer Society CRC statistics reveals ongoing disparities in screening based on race and ethnicity, with people of Asian descent demonstrating the lowest CRC screening rates despite being the fastest growing racial or ethnic group in the United States.2,3.

Impact of Care in an Interdisciplinary Inflammatory Bowel Disease Specialty Clinic on Outcomes in Patients Insured with Medicaid.

BACKGROUND: Inflammatory bowel disease (IBD) patients are known to benefit from care delivered in a specialized, interdisciplinary setting. We aimed to evaluate the impact of this model on health outcomes, quality metrics, and health care resource utilization (HRU) in IBD patients insured with Medicaid. MATERIALS AND METHODS: In July 2017, IBD patients at our tertiary hospital were transitioned from a fellows' general gastroenterology (GI) clinic to a fellows' interdisciplinary IBD clinic. IBD patients were included if they were insured with Medicaid, had at least 1 visit in the general GI clinic between July 1, 2016 and June 30, 2017, and at least 1 visit between July 1, 2017 and June 30, 2018 in the IBD clinic. Characteristics related to patients' IBD course, overall health care maintenance, and HRU were compared. RESULTS: A total of 170 patients (51% male, mean age 39 y) were included. After the transition to the IBD clinic, use of corticosteroids (37% vs. 25%; P =0.004) and combination therapy were significantly lower (55% vs. 38%; P =0.0004), although use of high-dose biologics numerically increased (58.5% vs. 67%; P =0.05). Posttransition, patients showed significantly lower levels of mean C-reactive protein ( P =0.04). After the transition, patients attended significantly fewer outpatient GI visits ( P =0.0008) but were more often seen by other health care specialists ( P =0.0003), and experienced a numeric decrease in HRU with fewer emergency department visits, hospitalizations, and surgeries. CONCLUSIONS: Care in an interdisciplinary, IBD specialty setting is associated with significantly decreased corticosteroid use, decreased C-reactive protein levels, and improved access to ancillary services in Medicaid patients.

Tools for deprescribing in severe dementia: A scoping review.

OBJECTIVES: Identification of inappropriate medications in people living with severe dementia is a complex task which has the potential to reduce avoidable adverse events and increase quality of life. This scoping review (i) identifies published tools intended to aid deprescribing in people living with severe dementia and (ii) describes evaluations of their usefulness in clinical practice. METHODS: A scoping review was undertaken, with Medline, Medline in Process, EMBASE, Cochrane Library, CINAHL, Scopus and Web of Science databases, from inception to April 2023, identifying tools for deprescribing in severe dementia. A tool was considered as any resource for deprescribing, including clinical study, scientific publication, health guideline, website, algorithm, model or framework. Two reviewers assessed the eligibility of articles through abstract and full text review. Data extracted from included studies were summarized through narrative synthesis. RESULTS: Twelve studies were identified from 18,633 articles screened. Tools were categorized into three groups: deprescribing interventions (n = 2), consensus-based deprescribing criteria (n = 5), and medication-specific recommendations (n = 5). Six studies developed tools using expert opinion and ten tools were tested in people living with severe dementia. Only one of the four studies that evaluated patient outcomes (cognitive change and adverse events) identified clear clinical benefit from medication withdrawal. CONCLUSIONS: Clinical application of current deprescribing tools is limited due to the lack of evidence-based research on the clinical effects of individual medication deprescribing in people with severe dementia. Further research on patient outcomes, including cognitive change and adverse events, will help clarify the role of these tools in clinical care.

Prenatal perfluoroalkyl substances exposure and maternal sex steroid hormones across pregnancy.

BACKGROUND: Poly- and perfluoroalkyl substances (PFAS) are ubiquitous and persistent environmental contaminants that may act as endocrine disruptors in utero, but the specific endocrine pathways are unknown. OBJECTIVE: We examined associations between maternal serum PFAS and sex steroid hormones at three time points during pregnancy. METHODS: Pregnant women participating in the Understanding Pregnancy Signals and Infant Development (UPSIDE) study contributed biospecimens, questionnaire, and medical record data in each trimester (n = 285). PFAS (including perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), perfluorononanoic acid (PFNA) and perfluorodecanoic acid (PFDA)) were analyzed in second-trimester serum samples by high-performance liquid chromatography and tandem mass spectrometry (LC-MS/MS). Total testosterone [TT], free testosterone [fT], estrone [E1], estradiol [E2], and estriol [E3]) were measured by LC-MS/MS in serum samples from each trimester. Linear mixed models with random intercepts were used to examine associations between log-transformed PFAS concentrations and hormone levels, adjusting for covariates, and stratifying by fetal sex. Results are presented as the mean percentage difference (Δ%) in hormone levels per ln-unit increase in PFAS concentration. RESULTS: In adjusted models, PFHxS was associated with higher TT (%Δ = 20.0, 95%CI: 1.7, 41.6), particularly among women carrying male fetuses (%Δ = 15.3, 95%CI: 1.2, 30.7); this association strengthened as the pregnancy progressed. PFNA (%Δ = 7.9, 95%CI: 3.4, 12.5) and PFDA (%Δ = 7.2, 95%CI: 4.9, 9.7) were associated with higher fT, with associations again observed only in women carrying male fetuses. PFHxS was associated with higher levels of E2 and E3 in women carrying female fetuses (%Δ = 13.2, 95%CI: 0.5, 29.1; %Δ = 17.9, 95%CI: 3.2, 34.8, respectively). No associations were observed for PFOS and PFOA. CONCLUSION: PFHxS, PFNA, and PFDA may disrupt androgenic and estrogenic pathways in pregnancy in a sex-dependent manner.

Associations between neighborhood stress and maternal sex steroid hormones in pregnancy.

BACKGROUND: Neighborhood stressors (e.g., crime and deprivation) have been associated with adverse pregnancy outcomes including preterm birth and low birth weight. A potential mechanism is disruption of maternal endocrine pathways. While stress hormones (e.g., cortisol) have received much attention, other relevant hormones, including sex steroids, have been overlooked. METHODS: Pregnant women in the Understanding Pregnancy Signals and Infant Development (UPSIDE) study contributed biospecimens, questionnaires, and medical record data (n = 262). In each trimester, maternal serum total testosterone [TT], estrone, estradiol, and estriol were measured using LC/MS-MS and serum free testosterone was measured by equilibrium dialysis. In the third trimester, participants reported on neighborhood stress over the last year through the validated City Stress Inventory. We examined two subscales: 11-item neighborhood disorder (e.g., vacant buildings, crime) and 7-item exposure to violence (personal experiences of violence). Composite scores were calculated and examined categorically (quartile (Q) for neighborhood disorder and any/none for exposure to violence). We fitted linear mixed models examining associations between neighborhood stressors and sex steroid hormones across pregnancy as well as trimester-specific linear regression models, all adjusting for confounders. Secondarily, we stratified by fetal sex. Results are presented as percentage change (∆%) and 95% confidence interval (CI) in hormones. RESULTS: Most participants (73%) reported one or more exposures to neighborhood disorder; 22% reported any exposure to violence. In adjusted models, neighborhood disorder was associated with higher TT across pregnancy (Q2: %∆= 37.3, 95%CI: 13.2, 66.5; Q3: %∆= 22.2, 95%CI: 1.2, 47.5; and Q4: %∆= 25.7, 95%CI: 1.6, 55.3), with the strongest associations observed in the third trimester (Q2: %∆= 38.0, 95%CI: 10.6, 72.1; Q3: %∆= 29.2, 95%CI: 4.4, 59.9; and Q4: %∆=33.4, 95%CI: 4.9, 69.6). In stratified models, neighborhood disorder was associated with higher TT among women carrying male fetuses (%∆ range: 48.2-84.8). Exposure to violence was not associated with any hormones. CONCLUSION: Neighborhood disorder is associated with higher maternal testosterone levels, which may have implications for maternal and child health. Additional research is needed to understand the mechanisms by which neighborhood stress impacts endocrine physiology.

Fixed prosthodontic rehabilitation for an adult with ectodermal dysplasia using a completely digital workflow.

This clinical report describes the fixed prosthodontic treatment of an adult patient with ectodermal dysplasia by using a completely digital workflow, from the initial consultation appointment to the fabrication of the definitive implant-supported prostheses.

A Systematic Review of Simulation Models to Track and Address the Opioid Crisis.

The opioid overdose crisis is driven by an intersecting set of social, structural, and economic forces. Simulation models are a tool to help us understand and address thiscomplex, dynamic, and nonlinear social phenomenon. We conducted a systematic review of the literature on simulation models of opioid use and overdose up to September 2019. We extracted modeling types, target populations, interventions, and findings; created a database of model parameters used for model calibration; and evaluated study transparency and reproducibility. Of the 1,398 articles screened, we identified 88 eligible articles. The most frequent types of models were compartmental (36%), Markov (20%), system dynamics (16%), and agent-based models (16%). Intervention cost-effectiveness was evaluated in 40% of the studies, and 39% focused on services for people with opioid use disorder (OUD). In 61% of the eligible articles, authors discussed calibrating their models to empirical data, and in 31%, validation approaches used in the modeling process were discussed. From the 63 studies that provided model parameters, we extracted the data sources on opioid use, OUD, OUD treatment, cessation or relapse, emergency medical services, and death parameters. From this database, potential model inputs can be identified and models can be compared with prior work. Simulation models should be used to tackle key methodological challenges, including the potential for bias in the choice of parameter inputs, investment in model calibration and validation, and transparency in the assumptions and mechanics of simulation models to facilitate reproducibility.

Dimethandrolone, a Potential Male Contraceptive Pill, is Primarily Metabolized by the Highly Polymorphic UDP-Glucuronosyltransferase 2B17 Enzyme in Human Intestine and Liver.

Dimethandrolone undecanoate (DMAU), an oral investigational male hormonal contraceptive, is a prodrug that is rapidly converted to its active metabolite, dimethandrolone (DMA). Poor and variable oral bioavailability of DMA after DMAU dosing is a critical challenge to develop it as an oral drug. The objective of our study was to elucidate the mechanisms of variable pharmacokinetics of DMA. We first identified DMA metabolites formed in vitro and in vivo in human hepatocyte incubation and serum samples following oral DMAU administration in men, respectively. The metabolite identification study revealed two metabolites, DMA-glucuronide (DMA-G; major) and the androstenedione analog of DMA (minor), in the hepatocyte incubations. After oral DMAU administration, only DMA-G was detected in serum, which was >100-fold compared with DMA levels, supporting glucuronidation as the major elimination mechanism for DMA. Next, 13 clinically relevant UDP-glucuronosyltransferase (UGT) enzymes were tested for their involvement in DMA-G formation, which revealed a major role of UDP-glucuronosyltransferase 2B17 (UGT2B17) isoform with a smaller contribution of UGT1A9 in DMA-G formation. These data were confirmed by dramatically higher DMA glucuronidation rates (>200- and sevenfold) in the high versus the null UGT2B17-expressing human intestinal and liver microsomes, respectively. Since human UGT2B17 is a highly variable enzyme with a 20%-80% gene deletion frequency, the in vitro data suggest a major role of UGT2B17 polymorphism on the first-pass metabolism of DMA. Further, considering DMA is a selective and sensitive UGT2B17 substrate, it could be used as a clinical probe of UGT2B17 activity. SIGNIFICANCE STATEMENT: Dimethandrolone (DMA) is an active metabolite of dimethandrolone undecanoate (DMAU), an investigational male hormonal contraceptive. Previous studies have indicated poor and inconsistent bioavailability of DMAU following oral administration. This study found that UDP-glucuronosyltransferase 2B17-mediated high intestinal first-pass metabolism is the key mechanism of variable DMA bioavailability.

Two-Year Analysis of a New Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men: Efficacy, Impact on Psychosexual Function, and Safety.

BACKGROUND: Long-term data evaluating the efficacy and safety of oral testosterone undecanoate (oral TU; JATENZO) in adult hypogonadal men provides important information for healthcare professionals who prescribe testosterone replacement therapy (TRT). AIM: To determine the efficacy and safety of long-term oral TU therapy, including its impact on total testosterone (T) levels and psychosexual functioning. METHODS: Hypogonadal men, between 18 and 75 years old, (mean age 56.2; 87.2% white) who completed a 12-month, open-label, multicenter, randomized, active-controlled trial were given the opportunity to enroll in a 12-month extension study. Among the 129 eligible TU-treated subjects, 86 chose this option, and 69 completed 24 months of uninterrupted oral TU therapy. OUTCOMES: The efficacy of oral TU was documented by measuring total serum T concentrations; sexual function was measured using the Psychosexual Daily Questionnaire (PDQ). For safety, liver function tests, cardiovascular endpoints, and prostate health were measured. RESULTS: Over 2 years, total serum T concentrations for patients treated with oral TU were in the eugonadal range (300-1,000 ng/dL [10-35 nmol/L]; mean ± SD: 617 ± 427 ng/dL [21 ± 15 nmol/L]) and increased significantly from baseline (P < .0001). For sexual function, mean score changes versus baseline for all PDQ domains at all time points were significantly improved (P < .0011 for all). For the sexual activity and sexual desire components, patient scores were consistently greater than validated thresholds for clinically meaningful change. Typical T-induced safety changes were observed, including a 3-6 mm Hg increase in systolic blood pressure (P < .05); a slight increase in hematocrit (P < .0001) that stayed <48% throughout the study; no clinically significant changes in prostate-specific antigen levels; and decreased high-density lipoprotein cholesterol (-9.8 ± 0.9 mg/dL from baseline; P < .0001). There were no clinically significant changes from baseline in liver function tests. CLINICAL IMPLICATIONS: Over 2 years of treatment, this novel oral TU formulation maintained total T concentrations in mideugonadal ranges, with improvements in sexual function and no clinically significant changes in liver function or other safety concerns previously associated with oral TRT. STRENGTHS & LIMITATIONS: These are the first long-term data to evaluate the efficacy and safety of a novel formulation of oral TU; the comparative long-term safety of oral TU would be strengthened by confirmatory studies versus other TRT formulations. CONCLUSION: Oral TU offers a safe and effective long-term treatment option for men with hypogonadism. Honig S, Gittelman M, Kaminetsky J, et al. Two-Year Analysis of a New Oral Testosterone Undecanoate (TU) Formulation in Hypogonadal Men: Efficacy, Impact on Psychosexual Function, and Safety. J Sex Med 2022;19:1750-1758.

Fixed prosthodontic rehabilitation with a fully digital workflow for a teenage patient with amelogenesis imperfecta: A 2-year follow-up.

Amelogenesis imperfecta is a hereditary disorder that affects the enamel formation of the primary and permanent dentition and has significant consequences because hypersensitivity causes difficulty with oral hygiene, function, self-esteem, and quality of life. Patients diagnosed with amelogenesis imperfecta often require extensive treatment, often at an early age. Prosthodontic intervention of adolescent patients with amelogenesis imperfecta presents specific clinical challenges. This clinical report describes the fixed prosthodontic rehabilitation of a teenage patient with amelogenesis imperfecta by using a fully digital workflow throughout the treatment process, which facilitated functional, biomechanical, esthetic, and sociopsychological improvements.

Fixed prosthodontic rehabilitation for an adolescent patient with ectodermal dysplasia using a fully digital workflow: Two-year follow-up.

Ectodermal dysplasia is a rare genetic disorder characterized by congenital abnormalities of tissues and structures of ectodermal origin, such as the hair, nails, skin, sweat glands, and teeth. Common dental characteristics include retained primary teeth, conical shaped incisors and canines, and hypodontia or oligodontia. Early prosthodontic intervention of young patients diagnosed with ectodermal dysplasia is essential as symptoms can have substantial esthetic, functional, and psychosocial impacts. This clinical report describes the fixed prosthodontic treatment of an adolescent patient with ectodermal dysplasia by using a fully digital workflow. Digital workflows streamlined the treatment process and allowed for esthetic, functional, and psychological improvements in an efficient manner.

Combined bone- and mucosa-supported 3D-printed guide for sinus slot preparation and prosthetically driven zygomatic implant placement.

The use of zygomatic implants to rehabilitate the severely atrophic maxilla has been well documented since first being introduced by Brånemark. Placement of zygomatic implants is technically complex, with catastrophic complications and numerous prosthetic challenges resulting from imprecise placement. The purpose of this report was to demonstrate a technique that allows transfer of the preoperatively planned sinus slot position to the surgical field by using cone beam computed tomography (CBCT) and an implant planning software program to fabricate a combined bone- and mucosa-supported 3D-printed surgical guide. This facilitates optimal zygomatic implant positioning and promotes favorable biomechanics with a predictable prosthetic outcome.

DZIP1 regulates mammalian cardiac valve development through a Cby1-ß-catenin mechanism.

BACKGROUND: Mitral valve prolapse (MVP) is a common and progressive cardiovascular disease with developmental origins. How developmental errors contribute to disease pathogenesis are not well understood. RESULTS: A multimeric complex was identified that consists of the MVP gene Dzip1, Cby1, and ß-catenin. Co-expression during valve development revealed overlap at the basal body of the primary cilia. Biochemical studies revealed a DZIP1 peptide required for stabilization of the complex and suppression of ß-catenin activities. Decoy peptides generated against this interaction motif altered nuclear vs cytosolic levels of ß-catenin with effects on transcriptional activity. A mutation within this domain was identified in a family with inherited non-syndromic MVP. This novel mutation and our previously identified DZIP1S24R variant resulted in reduced DZIP1 and CBY1 stability and increased ß-catenin activities. The ß-catenin target gene, MMP2 was up-regulated in the Dzip1S14R/+ valves and correlated with loss of collagenous ECM matrix and myxomatous phenotype. CONCLUSION: Dzip1 functions to restrain ß-catenin signaling through a CBY1 linker during cardiac development. Loss of these interactions results in increased nuclear ß-catenin/Lef1 and excess MMP2 production, which correlates with developmental and postnatal changes in ECM and generation of a myxomatous phenotype.

Desert hedgehog-primary cilia cross talk shapes mitral valve tissue by organizing smooth muscle actin.

Non-syndromic mitral valve prolapse (MVP) is the most common heart valve disease affecting 2.4% of the population. Recent studies have identified genetic defects in primary cilia as causative to MVP, although the mechanism of their action is currently unknown. Using a series of gene inactivation approaches, we define a paracrine mechanism by which endocardially-expressed Desert Hedgehog (DHH) activates primary cilia signaling on neighboring valve interstitial cells. High-resolution imaging and functional assays show that DHH de-represses smoothened at the primary cilia, resulting in kinase activation of RAC1 through the RAC1-GEF, TIAM1. Activation of this non-canonical hedgehog pathway stimulates α-smooth actin organization and ECM remodeling. Genetic or pharmacological perturbation of this pathway results in enlarged valves that progress to a myxomatous phenotype, similar to valves seen in MVP patients. These data identify a potential molecular origin for MVP as well as establish a paracrine DHH-primary cilium cross-talk mechanism that is likely applicable across developmental tissue types.

The IL-27 component EBI-3 and its receptor subunit IL-27Rα are essential for the cytoprotective action of humanin on male germ cells†.

Humanin (HN) is a mitochondrial-derived peptide that protects many cells/tissues from damage. We previously demonstrated that HN reduces stress-induced male germ cell apoptosis in rodents. HN action in neuronal cells is mediated through its binding to a trimeric cell membrane receptor composed of glycoprotein 130 (gp130), IL-27 receptor subunit (IL-27R, also known as WSX-1/TCCR), and ciliary neurotrophic factor receptor subunit (CNTFR). The mechanisms of HN action in testis remain unclear. We demonstrated in ex-vivo seminiferous tubules culture that HN prevented heat-induced germ cell apoptosis was blocked by specific anti-IL-27R, anti-gp130, and anti-EBI-3, but not by anti-CNTFR antibodies significantly. The cytoprotective action of HN was studied by using groups of il-27r-/- or ebi-3-/- mice administered the following treatment: (1) vehicle; (2) a single intraperitoneal (IP) injection of HN peptide; (3) testicular hyperthermia; and (4) testicular hyperthermia plus HN. We demonstrated that HN inhibited heat-induced germ cell apoptosis in wildtype but not in il-27r-/- or ebi-3-/- mice. HN restored heat-suppressed STAT3 phosphorylation in wildtype but not il-27r-/- or ebi-3-/- mice. Dot blot analyses showed the direct interaction of HN with IL-27R or EBI-3 peptide. Immunofluorescence staining showed the co-localization of IL-27R with HN and gp130 in Leydig cells and germ cells. We conclude that the anti-apoptotic effects of HN in mouse testes are mediated through interaction with EBI-3, IL-27R, and activation of gp130, whereas the role of CNTFR needs further studies. This suggests a multicomponent tissue-specific receptor for HN in the testis and links HN action with the IL-12/IL-27 family of cytokines.