HL144 / Nautilus, Daewoong Pharma - LARVOL DELTA

[VIRTUAL] Airway Reactivity to Optogenetic Parasympathetic Nerve Stimulation Is Enhanced by Acute but Not Chronic Eosinophilia in Mice (ATS 2021) - "Funding: HL144008, AI152498, HL145906 Rationale: Airway parasympathetic nerves provide the dominant control of airway tone... Both acute and chronic eosinophilia increase reflex bronchoconstriction to inhaled serotonin. After acute allergen challenge, airway parasympathetic neurons are hyperreactive to light stimulation. In contrast, chronic eosinophilia did not increase bronchoconstriction in response to parasympathetic nerve activation, which may suggest that increased sensory nerve activity is responsible for increased reflex bronchoconstriction in these mice."

Preclinical • Anesthesia • Eosinophilia • IL5

[VIRTUAL] Scn1b deletion results in sinoatrial node dysfunction, atrial remodeling, and increased susceptibility to atrial fibrillation in addition to developmental and epileptic encephalopathy (AES 2020) - "Scn1b LOF results in atrial remodeling and AF, demonstrating the critical role played by Scn1b in atrial physiology during early postnatal mouse development. Our results suggest that SCN1B LOF variants may significantly impact the developing pediatric heart in addition to the brain. These results, together with our work in other mouse models of sodium channelopathies, have led us to propose a neuro-cardiac mechanism for SUDEP."

Atrial Fibrillation • Cardiovascular • CNS Disorders • Epilepsy • Heart Failure • Pediatrics

[VIRTUAL] Self-report and Polysomnography Sleep and Mortality in Adults: A Machine Learning Replication Analysis (Sleep 2020) - "Sleep is a strong predictor of mortality in adults that should be considered among other more routinely used predictors. Future research should examine differences and similarities between SHHS and WSC that may explain the finding that different aspects of sleep were important in each cohort. Support: NIA grant AG056331, NHLBI grant HL114473, NHLBI grant R01HL62252, NIA grant R01AG036838, NIA grant R01AG058680"

Clinical • CNS Disorders • Obstructive Sleep Apnea • Psychiatry • Sleep Apnea • Sleep Disorder

[VIRTUAL] Hypoxemia During Sleep Disordered Breathing and Cardiovascular Disease: A Comparison of Different Oxygen Desaturation Measures (Sleep 2020) - "Different metrics of nocturnal hypoxemia derived from polysomnography were associated with CV risk in the SHHS. However, after covariate adjustment, only shorter average desaturation duration, and higher hypoxic burden and Tlt 90% were independent CV risk factors. Support: AASM Foundation (194-SR-18,188-SR-17); American Heart Association (19CDA34660137); NIH (U01HL53940,U 01HL53941,U01HL63463,U01HL53937, U01HL53938,U01H L53916,U01HL53934,U01HL63429,U01HL53931,HL114473, P01HL094307,HL134015,R35HL135818,1R21HL145492- 01,R01HL102321,R01HL128658); The State Research Funding (KUH: 5041767, 5041768; TUH: VTR3242, VTR3228, EVO2089), Academy of Finland (313697, 323536), Business Finland (5133/31/2018), Respiratory Foundation of Kuopio Region, Tampere Tuberculosis Foundation, Research Foundation of Pulmonary Diseases, Foundation of Finnish Anti-Tuberculosis Association."

CNS Disorders • Obstructive Sleep Apnea • Psychiatry • Sleep Disorder

Boosting NAD Level Suppresses Inflammatory Activation of PBMC in Heart Failure. (PubMed, J Clin Invest) - "These findings suggest that systemic inflammation in HF patients is causally linked to mitochondrial function of the PBMC. Increasing NAD levels may have the potential to improve mitochondrial respiration and attenuate proinflammatory activation of PBMC in HF. FundingThis study is funded by NIH R21 HL126209 (to RT and KO), NIH R01 HL144937 (to KO and RT) and University of Washington ITHS Catalyst Award (to DDW). Both BZ (18POST33990352) and DDW (18POST34030098) are funded by the AHA Postdoctoral Fellowships."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Immunology • Metabolic Disorders • Psychiatry

[VIRTUAL] TMEM16A Modulates TGFβ1-Induced MLC2 Phosphorylation in Human Airway Smooth Muscle (ATS-I 2020) - "Previously, we have shown that TGF-β1 significantly increases carbachol (CCh)-induced [Ca 2+ ] i levels, myosin light chain 2 (MLC2) and myosin phosphatase target subunit 1 (MYPT1) phosphorylation levels and augments CCh-induced bronchoconstriction. These results suggest a significant role for CaCCs, specifically TMEM16A, in TGF-β1-induced MLC2 phosphorylation and CCh-induced HASM contraction. Supported by NIH funding 2P01HL114471-06 and 1UL1TR003017-01"

Asthma • Immunology • Respiratory Diseases

[VIRTUAL] Aconitate Decarboxylase-1 Deficiency Promotes Bacterial Dissemination During Intrapulmonary Klebsiella Pneumoniae Infection (ATS-I 2020) - "ACOD1 is critical in controlling Klebsiella pneumoniae infection following extrapulmonary dissemination and improves host resilience during KP-induced sepsis. The host protective mechanism of ACOD1 may be due, in part, through secretion of itaconate and direct antimicrobial effect against KP. This abstract is funded by: National Institutes of Health, Burroughs Wellcome Fund, Winters Foundation Grant (to T.L.S.), National Institutes of Health P01 HL114453 (to R.K.M."

Infectious Disease • Pneumonia • Respiratory Diseases • Septic Shock • MPO

[VIRTUAL] Age-Associated ATP Citrate Lyase Deficiency Induces Resistance to Apoptosis in Myofibroblasts and Impairs Fibrosis Resolution (ATS-I 2020) - "Lung tissues from bleomycin-injured aged and young C57BL/6 mice were also compared for differences in ACLY and pro-fibrotic gene/protein expression. Both genetic and pharmacologic loss-of-function studies of ACLY indicate a phenotypic shift to a more activated, ECM-producing, apoptosis-resistant state in lung fibroblasts. A more sustained downregulation of ACLY is observed after injury in aged mice, which exhibit a diminished capacity for fibrosis resolution. Therapeutic reconstitution of ACLY expression may represent a metabolic strategy to restore sensitivity to myofibroblast apoptosis and to accelerate fibrosis resolution."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Respiratory Diseases • COL1A1

[VIRTUAL] SIRT3 Promotes Resolution of Persistent Lung Fibrosis Associated with Aging (ATS-I 2020) - " Cellular models included fibroblasts isolated from lungs of human subjects with IPF, and animal model of persistent lung fibrosis in aged (18 months of age) mice subjected to intratracheal bleomycin injury. Our results indicate that SIRT3 deficiency contributes to the reduced capacity for resolution of fibrosis associated with aging based on the following observations: (1) SIRT3 expression is decreased in IPF; (2) SIRT3 is suppressed during the fibrogenic phase of lung injury; (3) SIRT3 deficiency leads to senescence and apoptosis resistance; and (4) over-expression of SIRT3 promotes resolution and reverses established fibrosis in mice. These studies provide a premise to elucidate the primary molecular targets and activities through which SIRT3 exerts its protective and anti-fibrotic effects. Grants: NIH grants, P01 HL114470 and R01 AG046210; and a VA Merit Award, I01BX003056."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Respiratory Diseases

Royalty Pharma announces proposal to acquire Elan (PRNewswire) - "Royalty Pharma is proposing, on an indicative basis, to make an offer for Elan...of US$11[1] for every Elan Share and every Elan ADS...Royalty Pharma believes that the Proposal offers Elan Shareholders an attractive financial alternative that will allow them to realize value for their Elan Stock in cash immediately. Royalty Pharma notes that while Elan's management has demonstrated its ability to execute several significant disposals, including the sale of some or all of bapineuzumab."

Anticipated licensing / partnership • Sales • Alzheimer's Disease

Plasminogen Activator Inhibitor-1 Induces Alveolar Type 2 Cell Senescence Through Activating p53-p21-Rb Pathways In Vitro and In Vivo (ATS 2017) - "...PAI-1 shRNA also attenuates bleomycin- or doxorubicin-induced p53S18 phosphorylation, p53 expression, and L2 cell senescence [the activity of senescence-associated beta-galactosidase (SA-b-gal)]...In vivo studies using a newly developed tamoxifen inducible, ATII cell specific PAI-1 conditional knockout mouse model further show that knocking out the PAI-1 gene specifically in ATII cells in mice increases the basal level of Rb phosphorylation and attenuates bleomycin-induced increases in p53S18 phosphorylation, p53 and p21 protein levels, ATII cell senescence (SA-b-gal activity), and lung fibrosis in vivo... These results reveal novel functions of PAI-1 in regulating the expression/function of the key components in cell cycle control. The results also suggest that increased PAI-1 expression contributes importantly to ATII cell senescence in IPF/fibrotic lung.nFounding sources: This work was supported by NIH grants HL088141, AG046701, and R56HL131054 (to R-M Liu) and HL114470 (to

Preclinical • Biosimilar • Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Oncology • Ophthalmology

Age-Associated ATP Citrate Lyase Deficiency Induces Resistance to Apoptosis in Myofibroblasts and Impairs Fibrosis Resolution (ATS 2020) - "Lung tissues from bleomycin-injured aged and young C57BL/6 mice were also compared for differences in ACLY and pro-fibrotic gene/protein expression. Both genetic and pharmacologic loss-of-function studies of ACLY indicate a phenotypic shift to a more activated, ECM-producing, apoptosis-resistant state in lung fibroblasts. A more sustained downregulation of ACLY is observed after injury in aged mice, which exhibit a diminished capacity for fibrosis resolution. Therapeutic reconstitution of ACLY expression may represent a metabolic strategy to restore sensitivity to myofibroblast apoptosis and to accelerate fibrosis resolution.Funding: NIH grants; P01 HL114470 and R01 AG046210 (VJT), T32 5T32HL134640-02 (SRS), and VA Merit Award I01BX003056 (VJT)"

COL1A1

Aconitate Decarboxylase-1 Deficiency Promotes Bacterial Dissemination During Intrapulmonary Klebsiella Pneumoniae Infection (ATS 2020) - "ACOD1 is critical in controlling Klebsiella pneumoniae infection following extrapulmonary dissemination and improves host resilience during KP-induced sepsis. The host protective mechanism of ACOD1 may be due, in part, through secretion of itaconate and direct antimicrobial effect against KP.This abstract is funded by: National Institutes of Health, Burroughs Wellcome Fund, Winters Foundation Grant (to T.L.S.), National Institutes of Health P01 HL114453 (to R.K.M. and J.S.L.), S10OD023402 (to S.G.W.), R01 HL142084 and K24 HL14285 (to J.S.L.)."

MPO

TMEM16A Modulates TGFβ1-Induced MLC2 Phosphorylation in Human Airway Smooth Muscle (ATS 2020) - "Previously, we have shown that TGF-β1 significantly increases carbachol (CCh)-induced [Ca2+]i levels, myosin light chain 2 (MLC2) and myosin phosphatase target subunit 1 (MYPT1) phosphorylation levels and augments CCh-induced bronchoconstriction. These results suggest a significant role for CaCCs, specifically TMEM16A, in TGF-β1-induced MLC2 phosphorylation and CCh-induced HASM contraction.Supported by NIH funding 2P01HL114471-06 and 1UL1TR003017-01"

SIRT3 Promotes Resolution of Persistent Lung Fibrosis Associated with Aging (ATS 2020) - "In this study, we explored a role for SIRT3 in myofibroblast activation and age-associated fibrosis in murine models of lung fibrosis.Cellular models included fibroblasts isolated from lungs of human subjects with IPF, and animal model of persistent lung fibrosis in aged (18 months of age) mice subjected to intratracheal bleomycin injury. Our results indicate that SIRT3 deficiency contributes to the reduced capacity for resolution of fibrosis associated with aging based on the following observations: (1) SIRT3 expression is decreased in IPF; (2) SIRT3 is suppressed during the fibrogenic phase of lung injury; (3) SIRT3 deficiency leads to senescence and apoptosis resistance; and (4) over-expression of SIRT3 promotes resolution and reverses established fibrosis in mice. These studies provide a premise to elucidate the primary molecular targets and activities through which SIRT3 exerts its protective and anti-fibrotic effects.Grants:NIH grants, P01 HL114470 and R01..."

NF-YB1-YC12-bHLH144 complex directly activates Wx to regulate grain quality in rice (Oryza sativa L.). (PubMed, Plant Biotechnol J) - "NF-YC12 and bHLH144 maintain NF-YB1 stability from the degradation mediated by ubiquitin/26S proteasome, while NF-YB1 directly binds to the "G-box" domain of Wx promoter and activates Wx transcription, hence to regulate rice grain quality. In all, we revealed a novel grain quality regulatory pathway controlled by NF-YB1-YC12-bHLH144 complex, which has great potential for rice genetic improvement."

Journal

"Thank you for the love Katrin. Let me add @lbxmam001 @Lihle14492019" (@Cmfundisi)

Matrix Stiffness Regulates NADPH Oxidase 4 by Post-Transcriptional Mechanisms (ATS 2019) - "These data support a role for matrix stiffness dependent effects on the post-transcriptional regulation of NOX4.ConclusionsMatrix stiffness regulates NOX4 protein and activity, independent of TGF-β receptor(s) activation and mRNA regulation. Further studies on the post-transcriptional regulation of NOX4 are currently ongoing.Supported by NIH grants, P01 HL114470 and R01 AG046210"

PAI-1-Stimulated AT2 Cell SASP Promotes Profibrotic Polarization of Alveolar Macrophages (ATS 2019) - "PAI-1 mediates TGF-β1-induced AT2 cell senescence through inducing p16. Senescent AT2 cells secrete various profibrotic mediators in a PAI-1 dependent manner, which promote a profibrotic phenotype in alveolar macrophages. Founding sources:This work was supported by NIH grantsAG046701 and R56HL131054 (to R-M Liu) and HL114470 (to V.J. Thannickal)."

SYMPTOM SUBTYPES OF OBSTRUCTIVE SLEEP APNEA PREDICT INCIDENCE OF CARDIOVASCULAR OUTCOMES (Sleep 2019) - "OSA symptom subtypes are reproducible and associated with cardiovascular risk, providing important evidence of their clinical relevance. 234 Support (If Any): NIH (R01HL134015, P01HL094307, HL114473)."

RANGE AND REPRODUCIBILITY OF EEG BIOMARKERS FOR COGNITION ACROSS FIVE YEARS. (Sleep 2019) - "Spindle characteristics, alpha intrusion index and overall EEG power vary over very wide ranges among individuals but show high within individual correlations across 5 years, suggesting “trait-like” properties. AASM Foundation (194-SR-18), NHLBI R24 HL114473"

Biomarker

A NOVEL NON-INVASIVE APPROACH FOR MEASURING UPPER AIRWAY COLLAPSIBILITY IN MICE (Sleep 2019) - "Markers of expiratory airflow obstruction can be used to model upper airway collapsibility, and can provide sensitive measures of changes in airway collapsibility in rodents. This approach streamlines repeated non-invasive Pcrit measurements, and facilitates studies examining the impact of genetic, environmental, and pharmacologic factors on upper airway control. Support (If Any): NIH R01HL128970, R01HL133100, R01HL138932, R01HL144859"

Preclinical

SLEEP AND MORTALITY IN OLDER ADULTS: A MACHINE-LEARNING-BASED COMPARISON WITH OTHER RISK FACTORS (Sleep 2019) - "Multidimensional sleep is an important predictor of mortality that should be considered among other more routinely used predictors. Future research should develop tools for measuring multidimensional sleep, especially those incorporating duration, timing, and napping, and test mechanistic pathways through which these characteristics relate to mortality. Support (If Any): MrOS:HL071194;HL070848;HL070847;HL07 0842;HL070841;HL070837;HL070838;HL070839."

Clinical

Comparative functional genomics analysis of bHLH gene family in rice, maize and wheat. (PubMed, BMC Plant Biol) - "The present study identifies the bHLH family in rice, maize and wheat genomes, and detailedly discusses the evolutionary relationships, expression and function of bHLHs. This study provides some novel and detail information about bHLHs, and may facilitate understanding the molecular basis of the plant growth, development and stress physiology."

Journal