tbuckley/cabot-search huggingface dataset:
High Th2 cytokine levels and upper airway inflammation in human inherited T-bet deficiency
Authors: Rui Yang, Marc Weisshaar, Federico Mele, Ibtihal Benhsaien, Karim Dorgham, Jing Han, Carys A. Croft, Samuele Notarbartolo, Jérémie Rosain, Paul Bastard, Anne Puel, Bernhard Fleckenstein, Laurie H. Glimcher, James P. Di Santo, Cindy S. Ma, Guy Gorochov, Aziz Bousfiha, Laurent Abel, Stuart G. Tangye, Jean-Laurent Casanova, Jacinta Bustamante, Federica Sallusto
Journal: The Journal of Experimental Medicine (2021)

We have described a child suffering from Mendelian susceptibility to mycobacterial disease (MSMD) due to autosomal recessive, complete T-bet deficiency, which impairs IFN-γ production by innate and innate-like adaptive, but not mycobacterial-reactive purely adaptive, lymphocytes. Here, we explore the persistent upper airway inflammation (UAI) and blood eosinophilia of this patient. Unlike wild-type (WT) T-bet, the mutant form of T-bet from this patient did not inhibit the production of Th2 cytokines, including IL-4, IL-5, IL-9, and IL-13, when overexpressed in T helper 2 (Th2) cells. Moreover, Herpesvirus saimiri–immortalized T cells from the patient produced abnormally large amounts of Th2 cytokines, and the patient had markedly high plasma IL-5 and IL-13 concentrations. Finally, the patient’s CD4+ αβ T cells produced most of the Th2 cytokines in response to chronic stimulation, regardless of their antigen specificities, a phenotype reversed by the expression of WT T-bet. T-bet deficiency thus underlies the excessive production of Th2 cytokines, particularly IL-5 and IL-13, by CD4+ αβ T cells, causing blood eosinophilia and UAI. The MSMD of this patient results from defective IFN-γ production by innate and innate-like adaptive lymphocytes, whereas the UAI and eosinophilia result from excessive Th2 cytokine production by adaptive CD4+ αβ T lymphocytes.
心血管イベント率は,高Oct4,高Nanog幹細胞動員の早期増加を示したST上昇心筋梗塞患者において低下した
Authors: Hong Soon Jun, Choi Seung Cheol, Choi Ji-Hyun, Park Chi Yeon, Park Jae Hyoung, Ahn Chul-Min, Lim Do-Sun
Journal: Circulation (2013)
Molecular exploration for Mycoplasma amphoriforme, Mycoplasma fermentans and Ureaplasma spp. in patient samples previously investigated for Mycoplasma pneumoniae infection
Authors: Safi U Rehman, Jessica Day, Baharak Afshar, Richard S Rowlands, Harriet Billam, Amelia Joseph, Malcolm Guiver, Sarah E Maddocks, Victoria J Chalker, Michael L Beeton
Journal: Clinical Microbiology and Infection (2021)
Abstract 16081: Frequency of Potentially Clinically Relevant Variants of CYP2C19 And SLCO1B1 in a Large Direct-to-Consumer Genetic Database
Authors: Philip E Empey, Cindy Kosinski, Alison Chubb, Jianan Zhan, Hoang Nhan, Kelly E Caudle, Esther Kim
Journal: Circulation (2019)

Introduction: Pharmacogenetic testing holds great potential for supporting clinical decision making and optimizing medication outcomes. CYP2C19 and SLCO1B1 are two examples of cardiovascular pharma...
Population Pharmacokinetic and Exposure-Response Modeling for the EZH1/2 Dual Inhibitor DS-3201b in Patients with Non-Hodgkin Lymphomas
Authors: Ryo Atsumi, Satoshi Yoshiba, Dai Maruyama, Kensei Tobinai, Takashi Ishida, Kenji Ishitsuka, Yoshitaka Imaizumi, Shogo Takeuchi, Kunihiro Tsukasaki, Nobuaki Adachi, Sumiaki Fujitani, Masaya Tachibana, Kazutaka Yoshihara, Hitoshi Ishizuka
Journal: Blood (2017)
Abstract 3: The Survival Rate from Out-of-Hospital Cardiac Arrest is Superior with Passive Oxygen Insufflation Compared to Active Assisted Ventilation
Authors: Tyler F Vadeboncoeur, Bentley J Bobrow, Lani Clark, Vatsal Chikani, Gordon A Ewy
Journal: Circulation (2007)

OBJECTIVE: Experimental evidence suggests that excessive volume and rates of positive pressure ventilation during resuscitative efforts for out-of-hospital cardiac arrests (OOHCA) may be deleteriou...
SARS-CoV-2 new infections among health-care workers after the first dose of the BNT162b2 mRNA COVID-19 vaccine. A hospital-wide cohort study
Authors: Carlos Guijarro, Isabel Galán, Diana Martínez-Ponce, Elia Pérez-Fernández, Maria José Goyanes, Virgilio Castilla, María Velasco
Journal: Clinical Microbiology and Infection (2021)
Targeting WEE1 Kinase after G2/M Checkpoint Arrest Induces Apoptosis in Chronic Myeloid Leukemia Progenitors
Authors: Manuela Mancini, Sara De Santis, Cecilia Monaldi, Fausto Castagnetti, Luana Bavaro, Margherita Martelli, Gabriele Gugliotta, Gianantonio Rosti, Elena Tenti, Maria Alessandr Santucci, Michele Cavo, Giovanni Martinelli, Simona Soverini
Journal: Blood (2017)
Abstract 13026: Cost and Inpatient Burden of Peripheral Artery Disease: Findings From the National Inpatient Sample
Authors: Craig I Coleman, W. Frank Peacock, Thomas J Bunz, Mark J Alberts
Journal: Circulation (2018)

Introduction: Analysis of recent morbidity, mortality and cost burden data for hospitalizations in persons with peripheral artery disease (PAD) is needed. Objective: To examine the prevalence, demo...
Bidirectional Cross-talk between MAOA and AR Promotes Hormone-Dependent and Castration-Resistant Prostate Cancer
Authors: Jing Wei, Lijuan Yin, Jingjing Li, Jing Wang, Tianjie Pu, Peng Duan, Tzu-Ping Lin, Allen C. Gao, Boyang Jason Wu
Journal: Cancer Research (2021)

Abstract Androgen receptor (AR) is the primary oncogenic driver of prostate cancer, including aggressive castration-resistant prostate cancer (CRPC). The molecular mechanisms controlling AR activation in general and AR reactivation in CRPC remain elusive. Here we report that monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines, reciprocally interacts with AR in prostate cancer. MAOA was induced by androgens through direct AR binding to a novel intronic androgen response element of the MAOA gene, which in turn promoted AR transcriptional activity via upregulation of Shh/Gli-YAP1 signaling to enhance nuclear YAP1–AR interactions. Silencing MAOA suppressed AR-mediated prostate cancer development and growth, including CRPC, in mice. MAOA expression was elevated and positively associated with AR and YAP1 in human CRPC. Finally, genetic or pharmacologic targeting of MAOA enhanced the growth-inhibition efficacy of enzalutamide, darolutamide, and apalutamide in both androgen-dependent and CRPC cells. Collectively, these findings identify and characterize an MAOA–AR reciprocal regulatory circuit with coamplified effects in prostate cancer. Moreover, they suggest that cotargeting this complex may be a viable therapeutic strategy to treat prostate cancer and CRPC. Significance: MAOA and AR comprise a positive feedback loop in androgen-dependent and CRPC, providing a mechanistic rationale for combining MAOA inhibition with AR-targeted therapies for prostate cancer treatment.
Open-Label Phase II Prospective, Randomized, Controlled Study of Romyelocel-L Myeloid Progenitor Cells to Reduce Infection During Induction Chemotherapy for Acute Myeloid Leukemia
Authors: Pinkal M. Desai, Janice Brown, Saar Gill, Melham M. Solh, Luke P. Akard, Jack W. Hsu, Celalettin Ustun, Charalambos Andreadis, Olga Frankfurt, James M. Foran, John Lister, Gary J. Schiller, Matthew J. Wieduwilt, John M. Pagel, Patrick J. Stiff, Delong Liu, Irum Khan, Wendy Stock, Suman Kambhampati, Martin S. Tallman, Lawrence Morris, John Edwards, Iskra Pusic, Hagop M. Kantarjian, Richard Mamelok, Alicia Wong, Rodney Van Syoc, Lois Kellerman, Swapna Panuganti, Ramkumar Mandalam, Camille N. Abboud, Farhad Ravandi
Journal: Journal of Clinical Oncology (2021)

Standard cytotoxic induction chemotherapy for acute myeloid leukemia (AML) results in prolonged neutropenia and risk of infection. Romyelocel-L is a universal, allogeneic myeloid progenitor cell product being studied to reduce infection during induction chemotherapy.One hundred sixty-three patients with de novo AML (age ≥ 55 years) receiving induction chemotherapy were randomly assigned on day 0 (d0), of whom 120 were evaluable. Subjects received either romyelocel-L infusion on d9 with granulocyte colony-stimulating factor (G-CSF) starting daily d14 (treatment group) or G-CSF daily alone on d14 (control) until absolute neutrophil count recovery to 500/µL. End points included days in febrile episode, microbiologically defined infections, clinically diagnosed infection, and days in hospital.Mean days in febrile episode was shorter in the treatment arm from d15 through d28 (2.36 v 3.90; P = .02). Similarly, a trend toward decreased microbiologically defined infections and clinically diagnosed infection in the treatment arm was observed from d9 to d28 (35.6% v 47.5%; P = .09), reaching a statistically significant difference from d15 to d28 (6.8% v 27.9%; P = .002). Because of this, antibacterial or antifungal use for treatment of an infection was significantly less in the treatment group (d9-d28: 44.1% v 63.9%; P = .01). Significantly fewer patients in the treatment arm received empiric antifungals from d9 tod28 (42.4% v 63.9%; P = .02) and d15-d28 (42.4% v 62.3%; P = .02). Patients in the treatment arm also had 3.2 fewer hospital days compared with control (25.5 v 28.7; P = .001). Remission rates and days to absolute neutrophil count recovery were similar in the two groups. No patients in the romyelocel-L plus G-CSF group died because of infection compared with two patients in the control arm. No graft-versus-host disease was observed.Subjects receiving romyelocel-L showed a decreased incidence of infections, antimicrobial use, and hospitalization, suggesting that romyelocel-L may provide a new option to reduce infections in patients with AML undergoing induction therapy.
Plastic Rewiring of Sef1 Transcriptional Networks and the Potential of Nonfunctional Transcription Factor Binding in Facilitating Adaptive Evolution
Authors: Po-Chen Hsu, Tzu-Chiao Lu, Po-Hsiang Hung, Yu-Ting Jhou, Ahmed A A Amine, Chia-Wei Liao, Jun-Yi Leu
Journal: Molecular Biology and Evolution (2021)

Prior and extensive plastic rewiring of a transcriptional network, followed by a functional switch of the conserved transcriptional regulator, can shape the evolution of a new network with diverged functions. The presence of three distinct iron regulatory systems in fungi that use orthologous transcriptional regulators suggests that these systems evolved in that manner. Orthologs of the transcriptional activator Sef1 are believed to be central to how iron regulatory systems developed in fungi, involving gene gain, plastic network rewiring, and switches in regulatory function. We show that, in the protoploid yeast Lachancea kluyveri, plastic rewiring of the L. kluyveri Sef1 (Lk-Sef1) network, together with a functional switch, enabled Lk-Sef1 to regulate TCA cycle genes, unlike Candida albicans Sef1 that mainly regulates iron-uptake genes. Moreover, we observed pervasive nonfunctional binding of Sef1 to its target genes. Enhancing Lk-Sef1 activity resuscitated the corresponding transcriptional network, providing immediate adaptive benefits in changing environments. Our study not only sheds light on the evolution of Sef1-centered transcriptional networks but also shows the adaptive potential of nonfunctional transcription factor binding for evolving phenotypic novelty and diversity.
The Application of ‘Drug-Reversible’ CAR-T Cells Directed Against Recipient Hematopoietic Cells As a Selective Conditioning Strategy for Stem Cell Transplantation
Authors: Nina Timberlake, Maximilian Richter, Xinxin Wang, Nicholas Cam, Yening Tan, Eric M Ostertag, Devon J Shedlock, Julian D Down
Journal: Blood (2017)
Identification of T Cell Receptors Specific to Antigens Presented By HLA-B5401 on IPS Cell-Derived Hematopoietic Stem Cells in a Patient with Acquired Aplastic Anemia Carrying B5401-Lacking Leukocytes
Authors: Noriharu Nakagawa, Mahmoud Ibrahim Elbadry, Yoshiki Akatsuka, Hiroshi Hamana, Kiyomi Shitaoka, Yoshinori Yoshida, Kazuhisa Chonabayashi, Tatsuya Imi, Yoshitaka Zaimoku, Katsuto Takenaka, Hiroshi Fujiwara, Hiroyuki Kishi, Shinji Nakao
Journal: Blood (2017)
Experimental Assessment of Carbon Dioxide Content in Inhaled Air With or Without Face Masks in Healthy Children
Authors: Harald Walach, Ronald Weikl, Juliane Prentice, Andreas Diemer, Helmut Traindl, Anna Kappes, Stefan Hockertz
Journal: JAMA Pediatrics (2021)

This randomized clinical trial measured inhaled and exhaled carbon dioxide in children with and without face masks.
Abstract 393: The Intercalated Disc Protein Myozap: A Novel Player in Cardiac Proteinopathy
Authors: Ashraf Y Rangrez, Derk Frank, Liam Cassidy, Lynn Christen, Inka Geurink, Alexander Bernt, Martina Böttner, Hendrik Milting, Andreas Tholey, Jeffrey Robbins, Norbert Frey
Journal: Circulation Research (2016)

Background: A growing number of cardiac muscle diseases are characterized by depositions of misfolded proteins, including cardiac amyloidosis and desmin-releated cardiomyopathy (DRM). The continued presence and chronic accumulation of misfolded or unfolded proteins can lead to aggregation and/or the formation of soluble peptides that are proteotoxic. This in turn leads to compromised protein quality control and precipitates a downward spiral of the cell’s ability to maintain homeostasis and may eventually result in cell death. We recently identified massive protein aggregates in the hearts of transgenic mice overexpressing the intercalated disc (ID) protein myozap (Myozap-tg). We now sought to investigate the precise composition of these aggregates and the role of Myozap in other proteinopathies such as DRM. Methods and Results: We employed multi-dimensional proteomics, transcriptomics, confocal microscopy, and molecular biology approaches to decipher the underlying causes and consequences of protein aggregate formation in Myozap-tg mice. Transcriptome profiling of these mice revealed striking upregulation of autophagy, protein synthesis, and pro-inflammatory pathways, whereas protein degradation pathways were down-regulated. Surprisingly, proteomics analyses revealed Desmin and α-crystallin B (CryAB) as the major constituents of the aggregates, which was further validated by confocal microscopy. Moreover, we identified the presence of toxic preamyloid oligomers in Myozap-tg mouse hearts, a hallmark in many protein aggregation-based diseases including DRM. Most interestingly, we also observed co-localization of Myozap with protein aggregates observed in both transgenic mouse hearts overexpressing mutant Desmin (D7) and mutant CryAB (R120G), as well as in human DRM patients. Conclusion: The present study implies a new role for Myozap, which was previously reported to affect cardiac SRF signaling: (1) Myozap accumulates in various forms of experimental and human protein aggregation cardiomyopathy, suggesting involvement in protein homoestasis. (2) The fact that Myozap is now the third ID protein (after desmin and CryAB) to cause cardiac proteinopathy points to a general role of the ID in its molecular pathogenesis.
Abstract 17161: High-sensitivity Troponin T Predicts Mortality Independently Of Ventricular Dysfunction And Pulmonary Hypertension In Stable Chronic Obstructive Pulmonary Disease
Authors: Brede Kvisvik, Ingunn Skjørten, Janne M Hilde, Heidi Strand, Torbjørn Omland, Kjetil Steine
Journal: Circulation (2019)

Introduction: Patients with stable chronic obstructive pulmonary disease (COPD) are at increased risk of pulmonary hypertension and systolic dysfunction. Levels of high-sensitivity cardiac troponin...
Phase I Study of Stereotactic Body Radiotherapy plus Nivolumab and Urelumab or Cabiralizumab in Advanced Solid Tumors
Authors: Corey C. Foster, Gini F. Fleming, Theodore G. Karrison, Chih-Yi Liao, Ami V. Desai, John W. Moroney, Mark J. Ratain, Rita Nanda, Blase N. Polite, Olwen M. Hahn, Peter H. O'Donnell, Everett E. Vokes, Hedy L. Kindler, Robyn Hseu, Linda A. Janisch, Julia Dai, Mark D. Hoffman, Ralph R. Weichselbaum, Sean P. Pitroda, Steven J. Chmura, Jason J. Luke
Journal: Clinical Cancer Research (2021)

Abstract Purpose: CD137 agonism and CSF1R blockade augment stereotactic body radiotherapy (SBRT) and anti-programmed death-1 in preclinical models. We evaluated the safety and efficacy of SBRT with nivolumab+urelumab (CD137 agonist) or nivolumab+cabiralizumab (CSF1R inhibitor). Patients and Methods: This phase I clinical trial enrolled patients with advanced solid tumors that had progressed on standard therapies. SBRT was delivered to 1–4 metastases with nivolumab+urelumab or nivolumab+cabiralizumab given concurrently and following SBRT. Dose-limiting toxicity (DLT) was the primary endpoint with anatomic location-specific SBRT doses deemed safe if ≤33% DLT frequency was observed. Secondary endpoints included RECISTv1.1 response, progression-free survival (PFS), overall survival (OS), and molecular correlative studies. Results: Sixty patients were enrolled, and median follow-up for living patients is 13.8 months. Of these, 23 (38%) received SBRT+nivolumab+urelumab and 37 (62%) received SBRT+nivolumab+cabiralizumab. Seven patients (12%) experienced a DLT (n = 3 grade 3, n = 4 grade 4) in the following anatomic cohorts: abdominal/pelvic (3/17, 18%), liver (1/13, 8%), central lung (2/14, 14%), and peripheral lung (1/12, 8%). Of 41 patients radiographically evaluable for best overall response including 55 radiated and 23 unirradiated RECIST target lesions, 2 had complete responses (5%), 7 had partial responses (17%), 12 had stable disease (29%), and 20 had progression (49%). Median estimated PFS and OS are 3.0 months [95% confidence interval (CI), 2.9–4.8] and 17.0 months (95% CI, 6.8–undetermined), respectively. No patients with elevated pre-SBRT serum IL8 experienced a response. Conclusions: SBRT to ≤4 sites with nivolumab+urelumab or nivolumab+cabiralizumab for treating advanced solid tumors is feasible with acceptable toxicity and modest antitumor activity. See related commentary by Rodriguez-Ruiz et al., p. 5443
Vitamin A-coupled stem cell-derived extracellular vesicles regulate the fibrotic cascade by targeting activated hepatic stellate cells in vivo
Authors: Dong Gil You, Byeong Hoon Oh, Van Quy Nguyen, Gyeong Taek Lim, Wooram Um, Jae Min Jung, Jueun Jeon, Ji Suk Choi, Young Chan Choi, Youn Jae Jung, Jungmi Lee, Dong-Gyu Jo, Yong Woo Cho, Jae Hyung Park
Journal: Journal of Controlled Release (2021)
二次性顆粒タンパク質のうち主要塩基性タンパク質1(MBP-1)と好酸球ペルオキシダーゼ(EPX)の発現がマウスの好酸球産生に必要である
Authors: D Doyle Alfred, A Jacobsen Elizabeth, I Ochkur Sergei, P Mcgarry Michael, G Shim Kevin, T C Nguyen David, Protheroe Cheryl, Colbert Dana, Kloeber Jake, Neely Joseph, P Shim Kelly, D Dyer Kimberly, F Rosenberg Helene, J Lee James, A Lee Nancy
Journal: Blood (2013)
Abstract 48: Differentiation of Moderate and Severe Ischemic Heart Failure by Invasive and Non-invasive Assessments of Diastolic Function in a Rat Model of Chronic Heart Failure
Authors: Saffie Mohran, Jordan Lancaster, Pablo Sanchez, Steven Goldman, Elizabeth Juneman
Journal: Circulation Research (2016)

Background: This work is designed to determine if specific left ventricle (LV) pressure-volume relations, hemodynamic, and echo derived parameters of diastolic function are able to separate severe from moderate CHF in rats with left coronary artery occlusion. Hypothesis: Echocardiographic indices of diastolic function, end-diastolic pressure (EDP), dead volume, stiffness constants (k), and pressure volume relations predict the severity of CHF in infarcted rats. Methods: Male Sprague Dawley rats (N=14) were randomized to undergo left coronary artery ligation or sham operation. Echocardiography was performed at 3 and 6 weeks post coronary ligation. The rats were categorized into moderate or severe CHF according to their LVEDP at 6 weeks post ligation. Invasive hemodynamic measurements with solid state micro manometer pressure catheters as well as diastolic pressure-volume relation values were obtained at the 6 week end point. Results: Moderate and severe CHF rats had significantly (P&lt;0.05) elevated left ventricular (LV) end-diastolic pressure (LV EDPs), prolonged time constants of LV relaxation (tau), and decreased peak development pressures. When moderate versus severe CHF rats were separated based on LV EDP, early diastolic anterior wall radial relaxation velocity as well as e’, and E/e’ had strong correlations with invasive hemodynamic measurements of diastolic functions. There was a trend towards decreased compliance as measured by stiffness constants in severe heart failure group. Differences (P&lt;0.05) in dead volume, mean arterial pressure (MAP), tau, and ejection fraction (EF) were also displayed. End diastolic pressure-volume analyses illustrated significant differences in plot positioning and curvature. Conclusion: While it is possible to separate rats with moderate and severe CHF in the rat coronary artery ligation model, the separation is not simply based on a specific EF value. This work may be useful in deciding whether there is a differential effect of new treatments for severe versus moderate CHF.
COVID-19 vaccine mRNA-1273 elicits a protective immune profile in mice that is not associated with vaccine-enhanced disease upon SARS-CoV-2 challenge
Authors: Anthony T. DiPiazza, Sarah R. Leist, Olubukola M. Abiona, Juan I. Moliva, Anne Werner, Mahnaz Minai, Bianca M. Nagata, Kevin W. Bock, Emily Phung, Alexandra Schäfer, Kenneth H. Dinnon, Lauren A. Chang, Rebecca J. Loomis, Seyhan Boyoglu-Barnum, Gabriela S. Alvarado, Nancy J. Sullivan, Darin K. Edwards, Kaitlyn M. Morabito, John R. Mascola, Andrea Carfi, Kizzmekia S. Corbett, Ian N. Moore, Ralph S. Baric, Barney S. Graham, Tracy J. Ruckwardt
Journal: Immunity (2021)
Inhibiting Aurora Kinase B Sensitizes B-Cell Acute Lymphoblastic Leukemia to Glucocorticoids
Authors: Coralie Poulard, Hye Na Kim, Celine Gagnieux, Karina Kruth, Mimi Fang, Daniel Gerke, Deepa Bhojwani, Yong-Mi Kim, Michael R Stallcup, Miles A. Pufall
Journal: Blood (2017)
Positive expression and correlation of chemokine receptor CXCR4 with nodal metastasis and prognosis in colorectal cancer
Authors: K. Iqbal
Journal: Journal of Clinical Oncology (2009)

e15128 Background: Colorectal cancer is one of the leading causes of cancer related deaths,with recurrence and metastasis as the primary reasons for mortality. New evidence hasimplicated Chemokines as the likely cause. We studied the positive expression of CXCR4 chemokine receptors in colorectal carcinoma and investigated its correlations to clinicpathologic characteristics and prognosis. Methods: Tumor tissue specimens of patients with colorectalcarcinoma (n = 67) who underwent surgery from January 2003 to December 2004 at the Department of Surgery, Tongji Hospital were collected. CXCR4 expression levels and tumor micro vessel density were evaluated by immunohistochemistry. Specimens were immunostained using formalin-fixed, paraffin-embedded tissues. The correlation between the CXCR4 expression and clinicopathological factors was evaluated Results: In 67 cancer tissue specimens, CXCR4 was positively expressed in 38 cases; positive rate being 56.7%. Positive expression of CXCR4 is associated with an increase incidence of nodal involvement, higher clinic stage, higher tumor micro vessel density and a lower 3-year disease free survival rate as compared to those with negative CXCR4 expression (P&lt;0.05). Conclusions: Positive CXCR4 expression and high tumor micro vessel density are associated with poor prognosis and could be a potential predictive factor for recurrence or metastasis of colorectal cancer patients. So CXCR4 may be a potential target for specific therapeutic interventions in the future. No significant financial relationships to disclose.