tbuckley/cabot-search huggingface dataset:
A Phosphatase Anchor Weighs on the Heart
Authors: Kathleen C. Woulfe, Joshua G. Travers, Timothy A. McKinsey
Journal: Circulation (2020)

A Phosphatase Anchor Weighs on the HeartArticle, see p 948 H ypertrophic growth of the heart in response to pathogenic stress has historically been regarded as a compensatory mechanism to reduce wall stress and maximize ventricular performance.However, epidemiological studies have illustrated that chronic hypertrophy increases the risk of poor outcomes in patients with cardiovascular disease, and in preclinical models of heart failure (HF), suppression of hypertrophy is beneficial rather than detrimental. 1As such, there is great interest in defining the molecular underpinnings of cardiomyocyte hypertrophy to facilitate the development of targeted antihypertrophic therapies for HF.In 1998, Molkentin, Olson, and colleagues 2 published a landmark article describing a crucial role for the Ca 2+ /calmodulin-dependent protein phosphatase, calcineurin, in the control of pathological cardiac hypertrophy.Before this discovery, calcineurin had primarily been studied in lymphocytes, where it promotes cellular activation through dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor. 3Enthusiasm for the discovery of the link between calcineurin signaling and hypertrophy was bolstered by the existence of agents that inhibit calcineurin catalytic activity, such as the immunosuppressants FK506 and cyclosporine A, suggesting potential repurposing of these drugs to treat HF.However, given the diverse actions of calcineurin in immune as well as nonimmune cells, it is now widely accepted that selective inhibition of calcineurin in cardiomyocytes will be better tolerated and more efficacious than systemic inhibition in patients with HF.Thus, there is a need to better understand the molecular details of calcineurin regulation in the heart to illuminate cardiac-specific approaches for targeting this phosphatase as an antihypertrophic therapy for HF.Calcineurin exists as a heterodimer consisting of a catalytic subunit (CaNA) and a 19-kDa regulatory subunit (CaNB).Of the 3 CaNA isoforms (α, β and γ), CaNAβ appears to be the most important for the development of cardiac hypertrophy. 4inding of Ca 2+ to CaNB enables binding of a Ca 2+ /calmodulin complex to CaNA, thereby releasing autoinhibition and freeing the enzyme to dephosphorylate downstream substrates. 5As detailed below, in the current issue of Circulation, Li et al 6 describe the discovery of a CaNAβ binding protein, CDC42 interacting protein 4 (CIP4), which functions as a scaffold to sequester a pool of calcineurin near the sarcolemma of cardiomyocytes, where it regulates prohypertrophic signaling.The findings have important implications for understanding how cardiac calcineurin is selectively activated by stress signals as opposed to the Ca 2+ that floods cardiomyocytes during each contractile cycle.Furthermore, the data provide proof-ofconcept for an innovative therapeutic approach whereby CIP4 anchoring activity is selectively inhibited to block the action of a small, pathogenic cache of calcineurin as a means of treating HF.
Congenital Hypofibrinogenemia in Five Members of a Family
Journal: JAMA (1963)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Caffeine Dependence Syndrome
Authors: Richard H. Adamson
Journal: JAMA (1995)

<h3>To the Editor.</h3> —The conclusions by Dr Strain and colleagues<sup>1</sup>that "caffeine exhibits the features of a typical psychoactive substance of dependence" should be viewed with reservation. The 16 subjects in the small study selected from a larger group of 99 adults with self-identified caffeine dependence clearly do not represent a cross section of the US population. Ten of the 16 had a previous substance abuse disorder (most commonly alcohol), two had a psychiatric diagnosis, and 14 of 16 were of the same sex. In addition, although subjects were not assessed for nicotine dependence, five were smokers who had a higher caffeine consumption than the nonsmokers. Obviously, caffeine consumption is markedly different from the use of drugs of abuse. For example, steadily increasing doses are generally not associated with caffeine ingestion and, of course, the destructive antisocial behavior provoked by drugs of abuse is clearly not associated with caffeine
Community-Level Social Support Infrastructure and Adult Onset of Major Depressive Disorder in a South Asian Postconflict Setting
Authors: William G. Axinn, Karmel W. Choi, Dirgha J. Ghimire, Faith Cole, Sabrina Hermosilla, Corina Benjet, Melany C. Morgenstern, Younga H. Lee, Jordan W. Smoller
Journal: JAMA Psychiatry (2022)

Individual-level social support protects against major depressive disorder (MDD) among adults exposed to trauma. Little is known about the consequences of community-level interventions in the general population.To determine the potential consequences of neighborhood social infrastructure on incident MDD in a high-risk general population.This longitudinal, multilevel study estimated associations between a neighborhood-level program in a case-control design and subsequent individual outcomes across 10 years (2006-2015) in a cohort of young adults. Exogenously placed social programs simulate natural experiment conditions in a high-poverty population experiencing armed conflict (1998-2006). The western Chitwan valley in Nepal has a general population at high risk of MDD, with neighborhoods exposed to interventions to improve social support. From a random sample (response rate 93%) selected to represent the general population in 2016, participants aged 25 to 34 years in 2006 were studied. These individuals resided within 149 neighborhoods that varied in their availability of active social support programs. The analyses were conducted between October 2020 and November 2021.The Small Farmers Development Program (SFDP) uses shared, joint liability financial credit among neighbors to build social capital and cohesion within neighborhoods.Onset of DSM-IV MDD after the conflict, assessed by the Nepal-specific, clinically validated World Mental Health Composite International Diagnostic Interview with a life history calendar. The hypothesis tested was that exposure to SFDP reduced adult onset of MDD.Of the 1917 survey participants, 886 (46.2%) were women, and 856 (44.7%) were of Brahmin or Chhetri ethnicity. Of the 149 neighborhoods, 21 had an active SFDP group, and 156 of 1917 (8.1%) participants experienced MDD between 2006 and 2015. Discrete-time hazard models showed participants living in neighborhoods with an SFDP experienced incident MDD at nearly half the rate as others (odds ratio = 0.55; 95% CI, 0.30-1.02; P = .06). A multivariate, multilevel matching analysis showed the incidence of MDD among adults living in neighborhoods with an SFDP was 19 of 256 (7.4%), compared with 33 of 256 (12.9%) in the matched sample with no SFDP (z = 2.05; P = .04).Living in a neighborhood with community-level social support infrastructure was associated with reduced subsequent rates of adult-onset MDD, even in this high-risk population. Investments in such infrastructure may reduce population-level MDD, supporting clinical focus on potentially unpreventable cases.
Continuing Medical Education Directory and Source Book
Journal: JAMA (1992)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Adenosine and ATP: traffic regulators in the kidney
Authors: W. Kriz
Journal: Journal of Clinical Investigation (2004)

Glomerular filtration in the kidney is a continuous process that acts in concert with tubular reabsorption to prevent derangements of body fluid composition. Filtration is regulated by systemic factors, but it is also controlled by an intrinsic mechanism based on the anatomical connection between the distal nephron and the glomerular arterioles. Facing the threat of urinary salt loss, this mechanism causes vasoconstriction and reduces filtration by generating adenosine through the hydrolysis of nucleotide precursors such as 5′-AMP and possibly ATP .
Novel Classes and Evolutionary Turnover of Histone H2B Variants in the Mammalian Germline
Authors: Pravrutha Raman, Mary C Rominger, Janet M Young, Antoine Molaro, Toshio Tsukiyama, Harmit S Malik
Journal: Molecular Biology and Evolution (2022)

Histones and their posttranslational modifications facilitate diverse chromatin functions in eukaryotes. Core histones (H2A, H2B, H3, and H4) package genomes after DNA replication. In contrast, variant histones promote specialized chromatin functions, including DNA repair, genome stability, and epigenetic inheritance. Previous studies have identified only a few H2B variants in animals; their roles and evolutionary origins remain largely unknown. Here, using phylogenomic analyses, we reveal the presence of five H2B variants broadly present in mammalian genomes. Three of these variants have been previously described: H2B.1, H2B.L (also called subH2B), and H2B.W. In addition, we identify and describe two new variants: H2B.K and H2B.N. Four of these variants originated in mammals, whereas H2B.K arose prior to the last common ancestor of bony vertebrates. We find that though H2B variants are subject to high gene turnover, most are broadly retained in mammals, including humans. Despite an overall signature of purifying selection, H2B variants evolve more rapidly than core H2B with considerable divergence in sequence and length. All five H2B variants are expressed in the germline. H2B.K and H2B.N are predominantly expressed in oocytes, an atypical expression site for mammalian histone variants. Our findings suggest that H2B variants likely encode potentially redundant but vital functions via unusual chromatin packaging or nonchromatin functions in mammalian germline cells. Our discovery of novel histone variants highlights the advantages of comprehensive phylogenomic analyses and provides unique opportunities to study how innovations in chromatin function evolve.
Prevalence of post-acute COVID-19 syndrome symptoms at different follow-up periods: a systematic review and meta-analysis
Authors: Mohamad Salim Alkodaymi, Osama Ali Omrani, Nader A. Fawzy, Bader Abou Shaar, Raghed Almamlouk, Muhammad Riaz, Mustafa Obeidat, Yasin Obeidat, Dana Gerberi, Rand M. Taha, Zakaria Kashour, Tarek Kashour, Elie F. Berbari, Khaled Alkattan, Imad M. Tleyjeh
Journal: Clinical Microbiology and Infection (2022)
Adverse Events Reported by Patients With Cancer After Administration of a 2-Dose mRNA COVID-19 Vaccine
Authors: Rebecca M. Shulman, David S. Weinberg, Eric A. Ross, Karen Ruth, Glenn F. Rall, Anthony J. Olszanski, James Helstrom, Michael J. Hall, Julia Judd, David Y.T. Chen, Robert G. Uzzo, Timothy P. Dougherty, Riley Williams, Daniel M. Geynisman, Carolyn Y. Fang, Richard I. Fisher, Marshall Strother, Erica Huelsmann, Sunil Adige, Peter D. Whooley, Kevin Zarrabi, Brinda Gupta, Pritish Iyer, Melissa McShane, Hilario Yankey, Charles T. Lee, Nina Burbure, Lauren E. Laderman, Julie Giurintano, Samuel Reiss, Eric M. Horwitz
Journal: Journal of the National Comprehensive Cancer Network (2022)

Background: Most safety and efficacy trials of the SARS-CoV-2 vaccines excluded patients with cancer, yet these patients are more likely than healthy individuals to contract SARS-CoV-2 and more likely to become seriously ill after infection. Our objective was to record short-term adverse reactions to the COVID-19 vaccine in patients with cancer, to compare the magnitude and duration of these reactions with those of patients without cancer, and to determine whether adverse reactions are related to active cancer therapy. Patients and Methods: A prospective, single-institution observational study was performed at an NCI-designated Comprehensive Cancer Center. All study participants received 2 doses of the Pfizer BNT162b2 vaccine separated by approximately 3 weeks. A report of adverse reactions to dose 1 of the vaccine was completed upon return to the clinic for dose 2. Participants completed an identical survey either online or by telephone 2 weeks after the second vaccine dose. Results: The cohort of 1,753 patients included 67.5% who had a history of cancer and 12.0% who were receiving active cancer treatment. Local pain at the injection site was the most frequently reported symptom for all respondents and did not distinguish patients with cancer from those without cancer after either dose 1 (39.3% vs 43.9%; P =.07) or dose 2 (42.5% vs 40.3%; P =.45). Among patients with cancer, those receiving active treatment were less likely to report pain at the injection site after dose 1 compared with those not receiving active treatment (30.0% vs 41.4%; P =.002). The onset and duration of adverse events was otherwise unrelated to active cancer treatment. Conclusions: When patients with cancer were compared with those without cancer, few differences in reported adverse events were noted. Active cancer treatment had little impact on adverse event profiles.
CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression
Authors: Meiling Zhang, Zongzhi Z. Liu, Keisuke Aoshima, Wesley L. Cai, Hongyin Sun, Tianrui Xu, Yangyi Zhang, Yongyan An, Jocelyn F. Chen, Lok Hei Chan, Asako Aoshima, Sabine M. Lang, Zhenwei Tang, Xuanlin Che, Yao Li, Sara J. Rutter, Veerle Bossuyt, Xiang Chen, Jon S. Morrow, Lajos Pusztai, David L. Rimm, Mingzhu Yin, Qin Yan
Journal: Science Translational Medicine (2022)

Metastasis is the major cause of cancer-related deaths due to the lack of effective therapies. Emerging evidence suggests that certain epigenetic and transcriptional regulators drive cancer metastasis and could be targeted for metastasis treatment. To identify epigenetic regulators of breast cancer metastasis, we profiled the transcriptomes of matched pairs of primary breast tumors and metastases from human patients. We found that distant metastases are more immune inert with increased M2 macrophages compared to their matched primary tumors. The acetyl-lysine reader, cat eye syndrome chromosome region candidate 2 (CECR2), was the top up-regulated epigenetic regulator in metastases associated with an increased abundance of M2 macrophages and worse metastasis-free survival. CECR2 was required for breast cancer metastasis in multiple mouse models, with more profound effect in the immunocompetent setting. Mechanistically, the nuclear factor κB (NF-κB) family member v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) recruits CECR2 to increase chromatin accessibility and activate the expression of their target genes. These target genes include multiple metastasis-promoting genes, such as
Evaluating Long-term Efficacy of Neoadjuvant Chemoradiotherapy Plus Surgery for the Treatment of Locally Advanced Esophageal Squamous Cell Carcinoma—Reply
Authors: Ji-Bin Li, Zhuo-Chen Lin, Jian-Hua Fu
Journal: JAMA Surgery (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Co-circulation of SARS-CoV-2 Alpha and Gamma variants in Italy, February and March 2021
Authors: Paola Stefanelli, Filippo Trentini, Giorgio Guzzetta, Valentina Marziano, Alessia Mammone, Monica Sane Schepisi, Piero Poletti, Carla Molina Grané, Mattia Manica, Martina del Manso, Xanthi Andrianou, Marco Ajelli, Giovanni Rezza, Silvio Brusaferro, Stefano Merler
Journal: Eurosurveillance (2022)

BackgroundSeveral SARS-CoV-2 variants of concern (VOC) have emerged through 2020 and 2021. There is need for tools to estimate the relative transmissibility of emerging variants of SARS-CoV-2 with respect to circulating strains.AimWe aimed to assess the prevalence of co-circulating VOC in Italy and estimate their relative transmissibility.MethodsWe conducted two genomic surveillance surveys on 18 February and 18 March 2021 across the whole Italian territory covering 3,243 clinical samples and developed a mathematical model that describes the dynamics of co-circulating strains.ResultsThe Alpha variant was already dominant on 18 February in a majority of regions/autonomous provinces (national prevalence: 54%) and almost completely replaced historical lineages by 18 March (dominant across Italy, national prevalence: 86%). We found a substantial proportion of the Gamma variant on 18 February, almost exclusively in central Italy (prevalence: 19%), which remained similar on 18 March. Nationally, the mean relative transmissibility of Alpha ranged at 1.55-1.57 times the level of historical lineages (95% CrI: 1.45-1.66). The relative transmissibility of Gamma varied according to the assumed degree of cross-protection from infection with other lineages and ranged from 1.12 (95% CrI: 1.03-1.23) with complete immune evasion to 1.39 (95% CrI: 1.26-1.56) for complete cross-protection.ConclusionWe assessed the relative advantage of competing viral strains, using a mathematical model assuming different degrees of cross-protection. We found substantial co-circulation of Alpha and Gamma in Italy. Gamma was not able to outcompete Alpha, probably because of its lower transmissibility.
A Phase 1b/2 Study of the CD123-Targeting Antibody-Drug Conjugate IMGN632 As Monotherapy or in Combination with Venetoclax and/or Azacitidine for Patients with CD123-Positive Acute Myeloid Leukemia
Authors: Naval G. Daver, Harry P. Erba, Nikolaos Papadantonakis, Daniel J. DeAngelo, Eunice S. Wang, Marina Y Konopleva, Callum M. Sloss, Jiuzhou Wang, Kara E. Malcolm, Patrick A. Zweidler-McKay, Hagop M. Kantarjian
Journal: Blood (2019)
JAMA Pediatrics
Authors: Phil Fontanarosa, Annette Flanagin, Brenda Gregoline, Tracy Frey, Shannon Sparenga, Miriam Cintron, Paul Ruich, Diane Cannon, Connie Manno, Fred Marshall, Laura Copyreaders, Catherine Adamcyzk, Jan Alden, Mary Clavey, Gillian Coerver-Connolly, Laura Dickens, Juliann King, Donna Tarsney, Caroline Thordsen, Wanda Assistant, Larry Bryant, Monica Mungle, Elaine Williams, Lenette Gardner-Gullens, Fanny Brown, Paul Frank, Rachell Lozano, Michaela Mark, Kathryn Muskovich, J Neff, Kate Pezalla, Gale Saulsberry, Michael Berkwits, Michelle Kurzynski, Eric Butkus, Christopher Hastings, Craig Mccaffrey, Reuben Rios, Ronna Henry, Staff Bird, Alison Burke, Cassio Lynm, David Song, Deputy Livingston, Thomas Cole, Marla Hall, Deanna Willis, Yolanda Davis, Joseph Thornton, Deanna Bellandi, Jim Periodical, Thomas Staff, Monica Smith, Jeffery Bonistalli Manager, Kathy Staff, Mirna Monal, Tim Melroy, Thalia Moss, Tem Harrier, Susan Henning, Mark Thornbury, Tricia Castellano, Saskia Bolore, Gretchen Linder, Brian Mccartney, Rebecca Haas, Christine Hearne, Irma Lara, Audra Lawlor, Matt Herron, Elizabeth Solaro, Geoffrey Flick, Paul Gee Managers, Rick Bell, Michael Mcgraw, Sara Nagy, Stacy Staff, Millette Jackson-Bates, Karen Adams-Taylor, Karl Elvin, Sue Sherrill, Brian Shields Managers, David Antos, Chris Borden, Debbie Camp, Lydia Cruz, Diane Darnell, Colleen Kelly, Chris Meyer, Jaye Mize, Annemarie Neff, Sean O'donnell, Sean Ohlson, Phil O'leary, Ryan Patella, Susan Price, Denise Steinhauser, Production Services, Kim Boler, Rhonda Brown, Timothy Burke, Daniel Degroot, Jordynn Farrar, Euwanaha Joiner-Smith, Cindy Rendlen, Ellen Yoshihara, Circulation Services, Julie Burton, Dexter Golden, Erin Hinchcliff, Noemi Rivera, Geneine Van, Someren Composition, New Media, Gail Barrett, Regina Brownlee, Brenda Chandler-Grayer, Scott Curl, Amy Evers, Teri Hutchison, Mary Kuranda, Joshua Lampinen, Patricia Panek, La Son, Diggs Sledge, George Thomson Graphics, Joe Amft, Maria Duda, Fred Furtner, Carolyn Hall, Maria Kowalkowski, Proofreading Carol, Joy Farrell, Daniel James, Judith Literskis, Teresa Omiotek, James Madara, Bernard Hengesbaugh, Dimitri Christakis, Washington Joffe, Ron Keren, Suzanne Shuey, Benjamin French, Peter Cummings, Samir Shah, Howard Bauchner, Frederick Rivara, Joyce Lee, Ann Arbor, Cherrie Boyer, San Francisco, Robert Bradley, Maria Britto, John Campo, Aaron Carroll, Indiana Frank, Joseph Chaloupka, Mitchell Cohen, Chris Feudtner, Kathleen Janz, Iowa City, Terry Klassen, Michigan Michelle, Huckaby Lewis, Maryland Saiman, New York, York Samir, Martha Sola-Visner, Jean-Claude Carel, Shabir Madhi, Ben Marais, Frank Oberklaid, Susan Sawyer, Joan-Carles Surís
Journal: JAMA Pediatrics (2014)
SIX MONTH CLINICAL OUTCOMES FOLLOWING THE IMPLANTATION OF THE BIORESORBABLE EVEROLIMUS ELUTING VASCULAR SCAFFOLD IN VESSELS SMALLER OR LARGER THAN 2.5 MM
Authors: Roberto Diletti, Yoshinobu Onuma, Vasim Farooq, Josep Gomez-Lara, Salvatore Brugaletta, Robert Jan van Geuns, Evelyn Regar, Bernard de Bruyne, Dariusz Dudek, Leif Thuesen, Bernard Chevalier, Dougal McClean, Stephan Windecker, Robert Whitbourne, Dong Li, Susan Veldhof, Richard Rapoza, Krishnakutty Sudhir, Hector M. Garcia-Garcia, John A. Ormiston, Patrick W. Serruys
Journal: Journal of the American College of Cardiology (2011)