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Article ; Online: Adaptive Computational Solutions to Energy Efficiency in Cloud Computing Environment Using VM Consolidation.

Magotra, Bhagyalakshmi / Malhotra, Deepti / Dogra, Amit Kr

Archives of computational methods in engineering : state of the art reviews

2022 Volume 30, Issue 3, Page(s) 1789–1818

Abstract: Cloud Computing has emerged as a computing paradigm where services are provided through the internet in recent years. Offering on-demand services has transformed the IT companies' working environment, leading to a linearly increasing trend of its usage. ... ...

Abstract	Cloud Computing has emerged as a computing paradigm where services are provided through the internet in recent years. Offering on-demand services has transformed the IT companies' working environment, leading to a linearly increasing trend of its usage. The provisioning of the Computing infrastructure is achieved with the help of virtual machines. A great figure of physical devices is required to satisfy the users' resource requirements. To meet the requirements of the submitted workloads that are usually dynamic, the cloud data centers cause the over-provisioning of cloud resources. The result of this over-provisioning is the resource wastage with an increase in the levels of energy consumption, causing a raised operational cost. High CO
Language	English
Publishing date	2022-11-27
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2276736-8
ISSN	1886-1784 ; 1134-3060
ISSN (online)	1886-1784
ISSN	1134-3060
DOI	10.1007/s11831-022-09852-2
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Article: Wnts' fashion statement: from body stature to dysplasia.

Malhotra, Deepti / Yang, Yingzi

BoneKEy reports

2014 Volume 3, Page(s) 541

Abstract: Bone is constantly being made and remodeled to maintain bone volume and calcium homeostasis. Even small changes in the dosage, location and duration of int/Wingless (Wnt) signaling affect skeletal development and homeostasis. Wnt/β-catenin signaling ... ...

Abstract	Bone is constantly being made and remodeled to maintain bone volume and calcium homeostasis. Even small changes in the dosage, location and duration of int/Wingless (Wnt) signaling affect skeletal development and homeostasis. Wnt/β-catenin signaling controls cell fate determination, proliferation and survival by affecting a balance between bone-forming osteoblast and bone-resorbing osteoclast cell differentiation. During early skeletal development, Wnt/β-catenin signaling is required in directing mesenchymal progenitor cells toward the osteoblast lineage. Later, Wnt/β-catenin in chondrocytes of the growth plate promotes chondrocyte survival, hypertrophic differentiation and endochondral ossification. Gain- or loss-of-function mutations in the Wnt signaling components are causally linked to high or low bone mass in mice and humans. Inactivation of Wnt/β-catenin signaling leads to imbalance between bone formation and resorption because of accelerated osteoclastogenesis due to decline in the levels of osteoprotegerin (OPG) secreted by osteoblasts or directly via Frizzled 8 (Fzd8). In this review, we provide a landscape of the Wnt pathway components in influencing progenitor cell differentiation toward osteoblasts or osteoclasts under physiological conditions as well as pathological disorders resulting in various skeletal dysplasia syndromes.
Language	English
Publishing date	2014-06-11
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2816308-4
ISSN	2047-6396
ISSN	2047-6396
DOI	10.1038/bonekey.2014.36
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Article: Computational fluid dynamics simulation studies on pasteurization of egg in stationary and rotation modes

Ramachandran, Radhika / Malhotra, Deepti / Anishaparvin, A / Anandharamakrishnan, C

Innovative food science & emerging technologies. 2011 Jan., v. 12, no. 1

2011

Abstract: Eggs contain many nutritive compounds and are consumed all over the world. Pasteurization is an important unit operation for inactivation of pathogenic bacteria and is widely used for inactivation of Salmonella enteritidis. Experimental studies and ... ...

Abstract	Eggs contain many nutritive compounds and are consumed all over the world. Pasteurization is an important unit operation for inactivation of pathogenic bacteria and is widely used for inactivation of Salmonella enteritidis. Experimental studies and computational fluid dynamics (CFD) simulations were performed on thermal pasteurization of egg at 55.6°C. In this study, CFD simulation of temperature predictions was validated with experimental measurements of the temperature in the egg without yolk. After validation, a whole egg (with yolk) was simulated in CFD at two different modes namely stationary and rotation (at 2.5 and 5rpm). These results revealed that the stationary egg took about 30min to reach the pasteurization temperature, whereas, rotating egg needed only 9.5min. This reduction in processing time minimizes the thermal damage of the egg's nutrients. Hence, rotation of egg made the thermal pasteurization process more efficient. Moreover, prediction of inactivation of S. enteritidis based on the process value F (min) also reinforced the positive effect of rotation during thermal pasteurization. Industrial Relevance: In recent years, a rapid development in the application of CFD in food processing operations has been witnessed. The main need for CFD analysis of pasteurization is to determine the uniform and effective heat distribution in the egg and to examine the position of slowest heating zone (SHZ). Relatively few works have been published related to applications of CFD in thermal processing of egg. However, all the studies were performed for a stationary position of egg during thermal process. So far, no works have been published on the pasteurization of egg in a rotation mode. Hence, the present study was aimed at investigating the effects of pasteurization of egg at 55.6°C on pasteurization time. Rotation mode of pasteurization decreases the time of pasteurization by a large extent and makes more energy efficient process. Hence, it is advantageous for food industries to adopt rotation as an additional operation during pasteurization of eggs to produce high quality intact eggs without affecting its functional properties.
Keywords	Salmonella enteritidis ; bacteria ; egg quality ; egg yolk ; eggs ; fluid mechanics ; food industry ; food processing ; functional properties ; heat ; nutrients ; pasteurization ; prediction ; temperature
Language	English
Dates of publication	2011-01
Size	p. 38-44.
Publishing place	[Amsterdam]: Elsevier Science
Document type	Article
ZDB-ID	2025029-0
ISSN	1466-8564
ISSN	1466-8564
DOI	10.1016/j.ifset.2010.11.008
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Suppressed expression of T-box transcription factors is involved in senescence in chronic obstructive pulmonary disease.

Acquaah-Mensah, George K / Malhotra, Deepti / Vulimiri, Madhulika / McDermott, Jason E / Biswal, Shyam

PLoS computational biology

2012 Volume 8, Issue 7, Page(s) e1002597

Abstract: Chronic obstructive pulmonary disease (COPD) is a major global health problem. The etiology of COPD has been associated with apoptosis, oxidative stress, and inflammation. However, understanding of the molecular interactions that modulate COPD ... ...

Abstract	Chronic obstructive pulmonary disease (COPD) is a major global health problem. The etiology of COPD has been associated with apoptosis, oxidative stress, and inflammation. However, understanding of the molecular interactions that modulate COPD pathogenesis remains only partly resolved. We conducted an exploratory study on COPD etiology to identify the key molecular participants. We used information-theoretic algorithms including Context Likelihood of Relatedness (CLR), Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNE), and Inferelator. We captured direct functional associations among genes, given a compendium of gene expression profiles of human lung epithelial cells. A set of genes differentially expressed in COPD, as reported in a previous study were superposed with the resulting transcriptional regulatory networks. After factoring in the properties of the networks, an established COPD susceptibility locus and domain-domain interactions involving protein products of genes in the generated networks, several molecular candidates were predicted to be involved in the etiology of COPD. These include COL4A3, CFLAR, GULP1, PDCD1, CASP10, PAX3, BOK, HSPD1, PITX2, and PML. Furthermore, T-box (TBX) genes and cyclin-dependent kinase inhibitor 2A (CDKN2A), which are in a direct transcriptional regulatory relationship, emerged as preeminent participants in the etiology of COPD by means of senescence. Contrary to observations in neoplasms, our study reveals that the expression of genes and proteins in the lung samples from patients with COPD indicate an increased tendency towards cellular senescence. The expression of the anti-senescence mediators TBX transcription factors, chromatin modifiers histone deacetylases, and sirtuins was suppressed; while the expression of TBX-regulated cellular senescence markers such as CDKN2A, CDKN1A, and CAV1 was elevated in the peripheral lung tissue samples from patients with COPD. The critical balance between senescence and anti-senescence factors is disrupted towards senescence in COPD lungs.
MeSH term(s)	Aged ; Aged, 80 and over ; Apoptosis/genetics ; Cellular Senescence/genetics ; Databases, Genetic ; Female ; Gene Expression Profiling ; Humans ; Inflammation/genetics ; Inflammation/metabolism ; Inflammation/pathology ; Lung/chemistry ; Lung/metabolism ; Lung/pathology ; Male ; Middle Aged ; Oxidative Stress/genetics ; Pulmonary Disease, Chronic Obstructive/genetics ; Pulmonary Disease, Chronic Obstructive/metabolism ; Pulmonary Disease, Chronic Obstructive/pathology ; Signal Transduction ; T-Box Domain Proteins/biosynthesis ; T-Box Domain Proteins/genetics ; T-Box Domain Proteins/metabolism
Chemical Substances	T-Box Domain Proteins
Language	English
Publishing date	2012-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1002597
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Article: A screen for conserved sequences with biased base composition identifies noncoding RNAs in the A-T rich genome of Plasmodium falciparum.

Upadhyay, Roopam / Bawankar, Praveen / Malhotra, Deepti / Patankar, Swati

Molecular and biochemical parasitology

2005 Volume 144, Issue 2, Page(s) 149–158

Abstract: Noncoding RNAs (ncRNAs) such as snRNAs, snoRNAs and microRNAs play important roles in transcription and translation control. These ncRNAs have yet to be discovered in the malarial parasite Plasmodium falciparum, an organism in which these basic ... ...

Abstract	Noncoding RNAs (ncRNAs) such as snRNAs, snoRNAs and microRNAs play important roles in transcription and translation control. These ncRNAs have yet to be discovered in the malarial parasite Plasmodium falciparum, an organism in which these basic biological processes are poorly understood. Inspired by a report by Klein et al., we initiated a bioinformatics screen to uncover several candidate ncRNAs from the parasite genome using two simple criteria: first, elevated GC content in the highly A-T rich intergenic regions of the P. falciparum genome and second, conservation of sequence homology between malaria parasite species. We show that all the annotated tRNAs can be successfully identified in our screen as well as several new candidates that show homology to snRNAs and snoRNAs, and ten candidate ncRNAs of unknown function. Three of the candidate snRNAs, a predicted selenocysteine tRNA and two candidates of unknown function are expressed in asexual stage parasites, further validating the screen. With these results, the biological processes underlying RNA-mediated regulation of transcription, translation and splicing can be studied in an important human pathogen.
MeSH term(s)	Animals ; Base Composition ; Base Sequence ; Conserved Sequence ; DNA, Intergenic/genetics ; Genome, Protozoan ; Molecular Sequence Data ; Plasmodium falciparum/genetics ; RNA, Protozoan/genetics ; RNA, Untranslated/genetics ; Sequence Homology, Nucleic Acid ; Species Specificity
Chemical Substances	DNA, Intergenic ; RNA, Protozoan ; RNA, Untranslated
Language	English
Publishing date	2005-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	756166-0
ISSN	1872-9428 ; 0166-6851
ISSN (online)	1872-9428
ISSN	0166-6851
DOI	10.1016/j.molbiopara.2005.08.012
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Article ; Online: Network inference algorithms elucidate Nrf2 regulation of mouse lung oxidative stress.

Taylor, Ronald C / Acquaah-Mensah, George / Singhal, Mudita / Malhotra, Deepti / Biswal, Shyam

PLoS computational biology

2008 Volume 4, Issue 8, Page(s) e1000166

Abstract: A variety of cardiovascular, neurological, and neoplastic conditions have been associated with oxidative stress, i.e., conditions under which levels of reactive oxygen species (ROS) are elevated over significant periods. Nuclear factor erythroid 2- ... ...

Abstract	A variety of cardiovascular, neurological, and neoplastic conditions have been associated with oxidative stress, i.e., conditions under which levels of reactive oxygen species (ROS) are elevated over significant periods. Nuclear factor erythroid 2-related factor (Nrf2) regulates the transcription of several gene products involved in the protective response to oxidative stress. The transcriptional regulatory and signaling relationships linking gene products involved in the response to oxidative stress are, currently, only partially resolved. Microarray data constitute RNA abundance measures representing gene expression patterns. In some cases, these patterns can identify the molecular interactions of gene products. They can be, in effect, proxies for protein-protein and protein-DNA interactions. Traditional techniques used for clustering coregulated genes on high-throughput gene arrays are rarely capable of distinguishing between direct transcriptional regulatory interactions and indirect ones. In this study, newly developed information-theoretic algorithms that employ the concept of mutual information were used: the Algorithm for the Reconstruction of Accurate Cellular Networks (ARACNE), and Context Likelihood of Relatedness (CLR). These algorithms captured dependencies in the gene expression profiles of the mouse lung, allowing the regulatory effect of Nrf2 in response to oxidative stress to be determined more precisely. In addition, a characterization of promoter sequences of Nrf2 regulatory targets was conducted using a Support Vector Machine classification algorithm to corroborate ARACNE and CLR predictions. Inferred networks were analyzed, compared, and integrated using the Collective Analysis of Biological Interaction Networks (CABIN) plug-in of Cytoscape. Using the two network inference algorithms and one machine learning algorithm, a number of both previously known and novel targets of Nrf2 transcriptional activation were identified. Genes predicted as novel Nrf2 targets include Atf1, Srxn1, Prnp, Sod2, Als2, Nfkbib, and Ppp1r15b. Furthermore, microarray and quantitative RT-PCR experiments following cigarette-smoke-induced oxidative stress in Nrf2(+/+) and Nrf2(-/-) mouse lung affirmed many of the predictions made. Several new potential feed-forward regulatory loops involving Nrf2, Nqo1, Srxn1, Prdx1, Als2, Atf1, Sod1, and Park7 were predicted. This work shows the promise of network inference algorithms operating on high-throughput gene expression data in identifying transcriptional regulatory and other signaling relationships implicated in mammalian disease.
MeSH term(s)	Algorithms ; Animals ; Artificial Intelligence ; Gene Expression Profiling/methods ; Gene Regulatory Networks/drug effects ; Gene Regulatory Networks/genetics ; Guanine Nucleotide Exchange Factors/drug effects ; Guanine Nucleotide Exchange Factors/genetics ; Lung/metabolism ; Mice ; Mice, Knockout ; NF-E2-Related Factor 2/drug effects ; NF-E2-Related Factor 2/metabolism ; Oligonucleotide Array Sequence Analysis/methods ; Oxidative Stress/drug effects ; Oxidative Stress/genetics ; Oxidoreductases Acting on Sulfur Group Donors/drug effects ; Oxidoreductases Acting on Sulfur Group Donors/genetics ; Promoter Regions, Genetic ; Signal Transduction/genetics ; Smoking/adverse effects ; Smoking/genetics ; Software ; Transcription, Genetic/drug effects ; Transcription, Genetic/genetics
Chemical Substances	Als2 protein, mouse ; Guanine Nucleotide Exchange Factors ; NF-E2-Related Factor 2 ; Oxidoreductases Acting on Sulfur Group Donors (EC 1.8.-) ; sulfiredoxin protein, mouse (EC 1.8.-)
Language	English
Publishing date	2008-08-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2193340-6
ISSN	1553-7358 ; 1553-734X
ISSN (online)	1553-7358
ISSN	1553-734X
DOI	10.1371/journal.pcbi.1000166
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Article ; Online: Exposure to neonatal cigarette smoke causes durable lung changes but does not potentiate cigarette smoke-induced chronic obstructive pulmonary disease in adult mice.

McGrath-Morrow, Sharon / Malhotra, Deepti / Lauer, Thomas / Collaco, J Michael / Mitzner, Wayne / Neptune, Enid / Wise, Robert / Biswal, Shyam

Experimental lung research

2011 Volume 37, Issue 6, Page(s) 354–363

Abstract: The impact of early childhood cigarette smoke (CS) exposure on CS-induced chronic obstructive pulmonary disease (COPD) is unknown. This study was performed to evaluate the individual and combined effects of neonatal and adult CS exposure on lung ... ...

Abstract	The impact of early childhood cigarette smoke (CS) exposure on CS-induced chronic obstructive pulmonary disease (COPD) is unknown. This study was performed to evaluate the individual and combined effects of neonatal and adult CS exposure on lung structure, function, and gene expression in adult mice. To model a childhood CS exposure, neonatal C57/B6 mice were exposed to 14 days of CS (Neo CS). At 10 weeks of age, Neo CS and control mice were exposed to 4 months of CS. Pulmonary function tests, bronchoalveolar lavage, and lung morphometry were measured and gene expression profiling was performed on lung tissue. Mean chord lengths and lung volumes were increased in neonatal and/or adult CS-exposed mice. Differences in immune, cornified envelope protein, muscle, and erythrocyte genes were found in CS-exposed lung. Neonatal CS exposure caused durable structural and functional changes in the adult lung but did not potentiate CS-induced COPD changes. Cornified envelope protein gene expression was decreased in all CS-exposed mice, whereas myosin and erythrocyte gene expression was increased in mice exposed to both neonatal and adult CS, suggesting an adaptive response. Additional studies may be warranted to determine the utility of these genes as biomarkers of respiratory outcomes.
MeSH term(s)	Age Factors ; Animals ; Animals, Newborn ; Bronchoalveolar Lavage/methods ; Erythrocytes/metabolism ; Gene Expression Profiling/methods ; Lung/metabolism ; Lung/physiopathology ; Mice ; Mice, Inbred C57BL ; Myosins/genetics ; Pulmonary Disease, Chronic Obstructive/etiology ; Pulmonary Disease, Chronic Obstructive/genetics ; Pulmonary Disease, Chronic Obstructive/physiopathology ; Respiratory Function Tests/methods ; Smoking/adverse effects
Chemical Substances	Myosins (EC 3.6.4.1)
Language	English
Publishing date	2011-06-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	603791-4
ISSN	1521-0499 ; 0190-2148
ISSN (online)	1521-0499
ISSN	0190-2148
DOI	10.3109/01902148.2011.577268
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Article: Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis

Malhotra, Deepti / Portales-Casamar, Elodie / Singh, Anju / Srivastava, Siddhartha / Arenillas, David / Happel, Christine / Shyr, Casper / Wakabayashi, Nobunao / Kensler, Thomas W / Wasserman, Wyeth W / Biswal, Shyam

Nucleic acids research. 2010 Sept., v. 38, no. 17

2010

Abstract: The Nrf2 (nuclear factor E2 p45-related factor 2) transcription factor responds to diverse oxidative and electrophilic environmental stresses by circumventing repression by Keap1, translocating to the nucleus, and activating cytoprotective genes. Nrf2 ... ...

Abstract	The Nrf2 (nuclear factor E2 p45-related factor 2) transcription factor responds to diverse oxidative and electrophilic environmental stresses by circumventing repression by Keap1, translocating to the nucleus, and activating cytoprotective genes. Nrf2 responses provide protection against chemical carcinogenesis, chronic inflammation, neurodegeneration, emphysema, asthma and sepsis in murine models. Nrf2 regulates the expression of a plethora of genes that detoxify oxidants and electrophiles and repair or remove damaged macromolecules, such as through proteasomal processing. However, many direct targets of Nrf2 remain undefined. Here, mouse embryonic fibroblasts (MEF) with either constitutive nuclear accumulation (Keap1â»/â») or depletion (Nrf2â»/â») of Nrf2 were utilized to perform chromatin-immunoprecipitation with parallel sequencing (ChIP-Seq) and global transcription profiling. This unique Nrf2 ChIP-Seq dataset is highly enriched for Nrf2-binding motifs. Integrating ChIP-Seq and microarray analyses, we identified 645 basal and 654 inducible direct targets of Nrf2, with 244 genes at the intersection. Modulated pathways in stress response and cell proliferation distinguish the inducible and basal programs. Results were confirmed in an in vivo stress model of cigarette smoke-exposed mice. This study reveals global circuitry of the Nrf2 stress response emphasizing Nrf2 as a central node in cell survival response.
Keywords	Lewis acids ; animal models ; asthma ; binding sites ; carcinogenesis ; cell proliferation ; cell viability ; data collection ; fibroblasts ; genes ; inflammation ; mice ; neurodegenerative diseases ; nucleic acids ; oxidants ; pulmonary emphysema ; sepsis (infection) ; stress response ; transcription (genetics) ; transcription factors
Language	English
Dates of publication	2010-09
Size	p. 5718-5734.
Document type	Article
ZDB-ID	186809-3
ISSN	0301-5610 ; 0305-1048
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkq212
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Article ; Online: Deletion of Keap1 in the lung attenuates acute cigarette smoke-induced oxidative stress and inflammation.

Blake, David J / Singh, Anju / Kombairaju, Ponvijay / Malhotra, Deepti / Mariani, Thomas J / Tuder, Rubin M / Gabrielson, Edward / Biswal, Shyam

American journal of respiratory cell and molecular biology

2009 Volume 42, Issue 5, Page(s) 524–536

Abstract: Exposure to cigarette smoke (CS) is the primary factor associated with the development of chronic obstructive pulmonary disease (COPD). CS increases the level of oxidants in the lungs, resulting in a depletion of antioxidants, which promotes oxidative ... ...

Abstract	Exposure to cigarette smoke (CS) is the primary factor associated with the development of chronic obstructive pulmonary disease (COPD). CS increases the level of oxidants in the lungs, resulting in a depletion of antioxidants, which promotes oxidative stress and the destruction of alveolar tissue. In response to CS, pulmonary epithelial cells counteract increased levels of oxidants by activating Nrf2-dependent pathways to augment the expression of detoxification and antioxidant enzymes, thereby protecting the lung from injury. We hypothesize that increasing the pathways activated by Nrf2 will afford protection against CS-induced lung damage. To this end we have developed a novel mouse model in which the cytosolic inhibitor of Nrf2, Keap1, is genetically deleted in Clara cells, which predominate in the upper airways in mice. Deletion of Keap1 in Clara cells resulted in increased expression of Nrf2-dependent genes, such as Nqo1 and Gclm, as determined by microarray analysis and quantitative PCR. Deletion of Keap1 in airway epithelium decreased Keap1 protein levels and significantly increased the total level of glutathione in the lungs. Increased Nrf2 activation protected Clara cells against oxidative stress ex vivo and attenuated oxidative stress and CS-induced inflammation in vivo. Expression of KEAP1 was also decreased in human epithelial cells through siRNA transfection, which increased the expression of Nrf2-dependent genes and attenuated oxidative stress. In conclusion, activating Nrf2 pathways in tissue-specific Keap1 knockout mice represents an important genetic approach against oxidant-induced lung damage.
MeSH term(s)	Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Antioxidants/metabolism ; Cell Line ; Cell Separation ; Cytoskeletal Proteins/metabolism ; Epithelial Cells/drug effects ; Epithelial Cells/metabolism ; Epithelium/drug effects ; Epithelium/metabolism ; Epithelium/pathology ; Gene Deletion ; Humans ; Hydrogen Peroxide/pharmacology ; Integrases/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Kelch-Like ECH-Associated Protein 1 ; Lung/drug effects ; Lung/metabolism ; Lung/pathology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NF-E2-Related Factor 2/metabolism ; Organ Specificity/drug effects ; Oxidative Stress/drug effects ; Pneumonia/metabolism ; Pneumonia/pathology ; RNA, Small Interfering/metabolism ; Smoking/adverse effects
Chemical Substances	Adaptor Proteins, Signal Transducing ; Antioxidants ; Cytoskeletal Proteins ; Intracellular Signaling Peptides and Proteins ; KEAP1 protein, human ; Keap1 protein, mouse ; Kelch-Like ECH-Associated Protein 1 ; NF-E2-Related Factor 2 ; RNA, Small Interfering ; Hydrogen Peroxide (BBX060AN9V) ; Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-)
Language	English
Publishing date	2009-06-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1025960-0
ISSN	1535-4989 ; 1044-1549
ISSN (online)	1535-4989
ISSN	1044-1549
DOI	10.1165/rcmb.2009-0054OC
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Article ; Online: Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification.

Regard, Jean B / Malhotra, Deepti / Gvozdenovic-Jeremic, Jelena / Josey, Michelle / Chen, Min / Weinstein, Lee S / Lu, Jianming / Shore, Eileen M / Kaplan, Frederick S / Yang, Yingzi

Nature medicine

2013 Volume 19, Issue 11, Page(s) 1505–1512

Abstract: Heterotopic ossification, the pathologic formation of extraskeletal bone, occurs as a common complication of trauma or in genetic disorders and can be disabling and lethal. However, the underlying molecular mechanisms are largely unknown. Here we ... ...

Abstract	Heterotopic ossification, the pathologic formation of extraskeletal bone, occurs as a common complication of trauma or in genetic disorders and can be disabling and lethal. However, the underlying molecular mechanisms are largely unknown. Here we demonstrate that Gαs restricts bone formation to the skeleton by inhibiting Hedgehog signaling in mesenchymal progenitor cells. In progressive osseous heteroplasia, a human disease caused by null mutations in GNAS, which encodes Gαs, Hedgehog signaling is upregulated in ectopic osteoblasts and progenitor cells. In animal models, we show that genetically-mediated ectopic Hedgehog signaling is sufficient to induce heterotopic ossification, whereas inhibition of this signaling pathway by genetic or pharmacological means strongly reduces the severity of this condition. As our previous work has shown that GNAS gain-of-function mutations upregulate WNT-β-catenin signaling in osteoblast progenitor cells, resulting in their defective differentiation and fibrous dysplasia, we identify Gαs as a key regulator of proper osteoblast differentiation through its maintenance of a balance between the Wnt-β-catenin and Hedgehog pathways. Also, given the results here of the pharmacological studies in our mouse model, we propose that Hedgehog inhibitors currently used in the clinic for other conditions, such as cancer, may possibly be repurposed for treating heterotopic ossification and other diseases caused by GNAS inactivation.
MeSH term(s)	Animals ; Bone Diseases, Metabolic/genetics ; Bone Diseases, Metabolic/metabolism ; Bone Diseases, Metabolic/pathology ; Cell Differentiation ; Chromogranins ; Female ; GTP-Binding Protein alpha Subunits, Gs/deficiency ; GTP-Binding Protein alpha Subunits, Gs/genetics ; Hedgehog Proteins/antagonists & inhibitors ; Hedgehog Proteins/genetics ; Hedgehog Proteins/metabolism ; Humans ; Male ; Mice ; Mice, Knockout ; Mutation ; Ossification, Heterotopic/genetics ; Ossification, Heterotopic/metabolism ; Ossification, Heterotopic/pathology ; Osteoblasts/metabolism ; Osteoblasts/pathology ; Signal Transduction ; Skin Diseases, Genetic/genetics ; Skin Diseases, Genetic/metabolism ; Skin Diseases, Genetic/pathology ; Wnt Signaling Pathway ; beta Catenin/metabolism
Chemical Substances	Chromogranins ; Hedgehog Proteins ; beta Catenin ; GNAS protein, human (EC 3.6.1.-) ; Gnas protein, mouse (EC 3.6.1.-) ; GTP-Binding Protein alpha Subunits, Gs (EC 3.6.5.1)
Language	English
Publishing date	2013-09-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/nm.3314
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In stock of ZB MED Cologne/Königswinter

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