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Articles 31 - 60 of 74

Full-Text Articles in Medicine and Health Sciences

Dengue Virus Protein Recognition By Virus-Specific Murine Cd8+ Cytotoxic T Lymphocytes, Alan L. Rothman, Ichiro Kurane, Ching-Juh Lai, Michael Bray, Barry Falgout, Ruhe Men, Francis A. Ennis Aug 2014

Dengue Virus Protein Recognition By Virus-Specific Murine Cd8+ Cytotoxic T Lymphocytes, Alan L. Rothman, Ichiro Kurane, Ching-Juh Lai, Michael Bray, Barry Falgout, Ruhe Men, Francis A. Ennis

Alan Rothman

The identification of the protein targets for dengue virus-specific T lymphocytes may be useful for planning the development of subunit vaccines against dengue. We studied the recognition by murine dengue virus-specific major histocompatibility complex class I-restricted, CD8+ cytotoxic T lymphocytes (CTL) of dengue virus proteins using recombinant vaccinia viruses containing segments of the dengue virus genome. CTL from H-2k mice recognized a single serotype-cross-reactive epitope on the nonstructural (NS) protein NS3. CTL from H-2b mice recognized a serotype-cross-reactive epitope that was localized to NS4a or NS4b. CTL from H-2d mice recognized at least three epitopes: a serotype-specific epitope on one …

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Analysis Of Murine Cd8(+) T-Cell Clones Specific For The Dengue Virus Ns3 Protein: Flavivirus Cross-Reactivity And Influence Of Infecting Serotype, Anne C. Spaulding, Ichiro Kurane, Francis A. Ennis, Alan L. Rothman Aug 2014

Analysis Of Murine Cd8(+) T-Cell Clones Specific For The Dengue Virus Ns3 Protein: Flavivirus Cross-Reactivity And Influence Of Infecting Serotype, Anne C. Spaulding, Ichiro Kurane, Francis A. Ennis, Alan L. Rothman

Alan Rothman

Serotype-cross-reactive dengue virus-specific cytotoxic T lymphocytes (CTL) induced during a primary dengue virus infection are thought to play a role in the immunopathogenesis of dengue hemorrhagic fever (DHF) during a secondary dengue virus infection. Although there is no animal model of DHF, we previously reported that murine dengue virus-specific CTL responses are qualitatively similar to human dengue virus-specific CTL responses. We used BALB/c mice to study the specificity of the CTL response to an immunodominant epitope on the dengue virus NS3 protein. We mapped the minimal H-2Kd-restricted CTL epitope to residues 298 to 306 of the dengue type 2 virus …

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Robust Intrapulmonary Cd8 T Cell Responses And Protection With An Attenuated N1l Deleted Vaccinia Virus, Anuja Mathew, Joel O'Bryan, William L. Marshall, Girish J. Kotwal, Masanori Terajima, Sharone Green, Alan L. Rothman, Francis A. Ennis Aug 2014

Robust Intrapulmonary Cd8 T Cell Responses And Protection With An Attenuated N1l Deleted Vaccinia Virus, Anuja Mathew, Joel O'Bryan, William L. Marshall, Girish J. Kotwal, Masanori Terajima, Sharone Green, Alan L. Rothman, Francis A. Ennis

Alan Rothman

BACKGROUND: Vaccinia viruses have been used as a model for viral disease and as a protective live vaccine. METHODOLOGY AND PRINCIPAL FINDINGS: We investigated the immunogenicity of an attenuated strain of vaccinia virus engineered to inactivate the N1L gene (vGK5). Using the intranasal route, this recombinant virus was 2 logs less virulent compared to the wildtype VACV-WR. Infection by the intranasal, intraperitoneal, and tail scarification routes resulted in the robust induction of cytolytic virus-specific CD8 T cells in the spleens and the lungs. VACV-specific antibodies were also detected in the sera of mice infected 3-5 months prior with the attenuated …

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Dengue Virus-Specific Murine T-Lymphocyte Proliferation: Serotype Specificity And Response To Recombinant Viral Proteins, Alan L. Rothman, Ichiro Kurane, Yi-Ming Zhang, Ching-Juh Lai, Francis A. Ennis Aug 2014

Dengue Virus-Specific Murine T-Lymphocyte Proliferation: Serotype Specificity And Response To Recombinant Viral Proteins, Alan L. Rothman, Ichiro Kurane, Yi-Ming Zhang, Ching-Juh Lai, Francis A. Ennis

Alan Rothman

Definition of the T-lymphocyte responses to dengue viruses should aid in the development of safe and effective vaccines and help to explain the pathophysiology of dengue hemorrhagic fever and dengue shock syndrome. In this study, we demonstrated that dengue virus-specific T lymphocytes were detected in spleen cells from dengue virus-immune mice using an in vitro proliferation assay. Following immunization with a single dose of infectious dengue virus, murine lymphocytes showed increased proliferation when incubated in the presence of viral antigens of the same serotype but not in the presence of control antigens. Depletion experiments with antibody and complement showed that …

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The Public Health Impacts Of Concentrated Animal Feeding Operations On Local Communities, Michael Greger, Gowri Koneswaran May 2014

The Public Health Impacts Of Concentrated Animal Feeding Operations On Local Communities, Michael Greger, Gowri Koneswaran

Michael Greger, MD, FACLM

Large-scale farm animal production facilities, also known as concentrated animal feeding operations (CAFOs), release a significant amount of contaminants into the air and water. Adverse health effects related to exposure to these contaminants among CAFO workers have been welldocumented; however, less is known about their impact on the health of residents in nearby communities. Epidemiological research in this area suggests that neighboring residents are at increased risk of developing neurobehavioral symptoms and respiratory illnesses, including asthma. Additional research is needed to better understand community-scale exposures and health outcomes related to the management practices and emissions of CAFOs.

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Medical Training Using Simulation: Toward Fewer Animals And Safer Patients, Jonathan Balcombe May 2014

Medical Training Using Simulation: Toward Fewer Animals And Safer Patients, Jonathan Balcombe

Jonathan Balcombe, PhD

This paper presents the current status of computer-based simulation in medicine. Recent technological advances have enabled this field to emerge from esoteric explorations in academic laboratories to commercially available simulators designed to train users to perform medical procedures from start to finish. Today, more than a dozen companies are producing virtual reality simulators and interactive manikins for training in endoscopy, laparoscopy, anaesthesia, trauma management, angiography, and needle insertion. For many of these procedures, thousands of animals are still being used in training. Yet simulation has many advantages that can transcend scientific, ethical, economic and logistical problems that arise when using …

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The Genome Of Anopheles Darlingi, The Main Neotropical Malaria Vector, Osvaldo Marinotti, Adam R. Wespiser, Daniel R. Caffrey, Douglas T. Golenbock, Neal S. Silverman Apr 2014

The Genome Of Anopheles Darlingi, The Main Neotropical Malaria Vector, Osvaldo Marinotti, Adam R. Wespiser, Daniel R. Caffrey, Douglas T. Golenbock, Neal S. Silverman

Neal Silverman

Anopheles darlingi is the principal neotropical malaria vector, responsible for more than a million cases of malaria per year on the American continent. Anopheles darlingi diverged from the African and Asian malaria vectors approximately 100 million years ago (mya) and successfully adapted to the New World environment. Here we present an annotated reference A. darlingi genome, sequenced from a wild population of males and females collected in the Brazilian Amazon. A total of 10 481 predicted protein-coding genes were annotated, 72% of which have their closest counterpart in Anopheles gambiae and 21% have highest similarity with other mosquito species. In …

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Robust Intrapulmonary Cd8 T Cell Responses And Protection With An Attenuated N1l Deleted Vaccinia Virus, Anuja Mathew, Joel O'Bryan, William L. Marshall, Girish J. Kotwal, Masanori Terajima, Sharone Green, Alan L. Rothman, Francis A. Ennis Jan 2014

Robust Intrapulmonary Cd8 T Cell Responses And Protection With An Attenuated N1l Deleted Vaccinia Virus, Anuja Mathew, Joel O'Bryan, William L. Marshall, Girish J. Kotwal, Masanori Terajima, Sharone Green, Alan L. Rothman, Francis A. Ennis

Sharone Green

BACKGROUND: Vaccinia viruses have been used as a model for viral disease and as a protective live vaccine. METHODOLOGY AND PRINCIPAL FINDINGS: We investigated the immunogenicity of an attenuated strain of vaccinia virus engineered to inactivate the N1L gene (vGK5). Using the intranasal route, this recombinant virus was 2 logs less virulent compared to the wildtype VACV-WR. Infection by the intranasal, intraperitoneal, and tail scarification routes resulted in the robust induction of cytolytic virus-specific CD8 T cells in the spleens and the lungs. VACV-specific antibodies were also detected in the sera of mice infected 3-5 months prior with the attenuated …

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Lipopolysaccharide Induces And Activates The Nalp3 Inflammasome In The Liver, Michal Ganz, Timea Csak, Bharath D. Nath, Gyongyi Szabo Oct 2012

Lipopolysaccharide Induces And Activates The Nalp3 Inflammasome In The Liver, Michal Ganz, Timea Csak, Bharath D. Nath, Gyongyi Szabo

Gyongyi Szabo

AIM: To examine the activation of the Nalp3 inflammasome and its downstream targets following lipopolysaccharide (LPS)-induced stimulation in the liver. METHODS: Six-to-eight-week-old C57BL/6 chow fed mice were injected intraperitoneally with 0.5 mug/g bodyweight LPS and sacrificed 2, 4, 6, 18 or 24 h later. LPS-induced liver damage was confirmed by a biochemical assay to detect alanine aminotransferase (ALT) levels. To determine if LPS stimulation in the liver led to activation of the inflammasome, real-time quantitative polymerase chain reaction was used to evaluate the mRNA expression of components of the Nalp3 inflammasome. Enzyme-linked immunosorbent assays were used to determine the protein …

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Human Lens Lipids Differ Markedly From Those Of Commonly Used Experimental Animals, Jane Deeley, Todd W. Mitchell, Xiaojia Wei, Jurgen Korth, Jessica Hughes, Stephen J. Blanksby, Roger J. Truscott Oct 2012

Human Lens Lipids Differ Markedly From Those Of Commonly Used Experimental Animals, Jane Deeley, Todd W. Mitchell, Xiaojia Wei, Jurgen Korth, Jessica Hughes, Stephen J. Blanksby, Roger J. Truscott

Stephen Blanksby

Electrospray ionisation tandem mass spectrometry has allowed the unambiguous identification andquantification of individual lens phospholipids in human and six animal models. Using this approach ca. 100unique phospholipids have been characterised. Parallel analysis of the same lens extracts by a novel directinsertionelectron-ionization technique found the cholesterol content of human lenses to be significantlyhigher (ca. 6 times) than lenses from the other animals.The most abundant phospholipids in all the lenses examined were choline-containing phospholipids. In rat,mouse, sheep, cow, pig and chicken, thesewere present largely as phosphatidylcholines, in contrast 66% of thetotal phospholipid in Homo sapienswas sphingomyelin, with the most abundant being dihydrosphingomyelins,in …

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Rapid Inversion: Running Animals And Robots Swing Like A Pendulum Under Ledges, Jean-Michel Mongeau, Brian Mcrae, Ardian Jusufi, Paul Birkmeyer, Aaron M. Hoover, Ronald Fearing, Robert J. Full Jul 2012

Rapid Inversion: Running Animals And Robots Swing Like A Pendulum Under Ledges, Jean-Michel Mongeau, Brian Mcrae, Ardian Jusufi, Paul Birkmeyer, Aaron M. Hoover, Ronald Fearing, Robert J. Full

Aaron M. Hoover

Escaping from predators often demands that animals rapidly negotiate complex environments. The smallest animals attain relatively fast speeds with high frequency leg cycling, wing flapping or body undulations, but absolute speeds are slow compared to larger animals. Instead, small animals benefit from the advantages of enhanced maneuverability in part due to scaling. Here, we report a novel behavior in small, legged runners that may facilitate their escape by disappearance from predators. We video recorded cockroaches and geckos rapidly running up an incline toward a ledge, digitized their motion and created a simple model to generalize the behavior. Both species ran …

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Hovering Energetics And Thermal Balance In Anna's Hummingbirds (Calypte Anna), Dennis Evangelista, Maria J. Fernandez, Madalyn S. Berns, Aaron M. Hoover, Robert Dudley Jul 2012

Hovering Energetics And Thermal Balance In Anna's Hummingbirds (Calypte Anna), Dennis Evangelista, Maria J. Fernandez, Madalyn S. Berns, Aaron M. Hoover, Robert Dudley

Aaron M. Hoover

We studied the energetics of hover-feeding Anna's hummingbirds, using three different simultaneous techniques: heat loss as estimated via thermal imaging, metabolic rate as measured at a feeder mask using flow-through respirometry, and aerodynamic power estimated from wingbeat kinematic data. These three methods yielded comparable estimates of power output at ambient air temperatures ranging from 18 degrees to 26 degrees C, whereas heat imbalance at higher air temperatures (up to 34 degrees C) suggested loss by mechanisms other than convection and radiation from the body, such as evaporative cooling and enthalpy rise associated with exhaled air and excreted water and convective …

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Temporal And Functional Profile Of The Transcriptional Regulatory Network In The Early Regenerative Response To Partial Hepatectomy In The Rat., Egle Juskeviciute, Rajanikanth Vadigepalli, Jan B Hoek May 2012

Temporal And Functional Profile Of The Transcriptional Regulatory Network In The Early Regenerative Response To Partial Hepatectomy In The Rat., Egle Juskeviciute, Rajanikanth Vadigepalli, Jan B Hoek

Rajanikanth Vadigepalli

BACKGROUND: The goal of these studies was to characterize the transcriptional network regulating changes in gene expression in the remnant liver of the rat after 70% partial hepatectomy (PHx) during the early phase response including the transition of hepatocytes from the quiescent (G0) state and the onset of the G1 phase of the cell cycle. RESULTS: The transcriptome of remnant livers was monitored at 1, 2, 4, and 6 hours after PHx using cDNA microarrays. Differentially regulated genes were grouped into six clusters according their temporal expression profiles. Promoter regions of genes in these clusters were examined for shared transcription …

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Bladder Inflammatory Transcriptome In Response To Tachykinins: Neurokinin 1 Receptor-Dependent Genes And Transcription Regulatory Elements, Ricardo Saban, Cindy Simpson, Rajanikanth Vadigepalli, Sylvie Memet, Igor Dozmorov, Marcia R. Saban May 2012

Bladder Inflammatory Transcriptome In Response To Tachykinins: Neurokinin 1 Receptor-Dependent Genes And Transcription Regulatory Elements, Ricardo Saban, Cindy Simpson, Rajanikanth Vadigepalli, Sylvie Memet, Igor Dozmorov, Marcia R. Saban

Rajanikanth Vadigepalli

Background Tachykinins (TK), such as substance P, and their neurokinin receptors which are ubiquitously expressed in the human urinary tract, represent an endogenous system regulating bladder inflammatory, immune responses, and visceral hypersensitivity. Increasing evidence correlates alterations in the TK system with urinary tract diseases such as neurogenic bladders, outflow obstruction, idiopathic detrusor instability, and interstitial cystitis. However, despite promising effects in animal models, there seems to be no published clinical study showing that NK-receptor antagonists are an effective treatment of pain in general or urinary tract disorders, such as detrusor overactivity. In order to search for therapeutic targets that could …

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Transcriptional Regulatory Network Analysis During Epithelial-Mesenchymal Transformation Of Retinal Pigment Epithelium., Craig H Pratt, Rajanikanth Vadigepalli, Praveen Chakravarthula, Gregory E Gonye, Nancy J Philp, Gerald B Grunwald May 2012

Transcriptional Regulatory Network Analysis During Epithelial-Mesenchymal Transformation Of Retinal Pigment Epithelium., Craig H Pratt, Rajanikanth Vadigepalli, Praveen Chakravarthula, Gregory E Gonye, Nancy J Philp, Gerald B Grunwald

Rajanikanth Vadigepalli

PURPOSE: Phenotypic transformation of retinal pigment epithelial (RPE) cells contributes to the onset and progression of ocular proliferative disorders such as proliferative vitreoretinopathy (PVR). The formation of epiretinal membranes in PVR may involve an epithelial-mesenchymal transformation (EMT) of RPE cells as part of an aberrant wound healing response. While the underlying mechanism remains unclear, this likely involves changes in RPE cell gene expression under the control of specific transcription factors (TFs). Thus, the purpose of the present study was to identify TFs that may play a role in this process. METHODS: Regulatory regions of genes that are differentially regulated during …

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Agricultural Health In The Gambia I: Agricultural Practices And Developments, R. Kuye, K. Donham, S. Marquez, W. Sanderson, L. Fuortes, R. Rautiainen, M. Jones, Kennith R. Culp Mar 2012

Agricultural Health In The Gambia I: Agricultural Practices And Developments, R. Kuye, K. Donham, S. Marquez, W. Sanderson, L. Fuortes, R. Rautiainen, M. Jones, Kennith R. Culp

Kennith R. Culp

This manuscript reports results of our study to characterize the historical developments of agricultural practices in The Gambia and related health risks of farm workers. It surveys the various factors that shape production agriculture in the country and examines the degrees to which hand tools, animal traction, motorized traction and manual labour all contribute to the inherent hazards of farm work. The principal objective of this study is to lay the ground work for detailed research of occupational health hazards in Gambian agriculture; and development of policies and programmes to promote the health of Gambian farmers. The authors of this …

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Agricultural Health In The Gambia I: Agricultural Practices And Developments, R. Kuye, K. Donham, S. Marquez, W. Sanderson, L. Fuortes, R. Rautiainen, M. Jones, Kennith R. Culp Oct 2011

Agricultural Health In The Gambia I: Agricultural Practices And Developments, R. Kuye, K. Donham, S. Marquez, W. Sanderson, L. Fuortes, R. Rautiainen, M. Jones, Kennith R. Culp

Kennith R. Culp

This manuscript reports results of our study to characterize the historical developments of agricultural practices in The Gambia and related health risks of farm workers. It surveys the various factors that shape production agriculture in the country and examines the degrees to which hand tools, animal traction, motorized traction and manual labour all contribute to the inherent hazards of farm work. The principal objective of this study is to lay the ground work for detailed research of occupational health hazards in Gambian agriculture; and development of policies and programmes to promote the health of Gambian farmers. The authors of this …

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Complete Sequencing Shows A Role For Msx1 In Non-Syndromic Cleft Lip And Palate, P. A. Jezewski, A. R. Vieira, C. Nishimura, B. Ludwig, M. Johnson, S. E. O'Brien, Sandra Daack-Hirsch, R. E. Schultz, A. Weber, B. Nepomucena, P. A. Romitti, K. Christensen, I. M. Orioli, E. E. Castilla, J. Machida, N. Natsume, J. C. Murray Oct 2011

Complete Sequencing Shows A Role For Msx1 In Non-Syndromic Cleft Lip And Palate, P. A. Jezewski, A. R. Vieira, C. Nishimura, B. Ludwig, M. Johnson, S. E. O'Brien, Sandra Daack-Hirsch, R. E. Schultz, A. Weber, B. Nepomucena, P. A. Romitti, K. Christensen, I. M. Orioli, E. E. Castilla, J. Machida, N. Natsume, J. C. Murray

Sandra Daack-Hirsch

MSX1 has been proposed as a gene in which mutations may contribute to non-syndromic forms of cleft lip and/or cleft palate. Support for this comes from human linkage and linkage disequilibrium studies, chromosomal deletions resulting in haploinsufficiency, a large family with a stop codon mutation that includes clefting as a phenotype, and the Msx1 phenotype in a knockout mouse. This report describes a population based scan for mutations encompassing the sense and antisense transcribed sequence of MSX1 (two exons, one intron). We compare the completed genomic sequence of MSX1 to the mouse Msx1 sequence to identify non-coding homology regions, and …

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Nod2, Rip2 And Irf5 Play A Critical Role In The Type I Interferon Response To Mycobacterium Tuberculosis, Amit K. Pandey, Yibin Yang, Zhaozhao Jiang, Sarah M. Fortune, Francois Coulombe, Marcel A. Behr, Katherine A. Fitzgerald, Christopher M. Sassetti, Michelle A. Kelliher Jul 2011

Nod2, Rip2 And Irf5 Play A Critical Role In The Type I Interferon Response To Mycobacterium Tuberculosis, Amit K. Pandey, Yibin Yang, Zhaozhao Jiang, Sarah M. Fortune, Francois Coulombe, Marcel A. Behr, Katherine A. Fitzgerald, Christopher M. Sassetti, Michelle A. Kelliher

Katherine A. Fitzgerald

While the recognition of microbial infection often occurs at the cell surface via Toll-like receptors, the cytosol of the cell is also under surveillance for microbial products that breach the cell membrane. An important outcome of cytosolic recognition is the induction of IFNalpha and IFNbeta, which are critical mediators of immunity against both bacteria and viruses. Like many intracellular pathogens, a significant fraction of the transcriptional response to Mycobacterium tuberculosis infection depends on these type I interferons, but the recognition pathways responsible remain elusive. In this work, we demonstrate that intraphagosomal M. tuberculosis stimulates the cytosolic Nod2 pathway that responds …

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Myd88-Dependent Il-1 Receptor Signaling Is Essential For Gouty Inflammation Stimulated By Monosodium Urate Crystals, Chun-Jen Chen, Yan Shi, Arron Hearn, Katherine A. Fitzgerald, Douglas T. Golenbock, George W. Reed, Shizuo Akira, Kenneth L. Rock Jul 2011

Myd88-Dependent Il-1 Receptor Signaling Is Essential For Gouty Inflammation Stimulated By Monosodium Urate Crystals, Chun-Jen Chen, Yan Shi, Arron Hearn, Katherine A. Fitzgerald, Douglas T. Golenbock, George W. Reed, Shizuo Akira, Kenneth L. Rock

Katherine A. Fitzgerald

While it is known that monosodium urate (MSU) crystals cause the disease gout, the mechanism by which these crystals stimulate this inflammatory condition has not been clear. Here we find that the Toll/IL-1R (TIR) signal transduction adaptor myeloid differentiation primary response protein 88 (MyD88) is required for acute gouty inflammation. In contrast, other TIR adaptor molecules, TIRAP/Mal, TRIF, and TRAM, are not required for this process. The MyD88-dependent TLR1, -2, -4, -6, -7, -9, and -11 and IL-18 receptor (IL-18R) are not essential for MSU-induced inflammation. Moreover, MSU does not stimulate HEK cells expressing TLR1-11 to activate NF-kappaB. In contrast, …

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Lps-Tlr4 Signaling To Irf-3/7 And Nf-Kappab Involves The Toll Adapters Tram And Trif, Katherine A. Fitzgerald, Daniel C. Rowe, Betsy J. Barnes, Daniel R. Caffrey, Alberto Visintin, Eicke Latz, Brian G. Monks, Paula M. Pitha, Douglas T. Golenbock Jul 2011

Lps-Tlr4 Signaling To Irf-3/7 And Nf-Kappab Involves The Toll Adapters Tram And Trif, Katherine A. Fitzgerald, Daniel C. Rowe, Betsy J. Barnes, Daniel R. Caffrey, Alberto Visintin, Eicke Latz, Brian G. Monks, Paula M. Pitha, Douglas T. Golenbock

Katherine A. Fitzgerald

Toll-IL-1-resistance (TIR) domain-containing adaptor-inducing IFN-beta (TRIF)-related adaptor molecule (TRAM) is the fourth TIR domain-containing adaptor protein to be described that participates in Toll receptor signaling. Like TRIF, TRAM activates interferon regulatory factor (IRF)-3, IRF-7, and NF-kappaB-dependent signaling pathways. Toll-like receptor (TLR)3 and 4 activate these pathways to induce IFN-alpha/beta, regulated on activation, normal T cell expressed and secreted (RANTES), and gamma interferon-inducible protein 10 (IP-10) expression independently of the adaptor protein myeloid differentiation factor 88 (MyD88). Dominant negative and siRNA studies performed here demonstrate that TRIF functions downstream of both the TLR3 (dsRNA) and TLR4 (LPS) signaling pathways, whereas the …

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Evidence That Distinct States Of The Integrin Alpha6beta1 Interact With Laminin And An Adam, M. S. Chen, E. A. Almeida, A. P. Huovila, Y. Takahashi, Leslie M. Shaw, Arthur M. Mercurio, J. M. White Nov 2010

Evidence That Distinct States Of The Integrin Alpha6beta1 Interact With Laminin And An Adam, M. S. Chen, E. A. Almeida, A. P. Huovila, Y. Takahashi, Leslie M. Shaw, Arthur M. Mercurio, J. M. White

Arthur M. Mercurio

Integrins can exist in different functional states with low or high binding capacity for particular ligands. We previously provided evidence that the integrin alpha6beta1, on mouse eggs and on alpha6-transfected cells, interacted with the disintegrin domain of the sperm surface protein ADAM 2 (fertilin beta). In the present study we tested the hypothesis that different states of alpha6beta1 interact with fertilin and laminin, an extracellular matrix ligand for alpha6beta1. Using alpha6-transfected cells we found that treatments (e.g., with phorbol myristate acetate or MnCl2) that increased adhesion to laminin inhibited sperm binding. Conversely, treatments that inhibited laminin adhesion increased sperm binding. …

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The Integrin Alpha6beta4 Functions In Carcinoma Cell Migration On Laminin-1 By Mediating The Formation And Stabilization Of Actin-Containing Motility Structures, Isaac Rabinovitz, Arthur M. Mercurio Nov 2010

The Integrin Alpha6beta4 Functions In Carcinoma Cell Migration On Laminin-1 By Mediating The Formation And Stabilization Of Actin-Containing Motility Structures, Isaac Rabinovitz, Arthur M. Mercurio

Arthur M. Mercurio

Functional studies on the alpha6beta4 integrin have focused primarily on its role in the organization of hemidesmosomes, stable adhesive structures that associate with the intermediate filament cytoskeleton. In this study, we examined the function of the alpha6beta4 integrin in clone A cells, a colon carcinoma cell line that expresses alpha6beta4 but no alpha6beta1 integrin and exhibits dynamic adhesion and motility on laminin-1. Time-lapse videomicroscopy of clone A cells on laminin-1 revealed that their migration is characterized by filopodial extension and stabilization followed by lamellae that extend in the direction of stabilized filopodia. A function-blocking mAb specific for the alpha6beta4 integrin …

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Role Of E-Cadherin In The Response Of Tumor Cell Aggregates To Lymphatic, Venous And Arterial Flow: Measurement Of Cell-Cell Adhesion Strength, Stephen W. Byers, Connie L. Sommers, Becky Hoxter, Arthur M. Mercurio, Aydin Tozeren Nov 2010

Role Of E-Cadherin In The Response Of Tumor Cell Aggregates To Lymphatic, Venous And Arterial Flow: Measurement Of Cell-Cell Adhesion Strength, Stephen W. Byers, Connie L. Sommers, Becky Hoxter, Arthur M. Mercurio, Aydin Tozeren

Arthur M. Mercurio

Defects in the expression or function of the calcium dependent cell-cell adhesion molecule E-cadherin are common in invasive, metastatic carcinomas. In the present study the response of aggregates of breast epithelial cells and breast and colon carcinoma cells to forces imposed by laminar flow in a parallel plate flow channel was examined. Although E-cadherin negative tumor cells formed cell aggregates in the presence of calcium, these were significantly more likely than E-cadherin positive cell aggregates to disaggregate in response to low shear forces, such as those found in a lymphatic vessel or venule (< 3.5 dyn/cm2). E-cadherin positive normal breast epithelial cells and E-cadherin positive breast tumor cell aggregates could not be disaggregated when exposed to shear forces in excess of those found in arteries (> 100 dyn/cm2). E-cadherin negative cancer cells …

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Regulation Of Cellular Interactions With Laminin By Integrin Cytoplasmic Domains: The A And B Structural Variants Of The Alpha 6 Beta 1 Integrin Differentially Modulate The Adhesive Strength, Morphology, And Migration Of Macrophages, Leslie M. Shaw, Arthur M. Mercurio Nov 2010

Regulation Of Cellular Interactions With Laminin By Integrin Cytoplasmic Domains: The A And B Structural Variants Of The Alpha 6 Beta 1 Integrin Differentially Modulate The Adhesive Strength, Morphology, And Migration Of Macrophages, Leslie M. Shaw, Arthur M. Mercurio

Arthur M. Mercurio

Several integrin alpha subunits have structural variants that are identical in their extracellular and transmembrane domains but that differ in their cytoplasmic domains. The functional significance of these variants, however, is unknown. In the present study, we examined the possibility that the A and B variants of the alpha 6 beta 1 integrin laminin receptor differ in function. For this purpose, we expressed the alpha 6A and alpha 6B cDNAs, as well as a truncated alpha 6 cDNA (alpha 6-delta CYT) in which the cytoplasmic domain sequence was deleted after the GFFKR pentapeptide, in P388D1 cells, an alpha 6 deficient …

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Adam12 Induces Actin Cytoskeleton And Extracellular Matrix Reorganization During Early Adipocyte Differentiation By Regulating Beta1 Integrin Function, Nobuko Kawaguchi, Christina Sundberg, Marie Kveiborg, Behzad Moghadaszadeh, Meena Asmar, Nikolaj Dietrich, Charles Kumar Thodeti, Finn C. Nielsen, Peter Moller, Arthur M. Mercurio, Reidar Albrechtsen, Ulla M. Wewer Nov 2010

Adam12 Induces Actin Cytoskeleton And Extracellular Matrix Reorganization During Early Adipocyte Differentiation By Regulating Beta1 Integrin Function, Nobuko Kawaguchi, Christina Sundberg, Marie Kveiborg, Behzad Moghadaszadeh, Meena Asmar, Nikolaj Dietrich, Charles Kumar Thodeti, Finn C. Nielsen, Peter Moller, Arthur M. Mercurio, Reidar Albrechtsen, Ulla M. Wewer

Arthur M. Mercurio

Changes in cell shape are a morphological hallmark of differentiation. In this study we report that the expression of ADAM12, a disintegrin and metalloprotease, dramatically affects cell morphology in preadipocytes, changing them from a flattened, fibroblastic appearance to a more rounded shape. We showed that the highest levels of ADAM12 mRNA were detected in preadipocytes at the critical stage when preadipocytes become permissive for adipogenic differentiation. Furthermore, as assessed by immunostaining, ADAM12 was transiently expressed at the cell surface concomitant with the reduced activity of beta1 integrin. Co-immunoprecipitation studies indicated the formation of ADAM12/beta1 integrin complexes in these preadipocytes. Overexpression …

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Regulation Of Alpha 6 Beta 1 Integrin Laminin Receptor Function By The Cytoplasmic Domain Of The Alpha 6 Subunit, Leslie M. Shaw, Arthur M. Mercurio Nov 2010

Regulation Of Alpha 6 Beta 1 Integrin Laminin Receptor Function By The Cytoplasmic Domain Of The Alpha 6 Subunit, Leslie M. Shaw, Arthur M. Mercurio

Arthur M. Mercurio

The alpha 6 beta 1 integrin is expressed on the macrophage surface in an inactive state and requires cellular activation with PMA or cytokines to function as a laminin receptor (Shaw, L. M., J. M. Messier, and A. M. Mercurio. 1990. J. Cell Biol. 110:2167-2174). In the present study, the role of the alpha 6 subunit cytoplasmic domain in alpha 6 beta 1 integrin activation was examined. The use of P388D1 cells, an alpha 6-integrin deficient macrophage cell line, facilitated this analysis because expression of either the alpha 6A or alpha 6B subunit cDNAs restores their activation responsive laminin adhesion …

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Transcriptional Activation Of Integrin Beta6 During The Epithelial-Mesenchymal Transition Defines A Novel Prognostic Indicator Of Aggressive Colon Carcinoma, Richard C. Bates, David I. Bellovin, Courtney Brown, Elizabeth Maynard, Bingyan Wu, Hisaaki Kawakatsu, Dean Sheppard, Peter Oettgen, Arthur M. Mercurio Nov 2010

Transcriptional Activation Of Integrin Beta6 During The Epithelial-Mesenchymal Transition Defines A Novel Prognostic Indicator Of Aggressive Colon Carcinoma, Richard C. Bates, David I. Bellovin, Courtney Brown, Elizabeth Maynard, Bingyan Wu, Hisaaki Kawakatsu, Dean Sheppard, Peter Oettgen, Arthur M. Mercurio

Arthur M. Mercurio

We used a spheroid model of colon carcinoma to analyze integrin dynamics as a function of the epithelial-mesenchymal transition (EMT), a process that provides a paradigm for understanding how carcinoma cells acquire a more aggressive phenotype. This EMT involves transcriptional activation of the beta6 integrin subunit and a consequent induction of alphavbeta6 expression. This integrin enhances the tumorigenic properties of colon carcinoma, including activation of autocrine TGF-beta and migration on interstitial fibronectin. Importantly, this study validates the clinical relevance of the EMT. Kaplan-Meier analysis of beta6 expression in 488 colorectal carcinomas revealed a striking reduction in median survival time of …

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The Activation Dependent Adhesion Of Macrophages To Laminin Involves Cytoskeletal Anchoring And Phosphorylation Of The Alpha 6 Beta 1 Integrin, Leslie M. Shaw, Jeanne M. Messier, Arthur M. Mercurio Nov 2010

The Activation Dependent Adhesion Of Macrophages To Laminin Involves Cytoskeletal Anchoring And Phosphorylation Of The Alpha 6 Beta 1 Integrin, Leslie M. Shaw, Jeanne M. Messier, Arthur M. Mercurio

Arthur M. Mercurio

Macrophages require activation with either PMA (Mercurio, A. M., and L. M. Shaw. 1988. J. Cell Biol. 107:1873-1880) or interferon-gamma (Shaw, L. M., and A. M. Mercurio. 1989. J. Exp. Med. 169:303-308) to adhere to a laminin substratum. In the present study, we identified an integrin laminin receptor on macrophages and characterized cellular changes that occur in response to PMA activation that facilitate laminin adhesion. A monoclonal antibody (GoH3) that recognizes the integrin alpha 6 subunit (Sonnenberg, A., H. Janssen, F. Hogervorst, J. Calafat, and J. Hilgers. 1987. J. Biol. Chem. 262:10376-10383) specifically inhibited adhesion to laminin-coated surfaces. This antibody …

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Ape1- And Ape2-Dependent Dna Breaks In Immunoglobulin Class Switch Recombination, Jeroen E. J. Guikema, Erin K. Linehan, Daisuke Tsuchimoto, Yusaku Nakabeppu, Phyllis R. Strauss, Janet Stavnezer, Carol E. Schrader Jan 2010

Ape1- And Ape2-Dependent Dna Breaks In Immunoglobulin Class Switch Recombination, Jeroen E. J. Guikema, Erin K. Linehan, Daisuke Tsuchimoto, Yusaku Nakabeppu, Phyllis R. Strauss, Janet Stavnezer, Carol E. Schrader

Janet M. Stavnezer

Antibody class switch recombination (CSR) occurs by an intrachromosomal deletion requiring generation of double-stranded breaks (DSBs) in switch-region DNA. The initial steps in DSB formation have been elucidated, involving cytosine deamination by activation-induced cytidine deaminase and generation of abasic sites by uracil DNA glycosylase. However, it is not known how abasic sites are converted into single-stranded breaks and, subsequently, DSBs. Apurinic/apyrimidinic endonuclease (APE) efficiently nicks DNA at abasic sites, but it is unknown whether APE participates in CSR. We address the roles of the two major mammalian APEs, APE1 and APE2, in CSR. APE1 deficiency causes embryonic lethality in mice; …

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