Pramod K. Srivastava, Ph.D.
Professor of ImmunologyPhysicians Health Services Chair in Cancer Immunology
Director, Center for Immunotherapy of Cancer and Infectious Diseases
Director, Carole and Ray Neag Comprehensive Cancer Center
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Academic Office Location: Immunology University of Connecticut Health Center 263 Farmington Avenue Farmington, CT 06030-1601 |
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| Phone: | 860-679-4444 |
| Fax: | 860-679-7905 |
| Website(s): |
Immunology Graduate Program |
Education
Post-Graduate Training
Awards
| Degree | Institution | Major |
|---|---|---|
| M.D. | University of Connecticut School of Medicine | Medicine |
| Ph.D. | Center Cell & Molecular Biol. | Biochemistry |
| Other | Osaka University | Microbial genetics |
| M.S. | University of Allahabad | Botany (Palentology) |
| B.S. | University of Allahabad | Biology |
Post-Graduate Training
| Training | Institution | Specialty |
|---|---|---|
| Post Doctoral | Yale University | Molecular Dev. Biology |
| Post Doctoral | Sloan-Kettering Institute | Immunology |
Awards
| Name of Award/Honor | Awarding Organization |
|---|---|
| Member, Scientific Advisory Council | CRI |
| UICC Roll of Honor | |
| Mildred Scheel Lecturer at the Intl. Conf. on "Hyperthermia in Oncology", Munich | |
| Irma T. Hirshl Award | |
| Investigator Award of CRI | |
| John Hans and Edna Alice Old Postdoctoral Fellowship | Cancer Research Institute |
Our laboratory’s research interests lie in four areas: antigen presentation by MHC I and MHC II molecules, immune response to cancer, viral immunity, and autoimmunity. Our pursuit of these areas is linked to a key set of observations made by our laboratory over the past 20 years. These observations are: (1) Heat shock proteins (HSP) isolated from cells are always associated with a broad array of peptides. These peptides are derived from the proteins present in the cell and together, the HSP-associated peptide profile represents the total protein/peptide repertoire of a cell including the antigenic repertoire. (2) The HSP-peptide complexes, whether isolated from cells, or reconstituted in vitro, are potent immunogens against the peptides and cells presenting those peptides. The immune response elicited by such complexes is heavily skewed towards a cellular T cell response. (3) HSPs have remarkable immunomodulatory properties which derive from their interaction with macrophage and dendritic cells through a receptor, identified by us as CD91. Our laboratory has used these observations to explore new key aspects of antigen presentation and to develop innovative approaches for therapy of cancer, infections and autoimmune disorders. It is our view that the HSP-peptide interaction is an evolutionary precursor to the MHC-peptide interaction and lies at the center of a wide array of immunological phenomena.
Not accepting Lab Rotation Students at this time
Lab Rotation Projects
The following constitutes most of what we do. Students are encouraged to create rotation projects out of any of these areas.
(1) We study antigen presentation and cross-priming. We have uncovered a key role of heat shock proteins, the most highly conserved and abundant proteins in living systems, in both of these phenomena, which are central to immunology.
(2) Our studies with heat shock proteins have lead to novel approaches to immunotherapy of cancers and infectious diseases, which are in Phase 3 clinical trials in over 200 hospitals worldwide.
(3) We have also shown heat shock proteins to elicit regulatory CD4+ T cells; the mechanism of this phenomenon as well as its application to therapy of autoimmune diseases are of continuing interest to us.
(4) This laboratory has a new-found interest in neuro-immunology. We do not have much of a track record in this area, as we just published our first paper in it. Our interest is driven by the many observations that demonstrate a clear link between the nervous and the immune systems. We aim to explore those links through new phenomena and their mechanisms at the molecular, cellular and organismal levels.
Journal Articles
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Area under the curve as a tool to measure kinetics of tumor growth in experimental animals
(2012) J Immunol Methods
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Dendritic cells sequester antigenic epitopes for prolonged periods in the absence of antigen-encoding genetic information
(2012) Proc Natl Acad Sci U S A 43 (109) 17543-8
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Dendritic cells sequester antigenic epitopes for prolonged periods in the absence of antigen-encoding genetic information.
(2012) Proc. Natl. Acad. Sci. USA
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Oral ingestion of Capsaicin, the pungent component of chili pepper, enhances a discreet population of macrophages and confers protection from autoimmune diabetes.
(2012) Mucosal Immunology 1 (5 ) 76-86
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Modeling the repertoire of true tumor-specific MHC I epitopes in a human tumor
(2009) PLoS ONE 7 (4)
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An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial
(2008) The Lancet 9633 (372) 145-154
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Heat-shock protein 90 associates with N-terminal extended peptides and is required for direct and indirect antigen presentation
(2008) Proceedings of the National Academy of Sciences of the United States of America 5 (105) 1662-1667
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Phase III comparison of vitespen, an autologous tumor-derived heat shock protein gp96 peptide complex vaccine, with physician's choice of treatment for stage IV melanoma: The C-100-21 study group
(2008) Journal of Clinical Oncology 6 (26) 955-962
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A phase I pilot study of autologous heat shock protein vaccine HSPPC-96 in patients with resected pancreatic adenocarcinoma
(2007) Digestive Diseases and Sciences 8 (52) 1964-1972
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Experience with heat shock protein-peptide complex 96 vaccine therapy in patients with indolent non-hodgkin lymphoma
(2007) Cancer 1 (109) 77-83
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Heat Shock Protein gp96 Is a Master Chaperone for Toll-like Receptors and Is Important in the Innate Function of Macrophages
(2007) Immunity 2 (26) 215-226
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Specific immunogenicity of heat shock protein gp96 derives from chaperoned antigenic peptides and not from contaminating proteins
(2007) Journal of Immunology 11 (179) 7254-7261
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A phase II trial of vaccination with autologous, tumor-derived heat-shock protein peptide complexes Gp96, in combination with GM-CSF and interferon-α in metastatic melanoma patients
(2006) Cancer Immunology, Immunotherapy 8 (55) 958-968
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Heat shock up-regulates Imp2 and Imp7 and enhances presentation of immunoproteasome-dependent epitopes
(2006) Journal of Immunology 12 (177) 8393-8399
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Combination of imatinib mesylate with autologous leukocyte-derived heat shock protein and chronic myelogenous leukemia
(2005) Clinical Cancer Research 12 (11) 4460-4468
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Immunological role of neuronal receptor vanilloid receptor 1 expressed on dendritic cells.
(2005) Proc. Natl. Acad. Sci. USA 14 (102) 5120-5125
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Peptides chaperoned by heat-shock proteins are a necessary and sufficient source of antigen in the cross-priming of CD8+ T cells
(2005) Nature Immunology 6 (6) 593-599
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Essential role of CD91 in re-presentation of gp96-chaperoned peptides
(2004) Proceedings of the National Academy of Sciences of the United States of America 16 (101) 6128-6133
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Immune modulation with high-dose heat-schock protein gp96: Therapy of murine autoimmune diabetes and encephalomyelitis
(2004) International Immunology 4 (16) 615-624
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Cloning and expression of the Escherichia coli K1 outer membrane protein a receptor, a gp96 homologue
(2003) Infection and Immunity 4 (71) 1680-1688
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Fever-like temperature induces maturation of dendritic cells through induction of hsp90
(2003) International Immunology 9 (15) 1053-1061
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Human tumor-derived heat shock protein 96 mediates in vitro activation and in vivo expansion of melanoma- and colon carcinoma-specific T cells
(2003) Journal of Immunology 7 (171) 3467-3474
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Heat shock proteins gp96 and hsp70 activate the release of nitric oxide by APCs
(2002) Journal of Immunology 6 (168) 2997-3003
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Immunization against a dominant tumor antigen abrogates immunogenicity of the tumor.
(2002) Cancer Immun (2) 4
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Immunization against a dominant tumor antigen abrogates immunogenicity ofthe tumor
(2002) Cancer Immunity (5) 1-13
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Naturally formed or artificially reconstituted non-covalent alpha2-macroglobulin-peptide complexes elicit CD91-dependent cellular immunity.
(2002) Cancer Immun (2) 16
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Naturally formed or artificially reconstituted non-covalentalpha2-macroglobulin-peptide complexes elicit CD91-dependent cellular immunity
(2002) Cancer Immunity (5) 1-9
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Adjuvanticity of α2-macroglobulin, an independent ligand for the heat shock protein receptor CD91
(2001) Journal of Immunology 8 (166) 4968-4972
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An Endoplasmic Reticulum Protein Implicated in Chaperoning Peptides to Major Histocompatibility of Class I Is an Aminopeptidase
(2001) Journal of Biological Chemistry 36 (276) 33313-33318
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CD91 is a common receptor for heat shock proteins gp96, hsp90, hsp70, and calreticulin
(2001) Immunity 3 (14) 303-313
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Definition of a novel binding site on CD8 cells for a conserved region of the MHC class lb molecule Qa-1 that regulates IFN-γ expression
(2001) European Journal of Immunology 1 (31) 87-93
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Heat Shock Protein-chaperoned Peptides but not Free Peptides Introduced into the Cytosol are Presented Efficiently by Major Histocompatibility Complex I Molecules
(2001) Journal of Biological Chemistry 20 (276) 17163-17171
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Identification of a tumor-associated contact-dependent activity which reversibly downregulates cytolytic function of CD8+ T cells
(2001) Cancer Immunity (1) 1-14
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Identification of a tumor-associated contact-dependent activity which reversibly downregulates cytolytic function of CD8+ T cells.
(2001) Cancer Immun (1) 5
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Methods of purification of heat shock protein-peptide complexes for use as vaccines against cancers and infectious diseases.
(2001) Methods in molecular biology (Clifton, N.J.) (156) 175-186
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Phylogenetic conservation of the molecular and immunological properties of the chaperones gp96 and hsp70.
(2001) Eur J Immunol. 1 (31) 186-95
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Primary tumor tissue lysates are enriched in heat shock proteins and induce the maturation of human dendritic cells.
(2001) J Immunol. 9 (167) 4844-52
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The immunoprotective MHC II epitope of a chemically induced tumor harbors a unique mutation in a ribosomal protein
(2001) Proceedings of the National Academy of Sciences of the United States of America 7 (98) 3992-3997
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CD91: A receptor for heat shock protein gp96
(2000) Nature Immunology 2 (1) 151-155
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Cutting edge: Heat shock protein gp96 induces maturation and migration of CD11c+ cells in vivo
(2000) Journal of Immunology 11 (165) 6029-6035
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Heat shock proteins: The fountainhead of innate and adaptive immune responses
(2000) Cell Stress and Chaperones 5 (5) 443-451
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Immunization of cancer patients with autologous cancer-derived heat shock protein gp96 preparations: A pilot study
(2000) International Journal of Cancer 2 (88) 232-238
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Natural autoantibodies against heat-shock proteins hsp70 and gp96: Implications for immunotherapy using heat-shock proteins
(2000) Immunology 3 (101) 364-370
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Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway
(2000) International Immunology 11 (12) 1539-1546
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Saturation, competition, and specificity in interaction of heat shock proteins (hsp) gp96, hsp90, and hsp70 with CD11b+ cells
(2000) Journal of Immunology 5 (165) 2582-2587
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Association of peptides with heat shock protein gp96 occurs in vivo and not after cell lysis
(1999) Biochemical and Biophysical Research Communications 3 (262) 813-818
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Calreticulin, a peptide-binding chaperone of the endoplasmic reticulum, elicits tumor- and peptide-specific immunity
(1999) Journal of Experimental Medicine 5 (189) 797-802
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Isolation of MHC class I-restricted tumor antigen peptide and its precursors associated with heat shock proteins hsp70, hsp90, and gp96
(1999) Journal of Immunology 3 (162) 1303-1309
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The dual nature of specific immunological activity of tumor-derived gp96 preparations
(1999) Journal of Experimental Medicine 9 (189) 1437-1442
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Channeling of heat shock protein chaperoned peptides into the endogenous pathway of antigen presentation
(1998) FASEB Journal 5 (12)
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Protein disulfide isomerase, a peptide binding chaperone of the endoplasmic reticulum,elicits tumor specific and peptide specific immunity
(1998) FASEB Journal 4 (12)
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The endoplasmic reticular heat shock protein Gp96 is an aminopeptidase
(1998) FASEB Journal 4 (12)
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Heat shock protein-peptide complexes, reconstituted in vitro, elicit peptide-specific cytotoxic T lymphocyte response and tumor immunity
(1997) Journal of Experimental Medicine 8 (186) 1315-1322
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Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations
(1997) Science 5335 (278) 117-120
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Purification of immunogenic heat shock protein 70-peptide complexes by ADP-affinity chromatography
(1997) Journal of Immunological Methods 1 (204) 13-21
Book Chapters
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Heat shock proteins in immune response
(2003) PIR: Heat Shock Proteins and Inflammation
Conference Papers
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Vaccination with autologous tumor-derived heat-shock protein Gp96 after liver resection for metastatic colorectal cancer
(2003) Clinical Cancer Research 9 (9) 3235-3245
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Heat shock proteins: The 'Swiss Army Knife' vaccines against cancers and infectious agents
(2001) Vaccine 17-19 (19) 2590-2597
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Generation of tumor-specific cytotoxic T lymphocytes and memory T cells by immunization with tumor-derived heat shock protein gp96
(1998) Journal of Immunotherapy 4 (21) 269-227
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Heat shock protein-peptide interaction as the basis for a new generation of vaccines against cancers and infectious diseases
(1998) Journal of Biosciences 4 (23) 527-531
Editorials
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Heat shock protein - Receptor-based pharmacogenomics: The search for a new cancer antigens
(2007) Pharmacogenomics 2 (8) 117-120
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Tumour immunology
(2006) Current Opinion in Immunology 2 (18) 199-200
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Heat shock proteins-peptide complexes: Personalized medicines for immunotherapy of human cancer
(2005) Enhancer - Biotherapy of Cancer 3 (3) 2-7
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Heat shock proteins and immune response: Methods to madness
(2004) Methods 1 (32) 1-2
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Hypothesis: Controlled necrosis as a tool for immunotherapy of human cancer
(2003) Cancer Immunity (3) 1-5
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Hypothesis: controlled necrosis as a tool for immunotherapy of human cancer.
(2003) Cancer Immun (3) 4
Reviews
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Treating human cancers with heat shock protein-peptide complexes: The road ahead
(2009) Expert Opinion on Biological Therapy 2 (9) 179-186
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"It is the antigen(s), stupid" and other lessons from over a decade of vaccitherapy of human cancer
(2008) Seminars in Immunology 5 (20) 296-300
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Therapeutic cancer vaccines
(2006) Current Opinion in Immunology 2 (18) 201-205
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Immunotherapy for human cancer using heat shock protein-peptide complexes
(2005) Current Oncology Reports 2 (7) 104-108
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Heat shock proteins and their use as anticancer vaccines
(2004) Clinical Cancer Research 24 (10) 8142-8146
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Heat shock proteins: Biological functions and clinical application as personalized vaccines for human cancer
(2004) Cancer Immunology, Immunotherapy 3 (53) 227-233
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Heat-shock proteins.
(2004) Current protocols in immunology (Appendix 1)
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Kaposi's sarcoma as a model for cancer immunotherapy
(2004) Trends in Molecular Medicine 4 (10) 187-193
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The heat-shock protein receptors: Some answers and more questions
(2004) Tissue Antigens 4 (64) 442-451
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Interaction of heat shock proteins with peptides and antigen presenting cells: Chaperoning of the innate and adaptive immune responses
(2002) Annual Review of Immunology (20) 395-425
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Roles of heat-shock proteins in antigen presentation and cross-presentation
(2002) Current Opinion in Immunology 1 (14) 45-51
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Roles of heat-shock proteins in innate and adaptive immunity
(2002) Nature Reviews Immunology 3 (2) 185-194
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Heat shock protein-based novel immunotherapies
(2000) Drug News and Perspectives 9 (13) 517-522
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Heat, heat shock, heat shock proteins and death: A central link in innate and adaptive immune responses
(2000) Immunology Letters 1 (74) 35-39
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Immunotherapy of human cancer: Lessons from mice
(2000) Nature Immunology 5 (1) 363-366
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Heat shock protein-peptide complexes as immunotherapy for human cancer
(1998) Molecular Medicine Today 11 (4) 478-484
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Heat shock proteins come of age: Primitive functions acquire new roles in an adaptive world
(1998) Immunity 6 (8) 657-665
Short Surveys
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New jobs for ancient chaperones
(2008) Scientific American 1 (299) 50-55