The Sl (Steel) locus encodes Steel Factor (SLF), the ligand for the Kit receptor tyrosine kinase. Mice with a loss-of-function mutation in the Sl locus display defects in hematopoiesis, sterility, gut motility, spatial learning memory deficits, and nerve regeneration. Similar phenotypes are displayed in mice with mutations at the W/c-kit locus, which encodes the Kit receptor. This article will review the phenotypes displayed by Sl mutant mice, the molecular basis of the mutations, the differences in Kit/SLF signaling mediated by the membrane-bound and soluble forms of SLF, and the use of SLF in cell-based therapies.

Biochemist whose vision of cell signalling transformed cancer research.

OMICS: A Journal of Integrative BiologyVol. 15, No. 9 OpinionSystems Vaccinomics: The Road Ahead for VaccinologyAlan Bernstein, Bali Pulendran, and Rino RappuoliAlan BernsteinGlobal HIV Vaccine Enterprise, New York, New York.Search for more papers by this author, Bali PulendranEmory Vaccine Center, Yerkes National Primate Research Center, Atlanta, Georgia.Department of Pathology, Emory University School of Medicine, Atlanta, Georgia.Search for more papers by this author, and Rino RappuoliNovartis Vaccines and Diagnostics, Siena, Italy.Search for more papers by this authorPublished Online:1 Sep 2011https://doi.org/10.1089/omi.2011.0022AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited byVaxi-DL: An Artificial Intelligence-Enabled Platform for Vaccine Development1 June 2023A guide to investigating immune responses elicited by whole‐sporozoite pre‐erythrocytic vaccines against malaria1 June 2021 | The FEBS Journal, Vol. 289, No. 12Understanding the immunogenetics of human viral diseasesSIMON, an Automated Machine Learning System, Reveals Immune Signatures of Influenza Vaccine Responses1 August 2019 | The Journal of Immunology, Vol. 203, No. 3Transcriptomic signatures of cellular and humoral immune responses in older adults after seasonal influenza vaccination identified by data-driven clustering15 January 2018 | Scientific Reports, Vol. 8, No. 1Accelerating tuberculosis vaccine trials with diagnostic and prognostic biomarkers19 June 2017 | Expert Review of Vaccines, Vol. 16, No. 8Natural Vaccine Adjuvants and Immunopotentiators Derived From Plants, Fungi, Marine Organisms, and InsectsImmunosenescence-Related Transcriptomic and Immunologic Changes in Older Individuals Following Influenza Vaccination2 November 2016 | Frontiers in Immunology, Vol. 7Antigens and Epitopes12 March 2016Research Priorities and Trends in Infections Shared with Wildlife26 April 2016Anaplasma marginale : Diversity, Virulence, and Vaccine Landscape through a Genomics ApproachBioMed Research International, Vol. 2016Designing malaria vaccines to circumvent antigen variabilityVaccine, Vol. 33, No. 52Genomics and Public Health14 March 2015Influenza A Immunomics and Public Health Omics: The Dynamic Pathway Interplay in Host Response to H1N1 Infection Konstantina Dimitrakopoulou, Georgios N. Dimitrakopoulos, Esther Wilk, Charalampos Tsimpouris, Kyriakos N. Sgarbas, Klaus Schughart, and Anastasios Bezerianos25 February 2014 | OMICS: A Journal of Integrative Biology, Vol. 18, No. 3Current barriers, challenges and opportunities for the development of effective STI vaccines: Point of view of vaccine producers, biotech companies and funding agenciesVaccine, Vol. 32, No. 14Social Confounders of Vaccine ResponseConsiderations for Vaccine Design in the Postgenomic Era16 September 2013Vaccinomics, the new road to tick vaccinesVaccine, Vol. 31, No. 50Vaccine Development: History, Current Status, and Future Trends25 November 2013The Gracefully Aging Immune SystemScience Translational Medicine, Vol. 5, No. 185Vaccinomics, adversomics, and the immune response network theory: Individualized vaccinology in the 21st centurySeminars in Immunology, Vol. 25, No. 2The genetic basis for interindividual immune response variation to measles vaccine: new understanding and new vaccine approaches9 January 2014 | Expert Review of Vaccines, Vol. 12, No. 1Collective theranostics and postgenomics entrepreneurship: rethinking innovations as knowledge ecosystems built by complex collaboration9 January 2014 | Expert Review of Molecular Diagnostics, Vol. 12, No. 8Theranostics: rethinking postgenomic diagnostics9 January 2014 | Expert Review of Molecular Diagnostics, Vol. 12, No. 8Vaccinology: The name, the concept, the adjectivesVaccine, Vol. 30, No. 37Correlates of Vaccine-Induced Immunity: Historical Perspectives and Future Challenges20 June 2012Steering Vaccinomics Innovations with Anticipatory Governance and Participatory Foresight Vural Ozdemir, Samer A. Faraj, and Bartha M. Knoppers1 September 2011 | OMICS: A Journal of Integrative Biology, Vol. 15, No. 9 Volume 15Issue 9Sep 2011 InformationCopyright 2011, Mary Ann Liebert, Inc.To cite this article:Alan Bernstein, Bali Pulendran, and Rino Rappuoli.Systems Vaccinomics: The Road Ahead for Vaccinology.OMICS: A Journal of Integrative Biology.Sep 2011.529-531.http://doi.org/10.1089/omi.2011.0022Published in Volume: 15 Issue 9: September 1, 2011Online Ahead of Print:August 9, 2011PDF download

Purpose of reviewThis review covers the role of the Global HIV Vaccine Enterprise (the Enterprise), an alliance of independent organizations committed to development of a safe and effective HIV vaccine. It discusses the history, impact on the field, and future directions and initiatives of the alliance in the context of recent progress in HIV vaccine research and development.Recent findingsSignificant progress has been made in the field since the release of the 2005 Scientific Strategic Plan (the Plan) of the Enterprise. Over the last year, the Enterprise embarked on an impact assessment of the 2005 Plan and the development of the 2010 Plan. Enterprise Working Groups identified key priorities in the field, several of which are discussed in this review, including changing the nature, purpose and process of clinical trials, increasing and facilitating data sharing, and optimizing existing and mobilizing new resources.SummaryThis time is an important moment in HIV vaccine research. New clinical trial and laboratory results have created new opportunities to advance the search for an HIV vaccine and reinvigorated the field. The Enterprise will publish its 2010 Plan this year, providing a framework for setting new priorities and directions and encouraging new and existing partners to embark on a shared scientific agenda.

Later this month, researchers will gather at the Institut Pasteur in Paris to mark the quarter century since human immunodeficiency virus (HIV) was discovered as the cause of acquired immunodeficiency syndrome (AIDS). Since then, over 60 million people have been infected with the virus and over 25 million people have died. These numbers make the results of two "proof of concept" vaccine efficacy trials--the STEP and Phambili trials--extremely disappointing. Indeed, these results have raised questions about whether investments in HIV vaccine research are misplaced and whether a vaccine is even achievable. Those views are misguided. The failure of candidate vaccines or drugs is to be expected. More than ever, investigations in humans are essential to explore concepts, test hypotheses, and delineate the human immune response to HIV immunogens.

Gamma-secretase catalyzes intramembraneous proteolysis of several type I transmembrane proteins, including beta-amyloid precursor protein (APP), to generate amyloid beta protein (Abeta), a key player in the pathogenesis of Alzheimer's disease (AD). The critical components of the gamma-secretase complex include presenilin (PS), nicastrin (NCT), presenilin enhancer-2 (PEN-2) and anterior pharynx defective-1 (APH-1). Abnormalities of the ubiquitin-proteasome pathway have been implicated in the pathogenesis of AD; while PS and PEN-2 turnover is regulated by this pathway, it is unknown whether the ubiquitin-proteasome pathway is also involved in the degradation of APH-1 protein. In this study, we found that the expression of endogenous and exogenous APH-1 significantly increased in cells treated with proteasome-specific inhibitors. The effect of the proteasome inhibitors on APH-1 was dose- and time-dependent. APH-1 protein was ubiquitinated. Pulse-chase metabolic labeling experiments showed that the degradation of newly synthesized radiolabeled APH-1 proteins was inhibited by lactacystin. Disruption of the PS1 and PS2 genes did not affect the degradation of APH-1 by the ubiquitin-proteasome pathway. Furthermore, over-expression of APH-1 and inhibition of proteasomal APH-1 degradation facilitated gamma-secretase cleavage of APP to generate Abeta. These results demonstrate that the degradation of APH-1 protein is mediated by the ubiquitin-proteasome pathway.

This paper describes the approach taken by the Canadian Institutes of Health Research (CIHR) to develop a framework and indicators to measure the impact of health research. The development process included national and international consultations. Key methodology challenges and measurement requirements were identified. The framework that has resulted from this process includes definitions of key concepts, methodology guidelines, identification of the different stakeholders for impact information and the individual concerns of each stakeholder group. Indicators are classified within five categories that encompass a broad range of impacts. Sources of information and issues in attributing research impacts are discussed. An analysis of issues suggests that impact measurement and performance measurement are complementary activities, with the former focused on broad impacts of the health research sector and the latter on the degree of success achieved by funding agencies in contributing to the process of knowledge development and uptake. Introduction Accountability and value received for the use of public funds have become high priorities for governments around the world. Quantifying the value of publicly funded health research is a challenge for many countries. This paper describes the approach taken by the Canadian Institutes of Health Research (CIHR), Canada’s national health research funding agency, to develop a framework to measure the impact of its investments in health research and to begin to identify robust indicators that can be used to establish benchmarks and track progress through time. CIHR was created in 2000 with a broad mandate: ‘to excel, according to international standards of scientific excellence, in the creation of new knowledge and its translation into improved health, more effective health services and products, and a strengthened Canadian health care system.’ The Government of Canada has increased investments in health research from $289 million in 1999-2000 (the last year of CIHR's predecessor, the Medical Research Council) to $700 million in 2005-2006. A description of the CIHR operating model is shown in the text box on page 2. CIHR has taken a proactive approach to foster research that is relevant to important health issues and to anticipate the future demand for health research. In addition, it has committed to actively encouraging collaboration in multidisciplinary research. CIHR consists of a central office that sets strategic directions, engages in national initiatives and administers peer review for grant funding; and 13 Institutes, each with a unique research focus. Each Institute is headed by a scientific director and hosted by an academic or research institution. Each Institute provides a nexus for researchers in specific fields to collaborate and identify research priorities. CIHR funds both investigator-initiated (open) and strategic research. The Institutes play

The localization of certain mRNAs to dendrites and their local translation in synaptic regions are proposed to be involved in certain aspects of synaptic plasticity. A cis-acting element within the 3' untranslated region (3' UTR) of the targeted mRNAs, which is bound by a trans-acting RNA-binding protein, controls the dendritic mRNA localization. Here, we identified hematopoietic zinc finger (Hzf) as a trans-acting factor that regulates the dendritic mRNA localization of the type 1 inositol 1,4,5-trisphosphate receptor (IP(3)RI), a dendritically localized mRNA in cerebellar Purkinje cells, via binding to the 3' UTR. In Hzf-deficient mice, the dendritic localization of IP(3)RI mRNA and brain-derived neurotrophic factor-induced IP(3)RI protein synthesis in the cerebellum were impaired. These findings suggest that Hzf is an RNA-binding protein that controls the dendritic mRNA localization and activity-dependent translation of IP(3)RI, and may be involved in some aspects of synaptic plasticity.

Loss-of-function mutations in the murine dominantwhite spotting/c-kitlocus affect a diverse array of biological processes and cell lineages and cause a range of phenotypes, including severe anemia, defective pigmentation, sterility, mast cell deficits, a lack of interstitial cells of Cajal, spatial learning memory deficits, and defects in peripheral nerve regeneration. Here we show that tyrosine residues 567 and 569 in the juxtamembrane (Jx) domain of the murine Kit receptor tyrosine kinase are crucial for the function of Kit in melanogenesis and mast cell development, but are dispensable for the normal development of erythroid, interstitial cells of Cajal and germ cells. Furthermore, adult mice lacking both tyrosines exhibit splenomegaly, dysregulation of B-cell and megakaryocyte development, and enlarged stomachs. Analysis of signal transduction events induced by the mutant receptors after ligand stimulation indicates that Jx tyrosine mutations diminish receptor autophosphorylation and selectively attenuate activation of extracellular signal-regulated kinase/mitogen-activated protein kinases. Together, these observations demonstrate that the Jx domain of Kit plays a cell-type specific regulatory rolein vivoand illustrate how engineered mutations in Kit can be used to understand the complex biological and molecular events that result from activating a receptor tyrosine kinase.

Presenilin-1 (PS1) and presenilin 2 (PS2) are proposed to be transmembrane aspartyl proteases that cleave amyloid precursor protein and Notch. PS1- and PS2-mediated activities were individually characterized using blastocyst-derived (BD) cells and membranes from PS1+/--PS2-/- and PS1-/-PS2+/+ mice, respectively. The relative amounts of PS1 and PS2 in the various BD cells were determined from the intensities of the anti-PS1 and anti-PS2 immunoblot signals by comparison with standard curves using radiolabeled PS1 and PS2 standards produced by in vitro transcription and translation. Cellular membranes from wild type, PS1-/-PS2+/+, and PS1+/--PS2-/- but not PS1-/-PS2-/- BD cells generated the Abeta40 and Abeta42 products from the C100FLAG substrate. PS1-associated gamma-secretase displays considerably higher specific activity than PS2-associated gamma-secretase. Moreover, the PS1+/-PS2-/- BD cells and corresponding membranes exhibited much higher gamma-secretase activity as compared with other BD cells and membranes. The PS1-mediated gamma-secretase activity correlated better with the amount of PS1 that is modifiable by a photoactivated active site-directed gamma-secretase inhibitor rather than total PS1; hence, only a small portion (<14%) of the PS1 in wild-type membranes appears to be engaged in an active gamma-secretase complex. This finding suggests that PS1 may serve other biological functions in addition to that associated with its gamma-secretase activity. Furthermore, the PS1 gamma-secretase complex and the PS2 gamma-secretase complex activities can be discriminated on the basis of their susceptibility to inhibition by a potent gamma-secretase inhibitor. The distinct yet overlapping enzymatic properties of the PS1 gamma-secretase complex and the PS2 gamma-secretase complex imply that these two putative aspartyl class proteases may contribute to different biological processes.

The molecular mechanisms responsible for organ-specific differences in vascular development are not well established. Animals lacking the receptor tyrosine kinase Tie1 die of hemorrhage and pulmonary edema. Furthermore, cells lacking Tie1 are excluded from blood vessels of the mature lung. These findings suggest the importance of Tie1 in the pulmonary vasculature. We quantified the organ-specific expression of Tie1 during embryonic and postnatal murine development using both quantitative real-time polymerase chain reaction (PCR) and chemiluminescence employing a tie1.lacZ reporter. In the lung, Tie1 expression increases markedly immediately prior to birth and rises further in the newborn animal, a pattern not found in other organs. Furthermore, expression of Tie1 in the lung is also unique by its persistent increase in the adult animal. This unique pattern of Tie1 gene expression in the embryonic and mature lung supports a distinct role for Tie1 in the development and function of the pulmonary vasculature.

Despite its wide use as a marker for hematopoietic stem cells (HSCs), the function of stem cell antigen-1 (Sca-1) (also known as lymphocyte activation protein-6A [Ly-6A]) in hematopoiesis remains poorly defined. We have previously established that Sca-1(-/-) T cells develop normally, although they are hyperresponsive to antigen. Here, we report detailed analysis of hematopoiesis in Sca-1-deficient animals. The differentiation potential of Sca-1-null bone marrow was determined from examination of the most mature precursors (culture colony-forming units [CFU-Cs]) to less committed progenitors (spleen CFUs [CFU-Ss]) to long-term repopulating HSCs. Sca-1-null mice are mildly thrombocytopenic with a concomitant decrease in megakaryocytes and their precursors. Bone marrow cells derived from Sca-1(-/-) mice also have decreased multipotential granulocyte, erythroid, macrophage, and megakaryocyte CFU (GEMM-CFU) and CFU-S progenitor activity. Competitive repopulation assays demonstrated that Sca-1(-/-) HSCs are at a competitive disadvantage compared with wild-type HSCs. To further analyze the potential of Sca-1(-/-) HSCs, serial transplantations were performed. While secondary repopulations using wild-type bone marrow completely repopulated Sca-1(-/-) mice, Sca-1(-/-) bone marrow failed to rescue one third of lethally irradiated wild-type mice receiving secondary bone marrow transplants from irradiation-induced anemia and contributed poorly to the surviving transplant recipients. These data strongly suggest that Sca-1 is required for regulating HSC self-renewal and the development of committed progenitor cells, megakaryocytes, and platelets. Thus, our studies conclusively demonstrate that Sca-1, in addition to being a marker of HSCs, regulates the developmental program of HSCs and specific progenitor populations.

In mammals, the continuous production of hematopoietic cells (HCs) is sustained by a small number of hematopoietic stem cells (HSCs) residing in the bone marrow. Early HSC activity arises in the aorta-gonad mesonephros region, within cells localized to the ventral floor of the major blood vessels, suggesting that the first HSCs may be derived from cells capable of giving rise to the hematopoietic system and to the endothelial cells of the vasculature. TIE1 (TIE) and TIE2 (TEK) are related receptor tyrosine kinases with an embryonic expression pattern in endothelial cells, their precursors, and HCs, suggestive of a role in the divergence and function of both lineages. Indeed, gene targeting approaches have shown that TIE1, TIE2, and ligands for TIE2, the angiopoietins, are essential for vascular development and maintenance. To explore possible roles for these receptors in HCs, we have examined the ability of embryonic cells lacking both TIE1 and TIE2 to contribute to developmental and adult hematopoiesis by generating chimeric animals between normal embryonic cells and cells lacking these receptors. We show here that TIE receptors are not required for differentiation and proliferation of definitive hematopoietic lineages in the embryo and fetus; surprisingly, however, these receptors are specifically required during postnatal bone marrow hematopoiesis.

The roles of PDZ domain-containing proteins such as Dlg and Scrib have been well described for Drosophila; however, their requirement for mammalian development is poorly understood. Here we show that Dlg, Scrib, MAGI1, MAGI3, and MPDZ are expressed in the mouse ocular lens. We demonstrate that the increase in proliferation and defects in cellular adhesion and differentiation observed in epithelia of lenses that express E6, a viral oncoprotein that can bind to several PDZ proteins, including the human homologs of Dlg and Scrib, is dependent on E6's ability to bind these proteins via their PDZ domains. Analyses of lenses from mice carrying an insertional mutation in Dlg (dlg(gt)) show increased proliferation and proliferation in spatially inappropriate regions of the lens, a phenotype similar to that of lenses expressing E6. The results from this study indicate that multiple PDZ domain-containing proteins, including Dlg and Scrib, may be required for maintaining the normal pattern of growth and differentiation in the lens. Furthermore, the phenotypic similarities among the Drosophila dlg mutant, the lenses of dlg(gt) mice, and the lenses of E6 transgenic mice suggest that Dlg may have a conserved function in regulating epithelial cell growth and differentiation across species.

The Kit receptor tyrosine kinase is critical for the growth and development of hematopoietic cells, germ cells, and the interstitial cells of Cajal. Gain-of-function mutations in codon 816 of the catalytic domain of human Kit [codon 814 of murine Kit (mKit)] are found in patients with mastocytosis, leukemia, and germ cell tumors. There are no drugs that inhibit the activity of Kit catalytic domain mutants to a greater extent than wild-type Kit. The objective of this study was to understand the biochemical mechanisms mediating mast cell transformation by this Kit mutant to identify molecular targets for pharmacological intervention. To this end, we examined signaling pathways activated in the murine mast cell line IC2 infected with either wild-type (IC2-mKit) or mutant mKit (IC2-mKit(D814Y)). In this study, we show that mKit(D814Y) is constitutively phosphorylated on tyrosine 719, and this likely results in constitutive association with activated phosphatidylinositol 3'-kinase (PI3K). In vitro growth of IC2-mKit(D814Y) cells is more sensitive to inhibition of PI3K than SCF-induced growth of IC2-mKit cells. s.c. injection of IC2-mKit(D814Y) in syngeneic mice results in mast cell tumors. To determine whether inhibition of PI3K could reduce mKit(D814Y)-mediated tumorigenicity, mice were treated with 1.5 mg/kg wortmannin three times a week. Five weeks after injection of tumor cells, a 75% reduction in tumor weight was observed when wortmannin treatments were initiated 2 days after inoculation with tumor cells. A 66% reduction occurred when treatment was initiated 2 weeks after inoculation. Treatment with wortmannin increased necrosis in the tumors, and this was associated with apoptosis. Interestingly, there was no effect on tumor vasculature. Thus, PI3K is required for survival and growth of the IC2-mKit(D814Y) mast cell line both in vitro and in vivo. These findings may provide insight into designing strategies for treatment of mastocytosis and other diseases associated with mutations in the Kit catalytic domain.