Shenoy N.,Yeshiva University |
Vallumsetla N.,Yeshiva University |
Rachmilewitz E.,Edith Wolfson Medical Center |
Verma A.,Yeshiva University |
Ginzburg Y.,Lindsley F Kimball Research Institute
Blood | Year: 2014
Myelodysplastic syndromes (MDSs) are a group of heterogeneous clonal bone marrow disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias, and potential for malignant transformation. Lower/intermediate-risk MDSs are associated with longer survival and high red blood cell (RBC) transfusion requirements resulting in secondary iron overload. Recent data suggest that markers of iron overload portend a relatively poor prognosis, and retrospective analysis demonstrates that iron chelation therapy is associated with prolonged survival in transfusion-dependent MDS patients. New data provide concrete evidence of iron's adverse effects on erythroid precursors in vitro and in vivo. Renewed interest in the iron field was heralded by the discovery of hepcidin, the main serum peptide hormone negative regulator of body iron. Evidence from β-thalassemia suggests that regulation of hepcidin by erythropoiesis dominates regulation by iron. Because iron overload develops in some MDS patients who do not require RBC transfusions, the suppressive effect of ineffective erythropoiesis on hepcidin may also play a role in iron overload. We anticipate that additional novel tools for measuring iron overload and a molecular-mechanism-driven description of MDS subtypes will provide a deeper understanding of how iron metabolism and erythropoiesis intersect in MDSs and improve clinical management of this patient population. © 2014 by The American Society of Hematology.
Huang C.-H.,Lindsley F Kimball Research Institute |
Ye M.,Lindsley F Kimball Research Institute
Cellular and Molecular Life Sciences | Year: 2010
The Rh (Rhesus) genes encode a family of conserved proteins that share a structural fold of 12 transmembrane helices with members of the major facilitator superfamily. Interest in this family has arisen from the discovery of Rh factor's involvement in hemolytic disease in the fetus and newborn, and of its homologs widely expressed in epithelial tissues. The Rh factor and Rhassociated glycoprotein (RhAG), with epithelial cousins RhBG and RhCG, form four subgroups conferring upon vertebrates a genealogical commonality. The past decade has heralded significant advances in understanding the phylogenetics, allelic diversity, crystal structure, and biological function of Rh proteins. This review describes recent progress on this family and the molecular insights gleaned from its gene evolution, membrane biology, and disease association. The focus is on its long evolutionary history and surprising structural conservation from prokaryotes to humans, pointing to the importance of its functional role, related to but distinct from ammonium transport proteins. © Birkhäuser Verlag.
Gooyit M.,Scripps Research Institute |
Tricoche N.,Lindsley F Kimball Research Institute |
Lustigman S.,Lindsley F Kimball Research Institute |
Janda K.D.,Scripps Research Institute
Journal of Medicinal Chemistry | Year: 2014
The L3-stage-specific chitinase OvCHT1 has been implicated in the development of Onchocerca volvulus, the causative agent of onchocerciasis. Closantel, a known anthelmintic drug, was previously discovered as a potent and specific OvCHT1 inhibitor. As closantel is also a known protonophore, we performed a simple scaffold modulation to map out the structural features that are relevant for its individual or dual biochemical roles. Furthermore, we present that either OvCHT1 inhibition or protonophoric activity was capable of affecting O. volvulus L3 molting and that the presence of both activities in a single molecule yielded more potent inhibition of the nematode's developmental process. © 2014 American Chemical Society.
Bergquist R.,Ingerod |
Lustigman S.,Lindsley F Kimball Research Institute
Advances in Parasitology | Year: 2010
Among the tools available for the control of helminth infections, chemotherapy has come to totally dominate the field. In the veterinary field, development of drug resistance has appeared but this is not (yet) a problem in the control of human diseases. Although there is no vaccine commercially available for any human parasitic infection yet, recent progress in vaccine development is making this a future possibility for several diseases. The goal of chemotherapy is to alleviate infection and morbidity in the definitive host, or reduce transmission, while the effect of available vaccine candidates would mainly be to influence transmission through targeting the intermediate or reservoir host, when the infection is zoonotic. Apart from this general scheme, there are also vaccine candidates targeting the parasites in the definitive host, in particular the early developmental stages, which should reduce the risk of drug failure. Since the biological targets in most cases are different, vaccination would be synergistic with drug therapy. This review covers diseases caused by helminthes in both humans and animals and includes examples of diseases caused by cestodes, nematodes and trematodes. The focus is on infections for which vaccine development has been undertaken for a long time, resulting in products that could realistically become integrated into control strategies in the near future. © 2010 Elsevier Ltd.
Yang Y.,University of Minnesota |
Du L.,Lindsley F Kimball Research Institute |
Liu C.,University of Minnesota |
Wang L.,Lindsley F Kimball Research Institute |
And 6 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014
Middle East respiratory syndrome coronavirus (MERS-CoV) currently spreads in humans and causes ∼36% fatality in infected patients. Believed to have originated from bats, MERS-CoV is genetically related to bat coronaviruses HKU4 and HKU5. To understand how bat coronaviruses transmit to humans, we investigated the receptor usage and cell entry activity of the virus-surface spike proteins of HKU4 and HKU5. We found that dipeptidyl peptidase 4 (DPP4), the receptor for MERS-CoV, is also the receptor for HKU4, but not HKU5. Despite sharing a common receptor, MERS-CoV and HKU4 spikes demonstrated functional differences. First, whereas MERS-CoV prefers human DPP4 over bat DPP4 as its receptor, HKU4 shows the opposite trend. Second, in the absence of exogenous proteases, both MERS-CoV and HKU4 spikes mediate pseudovirus entry into bat cells, whereas only MERS-CoV spike, but not HKU4 spike, mediates pseudovirus entry into human cells. Thus, MERS-CoV, but not HKU4, has adapted to use human DPP4 and human cellular proteases for efficient human cell entry, contributing to the enhanced pathogenesis of MERS-CoV in humans. These results establish DPP4 as a functional receptor for HKU4 and host cellular proteases as a host range determinant for HKU4. They also suggest that DPP4-recognizing bat coronaviruses threaten human health because of their spikes' capability to adapt to human cells for cross-species transmissions.
Avanzi M.P.,Lindsley F Kimball Research Institute |
Mitchell W.B.,Lindsley F Kimball Research Institute
British Journal of Haematology | Year: 2014
Stem cell technology holds great promise for transfusion medicine, and generation of platelets from stem cells would be transformative. Platelet transfusions are life saving for millions of people and the clinical demand for platelets continues to increase: there is a real need to increase the supply of platelets. Accordingly, there is great interest in the potential of producing platelets from stem cells for clinical use. There has been initial success in ex vivo generation of platelets from stem cells using cord blood stem cells, embryonic stem cells and induced pluripotent stem cells. However, the platelet yields achieved by these strategies have not been sufficient for clinical purposes. This review provides updated information about the current strategies of ex vivo generation of platelets. Megakaryocytopoiesis and platelet generation, along with the importance of genetic determinants of these processes, are reviewed in the context of efforts to generate these products from stem cells. Current challenges and rate-limiting steps in ex vivo platelet generation are discussed, together with strategies to overcome them. While much work remains, great progress has been made, moving ex vivo generation of platelets ever closer to the clinic. © 2014 John Wiley & Sons Ltd.
Zhang N.,Lindsley F Kimball Research Institute |
Jiang S.,Lindsley F Kimball Research Institute |
Jiang S.,Fudan University |
Du L.,Lindsley F Kimball Research Institute
Expert Review of Vaccines | Year: 2014
Middle East respiratory syndrome (MERS) is a newly emerging infectious disease caused by a novel coronavirus, MERS-coronavirus (MERS-CoV), a new member in the lineage C of β-coronavirus (β-CoV). The increased human cases and high mortality rate of MERS-CoV infection make it essential to develop safe and effective vaccines. In this review, the current advancements and potential strategies in the development of MERS vaccines, particularly subunit vaccines based on MERS-CoV spike (S) protein and its receptor-binding domain (RBD), are discussed. How to improve the efficacy of subunit vaccines through novel adjuvant formulations and routes of administration as well as currently available animal models for evaluating the in vivo efficacy of MERS-CoV vaccines are also addressed. Overall, these strategies may have important implications for the development of effective and safe vaccines for MERS-CoV in the future. © 2014 Informa UK, Ltd.
Lobo C.A.,Lindsley F Kimball Research Institute |
Rodriguez M.,Lindsley F Kimball Research Institute |
Cursino-Santos J.R.,Lindsley F Kimball Research Institute
Current Opinion in Hematology | Year: 2012
Purpose of Review: Babesiosis is a zoonosis, a disease communicable from animals to humans and an important blood-borne human parasitic infection. Despite its public health impact, its study has largely been neglected. The objective of this review is to present up-to-date information on both parasite and red blood cell molecules that function at the host-parasite interface to facilitate successful invasion. Recent Findings: In the last few years, a number of parasite proteins have been identified from genome projects and from functional red cell-binding assays. However, their cognate receptors as well as the precise function these ligands perform in the cascade of invasive events remain umknown. There also appears to be a significant overlap in the structural and functional aspects of the invasion machinery between malaria and Babesia. Summary: Recognizing that Babesia is an expanding blood safety threat, there should be rapid progress in the development of viable interventions to detect and halt transmission of these pathogens via blood transfusions. By developing a detailed mechanistic understanding of invasion, we can then exploit the participating molecules to procure much needed reagents for diagnosis, epidemiology, treatment and prevention of human babesiosis. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Ney P.A.,Lindsley F Kimball Research Institute
Biochimica et Biophysica Acta - Molecular Cell Research | Year: 2015
Mitochondrial autophagy (mitophagy) is a core cellular activity. In this review, we consider mitophagy and related cellular processes and discuss their significance for human disease. Strong parallels exist between mitophagy and xenophagy employed in host defense. These mechanisms converge on receptors in the innate immune system in clinically relevant scenarios. Mitophagy is part of a cellular quality control mechanism, which is implicated in degenerative disease, especially neurodegenerative disease. Furthermore, mitophagy is an aspect of cellular remodeling, which is employed during development. BNIP3 and NIX are related multi-functional outer mitochondrial membrane proteins. BNIP3 regulates mitophagy during hypoxia, whereas NIX is required for mitophagy during development of the erythroid lineage. Recent advances in the field of BNIP3- and NIX-mediated mitophagy are discussed. This article is part of a Special Issue entitled: Mitophagy. © 2015 Elsevier B.V.
Debnath A.K.,Lindsley F Kimball Research Institute
Methods in Molecular Biology | Year: 2013
This chapter reviews studies that have used in silico techniques to design or identify potential HIV-1 entry inhibitors targeting cellular receptors CD4, CCR5, and CXCR4 and envelope glycoproteins, gp120 and gp41 of HIV-1. Both structure- and ligand-based design techniques have been used in those studies by applying diverse modeling techniques such as quantitative structure-activity relationship analysis, conformational analysis, molecular dynamics, pharmacophore generation, docking, virtual screening (using docking software and also shape-based ROCS techniques), and fragment-based design. © Springer Science+Business Media, LLC 2013.