Papers by Claude Nagamine
Affordable and effective antiviral therapies are needed worldwide, especially against agents such... more Affordable and effective antiviral therapies are needed worldwide, especially against agents such as dengue virus that are endemic in underserved regions. Many antiviral compounds have been studied in cultured cells but are unsuitable for clinical applications due to pharmacokinetic profiles, side effects, or inconsistent efficacy across dengue serotypes. Such tool compounds can, however, aid in identifying clinically useful treatments. Here, computational screening (Rapid Overlay of Chemical Structures) was used to identify entries in an in silico database of safe-in-human compounds (SWEETLEAD) that display high chemical similarities to known inhibitors of dengue virus. Molecules known to inhibit dengue proteinase NS2B/3, dengue capsid, and the host autophagy pathway were used as query compounds. Following computational and initial virological screening, three FDA-approved compounds that resemble the tool molecules structurally, cause little toxicity and display strong antiviral ac...
Journal of Virology
Determinants and mechanisms of cell attachment and entry steer adeno-associated virus (AAV) in it... more Determinants and mechanisms of cell attachment and entry steer adeno-associated virus (AAV) in its utility as a gene therapy vector. Thus far, a systematic assessment of how diverse AAV serotypes engage their proteinaceous receptor AAVR (KIAA0319L) to establish transduction has been lacking, despite potential implications for cell and tissue tropism. Here, a large set of human and simian AAVs as well as in silico -reconstructed ancestral AAV capsids were interrogated for AAVR usage. We identified a distinct AAV capsid lineage comprised of AAV4 and AAVrh32.33 that can bind and transduce cells in the absence of AAVR, independent of the multiplicity of infection. Virus overlay assays and rescue experiments in nonpermissive cells demonstrate that these AAVs are unable to bind to or use the AAVR protein for entry. Further evidence for a distinct entry pathway was observed in vivo , as AAVR knockout mice were equally as permissive to transduction by AAVrh32.33 as wild-type mice upon syste...
Comparative medicine, 2017
Zika virus has garnered great attention over the last several years, as outbreaks of the disease ... more Zika virus has garnered great attention over the last several years, as outbreaks of the disease have emerged throughout the Western Hemisphere. Until quite recently Zika virus was considered a fairly benign virus, with limited clinical severity in both people and animals. The size and scope of the outbreak in the Western Hemisphere has allowed for the identification of severe clinical disease that is associated with Zika virus infection, most notably microcephaly among newborns, and an association with Guillian-Barré syndrome in adults. This recent association with severe clinical disease, of which further analysis strongly suggested causation by Zika virus, has resulted in a massive increase in the amount of both basic and applied research of this virus. Both small and large animal models are being used to uncover the pathogenesis of this emerging disease and to develop vaccine and therapeutic strategies. Here we review the animal-model-based Zika virus research that has been perf...
Comparative medicine, 2017
The role of host type I IFN signaling and its interaction with other immune pathways during bacte... more The role of host type I IFN signaling and its interaction with other immune pathways during bacterial infections is incompletely understood. Type II IFN signaling plays a key role during numerous bacterial infections including granulocytic anaplasmosis (GA) caused by Anaplasma phagocytophilum infection. The function of combined type I and type II IFN signaling and their potential synergism during GA and similar tick-borne diseases is a topic of current research investigation. The goal of this study was to evaluate 2 mouse models of absent type I/type II IFN signaling in experimental A. phagocytophilum infection to determine the effects of background strain. Mice lacking both type I and type II IFN receptor signaling (IFNAR-/-/IFNGR-/-) on either the 129/SvEv or C57BL/6J genetic background were evaluated at days 0, 6, 8, and 12 of infection. Pathogen burden in multiple organs was largely similar between strains of infected mice, with few significant differences. Background strain inf...
Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging, Dec 28, 2017
It is well known that cancers exploit immune checkpoints (programmed death 1 receptor (PD-1) and ... more It is well known that cancers exploit immune checkpoints (programmed death 1 receptor (PD-1) and its ligand (PD-L1)) to evade anti-tumor immune responses. Although immune checkpoint (IC) blockade is a promising approach, not all patients respond. Hence, imaging of tumor-infiltrating lymphocytes (TILs) is of high specific interest, as they are known to express PD-1 during activation and subsequent exhaustion in the tumor microenvironment and are thought to be potentially predictive of therapeutic responses to IC blockade. We developed immune-tracers for positron emission tomography (PET) to image hPD-1 status of human peripheral blood mononuclear cells (hPBMCs) adoptively transferred to NOD-scid IL-2Rγ(null) (NSG) mice (hNSG) bearing A375 human skin melanoma tumors. The anti-PD-1 human antibody (IgG; keytruda) was labeled with either Zr-89 or Cu-64 radiometals to image PD-1-expressing human TILs in vivo. [(89)Zr] Keytruda (groups = 2; NSG-ctl (control) and hNSG-nblk (non-blocking), n...
Molecular Therapy, 2016
Gastrointestinal disorders such as inflammatory bowel disease, colitis and enteritis share signat... more Gastrointestinal disorders such as inflammatory bowel disease, colitis and enteritis share signatures of an aggravated and protracted inflammatory response. As the first line of defense, epithelial cells play an important role in secreting chemoattractants and cytokines to launch or attenuate the immune response. However, little is known about the regulation of immune responses in the gastrointestinal tract. To understand the role of colonic epithelial cells during inflammation in C57BL/6J mice, we examine the effects of dietary C18 saturated (stearic acid), unsaturated (oleic acid) fat and dextran sulfate salt (DSS) in acute colonic inflammation. Microarray analysis was conducted comparing changes in global gene expression signatures between colon samples of three treatment groups. Preliminary studies suggest that the saturated diet resulted in a colonic gene expression profile that is more closely associated to that of DSStreated. In addition, gene ontology analyses suggest that genes that overlap between all three treatment groups are mostly involved in immunological and metabolic diseases, as well as endocrine system disorders. Further interrogation revealed that an adipokine, angiopoietin-like 4 (ANGPTL4), modulates the degree and extent of colonic inflammation. We observed an elevated inflammation status, associated with massive immune cell infiltration, in ANGPTL4-/mice compared to its ANGPTL4 +/+ littermates during DSS-induced colonic inflammation. Our preliminary studies highlights the importance of regulating the colonic expression of ANGPTL4 as an avenue to attenuate gastrointestinal inflammation.
The Journal of clinical investigation, Jan 27, 2017
Global health is threatened by emerging viral infections, which largely lack effective vaccines o... more Global health is threatened by emerging viral infections, which largely lack effective vaccines or therapies. Targeting host pathways that are exploited by multiple viruses could offer broad-spectrum solutions. We previously reported that AAK1 and GAK, kinase regulators of the host adaptor proteins AP1 and AP2, are essential for hepatitis C virus (HCV) infection, but the underlying mechanism and relevance to other viruses or in vivo infections remained unknown. Here, we have discovered that AP1 and AP2 cotraffic with HCV particles in live cells. Moreover, we found that multiple viruses, including dengue and Ebola, exploit AAK1 and GAK during entry and infectious virus production. In cultured cells, treatment with sunitinib and erlotinib, approved anticancer drugs that inhibit AAK1 or GAK activity, or with more selective compounds inhibited intracellular trafficking of HCV and multiple unrelated RNA viruses with a high barrier to resistance. In murine models of dengue and Ebola infec...
Implantation of ovarian tissue into androgenic gland ablated male prawns, Macrobrachium rosenberg... more Implantation of ovarian tissue into androgenic gland ablated male prawns, Macrobrachium rosenbergii (de Man) induced the development of ovigerous and ovipositing setae and brood chambers, suggesting that in females, these secondary sexual characteristics are induced by the ovary. This model system has potential for the study of morphological changes associated with breeding in the Decapoda.
Infection and Immunity, 2008
Adenomatous polyposis coli (APC) mutations are linked to human and mouse colorectal cancers. The ... more Adenomatous polyposis coli (APC) mutations are linked to human and mouse colorectal cancers. The Apc multiple intestinal neoplasia (Min) mouse mutation causes adenomas to develop throughout the small and large intestines. The BALB-Min (C.B6-Apc Min/؉) congenic strain was generated by backcrossing into BALB/c the Apc Min allele from C57BL/6J-Apc Min/؉ mice. BALB-Min mice have a low tumor multiplicity (27.4 small intestine tumors/mouse) and a relatively long life span (>1 year) that makes them amenable to long-term studies. To investigate the interplay of the adaptive immune system and intestinal tumorigenesis, the immunodeficient compound mutant strain BALB-RagMin (C.Cg-Rag2 ؊/؊ Apc Min/؉) was generated. BALB-RagMin mice had a significant increase in tumors in the small, but not large, intestine relative to their BALB-Min counterparts (43.0 versus 24.0 tumors/mouse, respectively). The results suggest that the adaptive immune system plays a role in either the elimination or the equilibrium phase of cancer immunoediting in the small intestine in this model. We investigated the effect of the enterohepatic bacterial pathogen Helicobacter hepaticus on liver and intestine tumorigenesis in BALB-RagMin mice. H. hepaticus-infected BALB-RagMin mice developed moderate hepatitis, moderate typhlitis, and mild colitis. There were no differences in small intestine and cecal tumor multiplicity, regionality, or size relative to that in uninfected mice. However, H. hepaticus-infected BALB-RagMin mice had a significant increase in colon tumor incidence relative to uninfected BALB-RagMin mice (23.5% versus 1.7%, respectively). The data suggest that H. hepaticus, which is present in many research colonies, promotes colon tumorigenesis in the BALB-RagMin mouse and that it has the potential to confound colon tumorigenesis studies.
Http Dx Doi Org 10 1080 01688170 1987 10510268, May 22, 2012
Twenty-three immature female crayfish (Procambarus clarki (Girard); carapace length = 8.2–17.9 mm... more Twenty-three immature female crayfish (Procambarus clarki (Girard); carapace length = 8.2–17.9 mm), implanted with androgenic gland implants obtained from P. clarki males, were observed for 326 days for evidence of masculinization. Number of molts completed ranged from three to eight. Of eleven surviving females, three were masculinized as evidenced by the partial transformation of their first pair of pleopods into male-type gonopods. No other evidence of masculinization, either internal or external was seen. Masculinization of the first pair of pleopods was unequal and first noted 290 days post-implantation. We conclude that androgenic gland implantation can induce masculinization of P. clarki females, albeit only with great difficulty. This is the first report of masculinization of female macruran decapods by androgenic gland implantation.
Journal of the American Association For Laboratory Animal Science Jaalas, 2013
After rederivation of a mouse parvovirus (MPV)-contaminated transgenic mouse strain, serology and... more After rederivation of a mouse parvovirus (MPV)-contaminated transgenic mouse strain, serology and PCR testing of the surrogate dam showed it to be infected with mouse parvovirus strain 1 (MPV-1). The rederived pups (n = 3) also were MPV-positive, according to serology. Despite MPV seropositivity, fecal PCR tests of the pups were negative, as were serologic results from direct-contact sentinels. Only one rederived pup survived, and this male was bred successfully. None of its mates or progeny seroconverted to MPV. At 14.5 mo of age, the rederived male mouse was euthanized; tissues were collected and submitted for MPV testing; both serologic tests and PCR analysis of mesenteric lymph nodes were MPV-negative. One explanation for the rederived pups' MPV seropostivity is passive transfer of maternal antibodies or a nonproductive MPV infection. This case illustrates that although routine serological testing of surrogate mothers and pups is appropriate, any positive results should be further investigated by using transmissibility testing (fecal PCR or contact sentinels or both) prior to repeat rederivation.
Genomics, 1997
candidate oncogene lyt-10 homologous to NF-kB p50. Cell 67: tion in the fetal testis (13). In the... more candidate oncogene lyt-10 homologous to NF-kB p50. Cell 67: tion in the fetal testis (13). In the adult, Zfy transcripts are 1075-1087.
When the Y chromosome of the laboratory inbred mouse strain C57BL/6 (B6) is replaced by the Y of ... more When the Y chromosome of the laboratory inbred mouse strain C57BL/6 (B6) is replaced by the Y of certain strains of Mus musculus domesticus, testis determination fails and all XY fetuses develop either as hermaphrodites or XY females (XY sex reversal). This suggests the presence of at least two alleles of Sry, the male-determining gene on the Y: A4. m.
International Journal of Invertebrate Reproduction and Development, 1987
Implantation of ovarian tissue into androgenic gland ablated male prawns, Macrobrachium rosenberg... more Implantation of ovarian tissue into androgenic gland ablated male prawns, Macrobrachium rosenbergii (de Man) induced the development of ovigerous and ovipositing setae and brood chambers, suggesting that in females, these secondary sexual characteristics are induced by the ovary. This model system has potential for the study of morphological changes associated with breeding in the Decapoda.
mBio, 2015
ABSTRACTDengue virus is a major human pathogen responsible for 400 million infections yearly. As ... more ABSTRACTDengue virus is a major human pathogen responsible for 400 million infections yearly. As with other RNA viruses, daunting challenges to antiviral design exist due to the high error rates of RNA-dependent RNA synthesis. Indeed, treatment of dengue virus infection with a nucleoside analog resulted in the expected genetic selection of resistant viruses in tissue culture and in mice. However, when the function of the oligomeric core protein was inhibited, no detectable selection of drug resistance in tissue culture or in mice was detected, despite the presence of drug-resistant variants in the population. Suppressed selection of drug-resistant virus correlated with cooligomerization of the targeted drug-susceptible and drug-resistant core proteins. The concept of “dominant drug targets,” in which inhibition of oligomeric viral assemblages leads to the formation of drug-susceptible chimeras, can therefore be used to prevent the outgrowth of drug resistance during dengue virus inf...
Journal of the American Association for Laboratory Animal Science: JAALAS
Journal of the American Association for Laboratory Animal Science : JAALAS, 2012
Disposable individually ventilated cages have lids that restrict air exchange when the cage is no... more Disposable individually ventilated cages have lids that restrict air exchange when the cage is not mechanically ventilated. This design feature may cause intracage CO2 to increase and O2 to decrease (hypercapnic and hypoxic conditions, respectively) when the electrical supply to the ventilated rack fails, the ventilated rack malfunctions, cages are docked in the rack incorrectly, or cages are removed from the ventilated rack for extended periods of time. We investigated how quickly hypercapnic and hypoxic conditions developed within disposable individually ventilated cages after removal from mechanical ventilation and compared the data with nondisposable static cages, disposable static cages, and unventilated nondisposable individually ventilated cages. When disposable individually ventilated cages with 5 adult mice per cage were removed from mechanical ventilation, CO2 concentrations increased from less than 1% at 0 h to approximately 5% at 3 h and O2 levels dropped from more than ...
Journal of nematology, 1980
Blinding" and a leaf gall induced on Amsinckia intermedia Fisch. and Mey. by Anguina amsinckia (S... more Blinding" and a leaf gall induced on Amsinckia intermedia Fisch. and Mey. by Anguina amsinckia (Steiner and Scott) are described. A. anlsinckia induced blinding by galling the terminal apical meristem of its host. The leaf gall was formed by a ventral curling of the distal edge of the leaf. The absence of a rachis in the ovary of A. amsinckia is noted.
Development (Cambridge, England), 1996
The Y chromosome from certain populations of M. m. domesticus is incapable of normal testis deter... more The Y chromosome from certain populations of M. m. domesticus is incapable of normal testis determination in the B6 inbred strain resulting in XY hermaphrodites or XY females (XY(DOM) sex reversal). B6 consomic strains have been developed with either transient (B6-Y(AKR)) or severe (B6-Y(TIR)) XY(DOM) sex reversal. We report that a point mutation, the dominant white spotting oncogene allele, Kit(W-42J), exacerbates XY(DOM) sex reversal. In B6-Y(AKR), penetrance of the trait is low; however, in B6-Y(TIR), Kit(W-42J) exacerbated sex reversal to such an extent that almost all XY progeny developed into females. The exacerbation of sex reversal was not linked to retardation of early fetal growth or reduction of testis size. Furthermore, semiquantitative RT-PCR for the testis-determining gene, Sry, suggests that exacerbation of sex reversal in B6-Y(TIR) is not due to blockade of Sry expression, a substantial delay in initiation of Sry expression, or exceptionally low levels of Sry mRNAs. ...
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Papers by Claude Nagamine