排序方式: 共有13条查询结果,搜索用时 15 毫秒
1.
Kumar P Ban HS Kim SS Wu H Pearson T Greiner DL Laouar A Yao J Haridas V Habiro K Yang YG Jeong JH Lee KY Kim YH Kim SW Peipp M Fey GH Manjunath N Shultz LD Lee SK Shankar P 《Cell》2008,134(4):577-586
Evaluation of the therapeutic potential of RNAi for HIV infection has been hampered by the challenges of siRNA delivery and lack of suitable animal models. Using a delivery method for T cells, we show that siRNA treatment can dramatically suppress HIV infection. A CD7-specific single-chain antibody was conjugated to oligo-9-arginine peptide (scFvCD7-9R) for T cell-specific siRNA delivery in NOD/SCIDIL2rgamma-/- mice reconstituted with human lymphocytes (Hu-PBL) or CD34+ hematopoietic stem cells (Hu-HSC). In HIV-infected Hu-PBL mice, treatment with anti-CCR5 (viral coreceptor) and antiviral siRNAs complexed to scFvCD7-9R controlled viral replication and prevented the disease-associated CD4 T cell loss. This treatment also suppressed endogenous virus and restored CD4 T cell counts in mice reconstituted with HIV+ peripheral blood mononuclear cells. Moreover, scFvCD7-9R could deliver antiviral siRNAs to naive T cells in Hu-HSC mice and effectively suppress viremia in infected mice. Thus, siRNA therapy for HIV infection appears to be feasible in a preclinical animal model. 相似文献
2.
Targeting Ergosterol Biosynthesis in Leishmania donovani: Essentiality of Sterol 14alpha-demethylase
Laura-Isobel McCall Amale El Aroussi Jun Yong Choi Debora F. Vieira Geraldine De Muylder Jonathan B. Johnston Steven Chen Danielle Kellar Jair L. Siqueira-Neto William R. Roush Larissa M. Podust James H. McKerrow 《PLoS neglected tropical diseases》2015,9(3)
Leishmania protozoan parasites (Trypanosomatidae family) are the causative agents of cutaneous, mucocutaneous and visceral leishmaniasis worldwide. While these diseases are associated with significant morbidity and mortality, there are few adequate treatments available. Sterol 14alpha-demethylase (CYP51) in the parasite sterol biosynthesis pathway has been the focus of considerable interest as a novel drug target in Leishmania. However, its essentiality in Leishmania donovani has yet to be determined. Here, we use a dual biological and pharmacological approach to demonstrate that CYP51 is indispensable in L. donovani. We show via a facilitated knockout approach that chromosomal CYP51 genes can only be knocked out in the presence of episomal complementation and that this episome cannot be lost from the parasite even under negative selection. In addition, we treated wild-type L. donovani and CYP51-deficient strains with 4-aminopyridyl-based inhibitors designed specifically for Trypanosoma cruzi CYP51. While potency was lower than in T. cruzi, these inhibitors had increased efficacy in parasites lacking a CYP51 allele compared to complemented parasites, indicating inhibition of parasite growth via a CYP51-specific mechanism and confirming essentiality of CYP51 in L. donovani. Overall, these results provide support for further development of CYP51 inhibitors for the treatment of visceral leishmaniasis. 相似文献
3.
Lteif AA Fulford AD Considine RV Gelfand I Baron AD Mather KJ 《American journal of physiology. Endocrinology and metabolism》2008,295(6):E1510-E1517
Endogenous endothelin action is augmented in human obesity and type 2 diabetes and contributes to endothelial dysfunction and impairs insulin-mediated vasodilation in humans. We hypothesized that insulin resistance-associated hyperinsulinemia could preferentially drive endothelin-mediated vasoconstriction. We applied hyperinsulinemic-euglycemic clamps with higher insulin dosing in obese subjects than lean subjects (30 vs. 10 mU.m(-2).min(-1), respectively), with the goal of matching insulin's nitric oxide (NO)-mediated vascular effects. We predicted that, under these circumstances, insulin-stimulated endothelin-1 (ET-1) action (assessed with the type A endothelin receptor antagonist BQ-123) would be augmented in proportion to hyperinsulinemia. NO bioactivity was assessed using the nitric oxide synthase inhibitor N(G)-monomethyl-l-arginine. Insulin-mediated vasodilation and insulin-stimulated NO bioavailability were well matched across groups by this approach. As expected, steady-state insulin levels were approximately threefold higher in obese than lean subjects (109.2 +/- 10.2 pmol/l vs. 518.4 +/- 84.0, P = 0.03). Despite this, the augmentation of insulin-mediated vasodilation by BQ-123 was not different between groups. ET-1 flux across the leg was not augmented by insulin alone but was increased with the addition of BQ-123 to insulin (P = 0.01 BQ-123 effect, P = not significant comparing groups). Endothelin antagonism augmented insulin-stimulated NO bioavailability and NOx flux, but not differently between groups and not proportional to hyperinsulinemia. These findings do not support the hypothesis that insulin resistance-associated hyperinsulinemia preferentially drives endothelin-mediated vasoconstriction. 相似文献
4.
Clinical,genetic and neuropathological findings in a series of 138 fetuses with a corpus callosum malformation 下载免费PDF全文
Caroline Alby Valérie Malan Lucile Boutaud Maria Angela Marangoni Bettina Bessières Maryse Bonniere Amale Ichkou Nadia Elkhartoufi Nadia Bahi‐Buisson Pascale Sonigo Anne‐Elodie Millischer Sophie Thomas Yves Ville Michel Vekemans Férechté Encha‐Razavi Tania Attié‐Bitach 《Birth defects research. Part A, Clinical and molecular teratology》2016,106(1):36-46
5.
It is generally thought that during the contraction phase of an acute anti-viral T cell reponse, the effector T cells that escape activation-induced cell death eventually differentiate into central memory T cells over the next several weeks. Here we report that antigen-specific CD8T cells with the phenotype and function of central memory cells develop concomitantly with effector T cells during vaccinia virus (vv) infection. As soon as 5 days after an intraperitoneal infection with vv, we could identify a subset of CD44hi and CD62L+ vv-specific CD8 T cells in the peritoneal exudate lymphocytes. This population constituted approximately 10% of all antigen-specific T cells and like central memory T cells, they also expressed high levels of CCR7 and IL-7R but expressed little granzyme B. Importantly, upon adoptive transfer into naïve congenic hosts, CD62L+, but not CD62L− CD8 T cells were able to expand and mediate a rapid recall response to a new vv challenge initiated 6 weeks after transfer, confirming that the CD62L+ vv-specific CD8 T cells are bonafide memory cells. Our results are thus consistent with the branched differentiation model, where effector and memory cells develop simultaneously. These results are likely to have implications in the context of vaccine design, particularly those based on vaccinia virus recombinants. 相似文献
6.
Yogesh B. Surase Kirandeep Samby Sagar R. Amale Ruchi Sood Kedar P. Purnapatre Pawan K. Pareek Biswajit Das Kamna Nanda Subodh Kumar Ashwani K. Verma 《Bioorganic & medicinal chemistry letters》2017,27(15):3454-3459
A non-diaryl quinoline scaffold 6,7-dihydropyrazolo[1,5-a]pyrazin-4-one was identified by screening of diverse set of compounds against M. smegmatis ATP synthase. Herein, we disclose our efforts to develop the structure activity relationship against Mycobacterium tuberculosis (Mtb.H37Rv strain) around the identified hit 1. A scaffold hopping approach was used to identify compounds 14a, 14b and 24a with improved activity against MTb.H37Rv. 相似文献
7.
Noémie Coron Marc Pihet Emilie Fréalle Yolande Lemeille Claudine Pinel Hervé Pelloux Gilles Gargala Loic Favennec Isabelle Accoceberry Isabelle Durand-Joly Frédéric Dalle Frédéric Huet Annlyse Fanton Amale Boldron Guy-André Loeuille Philippe Domblides Bérengère Coltey Isabelle Pin Catherine Llerena Françoise Troussier Christine Person Christophe Marguet Nathalie Wizla Caroline Thumerelle Dominique Turck Stéphanie Bui Michael Fayon Alain Duhamel Anne Prévotat Benoit Wallaert Sylvie Leroy Jean-Philippe Bouchara Laurence Delhaes 《Mycopathologia》2018,183(1):101-117
Fungal respiratory colonization of cystic fibrosis (CF) patients emerges as a new concern; however, the heterogeneity of mycological protocols limits investigations. We first aimed at setting up an efficient standardized protocol for mycological analysis of CF sputa that was assessed during a prospective, multicenter study: “MucoFong” program (PHRC-06/1902). Sputa from 243 CF patients from seven centers in France were collected over a 15-month period and submitted to a standardized protocol based on 6 semi-selective media. After mucolytic pretreatment, sputa were plated in parallel on cycloheximide-enriched (ACT37), erythritol-enriched (ERY37), benomyl dichloran–rose bengal (BENO37) and chromogenic (CAN37) media incubated at 37 °C and on Sabouraud–chloramphenicol (SAB27) and erythritol-enriched (ERY27) media incubated at 20–27 °C. Each plate was checked twice a week during 3 weeks. Fungi were conventionally identified; time for detection of fungal growth was noted for each species. Fungal prevalences and media performances were assessed; an optimal combination of media was determined using the Chi-squared automatic interaction detector method. At least one fungal species was isolated from 81% of sputa. Candida albicans was the most prevalent species (58.8%), followed by Aspergillus fumigatus (35.4%). Cultivation on CAN37, SAB27, ACT37 and ERY27 during 16 days provided an optimal combination, detecting C. albicans, A. fumigatus, Scedosporium apiospermum complex and Exophiala spp. with sensitivities of 96.5, 98.8, 100 and 100%. Combination of these four culture media is recommended to ensure the growth of key fungal pathogens in CF respiratory specimens. The use of such consensual protocol is of major interest for merging results from future epidemiological studies. 相似文献
8.
Kieren J. Mather Amale A. Lteif Emily Veeneman Richard Fain Susan Giger Kevin Perry Gary D. Hutchins 《Obesity (Silver Spring, Md.)》2010,18(1):63-70
Endothelin is an important determinant of peripheral vascular tone, and increased endogenous endothelin activity contributes to peripheral vascular dysfunction in human obesity. The contributions of endothelin to the regulation of coronary vascular tone in health in humans have not been well studied. We hypothesized that the contribution of endothelin to the regulation of myocardial perfusion would be augmented in human obesity. Using [NH3]ammonia positron emission tomography (PET), we measured myocardial perfusion under resting and adenosine‐stimulated conditions on two separate days, with and without concurrent exposure to BQ123, an antagonist of type A endothelin receptors (1 µmol/min IV beginning 90 min before measurement). We studied 10 lean and 9 obese subjects without hypertension, hyperlipidemia, or diabetes mellitus. We observed a BQ123‐induced increase in resting myocardial perfusion of ~40%, not different between lean and obese subjects (BQ123‐induced increase in flow: lean 0.12 ± 0.20, obese 0.32 ± 0.51 ml/g/min, P = 0.02 BQ123 effect, P = 0.27 comparing response across groups). Although basal flow rates varied by region of the myocardium, the BQ123 effect was seen in all regions. BMI and cholesterol were significantly related to BQ123‐induced increases in basal tone in multivariable analysis. There was no baseline difference in the adenosine‐stimulated increase in blood flow between lean and obese subjects, and BQ123 failed to augment these responses in either group. These observations suggest that endothelin is an important contributor to the regulation of myocardial perfusion under resting conditions in healthy lean and obese humans, with increased contributions in proportion to increasing obesity. 相似文献
9.
Laouar A Manocha M Wan M Yagita H van Lier RA Manjunath N 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(2):652-656
NK cell receptors (NKRs) modulate T lymphocyte responses by modifying the Ag activation threshold. However, what governs their expression on T cells remains unclear. In this study we show that different NKRs are imprinted on CD8 T cells in the gut mucosa and periphery during the same Ag challenge. After a viral, bacterial, and tumor challenge, most CD8 peritoneal exudate lymphocytes expressed NKG2A but not 2B4. In contrast, most CD8 intraepithelial lymphocytes exhibited 2B4 but not NKG2A. Our data suggest that tissue-specific factors may determine the pattern of NKR expression. In the gut, CD70 licensing appears to promote 2B4 induction on mucosal CD8 T cells. Conversely, retinoic acid produced by the intestinal dendritic cells may suppress NKG2A expression. Thus, tissue-specific factors regulate NKR expression and may confer T cells with differing effector functions in a tissue and site-specific manner. 相似文献
10.
The gp49B1 inhibitory receptor regulates the IFN-gamma responses of T cells and NK cells 总被引:1,自引:0,他引:1
Gu X Laouar A Wan J Daheshia M Lieberman J Yokoyama WM Katz HR Manjunath N 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(8):4095-4101
The magnitude and diversity of Ag-specific T cell effector activity have been proposed to be controlled by an integration of positive signals transduced by the TCR and negative signals originating from inhibitory cell surface molecules. Although the lectin family of NK cell-associated inhibitory receptors has been reported to regulate the function of murine CTLs, gp49B1, the Ig superfamily member is not known to be expressed on T cells. Moreover, the consequences of the lack of an endogenously expressed NK cell-associated inhibitory receptor on T cell functions are not known. We report that gp49B1 is expressed by nearly all activated CD8 and CD4 T cells in addition to NK cells during an immune response to viral, bacterial, or tumor challenge. Kinetics of gp49B1 expression parallel functional capability and subside in the memory phase. Following vaccinia viral infection, IFN-gamma production by both subsets of T cells and NK cells is enhanced in gp49B1-deficient mice compared with gp49B1(+/+) mice. The stimulation threshold for IFN-gamma production is also lower in gp49B1-deficient T cells. In contrast, no significant differences were observed in the cytotoxic responses. We conclude that gp49B1 is a unique inhibitory receptor that is induced in multiple lineages of innate and adaptive immune cells during an infection and controls their IFN-gamma, but not cytotoxic responses. 相似文献