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1.
Kathryn S. Evans Janneke Wit Lewis Stevens Steffen R. Hahnel Briana Rodriguez Grace Park Mostafa Zamanian Shannon C. Brady Ellen Chao Katherine Introcaso Robyn E. Tanny Erik C. Andersen 《PLoS pathogens》2021,17(3)
Parasitic nematodes cause a massive worldwide burden on human health along with a loss of livestock and agriculture productivity. Anthelmintics have been widely successful in treating parasitic nematodes. However, resistance is increasing, and little is known about the molecular and genetic causes of resistance for most of these drugs. The free-living roundworm Caenorhabditis elegans provides a tractable model to identify genes that underlie resistance. Unlike parasitic nematodes, C. elegans is easy to maintain in the laboratory, has a complete and well annotated genome, and has many genetic tools. Using a combination of wild isolates and a panel of recombinant inbred lines constructed from crosses of two genetically and phenotypically divergent strains, we identified three genomic regions on chromosome V that underlie natural differences in response to the macrocyclic lactone (ML) abamectin. One locus was identified previously and encodes an alpha subunit of a glutamate-gated chloride channel (glc-1). Here, we validate and narrow two novel loci using near-isogenic lines. Additionally, we generate a list of prioritized candidate genes identified in C. elegans and in the parasite Haemonchus contortus by comparison of ML resistance loci. These genes could represent previously unidentified resistance genes shared across nematode species and should be evaluated in the future. Our work highlights the advantages of using C. elegans as a model to better understand ML resistance in parasitic nematodes. 相似文献
2.
Simona Picardi Briana Abrahms Emily Gelzer Thomas A. Morrison Tana Verzuh Jerod A. Merkle 《Ecology letters》2023,26(1):157-169
Site fidelity—the tendency to return to previously visited locations—is widespread across taxa. Returns may be driven by several mechanisms, including memory, habitat selection, or chance; however, pattern-based definitions group different generating mechanisms under the same label of ‘site fidelity’, often assuming memory as the main driver. We propose an operational definition of site fidelity as patterns of return that deviate from a null expectation derived from a memory-free movement model. First, using agent-based simulations, we show that without memory, intrinsic movement characteristics and extrinsic landscape characteristics are key determinants of return patterns and that even random movements may generate substantial probabilities of return. Second, we illustrate how to implement our framework empirically to establish ecologically meaningful, system-specific null expectations for site fidelity. Our approach provides a conceptual and operational framework to test hypotheses on site fidelity across systems and scales. 相似文献
3.
Phylogenetic distance among host species represents a proxy for host traits that act as biotic filters to shape host‐associated microbiome community structure. However, teasing apart potential biotic assembly mechanisms, such as host specificity or local species interactions, from abiotic factors, such as environmental specificity or dispersal barriers, in hyperdiverse, horizontally transmitted microbiomes remains a challenge. In this study, we tested whether host phylogenetic relatedness among 18 native Asteraceae plant species and spatial distance between replicated plots in a common garden affects foliar fungal endophyte (FFE) community structure. We found that FFE community structure varied significantly among host species, as well as host tribes, but not among host subfamilies. However, FFE community dissimilarity between host individuals was not significantly correlated with phylogenetic distance between host species. There was a significant effect of spatial distance among host individuals on FFE community dissimilarity within the common garden. The significant differences in FFE community structure among host species, but lack of a significant host phylogenetic effect, suggest functional differences among host species not accounted for by host phylogenetic distance, such as metabolic traits or phenology, may drive FFE community dissimilarity. Overall, our results indicate that host species identity and the spatial distance between plants can determine the similarity of their microbiomes, even across a single experimental field, but that host phylogeny is not closely tied to FFE community divergence in native Asteraceae. 相似文献
4.
SpoIIIE directionally pumps DNA across membranes during Bacillus subtilis sporulation and vegetative growth. The sequence-reading domain (γ domain) is required for directional DNA transport, and its deletion severely impairs sporulation. We selected suppressors of the spoIIIEΔγ sporulation defect. Unexpectedly, many suppressors were intragenic missense mutants, and some restore sporulation to near-wild-type levels. The mutant proteins are likely not more abundant, faster at translocating DNA, or sequence-sensitive, and rescue does not involve the SpoIIIE homolog SftA. Some mutants behave differently when co-expressed with spoIIIEΔγ, consistent with the idea that some, but not all, variants may form mixed oligomers. In full-length spoIIIE, these mutations do not affect sporulation, and yet the corresponding residues are rarely found in other SpoIIIE/FtsK family members. The suppressors do not rescue chromosome translocation defects during vegetative growth, indicating that the role of the γ domain cannot be fully replaced by these mutations. We present two models consistent with our findings: that the suppressors commit to transport in one arbitrarily-determined direction or delay spore development. It is surprising that missense mutations somehow rescue loss of an entire domain with a complex function, and this raises new questions about the mechanism by which SpoIIIE pumps DNA and the roles SpoIIIE plays in vivo. 相似文献
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6.
Abdollahi A Gruver BN Patriotis C Hamilton TC 《Biochemical and biophysical research communications》2003,307(1):188-197
Alteration in epidermal growth factor receptor (EGFR) family signaling is among the most frequently implicated effectors of human oncogenesis. Overexpression of members of this family of receptors has often been detected in many epithelial tumors and is believed to be associated with an overall poor prognosis in patients with cancer. Therefore, we hypothesized that identification of potential EGF target genes in normal cells will provide a basis for unbiased genetic analysis of this signaling pathway in cancer. We utilized Atlas Rat 1.2 nylon cDNA arrays (Clontech) to determine gene expression changes in normal rat ovarian surface epithelial (ROSE) cells following EGF treatment. The results indicate activation of genes involved in a wide variety of cellular mechanisms, including regulation of cell cycle and proliferation, apoptosis, and protein turnover. In addition, using an in vitro model of ovarian cancer, we demonstrated that malignant transformation of ROSE cells resulted in alteration of downstream effectors of the EGFR pathway, as exemplified by aberrant expression of p66Shc, c-Jun, c-Myc, c-Fos, Lot1, p21Cip/Waf, and cdc25A. These data suggest that knowledge of the downstream genetic lesions, which may result in loss of growth factor requirement of the affected cells, will be crucial for the selection of the EGFR pathway as an effective target for cancer therapy. 相似文献
7.
Fasciola hepatica cathepsin L-like proteases: biology,function, and potential in the development of first generation liver fluke vaccines 总被引:5,自引:0,他引:5
Dalton JP Neill SO Stack C Collins P Walshe A Sekiya M Doyle S Mulcahy G Hoyle D Khaznadji E Moiré N Brennan G Mousley A Kreshchenko N Maule AG Donnelly SM 《International journal for parasitology》2003,33(11):1173-1181
Fasciola hepatica secretes cathepsin L proteases that facilitate the penetration of the parasite through the tissues of its host, and also participate in functions such as feeding and immune evasion. The major proteases, cathepsin L1 (FheCL1) and cathepsin L2 (FheCL2) are members of a lineage that gave rise to the human cathepsin Ls, Ks and Ss, but while they exhibit similarities in their substrate specificities to these enzymes they differ in having a wider pH range for activity and an enhanced stability at neutral pH. There are presently 13 Fasciola cathepsin L cDNAs deposited in the public databases representing a gene family of at least seven distinct members, although the temporal and spatial expression of each of these members in the developmental stage of F. hepatica remains unclear. Immunolocalisation and in situ hybridisation studies, using antibody and DNA probes, respectively, show that the vast majority of cathepsin L gene expression is carried out in the epithelial cells lining the parasite gut. Within these cells the enzyme is packaged into secretory vesicles that release their contents into the gut lumen for the purpose of degrading ingested host tissue and blood. Liver flukes also express a novel multi-domain cystatin that may be involved in the regulation of cathepsin L activity. Vaccine trials in both sheep and cattle with purified native FheCL1 and FheCL2 have shown that these enzymes can induce protection, ranging from 33 to 79%, to experimental challenge with metacercariae of F. hepatica, and very potent anti-embryonation/hatch rate effects that would block parasite transmission. In this article we review the vaccine trials carried out over the past 8 years, the role of antibody and T cell responses in mediating protection and discuss the prospects of the cathepsin Ls in the development of first generation recombinant liver fluke vaccines. 相似文献
8.
Effects of cytotoxic T lymphocytes (CTL) directed against a single simian immunodeficiency virus (SIV) Gag CTL epitope on the course of SIVmac239 infection 下载免费PDF全文
Allen TM Jing P Calore B Horton H O'Connor DH Hanke T Piekarczyk M Ruddersdorf R Mothé BR Emerson C Wilson N Lifson JD Belyakov IM Berzofsky JA Wang C Allison DB Montefiori DC Desrosiers RC Wolinsky S Kunstman KJ Altman JD Sette A McMichael AJ Watkins DI 《Journal of virology》2002,76(20):10507-10511
Vaccine-induced cytotoxic T lymphocytes (CTL) have been implicated in the control of virus replication in simian immunodeficiency virus (SIV)-challenged and simian-human immunodeficiency virus-challenged macaques. Therefore, we wanted to test the impact that vaccine-induced CTL responses against an immunodominant Gag epitope might have in the absence of other immune responses. By themselves, these strong CTL responses failed to control SIVmac239 replication. 相似文献
9.
Tat-vaccinated macaques do not control simian immunodeficiency virus SIVmac239 replication 总被引:2,自引:0,他引:2 下载免费PDF全文
Allen TM Mortara L Mothé BR Liebl M Jing P Calore B Piekarczyk M Ruddersdorf R O'Connor DH Wang X Wang C Allison DB Altman JD Sette A Desrosiers RC Sutter G Watkins DI 《Journal of virology》2002,76(8):4108-4112
The regulatory proteins of human immunodeficiency virus may represent important vaccine targets. Here we assessed the role of Tat-specific cytotoxic T lymphocytes (CTL) in controlling pathogenic simian immunodeficiency virus SIVmac239 replication after using a DNA-prime, vaccinia virus Ankara-boost vaccine regimen. Despite the induction of Tat-specific CTL, there was no significant reduction in either peak or viral set point compared to that of controls. 相似文献
10.
Michela Manni Sanjay Gupta Briana G. Nixon Casey T. Weaver Rolf Jessberger Alessandra B. Pernis 《PloS one》2015,10(11)
Interferon Regulatory Factors (IRFs) play fundamental roles in dendritic cell (DC) differentiation and function. In particular, IRFs are critical transducers of TLR signaling and dysregulation in this family of factors is associated with the development of autoimmune disorders such as Systemic Lupus Erythematosus (SLE). While several IRFs are expressed in DCs their relative contribution to the aberrant phenotypic and functional characteristics that DCs acquire in autoimmune disease has not been fully delineated. Mice deficient in both DEF6 and SWAP-70 (= Double-knock-out or DKO mice), two members of a unique family of molecules that restrain IRF4 function, spontaneously develop a lupus-like disease. Although autoimmunity in DKO mice is accompanied by dysregulated IRF4 activity in both T and B cells, SWAP-70 is also known to regulate multiple aspects of DC biology leading us to directly evaluate DC development and function in these mice. By monitoring Blimp1 expression and IL-10 competency in DKO mice we demonstrate that DCs in these mice exhibit dysregulated IL-10 production, which is accompanied by aberrant Blimp1 expression in the spleen but not in the peripheral lymph nodes. We furthermore show that DCs from these mice are hyper-responsive to multiple TLR ligands and that IRF4 plays a differential role in in these responses by being required for the TLR4-mediated but not the TLR9-mediated upregulation of IL-10 expression. Thus, DC dysfunction in lupus-prone mice relies on both IRF4-dependent and IRF4-independent pathways. 相似文献