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PubMed1997

Canine rod transducin alpha-1: cloning of the cDNA and evaluation of the gene as a candidate for progressive retinal atrophy.

PURPOSE: Progressive retinal atrophy (PRA) represents a heterogeneous group of retinal dystrophies, distinct forms of which occur in different canine breeds. The present study was undertaken to evaluate the gene for the alpha-1 subunit of the rod specific G-protein transducin (GNAT1), a member of the phototransduction pathway, as a candidate for progressive rod cone degeneration (pred) in poodles, early retinal degeneration (erd) in elkhounds, and rod cone dysplasia 2 (rcd2) in collies. METHODS: Oligonucleotide primers were designed from the consensus region of known cDNA sequences for GNAT1 from other species. Canine GNAT1 cDNA was cloned and sequenced after reverse transcription (RT) and polymerase chain reaction (PCR) of total retinal RNA, and PCR amplification of specific sequences from a canine retinal cDNA library. Large, intron containing fragments of the canine transducin alpha-1 subunit gene were amplified from genomic DNA of individuals in PRA informative pedigrees, using canine-specific primers. PCR products were digested with Nci I, to enable typing of individuals in the PRA affected pedigrees for a previously identified GNAT1 restriction fragment length polymorphism (RFLP). RESULTS: The sequence of canine GNAT1 cDNA is reported (GenBank accession no. U65376). Over the coding region, the canine GNAT1 cDNA sequence presented here shares 92-95% identity with human, bovine and murine sequences. The canine cDNA encodes a polypeptide of 350 amino acids; its theoretical translation is 98-99% identical with the corresponding GNAT1 sequence from each of the other 3 species and it has no unique amino acids. In rcd2 and erd pedigrees informative for both the disease locus and the GNAT1 Nci I RFLP, a minimum of 3 and 2 recombinants were identified, respectively. Similarly, in a prcd pedigree, 3 of 7 progeny informative for both prcd and this RFLP were obligate recombinants. CONCLUSIONS: The canine GNAT1 gene has been excluded as a candidate for prcd, erd and rcd2. Sequence information of canine GNAT1 gene will enable testing this locus as a candidate in other canine hereditary retinal degenerations.

Amino Acid Sequence↗

PubMed2005

Ischemic preconditioning-mediated cardioprotection is disrupted in heterozygous Flt-1 (VEGFR-1) knockout mice.

This study attempts to address an important clinical issue by identifying potential candidates of VEGF signaling through Flt-1 receptor that trigger angiogenic signal under ischemic stress. To determine the significance of VEGF-Flt-1 (VEGFR1) signaling in ischemic preconditioned (PC) myocardium, we used heterozygous Flt-1 knockout (KO) mice to dissect the pathway and identify candidate genes involved in VEGF signaling. DNA microarrays were employed to detect, characterize and distinguish altered myocardial gene expression by comparing between wild type (WT) CD-1 and heterozygous Flt-1 KO mice when exposed to ischemia (30 min) and reperfusion (2 h). Moreover, KO mice demonstrated reduced beneficial effects of PC when compared to the WT with PC. In the KO and WT mice, the % recovery of the left ventricular developed pressure and the maximum first derivative of the developed pressure after ischemia/reperfusion without PC were similar. However, when animals were subjected to PC, the left ventricular functional recovery throughout the reperfusion period was significantly lower in KO mice than in WT mice. These results indicate for the first time that in the heterozygous Flt-1 KO mice, PC is not as effective as that found in WT. This observation may be due to downregulation of several important genes such as growth-regulated oncogene 1 (Gro1), heat shock proteins (HSP), I kappa B kinase beta (IKK beta), colony-stimulating factor-1 (CSF-1) and annexin A7, suggesting the importance of VEGF-Flt-1 receptor signaling during PC.

Animals↗

PubMed2004

p73alpha is a candidate effector in the p53 independent apoptosis pathway of cisplatin damaged primary murine colonocytes.

AIMS: Colonocytes were derived from wild-type (wt) and p53 deficient mice to investigate p53 dependent and independent death pathways after cisplatin treatment, and the role of p53 in growth regulation of primary, untransformed epithelial cells. METHODS: Wt and p53 null colonocytes were exposed to cisplatin and DNA synthesis, apoptosis, and p53, p21, and p73 expression were investigated after six, 12, and 24 hours. Major p73 isoforms were identified by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Cisplatin treated wt cells exhibited cell cycle arrest, whereas p53 null cells continued to synthesise DNA, although both cell types died. Apoptosis was significantly higher in cisplatin treated wt and p53 null colonocytes than in controls at all timepoints, although apoptosis was lower in cisplatin treated p53 null colonocytes than in wt cells. p53 expression was upregulated in cisplatin treated wt colonocytes. p21 expression was high and remained unchanged in cisplatin treated wt cells, although it was reduced in the absence of p53. p73 was investigated because it could account for p53 independent p21 expression and p53 independent death. RT-PCR detected full length p73alpha. p73 transcript levels remained unchanged, whereas p73 protein accumulated in the nucleus of cisplatin treated cells, irrespective of genotype. CONCLUSIONS: p53 is essential for cell cycle arrest, but not apoptosis in primary murine colonocytes. Apoptosis is reduced in cisplatin treated p53 null cells. Nuclear accumulation of endogenous p73 after cisplatin treatment suggests a proapoptotic role for p73alpha in the absence of p53 and collaboration with p53 in wt colonocytes.

Animals↗

PubMed2005

[SFRP, a family of new colorectal tumor suppressor candidate genes].

Aberrant Wnt pathway signaling is an early progression event in up to 90% of colorectal cancers (CRC). It occurs mainly through mutations of APC or beta-catenin. We have identified frequent promoter hypermethylation and gene silencing of the secreted frizzled-related protein (SFRP) genes in CRC. SFRPs possess a domain similar to one in the Wnt receptor Frizzled proteins and can inhibit Wnt receptor binding to downregulate pathway signaling in development. We next found that restoration of SFRP function in CRC cells attenuates Wnt signaling even in the presence of downstream mutations. We also show that the epigenetic loss of SFRP function occurs early in CRC progression and may, thus, provide constitutive Wnt signaling which is required to complement downstream mutations in the evolution of CRC.

Colorectal Neoplasms↗

PubMed2006

Profiling genetic variation along the androgen biosynthesis and metabolism pathways implicates several single nucleotide polymorphisms and their combinations as prostate cancer risk factors.

Several candidate genes along androgen pathway have been suggested to affect prostate cancer risk but no single gene seems to be overwhelmingly important for a large fraction of the patients. In this study, we first screened for variants in candidate genes and then chose to explore the association between 18 variants and prostate cancer risk by genotyping DNA samples from unselected (n = 847) and familial (n = 121) prostate cancer patients and population controls (n = 923). We identified a novel single nucleotide polymorphism (SNP) in the CYP19A1 gene, T201M, with a mild significant association with prostate cancer [odds ratio (OR), 2.04; 95% confidence interval (95% CI), 1.03-4.03; P = 0.04]. Stratified analysis revealed that this risk was most apparent in patients with organ-confined (T(1)-T(2)) and low-grade (WHO grade 1) tumors (OR, 5.42; 95% CI, 2.33-12.6; P < 0.0001). In contrast, CYP17A1 -34T>C alteration was associated with moderate to poorly differentiated (WHO grade 2-3) organ-confined disease (OR, 1.42; 95% CI, 1.09-1.83; P = 0.007). We also tested a multigenic model of prostate cancer risk by calculating the joint effect of CYP19A1 T201M with five other common SNPs. Individuals carrying both the CYP19A1 and KLK3 -252A>G variant alleles had a significantly increased risk for prostate cancer (OR, 2.87; 95% CI, 1.10-7.49; P = 0.03). In conclusion, our results suggest that several SNPs along the androgen pathway, especially in CYP19A1 and CYP17A1, may influence prostate cancer development and progression. These genes may have different contributions to distinct clinical subsets as well as combinatorial effects in others illustrating that profiling and joint analysis of several genes along each pathway may be needed to understand genetic contributions to prostate cancer etiology.

Aged↗

PubMed2002

From Zebrafish to human: modular medical models.

Genetic screens in Drosophila melanogaster, Caenorhabditis elegans, and Danio rerio clarified the logic of metazoan development by revealing critical unitary steps and pathways to embryogenesis. Can genetic screens similarly organize medicine? We here examine human diseases that resemble mutations in Danio rerio, the zebrafish, the one vertebrate species for which large-scale genetic screens have been performed and extensively analyzed. Zebrafish mutations faithfully phenocopy many human disorders. Each mutation, once cloned, provides candidate genes and pathways for evaluation in the human. The collection of mutations in their entirety potentially provides a medical taxonomy, one based in developmental biology and genetics.

Animals↗

PubMed1999

Terminals of paraventricular spinal neurones are closely associated with adrenal medullary sympathetic preganglionic neurones: immunocytochemical evidence for vasopressin as a possible neurotransmitter in this pathway.

A recent study using transsynaptically transported pseudorabies virus, injected into the adrenal gland, showed labelled neurones in the paraventricular nucleus (PVN) of the hypothalamus, indicating that these neurones send projections to sympathoadrenal preganglionic neurones (SPNs). However, this technique cannot conclusively demonstrate that the pathway is monosynaptic. In order to investigate the possibility of a direct projection from the PVN to SPNs, the present study used the anterograde tracer biotin dextran amine to label paraventricular spinal projections and the retrograde tracer cholera toxin B conjugated to horseradish peroxidase to label SPNs. In addition, because electrophysiological evidence suggests vasopressin to be a neurotransmitter candidate in this pathway, immunocytochemical identification of the peptide and retrograde labelling of SPNs to the adrenal medulla were used to investigate this. The results of these studies show spinally projecting paraventricular axons with terminal varicosities closely associated with SPNs. Therefore some of these associations may represent boutons forming synaptic contact on SPNs. Similarly, vasopressin fibres were found close to the dendrites and soma of SPNs. It is suggested that spinal axons originating from paraventricular neurones can provide a direct influence on adrenal medullary function, that vasopressin is a possible neurotransmitter involved in some of these connections and this is one means by which the paraventricular nucleus can generate a defence to stressful stimuli.

Adrenal Medulla↗

PubMedDate not supplied

Induction of allograft tolerance through costimulatory blockade: first selection of drugs in vitro.

The development of an in vitro assay predicting the chances of graft survival after treatment with immunoregulatory agents is a major topic in transplantation. Antibodies (Abs) interfering in the costimulatory pathway are promising candidates for the induction of tolerance. To evaluate these antibodies for clinical use studies non-human primates are the only feasible option due to species specificity of the antibodies. Peripheral blood mononuclear cells, isolated from a large panel of rhesus monkeys, were used in a unidirectional mixed lymphocyte reaction to evaluate the ability of antibodies blocking the costimulatory pathway, to affect both primary and secondary proliferative and cytolytic allospecific immune responses in vitro. These blocking antibodies were also used in protocols prolonging allograft survival in a life-supporting kidney allotransplant model in rhesus macaques. The ultimate aim is to establish a correlation between parameters obtained in vitro and the success of transplantation in vivo. The combination of anti-CD80 and anti-CD86 resulted in a complete abrogation of the primary alloresponse as measured in a proliferation assay. Adding anti-CD40 significantly reduced this inhibitory effect although the in vivo effects of this antibody have been shown to be beneficial. The secondary response was most prominently inhibited by the combination of anti-CD80/86. Paradoxically, anti-CD40 alone markedly inhibited the secondary proliferative response, but did not add to the inhibitory effect of the combination of anti-CD80/86. The cytolytic response was inhibited maximally only when CsA was added to the combination of anti-CD80/86. Treatment with monoclonal antibodies alone without immunosuppressive drugs was sufficient to maintain graft survival during the time of treatment in most animals. However, rejection was initiated as soon as the treatment ceased and no tolerance, resulting in long-term graft and patient survival, was established. The complete inhibition of primary alloresponses and the partial inhibition of secondary proliferative alloresponses correlate with prolonged graft survival during treatment, but have no predictive value for the success of tolerance induction for kidney allografts in rhesus monkeys.

Animals↗

PubMed1996

Affinity modulation of the platelet integrin alpha IIb beta 3 by alpha-chymotrypsin: a possible role for Na+/Ca2+ exchanger.

In the present study, we have investigated the mechanism of affinity modulation of alpha IIb beta 3 by chymotrypsin. We first confirmed that alpha-chymotrypsin could activate alpha IIb beta 3 (approximately 7,000 molecules per platelet) without major intracellular signaling. However, we unexpectedly found that high concentrations of amiloride dose-dependently inhibited 125I-fibrinogen binding to the chymotrypsin-treated platelets, as well as the platelet aggregation (IC50 [50% inhibitory concentration] for fibrinogen binding, 530 mumol/L). In contrast, amiloride did not inhibit alpha IIb beta 3 activation induced by anti-alpha IIb beta 3 monoclonal antibody PT25-2 or AP5. To identify the pathway involved, the effects of alteration of Na+ gradient in platelets were examined. Lowering Na+ gradient by replacing extracellular Na+ with tetramethylammonium (TMA) increased the number of activated alpha IIb beta 3 by twofold, as assessed by fibrinogen-binding assay. The incubation of platelets with ouabain, a Na+/K(+)-adenosine triphosphatase (ATPase) inhibitor, further augmented alpha IIb beta 3 activation. These data suggested that a likely candidate for the pathway was Na+/Ca2+ exchanger. At 140 mmol/L [Na+]o, 45Ca2+ influx to the chymotrypsin-treated platelets was twofold greater than that to non-treated platelets. Replacement of Na+ with TMA further increased the Ca2+ influx, and the increase was inhibited by amiloride dose-dependently. 3',4'-Dichlorobenzamil (DCB) and bepridil, relatively specific inhibitors of Na+/Ca2+ exchanger, also inhibited the chymotrypsin-induced alpha IIb beta 3 activation, and the IC50 values of these inhibitors for fibrinogen binding were 25 mumol/L and 52 mumol/L, respectively. Moreover, platelet aggregation induced by various physiologic agonists was inhibited by DCB or bepridil, while platelet agglutination by ristocetin was not. Our data newly suggest that Na+/Ca2+ exchanger operating in reverse mode may be directly involved in inside-out signaling that activates alpha IIb beta 3.

Amiloride↗

PubMed1982

Non-cerebellar visual afferents to the vestibular nuclei involving the prepositus hypoglossal complex: an autoradiographic study in the rat.

Radioactive amino-acids were injected into the nucleus reticularis tegmenti pontis (NRTP) and the pretectum (PT) in the rat. Beside the labeling of the several nuclei which are known to receive afferents of either the NRTP and/or the PT, monosynaptic projections from these two structures to the prepositus hypoglossal complex (PHN) were demonstrated. Pretectal visual inputs to the vestibular nuclei (VN) may thus be conveyed not only by the classical PT-inferior olive-cerebellar route, but also by two other non-cerebellar ones involving the strong efferent projections of the PHN onto the VN. These last two pathways are strong candidates to account for the residual visual sensitivity of VN neurons after cerebellectomy or inferior olive lesions.

Animals↗

PubMed2005

The pathway to femaleness: current knowledge on embryonic development of the ovary.

Increasing evidence indicates that organogenesis of the ovary is not a passive process arising by default in the absence of the testis pathway. A coordinated interaction is actually in force between somatic cells and female germ cells in embryonic ovaries, thus creating a unique microenvironment that facilitates the formation of follicles. Identification of the functional roles of several novel regulatory elements such as Figalpha, Foxl2, follistatin, and Wnt4 reveals the complexity of early ovarian organization. Challenges await us to establish the molecular connections of these molecules as well as to discover new candidates in the pathway of early ovarian development.

Animals↗

PubMed2006

Gene prioritization through genomic data fusion.

The identification of genes involved in health and disease remains a challenge. We describe a bioinformatics approach, together with a freely accessible, interactive and flexible software termed Endeavour, to prioritize candidate genes underlying biological processes or diseases, based on their similarity to known genes involved in these phenomena. Unlike previous approaches, ours generates distinct prioritizations for multiple heterogeneous data sources, which are then integrated, or fused, into a global ranking using order statistics. In addition, it offers the flexibility of including additional data sources. Validation of our approach revealed it was able to efficiently prioritize 627 genes in disease data sets and 76 genes in biological pathway sets, identify candidates of 16 mono- or polygenic diseases, and discover regulatory genes of myeloid differentiation. Furthermore, the approach identified a novel gene involved in craniofacial development from a 2-Mb chromosomal region, deleted in some patients with DiGeorge-like birth defects. The approach described here offers an alternative integrative method for gene discovery.

Algorithms↗

PubMed2026

Multi-omics Investigations of Immune Microenvironment of Human Colorectal Cancer.

BACKGROUND/AIM: Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. Although immunotherapy has improved outcomes for a subset of patients, its limited efficacy in many cases highlights the need for a more comprehensive understanding of the CRC immune microenvironment. This study aimed to characterize the molecular landscape of the CRC immune microenvironment using an integrated multi-omics approach and to identify candidate regulatory molecules associated with immune remodelling. MATERIALS AND METHODS: We integrated structural variation, DNA methylation, chromatin accessibility, proteomic, and phosphoproteomic data generated from an in-house CRC cohort with transcriptomic data from The Cancer Genome Atlas (TCGA). Analyses focused on 1,539 immune-related genes (IRGs) associated with CD4+ T cells, B cells, and natural killer (NK) cells. Multi-layered genomic and proteomic analyses were performed to identify altered immune-related pathways, hub genes, candidate transcription factors, and upstream kinases. RESULTS: Higher infiltration of CD4+ T cells, B cells, and NK cells was associated with CRC. IRGs exhibited widespread alterations across genomic, epigenomic, transcriptomic, proteomic, and phosphoproteomic levels. IL10, LEP, ITGAM, and EGFR emerged as candidate hub genes. EGFR phosphorylation at S991 and T693 was significantly decreased in CRC. STAT2 and HSF1 were identified as candidate upstream transcription factors, while CDK2 emerged as a candidate upstream kinase associated with immune infiltration and immune checkpoint expression. CONCLUSION: This study provides a systematic multi-omics characterization of immune microenvironment remodelling in CRC and identifies candidate molecular regulators that may serve as potential targets for future immunotherapy research.

Humans↗

PubMed2002

Phorbol ester stimulates a protein kinase C-mediated agatoxin-TK-sensitive calcium permeability pathway in human red blood cells.

Calcium entry into mature erythrocytes (red blood cells; RBCs) is associated with multiple changes in cell properties. At low intracellular Ca(2+), efflux of potassium and water predominates, leading to changes in erythrocyte rheology. At higher Ca(2+) content, activation of kinases and phosphatases, rupture of membrane-to-skeleton bridges, stimulation of a phospholipid scramblase and phospholipase C, and induction of transglutaminase-mediated protein cross-linking are also observed. Because the physiologic relevance of these latter responses depends partially on whether Ca(2+) entry involves a regulated channel or nonspecific leak, we explored mechanisms that initiate controlled Ca(2+) influx. Protein kinase C (PKC) was considered a prime candidate for the pathway regulator, and phorbol-12 myristate-13 acetate (PMA), a stimulator of PKC, was examined for its influence on erythrocyte Ca(2+). PMA was found to stimulate a rapid, dose-dependent influx of calcium, as demonstrated by the increased fluorescence of an entrapped Ca(2+)-sensitive dye, Fluo-3/AM. The PMA-induced entry was inhibited by staurosporine and the PKC-selective inhibitor chelerythrine chloride, but was activated by the phosphatase inhibitors okadaic acid and calyculin A. The PMA-promoted calcium influx was also inhibited by omega-agatoxin-TK, a calcium channel blocker specific for Ca(v)2.1 channels. To confirm that a Ca(v)2.1-like calcium channel exists in the mature erythrocyte membrane, RBC membrane preparations were immunoblotted with antiserum against the alpha(1A) subunit of the channel. A polypeptide of the expected molecular weight (190 kDa) was visualized. These studies indicate that an omega-agatoxin-TK-sensitive, Ca(v)2.1-like calcium permeability pathway is present in the RBC membrane and that it may function under the control of kinases and phosphatases.

Adult↗

PubMed2000

Huntingtin: an iron-regulated protein essential for normal nuclear and perinuclear organelles.

Huntington's disease (HD), with its selective neuronal cell loss, is caused by an elongated glutamine tract in the huntingtin protein. To discover the pathways that are candidates for the protein's normal and/or abnormal function, we surveyed 19 classes of organelle in Hdh(ex4/5)/Hdh(ex4/5) knock-out compared with wild-type embryonic stem cells to identify any that might be affected by huntingtin deficiency. Although the majority did not differ, dramatic changes in six classes revealed that huntingtin's function is essential for the normal nuclear (nucleoli, transcription factor-speckles) and perinuclear membrane (mitochondria, endoplasmic reticulum, Golgi and recycling endosomes) organelles and for proper regulation of the iron pathway. Moreover, upmodulation by deferoxamine mesylate implicates huntingtin as an iron-response protein. However, excess huntingtin produced abnormal organelles that resemble the deficiency phenotype, suggesting the importance of huntingtin level to the protein's normal pathway. Thus, organelles that require huntingtin to function suggest roles for the protein in RNA biogenesis, trafficking and iron homeostasis to be explored in HD pathogenesis.

Active Transport, Cell Nucleus↗

PubMed2004

Autoimmune regulator induced changes in the gene expression profile of human monocyte-dendritic cell-lineage.

The autoimmune regulator (AIRE) is a transcriptional regulator expressed in the thymic medullary epithelial cells and in the cells of the monocyte-dendritic lineage both in the thymus and in the secondary lymphoid organs. Mutations in the AIRE gene cause autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a recessively inherited disease characterized by loss of immunological self-tolerance to multiple endocrine organs. Recent mouse knockout studies suggest that AIRE is responsible for ectopic expression of peripheral self-antigens in the thymus. In the present study, we detected an increased level of endogenous AIRE expression during the differentiation process of the human monocyte derived dendritic cells (MoDCs). We subsequently identified candidates for AIRE-regulated genes by using cDNA microarray technology to analyse the changes in the gene expression profile brought about by overexpressing the AIRE protein in the monocytic U937 cells. The changes observed resembled those previously reported to occur during the maturation of DCs, including up-regulation of the CCL22, CD25, ICAM-1 and RelB genes. In contrast, increased expression of the steroidogenic enzymes P450c17, P450c21 and P450scc, the major autoantigens in APECED, was not found either in our cell model or in the dendritic cell cultures. We also identified the ERK signal transduction pathway as a candidate for mediating the signal that results in the altered expression profile. Our findings suggest that the role of AIRE in the DCs differs from its function in the thymus.

Cell Differentiation↗

PubMed2000

Dominant phenotypes produced by the HD mutation in STHdh(Q111) striatal cells.

Lengthening a glutamine tract in huntingtin confers a dominant attribute that initiates degeneration of striatal neurons in Huntington's disease (HD). To identify pathways that are candidates for the mutant protein's abnormal function, we compared striatal cell lines established from wild-type and Hdh(Q111) knock-in embryos. Alternate versions of full-length huntingtin, distinguished by epitope accessibility, were localized to different sets of nuclear and perinuclear organelles involved in RNA biogenesis and membrane trafficking. However, mutant STHdh(Q111) cells also exhibited additional forms of the full-length mutant protein and displayed dominant phenotypes that did not mirror phenotypes caused by either huntingtin deficiency or excess. These phenotypes indicate a disruption of striatal cell homeostasis by the mutant protein, via a mechanism that is separate from its normal activity. They also support specific stress pathways, including elevated p53, endoplasmic reticulum stress response and hypoxia, as potential players in HD.

Animals↗

PubMed2005

Transcriptome analysis of the Mg2+-responsive PhoP regulator in Yersinia pestis.

PhoP was previously shown to be important for Yersinia pestis survival in macrophage and under macrophage-induced stresses. In this work, a phoP disruptant of Y. pestis 201 was generated using the Red cloning procedure. The transcription profile of the wild-type Y. pestis was then compared with that of the phoP mutant under Mg2+-limiting conditions. It was revealed that PhoP/PhoQ governed a wide set of cellular pathways in Y. pestis, especially including the positive regulation of many metabolic processes, Mg2+ transport, peptidoglycan remodeling, lipopolysaccharide (LPS) modification and various stress-protective functions. The Mg2+ transport system regulated by PhoP may make Y. pestis to maintain the magnesium homeostasis under low Mg2+ environments. The PhoP-controlled stress-protective functions likely constitute the molecular basis for the observation that mutation of the phoP gene rendered the bacteria more sensitive to various macrophage-induced stresses. Modification of LPS mediated by PhoP is hypothesized to not only neutralize negative charges as normally done by Mg2+ ions, but also mediate the resistance of Y. pestis to antimicrobial peptides. The microarray results provide a population of candidate genes or pathways, and further biochemical experiments are needed to elucidate the PhoP-dependent mechanisms by which Y. pestis survives the antibacterial strategies employed by host macrophages.

Animals↗