scholarly journals Role of Plasminogen in Propagation of Scrapie

2005 ◽  
Vol 79 (17) ◽  
pp. 11225-11230 ◽  
Author(s):  
Mario Salmona ◽  
Raffaella Capobianco ◽  
Laura Colombo ◽  
Ada De Luigi ◽  
Giacomina Rossi ◽  
...  
Keyword(s):  
Immunohistochemical Analysis ◽  
Major Effect ◽  
Lymphoid Cells ◽  
Wild Type ◽  
Scrapie Agent ◽  
Significant Difference ◽  
Scrapie Strain ◽  
Scrapie Infection ◽  
The Brain

ABSTRACT To investigate whether plasminogen may feature in scrapie infection, we inoculated plasminogen-deficient (Plg−/−), heterozygous plasminogen-deficient (Plg+/−), and wild-type (Plg+/+) mice by the intracerebral or intraperitoneal (i.p.) route with the RML scrapie strain and monitored the onset of neurological signs of disease, survival time, brain, and accumulation of scrapie disease-associated forms of the prion protein (PrPSc). Only after i.p. inoculation, a slight, although significant, difference in survival (P < 0.05) between Plg−/− and Plg+/+ mice was observed. Neuropathological examination and Western blot analysis were carried out when the first signs of disease appeared in Plg+/+ animals (175 days after i.p. inoculation) and when mice reached the terminal stage of illness. At the onset of symptoms, PrPSc accumulation was higher in the brain and spleen of Plg+/+ and Plg+/− mice than in those of Plg−/− mice, and these differences were paralleled by differences in the severity of spongiform changes and astrogliosis in the cerebral cortex and subcortical gray structures. Immunohistochemical analysis of the spleens before inoculation did not show any impairment of the immune system affecting follicular dendritic or lymphoid cells in Plg−/− mice. Once the disease progressed and mice began to die of infection, differences were no longer apparent in either brains or spleens. In conclusion, our data indicate that plasminogen has no major effect on the survival of scrapie agent-infected mice.

The development of the sensory neuron pattern in the antennal disc of wild-type and mutant (lz3, ssa) Drosophila melanogaster

Development ◽  
1991 ◽  
Vol 112 (4) ◽  
pp. 1063-1075
Author(s):  
M.C. Lienhard ◽  
R.F. Stocker
Keyword(s):  
Drosophila Melanogaster ◽  
Sensory Neuron ◽  
Antennal Segment ◽  
Wild Type ◽  
Homeotic Mutant ◽  
In The Wild ◽  
The Brain ◽  
Antennal Disc ◽  
Antennal Nerve

The development of the sensory neuron pattern in the antennal disc of Drosophila melanogaster was studied with a neuron-specific monoclonal antibody (22C10). In the wild type, the earliest neurons become visible 3 h after pupariation, much later than in other imaginal discs. They lie in the center of the disc and correspond to the neurons of the adult aristal sensillum. Their axons join the larval antennal nerve and seem to establish the first connection towards the brain. Later on, three clusters of neurons appear in the periphery of the disc. Two of them most likely give rise to the Johnston's organ in the second antennal segment. Neurons of the olfactory third antennal segment are formed only after eversion of the antennal disc (clusters t1-t3). The adult pattern of antennal neurons is established at about 27% of metamorphosis. In the mutant lozenge3 (lz3), which lacks basiconic antennal sensilla, cluster t3 fails to develop. This indicates that, in the wild type, a homogeneous group of basiconic sensilla is formed by cluster t3. The possible role of the lozenge gene in sensillar determination is discussed. The homeotic mutant spineless-aristapedia (ssa) transforms the arista into a leg-like tarsus. Unlike leg discs, neurons are missing in the larval antennal disc of ssa. However, the first neurons differentiate earlier than in normal antennal discs. Despite these changes, the pattern of afferents in the ectopic tarsus appears leg specific, whereas in the non-transformed antennal segments a normal antennal pattern is formed. This suggests that neither larval leg neurons nor early aristal neurons are essential for the outgrowth of subsequent afferents.

Abstract MP06: Kinin B1 Receptor Mediates Orexin System Hyperactivity In Salt-sensitive Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Rohan U Parekh ◽  
Abdel A Abdel-rahman ◽  
Srinivas Sriramula
Keyword(s):  
Radio Telemetry ◽  
Mrna Levels ◽  
Wild Type ◽  
Salt Treatment ◽  
Neurogenic Hypertension ◽  
B1 Receptor ◽  
Kinin B1 Receptor ◽  
Salt Sensitive Hypertension ◽  
The Brain

Hyperactivity of the orexin system contributes to several animal models of hypertension and enhances arginine vasopressin (AVP) release. We previously reported higher neuronal kinin B1 receptor (B1R) expression and brain AVP levels in hypertensive mice. However, the role of B1R and its interaction with orexin system in neurogenic hypertension have not been studied. In the present study, we tested the hypothesis that kinin B1R contributes to hypertension by upregulation of orexin-AVP signaling in the brain. Deoxycorticosterone acetate (DOCA)-salt treatment (1 mg/g body weight DOCA, 1% saline in drinking water, 3 weeks) of wild-type (WT) male mice produced a significant increase in mean arterial pressure (MAP; radio-telemetry) (138 ±3 mmHg, n=8, p<0.01) that was blunted in B1R knockout mice (121±2 mmHg, P <0.05 vs. WT+DOCA). In WT mice, DOCA-salt, compared to vehicle, increased mRNA levels of orexin receptor 1 (2.5 fold, n=9, p<0.001), orexin receptor 2 (3 fold, n=9, p<0.001) and AVP (3 fold, n=9, p<0.01) in the hypothalamic paraventricular nucleus (PVN), and these DOCA-salt evoked effects were attenuated in B1RKO mice. Similarly, DOCA-salt evoked increases in protein expression of orexin receptor 1 and 2 in the hypothalamic PVN of WT mice were attenuated by 25±5% and 33±5% (p<0.05), respectively, in B1RKO vs WT+DOCA mice. Furthermore, DOCA-salt treatment increased plasma AVP levels in WT mice compared to vehicle treated mice (13.69±1.1 vs. 47.86±8.7 pg/ml, p<0.05), but not in B1RKO mice. Together, these data provide novel evidence that kinin B1R plays an important role in mediating DOCA-salt induced hypertension possibly via upregulating the orexin-AVP signaling in the brain.

scholarly journals Diagnostic and Treatment Approaches Involving Transthyretin in Amyloidogenic Diseases

2019 ◽  
Vol 20 (12) ◽  
pp. 2982 ◽  
Author(s):  
Gil Yong Park ◽  
Angelo Jamerlan ◽  
Kyu Hwan Shim ◽  
Seong Soo A. An
Keyword(s):  
Cerebrospinal Fluid ◽  
Genetic Mutations ◽  
Hormone Binding ◽  
Wild Type ◽  
Autonomic Motor ◽  
Hormone Binding Protein ◽  
The Brain ◽  
Tetrameric Form

Transthyretin (TTR) is a thyroid hormone-binding protein which transports thyroxine from the bloodstream to the brain. The structural stability of TTR in tetrameric form is crucial for maintaining its original functions in blood or cerebrospinal fluid (CSF). The altered structure of TTR due to genetic mutations or its deposits due to aggregation could cause several deadly diseases such as cardiomyopathy and neuropathy in autonomic, motor, and sensory systems. The early diagnoses for hereditary amyloid TTR with cardiomyopathy (ATTR-CM) and wild-type amyloid TTR (ATTRwt) amyloidosis, which result from amyloid TTR (ATTR) deposition, are difficult to distinguish due to the close similarities of symptoms. Thus, many researchers investigated the role of ATTR as a biomarker, especially its potential for differential diagnosis due to its varying pathogenic involvement in hereditary ATTR-CM and ATTRwt amyloidosis. As a result, the detection of ATTR became valuable in the diagnosis and determination of the best course of treatment for ATTR amyloidoses. Assessing the extent of ATTR deposition and genetic analysis could help in determining disease progression, and thus survival rate could be improved following the determination of the appropriate course of treatment for the patient. Here, the perspectives of ATTR in various diseases were presented.

OmpD but not OmpC is involved in adherence ofSalmonella entericaserovar Typhimurium to human cells

2004 ◽  
Vol 50 (9) ◽  
pp. 719-727 ◽  
Author(s):  
Bochiwe Hara-Kaonga ◽  
Thomas G Pistole
Keyword(s):  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Human Cells ◽  
Host Cells ◽  
Intestinal Epithelial ◽  
Wild Type ◽  
Human Macrophages ◽  
Significant Difference ◽  
Serovar Typhimurium

Conflicting reports exist regarding the role of porins OmpC and OmpD in infections due to Salmonella enterica serovar Typhimurium. This study investigated the role of these porins in bacterial adherence to human macrophages and intestinal epithelial cells. ompC and ompD mutant strains were created by transposon mutagenesis using P22-mediated transduction of Tn10 and Tn5 insertions, respectively, into wild-type strain 14028. Fluorescein-labeled wild-type and mutant bacteria were incubated with host cells at various bacteria to cell ratios for 1 h at 37 °C and analyzed by flow cytometry. The mean fluorescence intensity of cells with associated wild-type and mutant bacteria was used to estimate the number of bacteria bound per host cell. Adherence was also measured by fluorescence microscopy. Neither assay showed a significant difference in binding of the ompC mutant and wild-type strains to the human cells. In contrast, the ompD mutant exhibited lowered binding to both cell types. Our findings suggest that OmpD but not OmpC is involved in the recognition of Salmonella serovar Typhimurium by human macrophages and intestinal epithelial cells.Key words: Salmonella, adherence, porins, intestinal epithelial cells, macrophage.

scholarly journals GPR110 (ADGRF1) mediates anti-inflammatory effects of N-docosahexaenoylethanolamine

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Taeyeop Park ◽  
Huazhen Chen ◽  
Hee-Yong Kim
Keyword(s):  
Inflammatory Cytokine ◽  
Inflammatory Responses ◽  
Cytokine Expression ◽  
Regulatory Function ◽  
Enzyme Linked Immunosorbent Assay ◽  
Inflammatory Condition ◽  
Wild Type ◽  
Knock Out ◽  
The Brain

Abstract Background Neuroinflammation is a widely accepted underlying condition for various pathological processes in the brain. In a recent study, synaptamide, an endogenous metabolite derived from docosahexaenoic acid (DHA, 22:6n-3), was identified as a specific ligand to orphan adhesion G-protein-coupled receptor 110 (GPR110, ADGRF1). Synaptamide has been shown to suppress lipopolysaccharide (LPS)-induced neuroinflammation in mice, but involvement of GPR110 in this process has not been established. In this study, we investigated the possible immune regulatory role of GPR110 in mediating the anti-neuroinflammatory effects of synaptamide under a systemic inflammatory condition. Methods For in vitro studies, we assessed the role of GPR110 in synaptamide effects on LPS-induced inflammatory responses in adult primary mouse microglia, immortalized murine microglial cells (BV2), primary neutrophil, and peritoneal macrophage by using quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA) as well as neutrophil migration and ROS production assays. To evaluate in vivo effects, wild-type (WT) and GPR110 knock-out (KO) mice were injected with LPS intraperitoneally (i.p.) or TNF intravenously (i.v.) followed by synaptamide (i.p.), and expression of proinflammatory mediators was measured by qPCR, ELISA, and western blot analysis. Activated microglia in the brain and NF-kB activation in cells were examined microscopically after immunostaining for Iba-1 and RelA, respectively. Results Intraperitoneal (i.p.) administration of LPS increased TNF and IL-1β in the blood and induced pro-inflammatory cytokine expression in the brain. Subsequent i.p. injection of the GPR110 ligand synaptamide significantly reduced LPS-induced inflammatory responses in wild-type (WT) but not in GPR110 knock-out (KO) mice. In cultured microglia, synaptamide increased cAMP and inhibited LPS-induced proinflammatory cytokine expression by inhibiting the translocation of NF-κB subunit RelA into the nucleus. These effects were abolished by blocking synaptamide binding to GPR110 using an N-terminal targeting antibody. GPR110 expression was found to be high in neutrophils and macrophages where synaptamide also caused a GPR110-dependent increase in cAMP and inhibition of LPS-induced pro-inflammatory mediator expression. Intravenous injection of TNF, a pro-inflammatory cytokine that increases in the circulation after LPS treatment, elicited inflammatory responses in the brain which were dampened by the subsequent injection (i.p.) of synaptamide in a GPR110-dependent manner. Conclusion Our study demonstrates the immune-regulatory function of GPR110 in both brain and periphery, collectively contributing to the anti-neuroinflammatory effects of synaptamide under a systemic inflammatory condition. We suggest GPR110 activation as a novel therapeutic strategy to ameliorate inflammation in the brain as well as periphery.

scholarly journals Enhanced Hippocampal CA1 LTP but Normal Spatial Learning in Inositol 1,4,5-trisphosphate 3-kinase(A)-Deficient Mice

1998 ◽  
Vol 5 (4) ◽  
pp. 317-330 ◽  
Author(s):  
Kisun Jun ◽  
Gildon Choi ◽  
Sung-Gu Yang ◽  
Kwan Yong Choi ◽  
Hyun Kim ◽  
...  
Keyword(s):  
Spatial Learning ◽  
Mutant Mice ◽  
Wild Type ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Hippocampal Ca1 ◽  
Morris Water Maze Task ◽  
Significant Difference ◽  
Kinase A

To define the physiological role of IP33-kinase(A) in vivo, we have generated a mouse strain with a null mutation of the IP33-kinase(A) locus by gene targeting. Homozygous mutant mice were fully viable, fertile, apparently normal, and did not show any morphological anomaly in brain sections. In the mutant brain, the IP4 level was significantly decreased whereas the IP3 level did not change, demonstrating a major role of IP33-kinase(A) in the generation of IP4. Nevertheless, no significant difference was detected in the hippocampal neuronal cells of the wild-type and the mutant mice in the kinetics of Ca2+ regulation after glutamate stimulation. Electrophysiological analyses carried out in hippocampal slices showed that the mutation significantly enhanced the LTP in the hippocampal CA1 region, but had no effect on the LTP in dentate gyrus (DG). No difference was noted, however, between the mutant and the wild-type mice in the Morris water maze task. Our results indicate that IP33-kinase(A) may play an important role in the regulation of LTP in hippocampal CA1 region through the generation of IP4, but the enhanced LTP in the hippocampal CA1 does not affect spatial learning and memory.

Neuroretinal Dysfunctions in Regular Cannabis Users: An Impact of Cannabis on Retinal Neurotransmission?

2017 ◽  
Vol 41 (S1) ◽  
pp. S638-S638
Author(s):  
T. Schwitzer ◽  
R. Schwan ◽  
A. Giersch ◽  
E. Albuisson ◽  
K. Angioi-Duprez ◽  
...  
Keyword(s):  
Ganglion Cells ◽  
Endocannabinoid System ◽  
Implicit Time ◽  
Significant Difference ◽  
Transmission Of Information ◽  
Competing Interest ◽  
On And Off Pathways ◽  
The Waves ◽  
The Brain

IntroductionAlthough cannabis is very widespread worldwide, its brain toxicity is poorly understood. The neuroretina is an accessible extension of the brain and could be a relevant site for investigating neurotransmission abnormalities in neuropsychiatric disorders. The retina has a functional endocannabinoid system involved in the regulation of retinal neurotransmission. In animals, the modulation of this system led to retinal dysfunctions measured with the electroretinogram (ERG).ObjectivesTo assess whether the regular cannabis use could affect the neuroretinal function.AimsAssessments of the neuroretinal function in cannabis users compared with controls.MethodsRecordings of pattern, flash and on-off ERG were performed in 55 cannabis users and 29 controls. The amplitude and implicit time of the following waves were evaluated: N95 (pattern); a – and b – (flash); a –, b- and d1 – (on-off).ResultsCannabis users showed a significant increase in implicit time of the waves N95 (P = 0.0001), a- (P = 0.029) and b – (P = 0.002) for the flash ERG and b – (P = 0.016) and d1 – (P = 0.027) for the on-off ERG, compared with controls. No significant difference was found between groups in terms of wave's amplitudes.ConclusionsThese results show a delay in the response of cones, bipolar and ganglion cells of the on and off pathways to constitute a delay of ≈ 6 ms in the transmission of information from the retina to the brain in cannabis users. Cannabis could disrupt the regulatory role of the cannabinoid system and impair retinal glutamatergic neurotransmission. The consequences on visual perception should be explored in future studies.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals Influence of thePhotorhabdus luminescensPhosphomannose Isomerase Gene,manA, on Mannose Utilization, Exopolysaccharide Structure, and Biofilm Formation

2010 ◽  
Vol 77 (3) ◽  
pp. 776-785 ◽  
Author(s):  
Matthew R. Amos ◽  
Maria Sanchez-Contreras ◽  
Robert W. Jackson ◽  
Xavier Muñoz-Berbel ◽  
Todd A. Ciche ◽  
...  
Keyword(s):  
Biofilm Formation ◽  
Wild Type Strain ◽  
Compositional Analysis ◽  
Extracellular Polysaccharide ◽  
Major Effect ◽  
Photorhabdus Luminescens ◽  
Wild Type ◽  
Abiotic Surfaces ◽  
Structural Matrix

ABSTRACTExtracellular polysaccharide (EPS) is produced by diverse bacterial pathogens and fulfills assorted roles, including providing a structural matrix for biofilm formation and more specific functions in virulence, such as protection against immune defenses. We report here the first investigation of some of the genes important for biofilm formation inPhotorhabdus luminescensand demonstrate the key role of the phosphomannose isomerase gene,manA, in the structure of functional EPS. Phenotypic analyses of amanA-deficient mutant showed the importance of EPS in motility, insect virulence, and biofilm formation on abiotic surfaces as well as the requirement of this gene for the use of mannose as the sole carbon source. Conversely, this defect had no apparent impact on symbiosis with the heterorhabditid nematode vector. A more detailed analysis of biofilm formation revealed that themanAmutant was able to attach to surfaces with the same efficiency as that of the wild-type strain but could not develop the more extended biofilm matrix structures. A compositional analysis ofP. luminescensEPS reveals how themanAmutation has a major effect on the formation of a complete, branched EPS.

scholarly journals Role of CheB and CheR in the Complex Chemotactic and Aerotactic Pathway of Azospirillum brasilense

2006 ◽  
Vol 188 (13) ◽  
pp. 4759-4768 ◽  
Author(s):  
Bonnie B. Stephens ◽  
Star N. Loar ◽  
Gladys Alexandre
Keyword(s):  
Escherichia Coli ◽  
Steady State ◽  
Azospirillum Brasilense ◽  
Model Organism ◽  
Spatial Gradient ◽  
Wild Type ◽  
Temporal Gradient ◽  
E Coli ◽  
Significant Difference

ABSTRACT It has previously been reported that the alpha-proteobacterium Azospirillum brasilense undergoes methylation-independent chemotaxis; however, a recent study revealed cheB and cheR genes in this organism. We have constructed cheB, cheR, and cheBR mutants of A. brasilense and determined that the CheB and CheR proteins under study significantly influence chemotaxis and aerotaxis but are not essential for these behaviors to occur. First, we found that although cells lacking CheB, CheR, or both were no longer capable of responding to the addition of most chemoattractants in a temporal gradient assay, they did show a chemotactic response (albeit reduced) in a spatial gradient assay. Second, in comparison to the wild type, cheB and cheR mutants under steady-state conditions exhibited an altered swimming bias, whereas the cheBR mutant and the che operon mutant did not. Third, cheB and cheR mutants were null for aerotaxis, whereas the cheBR mutant showed reduced aerotaxis. In contrast to the swimming bias for the model organism Escherichia coli, the swimming bias in A. brasilense cells was dependent on the carbon source present and cells released methanol upon addition of some attractants and upon removal of other attractants. In comparison to the wild type, the cheB, cheR, and cheBR mutants showed various altered patterns of methanol release upon exposure to attractants. This study reveals a significant difference between the chemotaxis adaptation system of A. brasilense and that of the model organism E. coli and suggests that multiple chemotaxis systems are present and contribute to chemotaxis and aerotaxis in A. brasilense.

scholarly journals The mTOR Pathway in Platelets Contributes to the Pathophysiology of Experimental Cerebral Malaria

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 580-580
Author(s):  
Irina Portier ◽  
Frederik Denorme ◽  
Kimberly A Queisser ◽  
Yasuhiro Kosaka ◽  
Aaron C Petrey ◽  
...  
Keyword(s):  
Cerebral Malaria ◽  
Protein Translation ◽  
Mtor Pathway ◽  
Rna Seq ◽  
Wild Type ◽  
Advisory Committees ◽  
Experimental Cerebral Malaria ◽  
Inflammatory Monocytes ◽  
The Brain

Abstract Background: Cerebral malaria is a highly prevalent infectious disease in Sub-Saharan Africa caused by the Plasmodium parasite. The pathogenesis of cerebral malaria results from damaged vascular endothelium induced by parasite sequestration, inflammatory cytokine production and vascular leakage, which results in increased brain permeability and death. While maladaptive responses from immune cells are thought to contribute, growing evidence suggests a crucial role of platelets in malaria pathophysiology. The mammalian target of rapamycin (mTOR) pathway is critical in regulating outcomes in malaria. Previous studies have demonstrated an mTOR specific inhibitor, rapamycin, is protective in a mouse model of experimental cerebral malaria (ECM). However, if the mTOR pathway in platelets specifically contributes to the pathogenesis of malaria is unknown. Methods: Platelet-specific mTOR-deficient (mTOR plt-/-) mice and littermate controls were subjected to a well-established model of ECM, using Plasmodium berghei ANKA. In addition, platelets isolated from human malaria patients were examined for differential regulation of the mTOR pathway using RNA-seq. Results: Platelet RNA-seq and Ingenuity Pathway Analysis from patients infected with P. vivax demonstrated enrichment of mTOR-associated pathways in platelets, such as mTOR signaling and p70S6K signaling, indicating mTOR associated genes are upregulated in human platelets during malaria infection. In mice infected with P. berghei ANKA, the mTOR pathway was activated in bone marrow-megakaryocytes and platelets based on phosphorylation of mTOR and its downstream effector, 4E-BP1. As the mTOR pathway regulates protein translation in platelets, we examined de novo protein synthesis and observed increased protein translation in platelets isolated from mice infected with P. berghei ANKA compared to uninfected controls. To study the specific role of platelet mTOR during ECM pathogenesis, mTOR plt-/- mice and wild-type controls (mTOR plt+/+), were infected with P. berghei ANKA. Platelet deficient-mTOR mice had significantly (p=0.0336) prolonged survival compared to wild-type mice. Increased survival was independent of parasitemia, suggesting platelets did not alter parasite reproduction. While thrombocytopenia and anemia were similar in both genotypes, mTOR plt-/- mice had significantly reduced brain (p=0.0067) and lung (p&lt;0.0001) vascular permeability during late-stage ECM. Interestingly, flow cytometric assessment of leukocyte recruitment to the brain demonstrated a 1.7-fold (p=0.0442) reduction in inflammatory monocytes in platelet-deficient mTOR mice. However, mTOR plt-/- mice had significantly (1.4-fold, p=0.007) more inflammatory monocytes in the blood. Interestingly, circulating platelet-monocytes aggregates were significantly less in mTOR plt-/- compared to mTOR plt+/+ (p=0.0433). Taken together, these results suggest that platelets assist in the recruitment of leukocytes to the brain vasculature during ECM, which is impaired when mTOR is ablated. Conclusions: Our data demonstrates that the mTOR pathway in platelets plays a significant role in malaria pathogenesis. Deletion of platelet mTOR reduces vascular permeability and prolongs survival during ECM. We hypothesize that altered platelet-inflammatory monocyte interactions drive this phenotype. Disclosures Rondina: Platelet Transcriptomics: Patents & Royalties; Acticor Biotech: Membership on an entity's Board of Directors or advisory committees; Platelet Biogenesis: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding.

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