scholarly journals Understanding the Dynamics of SARS-CoV-2 Variants of Concern in Ontario, Canada: A Case Study

2021 ◽  
Author(s):  
Anita Layton ◽  
Mehrshad Sadria
Keyword(s):  
Vaccination Rate ◽  
Type Model ◽  
Wild Type ◽  
Inhibitory Effects ◽  
Booster Vaccine ◽  
Successful Vaccine ◽  
Rapid Deployment ◽  
Pharmaceutical Interventions

Abstract A year after the initial wild-type Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) strains began their devastation of the world, they were supplanted by new variants of concern (VOC). In Ontario, Canada, the wild type was overtaken first by the Alpha/B1.1.17 variant, and then by the Delta/B.1.617 variant. The principal objective of the present study is to develop and apply a much expanded Susceptible-Infection-Recovered-type model to better understand the spread of multiple VOC, and assess the effectiveness of vaccination and non-pharmaceutical interventions (NPI). The model represents competition among VOC, and reveals their mutual inhibitory effects. By separately tracking asymptomatic and symptomatic infections, model simulations identify a significant role of vaccine breakthrough in the spread of Delta. Furthermore, the severity of a Delta outbreak depends not only on the NPI and vaccination rate but also on the vaccine types. Alarmingly, despite Ontario’s existing NPI and relatively successful vaccine rollout, a future, more dangerous VOC could potentially infect a significant fraction of the province’s population and overwhelm the health care system. To stop that VOC, the province may need the simultaneous and rapid deployment of a third booster vaccine and stringent NPI.

scholarly journals An MDM2 inhibitor achieves synergistic cytotoxic effects with adenoviruses lacking E1B55kDa gene on mesothelioma with the wild-type p53 through augmenting NFI expression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Thao Thi Thanh Nguyen ◽  
Masato Shingyoji ◽  
Michiko Hanazono ◽  
Boya Zhong ◽  
Takao Morinaga ◽  
...  
Keyword(s):  
Wild Type ◽  
Inhibitory Effects ◽  
Cytotoxic Effects ◽  
P53 Expression ◽  
Nuclear Factor I ◽  
Infected Cells ◽  
Wild Type P53 ◽  
Mdm2 Inhibitor ◽  
P16 Expression

AbstractA majority of mesothelioma specimens were defective of p14 and p16 expression due to deletion of the INK4A/ARF region, and the p53 pathway was consequently inactivated by elevated MDM2 functions which facilitated p53 degradaton. We investigated a role of p53 elevation by MDM2 inhibitors, nutlin-3a and RG7112, in cytotoxicity of replication-competent adenoviruses (Ad) lacking the p53-binding E1B55kDa gene (Ad-delE1B). We found that a growth inhibition by p53-activating Ad-delE1B was irrelevant to p53 expression in the infected cells, but combination of Ad-delE1B and the MDM2 inhibitor produced synergistic inhibitory effects on mesothelioma with the wild-type but not mutated p53 genotype. The combination augmented p53 phosphorylation, activated apoptotic but not autophagic pathway, and enhanced DNA damage signals through ATM-Chk2 phosphorylation. The MDM2 inhibitors facilitated production of the Ad progenies through augmented expression of nuclear factor I (NFI), one of the transcriptional factors involved in Ad replications. Knocking down of p53 with siRNA did not increase the progeny production or the NFI expression. We also demonstrated anti-tumor effects by the combination of Ad-delE1B and the MDM2 inhibitors in an orthotopic animal model. These data collectively indicated that upregulation of wild-type p53 expression contributed to cytotoxicity by E1B55kDa-defective replicative Ad through NFI induction and suggested that replication-competent Ad together with augmented p53 levels was a therapeutic strategy for p53 wild-type mesothelioma.

The Role of Population Mobility and Non-Pharmaceutical Interventions on COVID-19 Infection: A Canadian Case Study of Granger-Causal Relationships

2021 ◽  
Author(s):  
Myrtha E. Reyna ◽  
Boxi Lin ◽  
Lehang Zhong ◽  
Michael Jongho Moon ◽  
Mohammad Kaviul Anam Khan ◽  
...  
Keyword(s):  
Causal Relationships ◽  
Population Mobility ◽  
Pharmaceutical Interventions

scholarly journals The role of Ca2+ in triggering inositol 1,4,5-trisphosphate receptor ubiquitination

2005 ◽  
Vol 392 (3) ◽  
pp. 601-606 ◽  
Author(s):  
Kamil J. Alzayady ◽  
Richard J. H. Wojcikiewicz
Keyword(s):  
Type I ◽  
Pituitary Cells ◽  
Wild Type ◽  
Inhibitory Effects ◽  
Mutant Type ◽  
Channel Opening ◽  
Inositol 1,4,5 Trisphosphate ◽  
Mouse Pituitary ◽  
Trisphosphate Receptor

The IP3R (inositol 1,4,5-trisphosphate receptor) forms tetrameric Ca2+ channels in ER (endoplasmic reticulum) membranes, where channel activity is largely under the control of the co-agonists IP3 and Ca2+. In cells stimulated using extracellular ligands that persistently elevate phosphoinositidase C activity, IP3Rs are rapidly ubiquitinated and then degraded by the proteasome through as yet undefined mechanisms. Whereas binding of IP3 has been suggested to be a key event in the triggering of IP3R ubiquitination the role of Ca2+ in this process remains unknown. In the present study we use αT3-1 mouse pituitary cells expressing exogenous wild-type or mutant-type-I IP3Rs (IP3R1) to provide several lines of evidence that Ca2+ is also a trigger. Firstly, depletion of ER Ca2+ stores with thapsigargin blocked wild-type IP3R1 ubiquitination. Secondly, ubiquitination was blocked by mutating Glu2100 to Asp, which is known to markedly suppress Ca2+-binding to IP3R1 and the potency of Ca2+ as a stimulus for channel opening. Thirdly, mutating Asp2550 to Ala, which inhibits Ca2+ flux through the channel pore, partially inhibited ubiquitination indicating that Ca2+ released via wild-type IP3R1 contributes to triggering ubiquitination. Fourthly, and consistent with this conclusion, although suppression of increases in cytoplasmic Ca2+ concentration did not inhibit the ubiquitination of wild-type IP3R1, it strongly inhibited the ubiquitination of the Asp2550 to Ala mutant. Overall, these results show that Ca2+ plays an important role in triggering IP3R ubiquitination. Additional experiments with IP3R1 containing an Arg265 to Gln mutation, which decreases IP3-binding affinity, confirmed that IP3-binding also plays a role. Finally, the mutations at Glu2100, Asp2550 and Arg265 inhibited IP3R1 degradation to an extent that paralleled their inhibitory effects on ubiquitination. We conclude that IP3R ubiquitination and degradation are triggered by the concerted action of IP3- and Ca2+-binding.

Prolonged exposure to ethylene stimulates the negative gravitropic responses of Arabidopsis inflorescence stems and hypocotyls

2002 ◽  
Vol 29 (8) ◽  
pp. 989 ◽  
Author(s):  
Bingwen Lu ◽  
Ho Yan Yu ◽  
Lai Kwan Pei ◽  
Man Yu Wong ◽  
Ning Li
Keyword(s):  
Prolonged Exposure ◽  
Plant Tissues ◽  
Wild Type ◽  
Inhibitory Effects ◽  
Short Term ◽  
Gravitropic Response ◽  
Inflorescence Stems ◽  
Opposing Effects ◽  
Dynamic Interplay

The actual effect of ethylene on shoot gravitropic response has been controversial. To elucidate the role of ethylene in the modulation of shoot gravitropic response, Arabidopsis inflorescences and light-grown seedlings were pretreated with 0.1-10 -1 of ethylene for either a long (12-48 h) or short term (0.5 h). When the gravicurvature was measured either in air or in ethylene, it was found that prolonged exposure to various levels of ethylene stimulated both inflorescence stem and hypocotyl gravicurvature in air, while the continued presence of ethylene immediately following reorientation of plant tissues inhibited gravicurvature of both tissues. Both stimulatory and inhibitory effects existed in inflorescence stems and hypocotyls when the plant tissues were exposed to a chosen concentration of ethylene. Stimulation by ethylene was stronger than its inhibition in inflorescence stems, while the reverse was true for the hypocotyls. Therefore, the continued presence of high levels of naturally produced ethylene in eto1-1 did not suppress the faster gravicurvature of inflorescence stems, whereas the removal of exogenously applied ethylene was necessary to observe faster gravicurvature of both the wild-type and eto1-1 hypocotyls. Both effects acted through the known ethylene receptor complex. These results strongly suggest that ethylene of a chosen concentration has opposing effects on the negative gravitropic responses of both inflorescence stems and hypocotyls. The ultimate negatively gravitropic behaviour of a plant tissue, when exposed to ethylene, depends on the dynamic interplay between these two opposing effects.

scholarly journals Gene deletion reveals roles for annexin A1 in the regulation of lipolysis and IL-6 release in epididymal adipose tissue

2006 ◽  
Vol 291 (6) ◽  
pp. E1264-E1273 ◽  
Author(s):  
James P. Warne ◽  
Christopher D. John ◽  
Helen C. Christian ◽  
John F. Morris ◽  
Roderick J. Flower ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Gene Deletion ◽  
Cell Number ◽  
Receptor Expression ◽  
Epididymal Adipose Tissue ◽  
Wild Type ◽  
Inhibitory Effects ◽  
Tissue Mass

In this study, epididymal adipose tissue from male annexin 1 (ANXA1)-null and wild-type control mice were used to explore the potential role of ANXA1 in adipocyte biology. ANXA1 was detected by Western blot analysis in wild-type tissue and localized predominantly to the stromal-vascular compartment. Epididymal fat pad mass was reduced by ANXA1 gene deletion, but adipocyte size was unchanged, suggesting that ANXA1 is required for the maintenance of adipocyte and/or preadipocyte cell number. Epididymal tissue from wild-type mice responded in vitro to noradrenaline and isoprenaline with increased glycerol release, reduced IL-6 release, and increased cAMP accumulation. Qualitatively similar but significantly attenuated responses to the catecholamines were observed in tissue from ANXA1-null mice, an effect that was not associated with changes in β-adrenoceptor mRNA expression. Lipopolysaccharide (LPS) also stimulated lipolysis in vitro, but its effects were muted by ANXA1 gene deletion. By contrast, LPS failed to influence IL-6 release from wild-type tissue but stimulated the release of the cytokine from tissue from ANXA1-null mice. ANXA1 gene deletion did not affect glucocorticoid receptor expression or the ability of dexamethasone to suppress catecholamine-induced lipolysis. It did, however, augment IL-6 expression and modify the inhibitory effects of glucocorticoids on IL-6 release. Collectively, these studies suggest that ANXA1 supports aspects of adipose tissue mass and alters the sensitivity of epididymal adipose tissue to catecholamines, glucocorticoids, and LPS, thereby modulating lipolysis and IL-6 release.

scholarly journals Phosphorylation of IGFBP-1 at Discrete Sites Elicits Variable Effects on IGF-I Receptor Autophosphorylation

Endocrinology ◽  
2013 ◽  
Vol 154 (3) ◽  
pp. 1130-1143 ◽  
Author(s):  
Majida Abu Shehab ◽  
Cristiana Iosef ◽  
Robert Wildgruber ◽  
Girish Sardana ◽  
Madhulika B. Gupta
Keyword(s):  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Phosphorylation Sites ◽  
Wild Type ◽  
Inhibitory Effects ◽  
Ovary Cells ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein

Abstract We previously demonstrated that hypoxia and leucine deprivation cause hyperphosphorylation of IGF-binding protein-1 (IGFBP-1) at discrete sites that markedly enhanced IGF-I affinity and inhibited IGF-I-stimulated cell growth. In this study we investigated the functional role of these phosphorylation sites using mutagenesis. We created three IGFBP-1 mutants in which individual serine (S119/S169/S98) residues were substituted with alanine and S101A was recreated for comparison. The wild-type (WT) and mutant IGFBP-1 were expressed in Chinese hamster ovary cells and IGFBP-1 in cell media was isolated using isoelectric-focusing-free-flow electrophoresis. BIACore analysis indicated that the changes in IGF-I affinity for S98A and S169A were moderate, whereas S119A greatly reduced the affinity of IGFBP-1 for IGF-I (100-fold, P < .0001). Similar results were obtained with S101A. The IGF-I affinity changes of the mutants were reflected in their ability to inhibit IGF-I-induced receptor autophosphorylation. Employing receptor-stimulation assay using IGF-IR-overexpressing P6 cells, we found that WT-IGFBP-1 inhibited IGF-IRβ autophosphorylation (∼2-fold, P < .001), possibly attributable to sequestration of IGF-I. Relative to WT, S98A and S169A mutants did not inhibit receptor autophosphorylation. S119A, on the other hand, greatly stimulated the receptor (2.3-fold, P < .05). The data with S101A matched S119A. In summary, we show that phosphorylation at S98 and S169 resulted in milder changes in IGF-I action; nonetheless most dramatic inhibitory effects on the biological activity of IGF-I were due to IGFBP-1 phosphorylation at S119. Our results provide novel demonstration that IGFBP-1 phosphorylation at S119 can enhance affinity for IGF-I possibly through stabilization of the IGF-IGFBP-1 complex. These data also propose that the synergistic interaction of distinct phosphorylation sites may be important in eliciting more pronounced effects on IGF-I affinity that needs further investigation.

scholarly journals CD301b+ dendritic cells suppress T follicular helper cells and antibody responses to protein antigens

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Yosuke Kumamoto ◽  
Toshiro Hirai ◽  
Patrick W Wong ◽  
Daniel H Kaplan ◽  
Akiko Iwasaki
Keyword(s):  
Dendritic Cells ◽  
Regulatory Mechanism ◽  
Antibody Responses ◽  
Wild Type ◽  
Protein Antigens ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Successful Vaccine

Strong antibody response is considered a hallmark of a successful vaccine. While dendritic cells (DCs) are important for T follicular helper (Tfh) cell priming, how this process is regulated in vivo is unclear. We show here that the depletion of CD301b+ DCs specifically enhanced the development of Tfh cells, germinal center B cells and antibody responses against protein antigens. Exaggerated antibody responses in mice depleted of CD301b+ DCs occurred in the absence of any adjuvants, and resulting antibodies had broader specificity and higher affinity to the immunogen. CD301b+ DCs express high levels of PD-1 ligands, PD-L1 and PD-L2. Blocking PD-1 or PD-L1 during priming in wild-type mice partially mimicked the phenotype of CD301b+ DC-depleted animals, suggesting their role in Tfh suppression. Transient depletion of CD301b+ DC results in the generation of autoreactive IgG responses. These results revealed a novel regulatory mechanism and a key role of CD301b+ DCs in blocking autoantibody generation.

The role of multiplicity in a cult: A case study

1987 ◽  
Author(s):  
William A. Worrall ◽  
Ann W. Stockman

Differential Role of Components of the Fibrinolytic System in the Formation and Removal of Thrombus Induced by Endothelial Injury

1999 ◽  
Vol 81 (04) ◽  
pp. 601-604 ◽  
Author(s):  
Hiroyuki Matsuno ◽  
Osamu Kozawa ◽  
Masayuki Niwa ◽  
Shigeru Ueshima ◽  
Osamu Matsuo ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Thrombus Formation ◽  
Endothelial Injury ◽  
Fibrinolytic System ◽  
Tissue Type ◽  
Clot Lysis ◽  
Wild Type ◽  
Type Plasminogen Activator ◽  
Pai 1

SummaryThe role of fibrinolytic system components in thrombus formation and removal in vivo was investigated in groups of six mice deficient in urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), or plasminogen activator inhibitor-1 (PAI-1) (u-PA-/-, t-PA-/- or PAI-1-/-, respectively) or of their wild type controls (u-PA+/+, t-PA+/+ or PAI-1+/+). Thrombus was induced in the murine carotid artery by endothelial injury using the photochemical reaction between rose bengal and green light (540 nm). Blood flow was continuously monitored for 90 min on day 0 and for 20 min on days 1, 2 and 3. The times to occlusion after the initiation of endothelial injury in u-PA+/+, t-PA+/+ or PAI-1+/+ mice were 9.4 ± 1.3, 9.8 ± 1.1 or 9.7 ± 1.6 min, respectively. u-PA-/- and t-PA-/- mice were indistinguishable from controls, whereas that of PAI-1-/- mice were significantly prolonged (18.4 ± 3.7 min). Occlusion persisted for the initial 90 min observation period in 10 of 18 wild type mice and was followed by cyclic reflow and reocclusion in the remaining 8 mice. At day 1, persistent occlusion was observed in 1 wild type mouse, 8 mice had cyclic reflow and reocclusion and 9 mice had persistent reflow. At day 2, all injured arteries had persistent reflow. Persistent occlusion for 90 min on day 0 was observed in 3 u-PA-/-, in all t-PA-/- mice at day 1 and in 2 of the t-PA-/-mice at day 2 (p <0.01 versus wild type mice). Persistent patency was observed in all PAI-1-/- mice at day 1 and in 5 of the 6 u-PA-/- mice at day 2 (both p <0.05 versus wild type mice). In conclusion, t-PA increases the rate of clot lysis after endothelial injury, PAI-1 reduces the time to occlusion and delays clot lysis, whereas u-PA has little effect on thrombus formation and spontaneous lysis.

Sign in / Sign up

Export Citation Format

Share Document