scholarly journals Country-specific Optimization Strategy for Testing Through Contact Tracing Can Help Maintain a Low Reproduction Number (R_0) During Unlock

2021 ◽  
Author(s):  
Uddipan Sarma ◽  
Bhaswar Ghosh
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Reproduction Number ◽  
Epidemic Models ◽  
Contact Tracing ◽  
Positive Feedback Loop ◽  
Trade Off ◽  
Spread Of Infection ◽  
Country Specific ◽  
Infection Spread

Abstract In response to the COVID19 pandemics, many countries have implemented lockdowns in multiple phases to ensure social distancing and quarantining of the infected subjects as a first step to contain the infection spread. Subsequent unlocks to reopen the economies started next waves and imposed extra burden on quarantine to keep the reproduction number ( R0<1 ). Even with initial strict lockdowns and recent launching of vaccination programs, many countries are still struggling to contain the infection which suggests that revisiting the mechanism of lockdown-unlock implementation and simultaneous underpinning of the potential sources diluting the effort of such lockdowns could help better contain the spread of infection. Here, building epidemic models and analyzing the metadata of 50 countries, we first found that the estimated values of R0, adjusted w.r.t the distribution of medical facilities and virus clades, correlates strongly with the testing rates across countries. However, testing capacity of a country is limited by its medical resources, hence, as we demonstrate, optimizing a cost-benefit trade-off between testing rate and unlocking extents implemented in a country specific manner can help in devising the strategies of unlocking the economy. Our study delineates a strategy to optimize this trade-off by utilizing country specific infection spread parameters estimated in the epidemic models and implementing them in a stochastic agent based contact tracing models. The analysis provides a quantitative estimate of testing rates required to maintain a low for different extents of unlock. We further found that a small fraction of superspreaders can drastically increase the number of infected individuals even during lockdowns, primarily due to a switch-like response stemming from the implicit systems-level positive feedback loop driving the spread of infection. Our model suggests that with a country specific optimal combination of unlock extents and testing rates, R0 <1 can be stabilized during a pandemic like COVID19. To harness the benefit of improved testing rates and minimize the infection spread, strict social distancing norms to restrict the movement of superspreaders is necessary, such that onset of the positive feedback loop mediated exponential infection spread can be avoided.

scholarly journals Country-specific optimization strategy for testing through contact tracing can help maintain a low reproduction number ($$R_{0}$$) during unlock

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Uddipan Sarma ◽  
Bhaswar Ghosh
Keyword(s):  
Positive Feedback ◽  
Reproduction Number ◽  
Cost Benefit ◽  
Contact Tracing ◽  
Optimization Strategy ◽  
Trade Off ◽  
Social Distancing ◽  
Medical Facilities ◽  
Country Specific ◽  
Infection Spread

AbstractIn response to the COVID19 pandemic, many countries have implemented lockdowns in multiple phases to ensure social distancing and quarantining of the infected subjects. Subsequent unlocks to reopen the economies started next waves of infection and imposed an extra burden on quarantine to keep the reproduction number ($$R_{0}$$ R 0 ) < 1. However, most countries could not effectively contain the infection spread, suggesting identification of the potential sources weakening the effect of lockdowns could help design better informed lockdown-unlock cycles in the future. Here, through building quantitative epidemic models and analyzing the metadata of 50 countries from across the continents we first found that the estimated value of $$R_{0}$$ R 0 , adjusted w.r.t the distribution of medical facilities and virus clades correlates strongly with the testing rates in a country. Since the testing capacity of a country is limited by its medical resources, we investigated if a cost–benefit trade-off can be designed connecting testing rate and extent of unlocking. We present a strategy to optimize this trade-off in a country specific manner by providing a quantitative estimate of testing and quarantine rates required to allow different extents of unlocks while aiming to maintain $$R_{0} < 1$$ R 0 < 1 . We further show that a small fraction of superspreaders can dramatically increase the number of infected individuals even during strict lockdowns by strengthening the positive feedback loop driving infection spread. Harnessing the benefit of optimized country-specific testing rates would critically require minimizing the movement of these superspreaders via strict social distancing norms, such that the positive feedback driven switch-like exponential spread phase of infection can be avoided/delayed.

scholarly journals A positive-feedback loop between HBx and ALKBH5 promotes hepatocellular carcinogenesis

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Siming Qu ◽  
Li Jin ◽  
Hanfei Huang ◽  
Jie Lin ◽  
Weiwu Gao ◽  
...  
Keyword(s):  
Positive Feedback ◽  
Feedback Loop ◽  
Hbv Infection ◽  
Cell Counting ◽  
Regulation Mechanism ◽  
Dependent Manner ◽  
Liver Carcinogenesis ◽  
Nude Mouse Model ◽  
Positive Feedback Loop

Abstract Background Hepatitis B Virus (HBV) contributes to liver carcinogenesis via various epigenetic mechanisms. The newly defined epigenetics, epitranscriptomics regulation, has been reported to involve in multiple cancers including Hepatocellular Carcinoma (HCC). Our previous study found that HBx, HBV encodes X protein, mediated H3K4me3 modification in WDR5-dependent manner to involve in HBV infection and contribute to oncogene expression. AlkB Homolog 5 (ALKBH5), one of epitranscriptomics enzymes, has been identified to be associated with various cancers. However, whether and how ALKBH5 is dysregulated in HBV-related HCC remains unclear yet. This study aims to investigate ALKBH5 function, clinical significance and mechanism in HBV related HCC (HBV-HCC) patients derived from Chinese people. Methods The expression pattern of ALKBH5 was evaluated by RT-qPCR, Western blot, data mining and immunohistochemistry in total of 373 HBV-HCC tissues and four HCC cell lines. Cell Counting Kit 8 (CCK8) assay, Transwell and nude mouse model were performed to assess ALKBH5 function by both small interference RNAs and lentiviral particles. The regulation mechanism of ALKBH5 was determined in HBx and WDR5 knockdown cells by CHIP-qPCR. The role of ALKBH5 in HBx mRNA N6-methyladenosine (m6A) modification was further evaluated by MeRIP-qPCR and Actinomycin D inhibitor experiment in HBV-driven cells and HBx overexpression cells. Result ALKBH5 increased in tumor tissues and predicts a poor prognosis of HBV-HCC. Mechanically, the highly expressed ALKBH5 is induced by HBx-mediated H3K4me3 modification of ALKBH5 gene promoter in a WDR5-dependent manner after HBV infection. The increased ALKBH5 protein catalyzes the m6A demethylation of HBx mRNA, thus stabilizing and favoring a higher HBx expression level. Furthermore, there are positive correlations between HBx and ALKBH5 in HBV-HCC tissues, and depletion of ALKBH5 significantly inhibits HBV-driven tumor cells’ growth and migration in vitro and in vivo. Conclusions HBx-ALKBH5 may form a positive-feedback loop to involve in the HBV-induced liver carcinogenesis, and targeting the loop at ALKBH5 may provide a potential way for HBV-HCC treatment.

scholarly journals CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 contributes to prostate carcinogenesis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jin-Chun Qi ◽  
Zhan Yang ◽  
Tao Lin ◽  
Long Ma ◽  
Ya-Xuan Wang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcriptional Activation ◽  
Positive Feedback ◽  
Feedback Loop ◽  
Biological Effects ◽  
Therapeutic Benefit ◽  
Loss Of Function ◽  
Positive Feedback Loop

Abstract Background Both E2F transcription factor and cyclin-dependent kinases (CDKs), which increase or decrease E2F activity by phosphorylating E2F or its partner, are involved in the control of cell proliferation, and some circRNAs and miRNAs regulate the expression of E2F and CDKs. However, little is known about whether dysregulation among E2Fs, CDKs, circRNAs and miRNAs occurs in human PCa. Methods The expression levels of CDK13 in PCa tissues and different cell lines were determined by quantitative real-time PCR and Western blot analysis. In vitro and in vivo assays were preformed to explore the biological effects of CDK13 in PCa cells. Co-immunoprecipitation anlysis coupled with mass spectrometry was used to identify E2F5 interaction with CDK13. A CRISPR-Cas9 complex was used to activate endogenous CDK13 and circCDK13 expression. Furthermore, the mechanism of circCDK13 was investigated by using loss-of-function and gain-of-function assays in vitro and in vivo. Results Here we show that CDK13 is significantly upregulated in human PCa tissues. CDK13 depletion and overexpression in PCa cells decrease and increase, respectively, cell proliferation, and the pro-proliferation effect of CDK13 is strengthened by its interaction with E2F5. Mechanistically, transcriptional activation of endogenous CDK13, but not the forced expression of CDK13 by its expression vector, remarkably promotes E2F5 protein expression by facilitating circCDK13 formation. Further, the upregulation of E2F5 enhances CDK13 transcription and promotes circCDK13 biogenesis, which in turn sponges miR-212-5p/449a and thus relieves their repression of the E2F5 expression, subsequently leading to the upregulation of E2F5 expression and PCa cell proliferation. Conclusions These findings suggest that CDK13 upregulation-induced formation of the positive feedback loop among circCDK13, miR-212-5p/miR-449a and E2F5 is responsible for PCa development. Targeting this newly identified regulatory axis may provide therapeutic benefit against PCa progression and drug resistance.

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