SARS-CoV-2 mechanistic correlates of protection: insight from modelling response to vaccines

The definition of correlates of protection is critical for the development of next generation SARS-CoV-2 vaccine platforms. Here, we propose a new framework for identifying mechanistic correlates of protection based on mathematical modelling of viral dynamics and data mining of immunological markers. The application to three different studies in non-human primates evaluating SARS-CoV-2 vaccines based on CD40-targeting, two-component spike nanoparticle and mRNA 1273 identifies and quantifies two main mechanisms that are a decrease of rate of cell infection and an increase in clearance of infected cells. Inhibition of RBD binding to ACE2 appears to be a robust mechanistic correlate of protection across the three vaccine platforms although not capturing the whole biological vaccine effect. The model shows that RBD/ACE2 binding inhibition represents a strong mechanism of protection which required significant reduction in blocking potency to effectively compromise the control of viral replication.

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COVID 19 – Eye Issues

Medical & Clinical Research ◽

10.33140/mcr.05.005 ◽

2020 ◽

Vol 5 (Special) ◽

Keyword(s):

Host Cell ◽

Target Cell ◽

Cell Receptor ◽

Human Tissues ◽

Type Ii ◽

Cell Infection ◽

Host Cell Receptor ◽

Infected Cells ◽

Cellular Entry

The coronavirus illness (COVID-19) is caused by a new recombinant SARS-CoV (SARS-CoV) virus (SARS-CoV-2). Target cell infection by SARS-CoV is mediated by the prickly protein of the coronavirus and host cell receptor, enzyme 2 converting angiotensin (ACE2) [3]. Similarly, a recent study suggests that cellular entry by SARS-CoV-2 is dependent on both ACE2 as well as type II transmembrane axial protease (TMPRSS2) [4]. This means that detection of ACE2 and PRSS2 expression in human tissues can predict potential infected cells and their respective effects in COVID-19 patients [1].

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Infection of CD8+CD45RO+ Memory T-Cells by HIV-1 and Their Proliferative Response

The Open AIDS Journal ◽

10.2174/1874613600802010043 ◽

2008 ◽

Vol 2 (1) ◽

pp. 43-57 ◽

Cited By ~ 7

Author(s):

Naveed Gulzar ◽

Sowyma Balasubramanian ◽

Greg Harris ◽

Jaime Sanchez-Dardon ◽

Karen F.T. Copeland

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Proliferative Response ◽

Cell Infection ◽

Cellular Target ◽

Potential Reservoir ◽

Infected Cells ◽

Hiv 1

CD8+ T-cells are involved in controlling HIV-1 infection by eliminating infected cells and secreting soluble factors that inhibit viral replication. To investigate the mechanism and significance of infection of CD8+ T-cells by HIV-1in vitro, we examined the susceptibility of these cells and their subsets to infection. CD8+ T-cells supported greater levels of replication with T-cell tropic strains of HIV-1, though viral production was lower than that observed in CD4+ T-cells. CD8+ T-cell infection was found to be productive through ELISA, RT-PCR and flow cytometric analyses. In addition, the CD8+CD45RO+ memory T-cell population supported higher levels of HIV-1 replication than CD8+CD45RA+ naïve T-cells. However, infection of CD8+CD45RO+ T-cells did not affect their proliferative response to the majority of mitogens tested. We conclude, with numerous lines of evidence detecting and measuring infection of CD8+ T-cells and their subsets, that this cellular target and potential reservoir may be central to HIV-1 pathogenesis.

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Open issues and perspectives of the present arrangements between FR of Yugoslavia and international financial institutions

Privredna izgradnja ◽

10.2298/priz0302055p ◽

2003 ◽

Vol 46 (1-2) ◽

pp. 55-72

Author(s):

Pero Petrovic

Keyword(s):

Financial Institutions ◽

Free Market ◽

Banking System ◽

Macroeconomic Policy ◽

Legal Framework ◽

International Financial Institutions ◽

Open Questions ◽

Foreign Countries ◽

Definition Of ◽

New Framework

The economic-financial relations with foreign countries and organizations and that is include transition of the Yugoslav politics and it is complex subject about characteristics of the actual arrangements of the FR Yugoslavia with international financial institutions and organizations and that is only one important part. But interrelations that processes is obviously for this article main subject are open questions and dealed with it a perspective of the future arrangements. We must take micro and macroeconomic measures dealed with problems of our society and economy that arrangements will be important factors of the development of the economic development. International Monetary Found is concluded that FR of Yugoslavia have a great successes in the reforms of macroeconomic policy and in the first part dealing with inflation and growth of the currency reserves and growth of the industry production. Dealing with new macroeconomic policy bring the results and new tax politics and liberalization of the tax policy an currency system at the beginning of this year. New framework of the privatization and definition of banking system there is create a new legal framework with goal of transformation economy to free market economy.

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Chronometric Height: a relativistic height definition by generalizing geopotential numbers

10.5194/egusphere-egu21-9889 ◽

2021 ◽

Author(s):

Dennis Philipp

Keyword(s):

Weak Field ◽

Point Of View ◽

Theoretical Point ◽

Theoretical Formulation ◽

Spacetime Geometry ◽

Weak Field Limit ◽

Measurement Results ◽

Fundamental Insight ◽

Definition Of ◽

New Framework

A height definition in terms of geopotential numbers offers a variety of advantages. Moreover, from the theoretical point of view, such a definition is considered more fundamental.&#160;We know, however, that relativistic gravity (here General Relativity) requires to reformulate the basic geodetic notions and to develop a consistent theoretical framework, relativistic geodesy, to yield an undoubtedly correct interpretation of measurement results.The new framework of chronometric geodesy that builds on the comparison of clocks offers fundamental insight into the spacetime geometry if a solid theoretical formulation of observables is underlying modern high-precision measurements. Here we approach a genuine relativistic definition of the concept of height. Based on the relativistic generalization of geopotential numbers, a definition of chronometric height is suggested, which reduces to the well-known notions in the weak-field limit.

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Simulating the entire natural course of HIV infection by extending the basic viral dynamics equations to include declining viral clearance

Pathogens and Disease ◽

10.1093/femspd/ftz043 ◽

2019 ◽

Vol 77 (4) ◽

Cited By ~ 1

Author(s):

Janka Petravic ◽

David P Wilson

Keyword(s):

Hiv Infection ◽

Antiretroviral Treatment ◽

Viral Clearance ◽

Natural Course ◽

Viral Dynamics ◽

Proof Of Concept ◽

Basic Model ◽

Simple Set ◽

Infected Cells

ABSTRACT The basic model of viral dynamics is a relatively simple set of equations describing the most essential features of the host–pathogen interactions. Coupled with data, it has been used extensively and successfully to reproduce and explain the features of the early acute phase of HIV infection and the effects of antiretroviral treatment, as well as to estimate the lifespan of infected cells, viral growth and clearance rates and predict early outcomes under different circumstances. However, it cannot reproduce the entire natural course of untreated HIV infection consistently with constant parameters. Here we show that it is possible to qualitatively reproduce the whole course of untreated HIV infection within the general framework of the basic model by assuming progressively declining viral clearance coupled with viral load. We discuss the interpretation of this model as proof-of-concept that may inspire further research into the role of viral clearance in HIV infection.

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The Identification and Decomposition of Hierarchical Tasks

American Educational Research Journal ◽

10.3102/00028312014003189 ◽

1977 ◽

Vol 14 (3) ◽

pp. 189-212 ◽

Cited By ~ 11

Author(s):

John W. Cotton ◽

John P. Gallagher ◽

Sandra P. Marshall

Keyword(s):

Mathematical Model ◽

Experimental Design ◽

Experimental Evidence ◽

Hierarchical Structure ◽

Alternate Route ◽

Component Task ◽

Two Component ◽

Hierarchical Ordering ◽

Definition Of

The definition of hierarchical structure is reviewed, together with psychometric and experimental evidence regarding the existence of specific structures. Exceptions to hierarchical ordering are frequent enough to merit consideration of an assumption that skill on an item may simply transfer to the next higher item rather than being fully prerequisite to it. In some cases an alternate route hierarchy may occur, with persons either learning an item and then the next item or learning both at the same time. A mathematical model including hierarchical and nonhierarchical options fir a two-component task is presented; an experimental design appropriate to testing the model and related transfer hypotheses is also presented.

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Descent into Murder: Provocation's Stricture—The Prognosis for Women Who Kill Men Who Abuse Them

The Journal of Criminal Law ◽

10.1350/jcla.2007.71.4.342 ◽

2007 ◽

Vol 71 (4) ◽

pp. 342-361 ◽

Cited By ~ 1

Author(s):

Susan Edwards

Keyword(s):

Battered Women ◽

Attorney General ◽

Self Control ◽

Judicial Discretion ◽

Reasonable Person ◽

Women Who Kill ◽

The Law ◽

Definition Of ◽

Mandatory Sentence ◽

New Framework

This article considers the ruling in Attorney-General for Jersey v Holley1 and its impact on limiting the ambit of the defence of provocation by restoring to the reasonable person a normative capacity for self-control. In particular, the implications of this limitation on legal outcome in cases where women kill men who abuse them are explored. The inevitable demise of provocation as a defence, which follows from the ruling in Holley, is of particular concern as is the new framework for sentencing in convictions for murder2 which in removing judicial discretion from the sentencing decision prohibits judges from tempering the harshness of the mandatory sentence. This new murder/sentencing regime will undoubtedly result in injustice, especially in those cases where battered women kill, which, although deserving of mitigation, nevertheless fail to satisfy the strictures of provocation's requirements post Holley, thereby resulting in an increase in convictions for murder. The Law Commission's report on Murder, Manslaughter and Infanticide3 recommends a new framework for murder and manslaughter, including a new definition of provocation and also a new direction in the murder sentencing framework. This area of the law is still far from fixed.

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Coxiella burnetiiblocks intracellular IL-17 signaling in macrophages

10.1101/367920 ◽

2018 ◽

Author(s):

Tatiana M. Clemente ◽

Minal Mulye ◽

Anna V. Justis ◽

Srinivas Nallandhighal ◽

Tuan M. Tran ◽

...

Keyword(s):

Host Cell ◽

Q Fever ◽

Protective Role ◽

Effector Proteins ◽

Antimicrobial Protein ◽

Dependent Manner ◽

Cell Infection ◽

Protein Levels ◽

Host Cytoplasm ◽

Infected Cells

AbstractCoxiella burnetiiis an obligate intracellular bacterium and the etiological agent of Q fever. Successful host cell infection requires theCoxiellaType IVB Secretion System (T4BSS), which translocates bacterial effector proteins across the vacuole membrane into the host cytoplasm, where they manipulate a variety of cell processes. To identify host cell targets ofCoxiellaT4BSS effector proteins, we determined the transcriptome of murine alveolar macrophages infected with aCoxiellaT4BSS effector mutant. We identified a set of inflammatory genes that are significantly upregulated in T4BSS mutant-infected cells compared to mock-infected cells or cells infected with wild type (WT) bacteria, suggestingCoxiellaT4BSS effector proteins downregulate expression of these genes. In addition, the IL-17 signaling pathway was identified as one of the top pathways affected by the bacteria. While previous studies demonstrated that IL-17 plays a protective role against several pathogens, the role of IL-17 duringCoxiellainfection is unknown. We found that IL-17 kills intracellularCoxiellain a dose-dependent manner, with the T4BSS mutant exhibiting significantly more sensitivity to IL-17 than WT bacteria. In addition, quantitative PCR confirmed increased expression of IL-17 downstream signaling genes in T4BSS mutant-infected cells compared to WT or mock-infected cells, including the pro-inflammatory cytokinesI11a, Il1bandTnfa, the chemokinesCxcl2andCcl5, and the antimicrobial proteinLcn2. We further confirmed that theCoxiellaT4BSS downregulates macrophage CXCL2/MIP-2 and CCL5/RANTES protein levels following IL-17 stimulation. Together, these data suggest thatCoxielladownregulates IL-17 signaling in a T4BSS-dependent manner in order to escape the macrophage immune response.

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Religiøs argumentation som religionsfænomenologisk forskningsområde

Religionsvidenskabeligt Tidsskrift ◽

10.7146/rt.v0i21.5329 ◽

1992 ◽

Author(s):

Mikael Aktor

Keyword(s):

Mystical Experience ◽

Point Of View ◽

Essential Difference ◽

Specific Character ◽

Concrete Material ◽

Material World ◽

Basic Point ◽

Two Component ◽

The World ◽

Definition Of

This article is a reflection on the specific character of religious assertations and religious arguments. The basic point of view is that these religious practices should not be investigated as isolated religious phenomena sui generis, but on the contrary, that they are conditioned by and derived from common linguistic and epistemological practices that relate to the concrete material world. Religious assertations join together finction and description of the world, whereas religious arguments refer todata which are either quasi-empiric (a holy scripture for instance) or quasi-public (a mystical experience for instance). in four text examples these derivations are investigated in the light of a two-component definition of religion, which stresses the concept of an essential difference as well as the concept of a possibility of a passage to an fro between essentially differenct categories.

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A Nationwide Survey on Chronic Active Epstein-Barr Virus Infection in Japan Based on New Diagnostic Criteria: Clinical Features and Treatment Strategies

Blood ◽

10.1182/blood-2018-99-117854 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1631-1631

Author(s):

Ayako Arai ◽

Ichiro Yonese ◽

Chizuko Sakashita ◽

Ken-Ichi Imadome ◽

Tohru Kobayashi ◽

...

Keyword(s):

Disease Activity ◽

Nationwide Survey ◽

Skin Lesions ◽

Epstein Barr Virus Infection ◽

Barr Virus ◽

Infected Cells ◽

Ebv Dna ◽

Epstein Barr ◽

Barr Virus Infection ◽

Definition Of

Abstract Background and aims Chronic active Epstein-Barr virus infection (CAEBV) is classified into T- or NK-cell neoplasms in the new WHO classification revised in 2017. Allogeneic stem cell transplantation (allo-HSCT) has recently been reported to be an effective treatment for this disorder. Conversely, effects of chemotherapies on CAEBV have not yet been examined in a large number of patients. To clarify clinical features and the current state of chemotherapies for CAEBV under the new definition of the disease, we performed a nationwide survey in Japan. Methods Questionnaires were sent to all educational hospitals certified by the Japanese Society of Hematology and the Japanese Pediatric Society. Subjects were patients newly diagnosed with CAEBV between January 2003 and March 2016. CAEBV was diagnosed according to criteria suggested by the Research group of Measures against Intractable Diseases by Ministry of Health, Labour and Welfare of Japan in 2016: (1) elevated EBV DNA load in peripheral blood (PB) (>102.5 copies/μg DNA); (2) detection of EBV infection in T or NK cells from the affected tissues or PB; (3) systemic inflammatory symptoms (such as fever, lymphadenopathy, liver dysfunction, progressive skin lesions, vasculitis, and uveitis) persisting for >3 months; and (4) exclusion of other possible diagnoses, such as primary EBV infection, autoimmune disease, immunodeficiencies, and lymphomas. Patients who fulfilled (1)-(4) were diagnosed with CAEBV. These criteria were established based on those proposed by Okano et al.(Am J Hematol. 2005;80,p64) and Kimura et al.(Blood. 2012;119,p673) and were compatible with the definition of CAEBV described by WHO in 2017. The disease activity was defined according to the previous reports (Blood. 2012;119,p673 and BMT. 2016;51,p879) as follows: positive for fever, ALT level elevation, vasculitis, progressive skin lesions, or uveitis. Effects of treatments were evaluated as follows: partial response (PR), partial resolution of disease activity; complete response (CR), complete resolution of disease activity with EBV load in PB remaining high (>102.5 copies/μg DNA, which is the upper limit for healthy people); virological CR (vCR), CR with a significant decrease in the EBV DNA load in PB (<102.5 copies/μg DNA). Results Completed questionnaires were returned by 29 institutes and 100 patients were evaluated. They were 53 males and 47 females aged 1-78 (median, 21) years. Types of EBV-infected cells were as follows: CD4 (n = 25), CD8 (n = 13), and CD56 (n = 28). The 3-year overall survival (OS) from diagnosis was 58%. Because different outcomes have been reported between children and adults with CAEBV, we divided patients into three groups according to their onset ages: childhood onset (CO) with patients aged <9 years, adolescent- and adult-onset (AAO), and advanced age-onset (AO) with patients aged >45 years. Seventy-eight percent patients in the CO group were males. Conversely, 85% patients in the AO group were females. The 3-year OS from diagnosis in the CO, AAO, and AO groups were 83%, 57%, and 31%, respectively. The prognosis of CO of CAEBV was significantly better than that of AAO (p = 0.0151) and AO (p = 0.0034) of CAEBV. Spontaneous regression was not observed in patients with active disease. Main chemotherapies employed were a combination of cyclosporine A, steroids, and etoposide (cooling therapy) in 52 patients and CHOP in 45 patients. The rate of CR + PR was as follows: cooling therapy, 57% and CHOP, 39%. Viral CR was not observed. Three-year OS from the start of treatment was 0% in patients treated with only chemotherapy (n = 20) and 69% in those who received allo-HSCT (n = 59). Conclusions Based on the difference in OS and increased prevalence of males in the CO group, it can be concluded that CO of CAEBV may be independent from AO and AAO of CAEBV. Chemotherapy alone is currently insufficient for eradicating infected cells and resolving CAEBV. The development of an effective treatment reagent is an urgent issue. Disclosures No relevant conflicts of interest to declare.

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