scholarly journals Ebola-GP DNA Prime rAd5-GP Boost: Influence of Prime Frequency and Prime/Boost Time Interval on the Immune Response in Non-human Primates

2021 ◽  
Vol 12 ◽  
Author(s):  
Hadar Marcus ◽  
Emily Thompson ◽  
Yan Zhou ◽  
Michael Bailey ◽  
Mitzi M. Donaldson ◽  
...  
Keyword(s):  
T Cell ◽  
Ebola Virus ◽  
Time Interval ◽  
Hemorrhagic Disease ◽  
Double Positive ◽  
Lethal Challenge ◽  
Common Strategy ◽  
Boost Immunization ◽  
Long Time ◽  
The Impact

Heterologous prime-boost immunization regimens are a common strategy for many vaccines. DNA prime rAd5-GP boost immunization has been demonstrated to protect non-human primates against a lethal challenge of Ebola virus, a pathogen that causes fatal hemorrhagic disease in humans. This protection correlates with antibody responses and is also associated with IFNγ+ TNFα+ double positive CD8+ T-cells. In this study, we compared single DNA vs. multiple DNA prime immunizations, and short vs. long time intervals between the DNA prime and the rAd5 boost to evaluate the impact of these different prime-boost strategies on vaccine-induced humoral and cellular responses in non-human primates. We demonstrated that DNA/rAd5 prime-boost strategies can be tailored to induce either CD4+ T-cell or CD8+ T-cell dominant responses while maintaining a high magnitude antibody response. Additionally, a single DNA prime immunization generated a stable memory response that could be boosted by rAd5 3 years later. These results suggest DNA/rAd5 prime-boost provides a flexible platform that can be fine-tuned to generate desirable T-cell memory responses.

scholarly journals K-RasG12D–induced T-cell lymphoblastic lymphoma/leukemias harbor Notch1 mutations and are sensitive to γ-secretase inhibitors

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3373-3382 ◽  
Author(s):  
Thomas Kindler ◽  
Melanie G. Cornejo ◽  
Claudia Scholl ◽  
Jianing Liu ◽  
Dena S. Leeman ◽  
...  
Keyword(s):  
T Cell ◽  
Target Genes ◽  
Bone Marrow Cells ◽  
Mapk Pathway ◽  
Notch Pathway ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Double Positive ◽  
The Impact ◽  
Notch1 Mutations

Abstract To study the impact of oncogenic K-Ras on T-cell leukemia/lymphoma development and progression, we made use of a conditional K-RasG12D murine knockin model, in which oncogenic K-Ras is expressed from its endogenous promoter. Transplantation of whole bone marrow cells that express oncogenic K-Ras into wild-type recipient mice resulted in a highly penetrant, aggressive T-cell leukemia/lymphoma. The lymphoblasts were composed of a CD4/CD8 double-positive population that aberrantly expressed CD44. Thymi of primary donor mice showed reduced cellularity, and immunophenotypic analysis demonstrated a block in differentiation at the double-negative 1 stage. With progression of disease, approximately 50% of mice acquired Notch1 mutations within the PEST domain. Of note, primary lymphoblasts were hypersensitive to γ-secretase inhibitor treatment, which is known to impair Notch signaling. This inhibition was Notch-specific as assessed by down-regulation of Notch1 target genes and intracellular cleaved Notch. We also observed that the oncogenic K-Ras-induced T-cell disease was responsive to rapamycin and inhibitors of the RAS/MAPK pathway. These data indicate that patients with T-cell leukemia with K-Ras mutations may benefit from therapies that target the NOTCH pathway alone or in combination with inhibition of the PI3K/AKT/MTOR and RAS/MAPK pathways.

scholarly journals Protective Efficacy and Long-Term Immunogenicity in Cynomolgus Macaques by Ebola Virus Glycoprotein Synthetic DNA Vaccines

2018 ◽  
Vol 219 (4) ◽  
pp. 544-555 ◽  
Author(s):  
Ami Patel ◽  
Emma L Reuschel ◽  
Kimberly A Kraynyak ◽  
Trina Racine ◽  
Daniel H Park ◽  
...  
Keyword(s):  
Immune Responses ◽  
Ebola Virus ◽  
Dna Vaccines ◽  
Viral Vector ◽  
Protective Efficacy ◽  
Lethal Challenge ◽  
Virus Glycoprotein ◽  
Cynomolgus Macaques ◽  
The Impact

Abstract Background There remains an important need for prophylactic anti-Ebola virus vaccine candidates that elicit long-lasting immune responses and can be delivered to vulnerable populations that are unable to receive live-attenuated or viral vector vaccines. Methods We designed novel synthetic anti-Ebola virus glycoprotein (EBOV-GP) DNA vaccines as a strategy to expand protective breadth against diverse EBOV strains and evaluated the impact of vaccine dosing and route of administration on protection against lethal EBOV-Makona challenge in cynomolgus macaques. Long-term immunogenicity was monitored in nonhuman primates for >1 year, followed by a 12-month boost. Results Multiple-injection regimens of the EBOV-GP DNA vaccine, delivered by intramuscular administration followed by electroporation, were 100% protective against lethal EBOV-Makona challenge. Impressively, 2 injections of a simple, more tolerable, and dose-sparing intradermal administration followed by electroporation generated strong immunogenicity and was 100% protective against lethal challenge. In parallel, we observed that EBOV-GP DNA vaccination induced long-term immune responses in macaques that were detectable for at least 1 year after final vaccination and generated a strong recall response after the final boost. Conclusions These data support that this simple intradermal-administered, serology-independent approach is likely important for additional study towards the goal of induction of anti-EBOV immunity in multiple at-risk populations.

scholarly journals On the Impact of the Data Acquisition Protocol on ECG Biometric Identification

Sensors ◽  
2021 ◽  
Vol 21 (14) ◽  
pp. 4645
Author(s):  
Mariana S. Ramos ◽  
João M. Carvalho ◽  
Armando J. Pinho ◽  
Susana Brás
Keyword(s):  
Data Acquisition ◽  
Signal Wave ◽  
Biometric Identification ◽  
Identification System ◽  
Time Interval ◽  
Essential Information ◽  
Ecg Signals ◽  
Movement Data ◽  
Long Time ◽  
The Impact

Electrocardiographic (ECG) signals have been used for clinical purposes for a long time. Notwithstanding, they may also be used as the input for a biometric identification system. Several studies, as well as some prototypes, are already based on this principle. One of the methods already used for biometric identification relies on a measure of similarity based on the Kolmogorov Complexity, called the Normalized Relative Compression (NRC)—this approach evaluates the similarity between two ECG segments without the need to delineate the signal wave. This methodology is the basis of the present work. We have collected a dataset of ECG signals from twenty participants on two different sessions, making use of three different kits simultaneously—one of them using dry electrodes, placed on their fingers; the other two using wet sensors placed on their wrists and chests. The aim of this work was to study the influence of the ECG protocol collection, regarding the biometric identification system’s performance. Several variables in the data acquisition are not controllable, so some of them will be inspected to understand their influence in the system. Movement, data collection point, time interval between train and test datasets and ECG segment duration are examples of variables that may affect the system, and they are studied in this paper. Through this study, it was concluded that this biometric identification system needs at least 10 s of data to guarantee that the system learns the essential information. It was also observed that “off-the-person” data acquisition led to a better performance over time, when compared to “on-the-person” places.

Dysregulation of T-Cell Development in Adrenal Glucocorticoid-Deprived Rats

2009 ◽  
Vol 234 (9) ◽  
pp. 1067-1074 ◽  
Author(s):  
Zorica Stojić-Vukanić ◽  
Aleksandra Rauški ◽  
Duško Kosec ◽  
Katarina Radojević ◽  
Ivan Pilipović ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
T Cell ◽  
T Cell Development ◽  
Cell Development ◽  
T Cell Differentiation ◽  
Male Rats ◽  
Double Positive ◽  
Cell Repertoire ◽  
Single Positive ◽  
The Impact

A number of different experimental approaches have been used to elucidate the impact of basal levels of adrenal gland-derived glucocorticoids (GCs) on T cell development, and thereby T cell-mediated immune responses. However, the relevance of the adrenal GCs to T cell development is still far from clear. This study was undertaken to explore the relevance of basal levels of GCs to T cell differentiation/maturation. Eight days post-adrenalectomy in adult male rats the thymocyte yield, apoptotic and proliferative rate and the relationship amongst major thymocyte subsets, as defined by TCRαβ/CD4/CD8 expression, were examined using flow cytometry. Adrenal GC deprivation decreased thymocyte apoptosis and altered the kinetics of T cell differentiation/maturation. In the adrenalectomized rats there was increased thymic hypercellularity and an over-representation of the CD4+CD8+ double positive (DP) TCRαβlow cells entering selection, as well as increased numbers of their DP TCRαβ− immediate precursors. These changes were accompanied with under-representation of the postselected DP TCRαβhigh and the most mature CD4−CD8+ and, particularly, CD4+CD8− single positive (SP) TCRαβhigh cells. This data suggests that withdrawal of adrenal GCs produces alterations in the thymocyte selection processes, possibly affecting the diversity of functional T cell repertoire and generation of potentially self-reactive cells as indicated by the reduced proportion and number of CD4−CD8− double negative TCRαβhigh cells. In addition, it indicates that GCs influence the post-selection maturation of thymocytes and plays a regulatory role in controlling the ratio of mature CD4+CD8−/CD4−CD8+ SP TCRαβhigh cells.

scholarly journals Influenza A virus-induced thymus atrophy differentially affects dynamics of conventional and regulatory T cell development

2020 ◽  
Author(s):  
Yassin Elfaki ◽  
Philippe A. Robert ◽  
Christoph Binz ◽  
Christine S. Falk ◽  
Dunja Bruder ◽  
...  
Keyword(s):  
T Cell ◽  
Influenza A Virus ◽  
Influenza A ◽  
Cell Receptor ◽  
Cell Development ◽  
Thymic Involution ◽  
Double Positive ◽  
Tcr Repertoire ◽  
Thymus Atrophy ◽  
The Impact

ABSTRACTFoxp3+regulatory T (Treg) cells, which are crucial for maintenance of self-tolerance, mainly develop within the thymus, where they arise from CD25+Foxp3-or CD25-Foxp3+ Treg cell precursors. Although it is known that infections can cause transient thymic involution, the impact of infection-induced thymus atrophy on thymic Treg (tTreg) cell development is unknown. Here, we infected mice with influenza A virus (IAV) and studied thymocyte population dynamics post infection. IAV infection caused a massive, but transient thymic involution, dominated by a loss of CD4+CD8+ double-positive (DP) thymocytes, which was accompanied by a significant increase in the frequency of CD25+Foxp3+ tTreg cells. Differential apoptosis susceptibility could be experimentally excluded as a reason for the relative tTreg cell increase, and mathematical modeling suggested that enhanced tTreg cell generation cannot explain the increased frequency of tTreg cells. Yet, an increased death of DP thymocytes and augmented exit of single-positive (SP) thymocytes was suggested to be causative. Interestingly, IAV-induced thymus atrophy resulted in a significantly reduced T cell receptor (TCR) repertoire diversity of newly produced tTreg cells. Taken together, IAV-induced thymus atrophy is substantially altering the dynamics of major thymocyte populations, finally resulting in a relative increase of tTreg cells with an altered TCR repertoire.

scholarly journals Pure T-cell mediated rejection following kidney transplant according to response to treatment

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0256898
Author(s):  
Hyunwook Kwon ◽  
Young Hoon Kim ◽  
Youngmin Ko ◽  
Seong Jun Lim ◽  
Joo Hee Jung ◽  
...  
Keyword(s):  
T Cell ◽  
Graft Failure ◽  
Significant Risk ◽  
Diagnostic System ◽  
Significant Risk Factor ◽  
Response To Treatment ◽  
Histologic Diagnosis ◽  
Antibody Mediated Rejection ◽  
Long Time ◽  
The Impact

The focus of studies on kidney transplantation (KT) has largely shifted from T-cell mediated rejection (TCMR) to antibody-mediated rejection (ABMR). However, there are still cases of pure acute TCMR in histological reports, even after a long time following transplant. We thus evaluated the impact of pure TCMR on graft survival (GS) according to treatment response. We also performed molecular diagnosis using a molecular microscope diagnostic system on a separate group of 23 patients. A total of 63 patients were divided into non-responders (N = 22) and responders (N = 44). Non-response to rejection treatment was significantly associated with the following factors: glomerular filtration rate (GFR) at biopsy, ΔGFR, TCMR within one year, t score, and IF/TA score. We also found that non-responder vs. responder (OR = 3.31; P = 0.036) and lower GFR at biopsy (OR = 0.56; P = 0.026) were independent risk factors of graft failure. The responders had a significantly superior overall GS rate compared with the non-responders (P = 0.004). Molecular assessment showed a good correlation with histologic diagnosis in ABMR, but not in TCMR. Solitary TCMR was a significant risk factor of graft failure in patients who did not respond to rejection treatment.

An Adaptive and Learning System for Feedback-Controlled Evoked Response Studies

1981 ◽  
Vol 20 (03) ◽  
pp. 169-173
Author(s):  
J. Wagner ◽  
G. Pfurtscheixer
Keyword(s):  
Brain Activity ◽  
Evoked Response ◽  
Learning System ◽  
Time Interval ◽  
Electrical Brain Activity ◽  
Long Time ◽  
The Subject ◽  
Eeg Power ◽  
Stimulation System ◽  
Background Eeg

The shape, latency and amplitude of changes in electrical brain activity related to a stimulus (Evoked Potential) depend both on the stimulus parameters and on the background EEG at the time of stimulation. An adaptive, learnable stimulation system is introduced, whereby the subject is stimulated (e.g. with light), whenever the EEG power is subthreshold and minimal. Additionally, the system is conceived in such a way that a certain number of stimuli could be given within a particular time interval. Related to this time criterion, the threshold specific for each subject is calculated at the beginning of the experiment (preprocessing) and adapted to the EEG power during the processing mode because of long-time fluctuations and trends in the EEG. The process of adaptation is directed by a table which contains the necessary correction numbers for the threshold. Experiences of the stimulation system are reflected in an automatic correction of this table. Because the corrected and improved table is stored after each experiment and is used as the starting table for the next experiment, the system >learns<. The system introduced here can be used both for evoked response studies and for alpha-feedback experiments.

Euratom and Brexit: Could the United Kingdom Maintain One Foot in the European Union? Current Scenarios and Future Prospects of British withdrawal from the EAEC

2018 ◽  
Vol 18 (2) ◽  
pp. 134-151
Author(s):  
Andrea Circolo ◽  
Ondrej Hamuľák
Keyword(s):  
European Union ◽  
United Kingdom ◽  
Independent Solution ◽  
Legal Regulation ◽  
The European Union ◽  
The United Kingdom ◽  
The Status ◽  
Long Time ◽  
Energy Community ◽  
The Impact

Abstract The paper focuses on the very topical issue of conclusion of the membership of the State, namely the United Kingdom, in European integration structures. The ques­tion of termination of membership in European Communities and European Union has not been tackled for a long time in the sources of European law. With the adop­tion of the Treaty of Lisbon (2009), the institute of 'unilateral' withdrawal was intro­duced. It´s worth to say that exit clause was intended as symbolic in its nature, in fact underlining the status of Member States as sovereign entities. That is why this institute is very general and the legal regulation of the exercise of withdrawal contains many gaps. One of them is a question of absolute or relative nature of exiting from integration structures. Today’s “exit clause” (Art. 50 of Treaty on European Union) regulates only the termination of membership in the European Union and is silent on the impact of such a step on membership in the European Atomic Energy Community. The presented paper offers an analysis of different variations of the interpretation and solution of the problem. It´s based on the independent solution thesis and therefore rejects an automa­tism approach. The paper and topic is important and original especially because in the multitude of scholarly writings devoted to Brexit questions, vast majority of them deals with institutional questions, the interpretation of Art. 50 of Treaty on European Union; the constitutional matters at national UK level; future relation between EU and UK and political bargaining behind such as all that. The question of impact on withdrawal on Euratom membership is somehow underrepresented. Present paper attempts to fill this gap and accelerate the scholarly debate on this matter globally, because all consequences of Brexit already have and will definitely give rise to more world-wide effects.

A general practice provider federation in a mixed health economy in England: a case study investigation

2018 ◽  
Vol 68 (suppl 1) ◽  
pp. bjgp18X696929
Author(s):  
Jill Mitchell
Keyword(s):  
General Practice ◽  
Shared Vision ◽  
Health Economy ◽  
Structured Interviews ◽  
The North ◽  
Common Strategy ◽  
Common Purpose ◽  
Collaborative Working ◽  
The Impact

BackgroundThere is an emerging debate that general practice in its current format is out-dated and there is a requirement to move to a federated model of provision where groups of Practices come together. The emergence of federations has developed over the past 5 years but the factors that influence how federations develop and the impact of this new model is an under researched area.AimThe study explored the rationale around why a group of independent GP practices opted to pursue an alternative business venture and the benefits that this strategy offered.MethodA single organisational case study of a federation in the North of England was conducted between 2011–2016. Mixed methods data collection included individual and group semi-structured interviews and quantitative surveys.ResultsFederations promote collaborative working, relying on strategic coherence of multiple individual GP practices through a shared vision and common purpose. Findings revealed many complexities in implementing a common strategy across multiple independent businesses. The ability of the federation to gain legitimacy was two dimensional – externally and internally. The venture had mixed successes, but their approach to quality improvement proved innovative and demonstrated outcomes on a population basis. The study identified significant pressures that practices were experiencing and the need to seek alternative ways of working but there was no shared vision or inclination to relinquish individual practice autonomy.ConclusionOrganisational development support is critical to reform General Practice. Whether central funding through the GP Five Year Forward View will achieve the scale of change required is yet to be evidenced.

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