Biology subjects

Babel, N.

Publications and source records attributed to Babel, N..

9 recordsLinked to original sources

bioRxiv2025

A complex osteoporotic milieu is associated with arterial stiffening and PDGF-BB-mediated calcification of human smooth muscle cells

Accumulating evidence links skeletal and vascular aging, yet the pathological cross-talk between osteoporotic bone and vascular calcification remains insufficiently understood. In this retrospective exploratory study, we show that osteoporotic individuals exhibit a distinct systemic milieu characterized by elevated eosinophil, neutrophil, and platelet counts, as well as altered levels of sCD40L, PDGF-BB, osteopontin, and SDF-1. These changes correlate with both bone metabolism and arterial stiffness, indicating a multifactorial bone-vascular interplay. Moreover, osteoporotic sera accelerated calcification of human vascular smooth muscle cells in vitro, with PDGF-BB emerging as a central mediator. Inhibition of PDGF-BB downstream signaling blocked this effect, suggesting a mechanistic role of PDGF-BB in linking the osteoporotic milieu to vascular calcification. Conceptualizing this cross-talk as a complex adaptive system advances our understanding of the disease dynamics between localized bone loss and vascular pathologies. Furthermore, it may guide therapeutic strategies, with PDGF-BB as a potential target, to support healthier aging.

cell biology↗

bioRxiv2023

Stable Equilibria under Random Fitness and Recombination Rates

We develop and analyze a two-locus biallelic genetic model with randomized recombination rates and fitness matrices. While deterministic models reveal a trajectory toward the simplex center before stabilizing at polymorphisms, introducing random recombination pinpointed regions of attraction dependent on the fitness matrix and recombination fraction range. As recombination randomness intensifies, transitions in these attraction regions are observed. Analysis with random fitness matrices highlighted genotype attraction towards the tetrahedron vertices with edges guiding genotypic clustering.

evolutionary biology↗

bioRxiv2022

Increased migratory/activated CD8+ T cell and low avidity SARS-CoV-2 reactive cellular response in post-acute COVID-19 syndrome

The role of autoimmunity in post-acute sequelae of COVID-19 (PASC) is not well explored, although clinicians observe a growing population of convalescent COVID-19 patients with manifestation of post-acute sequelae of COVID-19. We analyzed the immune response in 40 post-acute sequelae of COVID-19 patients with non-specific PASC manifestation and 15 COVID-19 convalescent healthy donors. The phenotyping of lymphocytes showed a significantly higher number of CD8+ T cells expressing the Epstein-Barr virus induced G protein coupled receptor 2, chemokine receptor CXCR3 and C-C chemokine receptor type 5 playing an important role in inflammation and migration in PASC patients compared to controls. Additionally, a stronger, SARS-CoV-2 reactive CD8+ T cell response, characterized by IFN{gamma} production and predominant TEMRA phenotype but low SARS-CoV-2 avidity was detected in PASC patients compared to controls. Furthermore, higher titers of several autoantibodies were detected among PASC patients. Our data suggest that a persistent inflammatory response triggered by SARS-CoV-2 might be responsible for the observed sequelae in PASC patients. These results may have implications on future therapeutic strategies.

immunology↗

bioRxiv2020

Impaired cytotoxic CD8+ T cell response in elderly COVID-19 patients

SARS-CoV-2 infection induces a T cell response that most likely contributes to virus control in COVID-19 patients, but may also induce immunopathology. Until now, the cytotoxic T cell response has not been very well characterized in COVID-19 patients. Here, we analyzed the differentiation and cytotoxic profile of T cells in 30 cases of mild COVID-19 during acute infection. SARS-CoV-2 infection induced a cytotoxic response of CD8+ T cells, but not CD4+ T cells, characterized by the simultaneous production of granzyme A and B, as well as perforin within different effector CD8+ T cell subsets. PD-1 expressing CD8+ T cells also produced cytotoxic molecules during acute infection indicating that they were not functionally exhausted. However, in COVID-19 patients over the age of 80 years the cytotoxic T cell potential was diminished, especially in effector memory and terminally differentiated effector CD8+ cells, showing that elderly patients have impaired cellular immunity against SARS-CoV-2. Our data provides valuable information about T cell responses in COVID-19 patients that may also have important implications for vaccine development. ImportanceCytotoxic T cells are responsible for the elimination of infected cells and are key players for the control of viruses. CD8+ T cells with an effector phenotype express cytotoxic molecules and are able to perform target cell killing. COVID-19 patients with a mild disease course were analyzed for the differentiation status and cytotoxic profile of CD8+ T cells. SARS-CoV-2 infection induced a vigorous cytotoxic CD8+ T cell response. However, this cytotoxic profile of T cells was not detected in COVID-19 patients over the age of 80 years. Thus, the absence of a cytotoxic response in elderly patients might be a possible reason for the more frequent severity of COVID-19 in this age group in comparison to younger patients.

immunology↗

bioRxiv2020

SARS-CoV-2 reactive T cells in uninfected individuals are likely expanded by beta-coronaviruses

The current pandemic is caused by the SARS-CoV-2 virus and large progress in understanding the pathology of the virus has been made since its emergence in late 2019. Several reports indicate short lasting immunity against endemic coronaviruses, which contrasts repeated reports that biobanked venous blood contains SARS-CoV-2 reactive T cells even before the outbreak in Wuhan. This suggests there exists a preformed T cell memory in individuals not exposed to the pandemic virus. Given the similarity of SARS-CoV-2 to other members of the Coronaviridae family, the endemic coronaviruses appear likely candidates to generate this T cell memory. However, given the apparent poor immunological memory created by the endemic coronaviruses, other immunity against other common pathogens might offer an alternative explanation. Here, we utilize a combination of epitope prediction and similarity to common human pathogens to identify potential sources of the SARS-CoV-2 T cell memory. We find that no common human virus, other than beta-coronaviruses, can explain the pre-existing SARS-CoV-2 reactive T cells in uninfected individuals. Our study suggests OC43 and HKU1 are the most likely pathogens giving rise to SARS-CoV-2 preformed immunity.Competing Interest StatementThe authors have declared no competing interest.View Full Text

immunology↗

bioRxiv2020

Rapid T cell receptor interaction grouping with ting

MotivationClustering of antigen-specific T cell receptor repertoire (TCRR) sequences is challenging. The recently published tool GLIPH aims to solve this problem. However, clustering large repertoires takes several days to weeks, making its use impractical in larger studies. In addition, the methodology used in GLIPH suffers from several shortcomings, including non-determinism, potential loss of significant antigen-specific sequences or inclusion of too many unspecific sequences. ResultsWe present an algorithm for clustering TCRR sequences that scales efficiently to large repertoires. We clustered 26 real datasets with up to 62 000 unique CDR3{beta} sequences using both GLIPH and an implementation of our method called ting. While GLIPH required multiple weeks, ting only needed about one hour for the same task. In addition, we found that in naive repertoires, where no or very few antigen-specific CDR3 sequences or clusters should exist, our method indeed selects fewer sequences. AvailabilityOur method has been implemented in Python as a tool called ting, using numpy and NetworkX. It is available on GitHub (https://github.com/FelixMoelder/ting) and on PyPI under the MIT license. Contactfelix.moelder@uni-due.de or sven.rahmann@uni-due.de

bioinformatics↗

bioRxiv2019

Sex-associated differences in cytomegalovirus prevention: Prophylactic strategy is associated with a strong kidney function impairment in female renal transplant patients

Post-transplantation cytomegalovirus (CMV) syndrome can be prevented using the antiviral drug (val)ganciclovir. (Val)ganciclovir is typically administered following a prophylactic or a pre-emptive strategy. The prophylactic strategy entails early universal administration, the pre-emptive strategy, early treatment in case of infection. However, it is not clear which strategy is superior with respect to transplantation outcome; sex-specific effects of these prevention strategies are not known. We have retrospectively analysed 540 patients from the multi-centre Harmony study along eight pre-defined visits: 308 were treated according to a prophylactic, 232 according to a pre-emptive strategy. As expected, we observed an association of prophylactic strategy with lower incidence of CMV syndrome, delayed onset and lower viral loads compared to the pre-emptive strategy. However, in female patients, the prophylactic strategy was associated with a strong impairment of glomerular filtration rate one year post-transplant (difference: -12.0{+/-}4.2 mL{middle dot}min-1{middle dot}1.73m-2, P=0.005). Additionally, we observed a tendency of higher incidence of acute rejection and severe BK virus reactivation in the prophylactic strategy group. While the prophylactic strategy was more effective for preventing CMV syndrome, our results suggest for the first time that the prophylactic strategy might lead to inferior transplantation outcomes in female patients, providing evidence for a strong association with sex.

pharmacology and toxicology↗

bioRxiv2019

BKV clearance time correlates with exhaustion state and T-cell receptor repertoire shape of BKV-specific T-cells in renal transplant patients

Reactivation of the BK polyomavirus is known to lead to severe complications in kidney transplant patients. The current treatment strategy relies on decreasing the immunosuppression to allow the immune system to clear the virus. Recently, we demonstrated a clear association between the resolution of BKV reactivation and reconstitution of BKV-specific CD4+ T-cells. However, which factors determine the duration of viral infection clearance remains so far unclear. Here we apply a combination of in-depth multi-parametric flow cytometry and NGS-based CDR3 beta chain receptor repertoire analysis of BKV-specific T-cells to a cohort of 7 kidney transplant patients during the clinical course of BKV reactivation. This way we followed TCR repertoires at single clone levels and functional activity of BKV-specific T-cells during the resolution of BKV infection. The duration of BKV clearance did not depend on the number of peripheral blood BKV-specific T-cells nor on a few immunodominant BKV-specific T-cell clones. Rather, the T-cell receptor repertoire diversity and exhaustion status of BKV-specific T-cells affected the duration of viral clearance: high clonotype diversity and lack of PD1 and TIM3 exhaustion markers on BKV-specific T-cells was associated with short clearance time. Our data thus demonstrate how the diversity and the exhaustion state of the T-cells can determine the clinical course of BKV infection.

immunology↗

bioRxiv2018

A novel approach reveals that HLA class 1 single antigen bead-signatures provide a means of high-accuracy pre-transplant risk assessment of acute cellular rejection

Acute cellular rejection (ACR) is associated with complications after kidney transplantation, such as graft dysfunction and graft loss. Early risk assessment is therefore critical for the improvement of transplantation outcomes. In this work, we retrospectively analyzed a pre-transplant HLA antigen bead assay data set that was acquired by the e:KID consortium as part of a systems medicine approach. The data set included single antigen bead (SAB) reactivity profiles of 52 low-risk graft recipients (negative complement dependent cytotoxicity crossmatch, PRA<30%) who showed detectable pre-transplant anti-HLA 1 antibodies. To assess whether the reactivity profiles provide a means for ACR risk assessment, we established a novel approach which differs from standard approaches in two aspects: the use of quantitative continuous data and the use of a multiparameter classification method. Remarkably, it achieved significant prediction of the 38 graft recipients who experienced ACR with a balanced accuracy of 82.7% (sensitivity=76.5%, specificity= 88.9%). The resultant classifier achieved one of the highest prediction accuracies in the literature for pre-transplant risk assessment of ACR. Importantly, it can facilitate risk assessment in non-sensitized patients who lack donor-specific antibodies. As the classifier is based on continuous data and includes weak signals, our results emphasize that not only strong but also weak binding interactions of antibodies and HLA 1 antigens contain predictive information.

immunology↗