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Sahoo, R. K.

Publications and source records attributed to Sahoo, R. K..

13 recordsLinked to original sources

Population genomics of a biocontrol agent: Insights into post-introduction establishment in parthenium beetle

Biological control agents often experience demographic bottlenecks during introduction, which can reshape genetic diversity and inbreeding pattern influencing establishment and long-term ecological success in the introduced populations. The leaf-feeding beetle Calligrapha (Zygogramma) bicolorata, introduced in multiple countries across the globe to control the weed Parthenium hysterophorus, provides an opportunity to examine how introduction bottleneck and post-introduction breeding practices shape genomic variation and inbreeding patterns. We analyzed whole-genome variation in the introduced beetle population in India by sampling six regions encompassing its current distribution in the country. Using genome-wide variation data, we assessed population structure, genetic diversity, and inbreeding patterns across regions, and inferred historical changes in effective population size to reconstruct post-introduction demographic trajectories. The analyses reveal subtle genetic structure across regions, with overall genetic diversity relatively low compared to other invasive and biocontrol insects. Inbreeding patterns vary among populations, with some regions exhibiting higher cumulative runs of homozygosity than others. Notably, regions subjected to intensive propagation of beetle populations show elevated signature of inbreeding alongside reduced historical effective population size. These results underscore the dynamic genomic consequences of biocontrol introduction and subsequent breeding practices, providing insight into the evolutionary trajectories of introduced biocontrol agents.

evolutionary biology↗

Effects of cross-generational inbreeding and Wolbachia infection on sex ratio and life-history traits in parthenium beetle

Sex ratio is a key demographic parameter shaping population dynamics and evolutionary trajectories. In biocontrol agents, demographic bottlenecks during species introduction to a new habitat and subsequent mass rearing can elevate inbreeding, potentially biasing sex ratios through sex-specific mortality associated with inbreeding depression. Moreover, reproductive endosymbionts such as Wolbachia are known to manipulate host reproduction and further skew sex ratios. However, the relative contributions of these processes to sex-ratio variation remain poorly resolved. In this study, we evaluated the effects of cross-generational full-sibling inbreeding and Wolbachia infection on sex ratio and key life-history traits in the biocontrol beetle Zygogramma bicolorata using controlled laboratory crosses across three generations. Inbreeding did not significantly alter offspring sex ratio, which remained close to parity across generations, while pupal mortality increased in later generations, consistent with delayed expression of inbreeding depression. Adult body weight remained largely unaffected by inbreeding. Wolbachia infection was detected in a subset of females and was associated with a modest but significant increase in female-biased offspring production, although the effect was variable across lineages. Strain typing identified a single supergroup A Wolbachia, consistent with previous descriptions of the wBic strain from this species. These findings indicate that sex-ratio variation in introduced populations of Z. bicolorata is not driven by inbreeding alone but instead emerges from the interaction between demographic processes and symbiont-mediated effects, providing crucial insights for optimizing biocontrol programs where sex-ratio stability is essential for population establishment and persistence. SignificanceSex ratio is a key determinant of population growth and stability - the essential parameters determining success of biocontrol programs. Yet, the mechanisms shaping sex-ratio variation remain poorly resolved. Using controlled crosses in Zygogramma bicolorata, we show that short-term inbreeding does not directly alter sex allocation, despite inducing delayed fitness costs through increased pupal mortality. In contrast, Wolbachia infection contributes to female-biased offspring production, although with variable outcome across lineages. These findings demonstrate that sex-ratio variation in Z. bicolorata arises from the interaction of demographic processes and symbiont effects, rather than a single mechanism, with important implications for predicting the establishment, persistence, and efficacy of mass-reared biocontrol populations.

ecology↗

Structural reorganization and genomic context define a divergent lineage of the Wolbachia male-killing gene wmk

Patterns of diversity in symbiont effector genes provide insight into the evolutionary processes that shape their diversification, particularly those arising from host-symbiont interactions. In one of the most widespread symbiont genera, Wolbachia, the male-killing candidate gene wmk encodes a putative transcriptional regulator. Sequence divergence of this effector gene from a limited number of strains has revealed at least five phylogenetic types. However, additional wmk variants characterized by a large inframe deletion and protein reorganization suggest that diversity in wmk extends beyond sequence variation alone. To gain further insight into wmk effector diversity, homologous proteins from 251 Wolbachia genomes were analyzed using comparative sequence and structure-informed approaches. The results show that sequence and structural diversification largely follow similar patterns; however, one lineage newly identified in this analysis stands out due to pronounced structural reorganization. The distinct genomic neighborhood of this divergent lineage, relative to other wmk lineages, suggests additional diversity at the regulatory level. Together, these findings demonstrate that variation in protein structure and genomic context complements sequence-level polymorphism in shaping wmk effector diversity in Wolbachia. Further analyses indicate that symbiont supergroup and host taxonomic order constrain the distribution of the divergent wmk lineage.

evolutionary biology↗

Comparative metabolomics of released pollen during dispersal reveals metabolic adaptations to cold and heat stress

Heat and cold stress can severely impair released pollen, reducing pollen viability and ultimately limiting fertilization and crop productivity. Following release, pollen is directly exposed to fluctuating environmental temperatures, necessitating adaptive metabolic mechanisms to sustain viability during dispersal. In response to temperature stress, pollen undergoes metabolic reprogramming that supports biochemical and physiological adaptation. However, the metabolic basis of pollen tolerance to extreme temperatures remains incompletely understood. In this study, biochemical assays combined with LC-MS-based untargeted metabolomic profiling were employed to investigate metabolic changes in released pollen exposed to low (15 {degrees}C) and high (35 {degrees}C) temperature stress. A total of 484 metabolites were detected, of which 147 were significantly altered between cold- and heat-stressed pollen, including 61 upregulated and 86 downregulated metabolites. Differentially regulated metabolites spanned multiple classes, including amino acids, flavonoids, long-chain fatty acids, sugars, and polyamines. Pathway enrichment analysis highlighted biologically relevant perturbations in amino acid and nucleic acid metabolism, including purine metabolism, arginine biosynthesis, and glutathione metabolism. Collectively, these findings demonstrate temperature-dependent metabolic adjustments in released pollen and provide new insights into the biochemical strategies underlying pollen tolerance to heat and cold stress. This work advances our understanding of pollen metabolic adaptation during dispersal and provides a foundation for identifying metabolic indicators relevant to crop fertility under changing climatic conditions. These findings provide a metabolomic framework for understanding pollen thermotolerance during dispersal and offer a resource for future studies on reproductive resilience under climate change.

plant biology↗

Dual Preconditioned Mesenchymal Stem Cells-Derived Culture Conditioned Media Augment Immunomodulation and Drive Metabolic Reprogramming in Acute Graft-versus-Host Disease

BackgroundThe toxicity associated with conventional conditioning regimens limits treatment outcomes in autoimmune disorders such as acute graft-versus-host disease (aGVHD). Developing effective adjunctive interventions to restore immune balance is therefore essential. This study investigated the immunomodulatory potential of mesenchymal stem cells (MSCs)-derived culture-conditioned media (CCM) from naive and preconditioned MSCs-hypoxic (MSCsHYP), apoptotic (MSCsAPO), and dual preconditioned (MSCsHYP+APO) in aGVHD. MethodsHuman MSCs isolated from bone marrow and Whartons Jelly were preconditioned under hypoxia (1% O2), apoptosis (1 {micro}M staurosporine, 24 h), or both. The immunoregulatory and antioxidant properties of their CCM were evaluated through T-cell proliferation assays, Treg induction, macrophage polarization, mitochondrial function, and T-cell bioenergetics. Comparative proteomic profiling of CCM from WJ-MSCs and WJ-MSCsHYP+APO co-cultured with aGVHD patient-derived activated PBMNCs was performed using LC-MS/MS, alongside in vivo validation in a chemotherapy-induced aGVHD murine model. ResultsWJ-MSCsHYP+APO-CCM exhibited superior immunomodulatory efficacy, suppressing T-cell proliferation, promoting Treg and Th2/Th9 differentiation, and driving M2 macrophage polarization. It reduced mitochondrial ROS, enhanced mitochondrial polarization, and shifted T-cell metabolism from glycolysis toward oxidative phosphorylation. Proteomic analysis revealed modulation of IL-12, IL-17, and JAK-STAT pathways, along with regulation of complement, coagulation, and metabolic cascades. Interaction with immune cells further enhanced its antioxidant and tissue-reparative properties via extracellular matrix remodeling. ConclusionDual preconditioning under hypoxia and apoptosis amplifies the immunomodulatory, antioxidant, and reparative efficacy of WJ-MSC-CCM, offering a potent non-cellular therapeutic strategy for aGVHD management. GRAPHICAL ABSTRACTImmunomodulatory and immune metabolic reprogramming potential of naive and preconditioned MSCs (MSCs, MSCsHYP, MSCsAPO, MSCsHYP+APO) derived CCM in Acute GVHD (created using Biorender.com) O_FIG O_LINKSMALLFIG WIDTH=95 HEIGHT=200 SRC="FIGDIR/small/686182v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@f7ed73org.highwire.dtl.DTLVardef@1063015org.highwire.dtl.DTLVardef@13ed827org.highwire.dtl.DTLVardef@e103c0_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

The HOTAIRM1-miR-222 Axis Regulates Venetoclax Resistance and Defines a High-Risk Subset in Pediatric t(8;21) Acute Myeloid Leukemia

Although acute myeloid leukemia (AML) with the RUNX1::RUNX1T1 fusion [t(8;21)(q22;q22.1)] defines a distinct cytogenetic subtype, differences in treatment response suggest additional molecular contributors beyond chromosomal abnormalities. Deregulated hematopoietic lineage-specific long non-coding RNAs (lncRNAs) contribute to leukemogenesis and therapy resistance. To investigate their role in t(8;21) AML, we performed whole-transcriptome sequencing of pediatric patients and age-matched healthy controls, identifying significant downregulation of lncRNA HOTAIRM1, a regulator of myeloid differentiation (adjusted P < 0.05). This was confirmed in a single-cell RNA-sequencing dataset (GSE116256) and the Leukemia MILE dataset (GSE13159, P=0.03). Validation of expression in our study cohort using qPCR specifically demonstrated significant downregulation of the myeloid specific isoform, HOTAIRM1 - HM1V2 (P<0.0001). Analysis of downstream pathways activated by HM1V2 loss identified miR-222, an oncomiR, as a de-repressed target (P=0.01). Elevated miR-222 expression was observed across AML cell lines (P<0.05), leukemic stem and progenitor cells (GSE117090, P<0.05), AML plasma-derived exosomes (GSE142699, P<0.0001), the current study dataset (P<0.0001), and the TARGET AML dataset (P<0.0001). Restoring HM1V2 expression with epigenetic agents azacytidine and panobinostat induced apoptosis in venetoclax-resistant Kasumi-1 cells (P < 0.01), through suppression of miR-222 (P < 0.01) and downregulation of anti-apoptotic proteins BCL-xL and MCL-1 (P < 0.05), key mediators of the venetoclax resistance mechanism. Machine learning based feature selection and Cox regression analysis showed that high miR-222 expression predicts poor outcome in pediatric t(8;21) AML, validated in both our institutional pediatric AML cohort (P < 0.05) and the multi-institutional TARGET cohort (P < 0.0001). Together, our findings highlight an epigenetic based approach to restore isoform-specific HM1V2 pathway function in venetoclax-resistant AML cells, and identifies miR-222 as a prognostic marker to refine risk stratification within the traditionally favorable-risk t(8;21) AML subgroup. Key PointsO_LILoss of myeloid lineage specific isoform of lncRNA HOTAIRM1 - HOTAIRM1 variant 2, results in de-repression of microRNA miR-222, and contributes to venetoclax resistance in pediatric AML patients harbouring the t(8;21)(q22;q22.1)/RUNX1::RUNX1T1 fusion. C_LIO_LIMicroRNA miR-222 shows potential as a single marker predictor that complements current risk stratification by identifying a subset of pediatric t(8;21) AML patients with poor prognosis. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/663834v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@19a0931org.highwire.dtl.DTLVardef@1d1a51aorg.highwire.dtl.DTLVardef@ae6783org.highwire.dtl.DTLVardef@de78e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

Predictive Modeling of acute Graft-versus-Host-Disease using Machine Learning on Immune Cell and Cytokine Profiles at Engraftment

BackgroundAcute Graft-versus-Host-Disease (aGvHD) is a major immune complication following allogenic hematopoietic stem cell transplantation (Allo-HSCT), initiated by conditioning regimen-associated tissue damage. It involves the complex interplay of immune cells and cytokines. Our study aims to leverage machine learning (ML) algorithms on the immune and cytokine profile of Allo-HSCT recipients to develop biomarker-based classification models to predict the onset of aGvHD at the time of engraftment. Materials and MethodsSeventy patients diagnosed with hematological disorders who had undergone Ist Allo-HSCT were recruited from All India Institute of Medical Sciences, New Delhi, India. Peripheral blood (PB) was collected from the patients at the time of engraftment, and the immune cell subtypes and cytokine profiles were analyzed using flow cytometry and ELISA respectively. The individual cell counts were then processed using basic ML models, including support vector classifier with RBF kernel, Decision Tree, and Random Forest, chosen for their mathematical simplicity and feature importance advantage of Decision Trees and Random Forests. Various data settings were utilized in the study: combined immune and cytokine counts, immune cell counts only, cytokine counts only, T-cell counts only, NK cell counts only, dendritic cell counts only, and B-cell counts only. These configurations were selected to investigate how different data sets impact the prediction of aGvHD before its onset. ResultsAt the engraftment flow cytometric analysis of reconstituted lymphocytes in patients who developed aGvHD revealed that there was a remarkable decrease in the ratio of CD4+/CD8+ T-cell and Tregs, with an increase in the cytotoxic regulatory NK-cell, dendritic cells, and B-cell. The levels of pro-inflammatory cytokines (IFN-{gamma}, IL-1{beta}, IP-10, TNF-, IL-17, IL-12p70, MIP-1, MIP-1{beta}, RANTES), and Th17-and Th1-cells were elevated with consequent decline of the levels of anti-inflammatory cytokine IL-10, IL-2, IL-4 and Th2-, Th9-cells. Machine learning based on 48 parameters [all immune cell subsets n=34 and all cytokines (n=14)]. The correlation heat map shows a higher correlation of aGvHD with the cytokine profile with or without immune cells (accuracy: 1), T-cell alone (accuracy: 0.96); NK-cell alone (accuracy: 0.93); dendritic cells alone (accuracy: 0.90), B-cell alone (accuracy: 0.86). ConclusionThe current models classify perfectly, indicating the potential for a ML algorithm in predicting the onset of aGvHD. However, a study with a larger sample size is required to validate these classification models and mitigate the risk of overfitting observed due to the consistently high performance. The study also highlights the potential of cytokine profiles as a viable alternative to T-cell counts, as evidenced by the correlation heat map and classifier models. These findings provide valuable insights into dataset requirements and future directions for integrating ML models into aGvHD prediction.

immunology↗

Dose-Response Immunomodulatory Effects of Mesenchymal Stem Cells-Derived Culture-Conditioned Media in Acute Graft-versus-Host-Disease

BackgroundMesenchymal stem cell-based therapy faces challenges that have driven interest in MSCs-derived culture-conditioned media (CCM) as a cell-free alternative. Our study aims to optimize the dose, and collection timing of CCM to enhance its therapeutic efficacy in aGVHD, while also standardizing co-culture conditions for CD3+ T-cell interaction with CCM. Material and MethodsHuman MSCs were isolated from BM and WJ and subsequently preconditioned under hypoxic conditions (1% O2) for 24 hours in a tri-gas incubator. Culture-conditioned media (CCM) was collected from both naive and hypoxia-preconditioned MSCs at 24, 48, and 72 hours and filtered using a 0.2 m membrane filter. CD3+ T-cell were isolated from PBMNCs derived from aGVHD patients. These T-cell were co-cultured at varying densities (2*106, 5*106, and 10*106 cells/ml) with different concentrations of CCM (25%, 50%, and 100%), and cell proliferation was assessed using the MTS assay. Furthermore, CD3+ T-cell proliferation and activation status were evaluated in a 2D co-culture model of CD3+ T-cell and CCM using flow cytometry. ResultsOur findings revealed that CCM collected at 48 hours, at a 50% concentration, exerted the most pronounced inhibitory effect on CD3+ T-cell proliferation, particularly at a density of 5*106 cells/ml, irrespective of the MSCs source. Hypoxia preconditioning significantly enhanced the immunomodulatory effects, with WJ-MSCsHYP-CCM demonstrating superior efficacy in suppressing T-cell proliferation, increasing the CD4+/CD8+ T-cell ratio, and reducing CD4+ T-cell activation compared to BM-MSCsHYP-CCM. ConclusionThese results emphasize the critical role of optimizing CCM collection timing and concentration to maximize therapeutic potential. Our study paves the way for the development of standardized, scalable, and effective cell-free therapies for aGVHD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/640019v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@16ecc48org.highwire.dtl.DTLVardef@12591dborg.highwire.dtl.DTLVardef@18af4beorg.highwire.dtl.DTLVardef@1c9e8c9_HPS_FORMAT_FIGEXP M_FIG C_FIG Optimum conditions for CCM dose, collection time point, and CD3+ T-cell dose for effective immunomodulatory effect of MSCs-derived CCM in aGVHD. (created using Biorender.com)

immunology↗

Hypoxia-Mediated Molecular Interactions of Tissue-Specific Mesenchymal Stem Cells Drive Metabolic Reprogramming and Immunomodulation in Acute Graft-versus-Host Disease

BackgroundMesenchymal stem cells (MSCs) mediate immunomodulation through various mechanisms, including apoptosis, efferocytosis, and mitochondrial transfer. Our study investigates the impact of hypoxia preconditioning on the immune metabolic reprogramming and immunomodulatory potential of MSCs in acute graft-versus-host disease (aGVHD). Additionally, we explored the differential immunomodulatory effects of tissue-specific MSCs, specifically bone marrow (BM) and Whartons Jelly (WJ), and elucidated the mechanisms underlying variability in their therapeutic efficacy. MethodsMSCs were isolated from BM and WJ and subjected to hypoxia preconditioning. Their immunometabolic programming potential was assessed by evaluating T-cell proliferation, regulatory T-cell (Treg) induction, effector T-cell differentiation toward Th2, Th9 phenotypes, and macrophage polarization, T-cell bioenergetics in the direct co-culture systems. ResultsWJ-MSCsHYP exhibited superior immunomodulatory properties compared to BM-MSCsHYP, by inhibiting T-cell proliferation, enhancing Treg induction, and promoting anti-inflammatory macrophage polarization. WJ-MSCsHYP demonstrated enhanced mitochondrial transfer to T-cell, improving mitochondrial health, reducing ROS, and promoting oxidative phosphorylation, leading to immune homeostasis. Unlike BM-MSCs, WJ-MSCs exhibited higher rates of apoptosis, which facilitated immune modulation through mechanisms independent of efferocytosis. ConclusionOur findings highlight that WJ-MSCsHYP is a superior candidate for aGVHD by utilizing apoptosis, mitochondrial transfer, and metabolic reprogramming to achieve immune regulation.

immunology↗

A Comparative assessment of T-Cell response of Healthy donors and Acute Graft-versus-Host-Disease Patients: Customizing immune monitoring platform

BackgroundT-cell activation and proliferation are critical for understanding immune responses in both healthy and pathological conditions such as acute graft-versus-host disease (aGVHD). Phytohemagglutinin (PHA) and interleukin-2 (IL-2) are commonly used in in vitro assays to study T-cell responses. In view of the discrete response of T cells from aGvHD patients cohorts, our study optimized PHA / IL-2 based T-cell response among healthy individuals versus aGVHD patients. MethodsPeripheral blood was collected from age- and sex-matched healthy individuals (n=10) and aGVHD patients (n=10). CD3+ T-cell were isolated and stimulated with varying concentrations of PHA (1-10g/ml) and IL-2 (50-500 IU/ml). Cell proliferation was assessed using MTS and CFSE assays, while their apoptosis was evaluated with Annexin V/7-AAD staining. ResultsWe observed enhanced proliferation of healthy individuals at higher PHA concentrations (5-10g/ml), whereas aGVHD patients exhibited heightened proliferation even at lower PHA concentrations (1-2.5g/ml) at 48 hours. Prolonged exposure of T cells from GvHD patients to PHA led to decreased proliferation while it increased in the T cells from healthy donors.IL-2 supplementation (50 IU/ml) of T-cells from healthy donors significantly enhanced their proliferation and survival, with the optimal concentration supporting robust proliferation over extended culture periods. ConclusionOur study optimized PHA and IL-2 concentrations required for T-cell proliferation studies among healthy individuals and aGVHD patients. and underscored experimental conditions required for studying T-cell behavior/dysregulation in aGVHD condition. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/611044v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@ab3c47org.highwire.dtl.DTLVardef@2786forg.highwire.dtl.DTLVardef@30c698org.highwire.dtl.DTLVardef@3e4821_HPS_FORMAT_FIGEXP M_FIG C_FIG Highlights of the studyO_LILower doses of PHA (1.0g/ml) and IL-2 (50IU/ml) are optimum conditions for aGVHD patients derived CD3+ T-cell proliferation under in vitro conditions. C_LIO_LIThe maximum T-cell proliferation in healthy individuals occurs with 7.5g/ml PHA and 50IU/ml IL-2. C_LIO_LIHigher doses of PHA induce cytotoxicity in both cohorts. C_LIO_LIIL-2 significantly enhances T-cell survival, with 50IU/ml maintaining robust proliferation over extended periods. C_LI

immunology↗

Uncovering the bequeathing potential of Apoptotic Mesenchymal Stem Cells via small Extracellular Vesicles for its enhanced immunomodulatory ability

Small Extracellular Vesicles (sEVs) derived from Mesenchymal Stem Cells (MSCs) have emerged as a promising avenue for cell-free therapeutics in regenerative medicine. These vesicles, endowed with regenerative cargo inherited from their parent cells, have attracted attention for their role in immunomodulation and ROS alleviation. Notably, the deliberate induction of apoptosis in MSCs prior to Extracellular Vesicles (EVs) isolation has been identified as a strategy to augment the regenerative capabilities of MSCs-EVs, as certain reports have suggested that MSCs undergo apoptosis to exert their therapeutic effect post-transplantation. Moreover, selecting an optimal tissue source for deriving MSC-sEVs is equally crucial to ensure consistent and improved clinical outcomes. Multiple attributes of MSCs like their antioxidant, Immunomodulatory & regenerative properties make them particularly appealing for clinical studies, wherein mechanisms such as paracrine secretions and efferocytosis play pivotal roles. This investigation meticulously explores the comparative immunomodulatory & antioxidant capabilities of Apoptotic sEVs (Apo-sEVs) with Viable sEVs (V-sEVs) obtained from both Bone Marrow (BM) and Whartons Jelly (WJ)-derived MSCs, using an in vitro liver injury model. The findings from the present study contribute valuable insights into the comparative efficacy of Apo-sEVs and V-sEVs. This will aid in addressing a critical gap in understanding the role of apoptosis in enhancing the reparative capability of MSCs-sEVs. It also aims to shed light on the optimal source of MSCs for generating Apo-sEVs in translational applications. GRAPHICAL ABSTARCT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/590581v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1392183org.highwire.dtl.DTLVardef@1c72d6borg.highwire.dtl.DTLVardef@176ee90org.highwire.dtl.DTLVardef@128559e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

Synergistic Hypoxia and Apoptosis Conditioning Unleashes Superior Mesenchymal Stem Cells Efficacy in Acute Graft-versus-Host-Disease

Mesenchymal stem cells (MSCs) have emerged as promising candidates for immune modulation in various diseases that are associated with dysregulated immune responses like Graft-versus-Host-Disease (GVHD). MSCs are pleiotropic and the fate of MSCs following administration is a major determinant of their therapeutic efficacy. In this context, we here demonstrate that hypoxia preconditioned apoptotic MSCs [bone marrow (BM), Whartons Jelly (WJ)] bear more immune programming ability in a cellular model of acute Graft-versus-Host-Disease (aGVHD). To this purpose, we programmed MSCs by exposing them to hypoxia and inducing apoptosis both sequentially as well as simultaneously. Our findings demonstrated that WJ MSCs that were conditioned with indicated approaches simultaneously induced the differentiation of CD4+T-cell towards Tregs, enhanced Th2 effector, and concomitantly mitigated Th1 and Th17, with polarization of M1 effector macrophages towards their M2 phenotype, and more interestingly enhanced efferocytosis by macrophages indicated Th2 programming ability of MSCs programmed by conjunctional approaches Overall, our study highlights the potential of WJ-MSCs conditioned with hypoxia and apoptosis concurrently, as a promising therapeutic strategy for aGVHD and underscores the importance of considering MSC apoptosis in optimizing MSCs-based cellular therapy protocols for enhanced therapeutic efficacy in aGvHD. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=123 HEIGHT=200 SRC="FIGDIR/small/588248v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@92c102org.highwire.dtl.DTLVardef@bd895forg.highwire.dtl.DTLVardef@185e041org.highwire.dtl.DTLVardef@45ef0f_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

The Trials and Tribulations of Priors and Posteriors in Bayesian Timing of Divergence Analyses: the Age of Butterflies Revisited

The need for robust estimates of times of divergence is essential for downstream analyses, yet assessing this robustness is still rare. We generated a time-calibrated genus-level phylogeny of butterflies (Papilionoidea), including 994 taxa, up to 10 gene fragments and an unprecedented set of 12 fossils and 10 host-plant node calibration points. We compared marginal priors and posterior distributions to assess the relative importance of the former on the latter. This approach revealed a strong influence of the set of priors on the root age but for most calibrated nodes posterior distributions shifted from the marginal prior, indicating significant information in the molecular dataset. We also tested the effects of changing assumptions for fossil calibration priors and the tree prior. Using a very conservative approach we estimated an origin of butterflies at 107.6 Ma, approximately equivalent to the Early Cretaceous-Late Cretaceous boundary, with a credibility interval ranging from 89.5 Ma (mid Late Cretaceous) to 129.5 Ma (mid Early Cretaceous). This estimate was robust to alternative analyses changing core assumptions. With 994 genera, this tree provides a comprehensive source of secondary calibrations for studies on butterflies.

evolutionary biology↗