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Pre-clinical safety and efficacy evaluation of HelicobacterPylori neutrophil-activating protein (NAP)-armed CAR-T cells targeting B cell lymphomas
Get PDFCD19 CAR-T cell therapy shows striking results in treating B cell malignancies. However, approximately two-thirds of the lymphoma patients eventually relapse, with about one-third displaying CD19-negative tumors at relapse. Our previous study showed that CAR-T cells armed with the Helicobacterpylori neutrophil-activating protein (NAP), CAR(NAP)-T cells, can trigger a bystander immune response and eliminate CAR-target-antigen-negative tumor cells. Here, we report the development of CD20-targeted CAR-T cells (CAR20-T cells), with the targeting moiety from rituximab, and the safety and efficacy of NAP-armed CAR-T cells. CAR20-T cells displayed efficient and specific cytotoxic potential against multiple human B cell lymphoma cell lines in vitro. In addition, primary mantle cell lymphoma cells, isolated from a patient who relapsed after rituximab treatment, can also be eliminated by CAR20-T cells. CAR20(NAP)-T cells delayed tumor growth and prolonged survival of mice with lymphoma. No obvious histopathological alteration in major organs were observed in mice treated with CAR(NAP)-T cells. Further, no excessive cytokine release or immune cell activation was observed when human blood from healthy volunteers was exposed to recombinant NAP protein in an ex vivo blood loop assay, suggesting a safe therapeutic profile for NAP. Taken together, these results warrant the clinical investigation of CAR20(NAP)-T cells
The Q-Warg Pipeline: A Robust and Versatile Workflow for Quantitative Analysis of Protoplast Culture Conditions
Get PDFSingle cells offer a simplified model for investigating complex mechanisms such as cell-cell adhesion. Protoplasts, plant cells without cell walls (CWs), have been instrumental in plant research, industrial applications, and breeding. However, because of the absence of a CW, protoplasts are not considered "true" plant cells, making them less relevant for biophysical studies. Current protocols for CW recovery in protoplasts vary widely among laboratories and starting materials, requiring lab-specific optimizations that often depend on expert knowledge and qualitative assessments. To address this, we have developed a user-friendly streamlined workflow, the Q-Warg pipeline, which enables quantitative comparison of various conditions for CW recovery post-protoplasting. This pipeline employs fluorescence imaging and tailored processing to measure parameters such as morphometry, cell viability, and CW staining intensity. Using this approach, we optimized culture conditions to obtain single plant cells (SPCs) with recovered CWs. Additionally, we demonstrated the robustness and versatility of the workflow by quantifying different fluorescent signals in protoplast suspensions. Overall, the Q-Warg pipeline provides a widely accessible and user-friendly solution for robust and unbiased characterization of protoplasts culture. The quantitative data generated by the pipeline will be useful in the future to decipher the mechanisms regulating protoplast viability and regeneration
Interplay between antipredator behavior, parasitism, and gut microbiome in wild stickleback populations
Get PDFThe impact of microbial composition on stress-related behavior in aquatic organisms is poorly understood. This study explored the link between antipredator behavior, parasitism, and the gut microbiome in wild stickleback from two lakes: clear, spring-fed Galtab & oacute;l and turbid, glacial-fed & THORN;ristikla. Behavioral analysis revealed differences between populations, with each exhibiting unique baseline behaviors. Microbiome analysis showed that a small proportion of its variation was explained by population, likely reflecting differences in lake environments. Only the marine genus Pseudoalteromonas abundance differed between populations. Our findings suggest that behavior and microbiome correlations may primarily reflect environmental adaptations and parasite status rather than direct gut-brain interactions. However, some tentative evidence suggests a potential innate connection between some antipredator behavior and microbiome composition. The study highlights the complexity of the gut-brain axis in wild populations and suggests future research directions, including experimental manipulations to uncover causal relationships between microbiome composition and behavior
Nomenclatural review of names published in the fungal genus Dermoloma (Basidiomycota, Agaricales, Tricholomataceae) based on morphological analyses of type specimens
Get PDFBackground The majority of members of the fungal genus Dermoloma have been described, based on morphology and without molecular support. Sequencing most Dermoloma type specimens has been unsuccessful, probably due to degraded DNA, leaving their taxonomy primarily reliant on morphological characters. In this study, we re-described nine Dermoloma types, providing standardised morphological descriptions that include observations of previously undocumented microscopic structures. New information The pileipellis structure of D. hybridum, D. inconspicuum and D. intermedium var. coniferarum differs strongly from the typical Dermoloma pileipellis and these taxa do not belong to this genus. Dermoloma atrobrunneum and D. hymenocephalum are distinct taxa which have not been reported recently. The concept of Dermoloma cuneifolium var. punctipes is based on the presence of dark spots on the stipe. However, our examination of the type material reveals that its spores are more consistent with those of D. atrocinereum, a species that can also exhibit dark dots. Dermoloma longibasidiatum is likely a synonym of this species as well. The name D. pseudocuneifolium has been misapplied for a species with amyloid spores, but the type has inamyloid narrow spores characteristic for D. bellerianum. Dermoloma pragense probably represents a distinct, but recently unrecorded European species defined by large basidiomata and small spores. The data presented here are essential for future nomenclatural treatments within Dermoloma, as current phylogenetic studies suggest the presence of a large number of undescribed species
Individual heterozygosity and fitness in bottlenecked populations during early colonisation
Get PDFSome populations of alien species, established by a small number of individuals, spread rapidly. This is the 'genetic paradox of invasions' as they must overcome the negative effects of the demographic bottleneck during the establishment phase, which reduces genetic diversity, fitness and evolutionary potential. Using a set of experimentally introduced populations of the Roesel's bush-cricket (Roeseliana roeselii), a nuptial gift-giving insect, we investigated this paradox by examining the relationships between individual heterozygosity (SNP markers), body size (an indicator of insect fitness) and population growth. We found that populations with a lower growth rate (annual increase in the number of stridulating males around the introduction patch) also had lower genetic variation and effective size. Females exhibited significantly higher individual heterozygosity than males. Body size (length of hind femur) increased in females with individual heterozygosity, whereas this was not observed in males. However, population growth was related to heterozygosity in males. Since female body size and male heterozygosity in these insects are related to fecundity and nuptial gift quality, respectively, our results suggest that potential selection on fitness-related phenotypic traits may mitigate effects of inbreeding depression and increase population growth during the establishment phase. The present results cannot fully disentangle complex mechanisms underlying the success of colonisation, but we believe that they will stimulate further experimental research in the field of invasion biology
Damage activates EXG1 and RLP44 to suppress vascular differentiation during regeneration in Arabidopsis
Get PDFPlants possess remarkable regenerative abilities to form de novo vasculature after damage and in response to pathogens that invade and withdraw nutrients. To identify common factors that affect vascular formation upon stress, we searched for Arabidopsis thaliana genes differentially expressed upon Agrobacterium infection, nematode infection, and plant grafting. One such gene is cell wall-related and highly induced by all three stresses, which we named ENHANCED XYLEM AND GRAFTING1 (EXG1), since its mutations promote ectopic xylem formation in a vascular cell induction system and enhance graft formation. Further observations revealed that exg1 mutants show inhibited cambium development and callus formation but enhanced tissue attachment, syncytium size, phloem reconnection, and xylem formation. Given that brassinosteroids also promote xylem differentiation, we analyzed brassinosteroid-related genes and found that mutations in RLP44 encoding a receptor-like protein cause similar regeneration-related phenotypes as mutations in EXG1. Like EXG1, RLP44 expression is also induced by grafting and wounding. Mutations in EXG1 and RLP44 affect the expression of many genes in common, including those related to cell walls and genes important for vascular regeneration. Our results suggest that EXG1 integrates information from wounding or pathogen stress and functions with RLP44 to suppress vascular differentiation during regeneration and healing
Cross-generational genomic prediction of Norway spruce (Picea abies) wood properties: an evaluation using independent validation
Get PDFBackground The evaluation of genomic selection (GS) efficiency in forestry has primarily relied on cross-validation schemes that split the same population within a single generation for both training and validation. While useful, this approach may not be reliable for multigenerational breeding. To our knowledge, this is the first study to assess genomic prediction in Norway spruce using a large dataset spanning two generations in two environments. We trained pedigree-based (ABLUP) and marker-based (GBLUP) prediction models under three approaches: forward prediction, backward prediction, and across-environment prediction. The models were evaluated for ring-width, solid-wood and tracheid characteristics, using similar to 6,000 phenotyped and similar to 2,500 genotyped individual. Predictive ability (PA) and prediction accuracy (ACC) were estimated using an independent validation method, ensuring no individuals were shared between training and validation datasets. To assess the trade-off between comprehensive radial history and practical direct methods, we compared GBLUP models trained with cumulative area-weighted density (AWE-GBLUP) and single annual-ring density (SAD-GBLUP) from mother plus-trees. These models were validated using early and mature-stage progeny density measurements across two trials.Results Despite the smaller number of individuals used in the GBLUP models, both PA and ACC were generally comparable to those of the ABLUP model, particularly for cross-environment predictions. Overall, forward and backward predictions were significantly higher for density-related and tracheid properties, suggesting that across-generation predictions are feasible for wood properties but may be challenging for growth and low-heritability traits. Notably, SAD-GBLUP provided comparable prediction accuracies to AWE-GBLUP, supporting the use of more practical and cost-effective phenotyping methods in operational breeding programs.Conclusions Our findings highlight the need for context-specific models to improve the accuracy and reliability of genomic prediction in forest tree breeding. Future efforts might aim to expand training populations, incorporate non-additive genetic effects, and validate model performance across cambial ages while accounting for climatic variability during the corresponding growth years. Overall, this study offers a valuable foundation for implementing GS in Norway spruce breeding programs
Seasonal variability of the rumen microbiome in indigenous African cattle: a bioinformatics approach
Get PDFThe Ethiopian climate causes cattle to frequently experience cycles of abundant feed availability during the rainy season and severe feed scarcity during the dry season. Using a bioinformatics-driven metagenomics approach, this study reveals how the rainy season favours fibre-degrading taxa and expanded methanogenic and biosynthetic potential. In contrast, the dry season is characterised by reduced metabolic diversity and an increase in opportunistic taxa. To achieve this, novel computational tools were developed and refined, including MUFFIN and PANKEGG. The results collected from extreme drought conditions provide valuable information to ensure that ongoing work to reduce methane emissions through breeding or feed additives does not negatively impact the ability of ruminants to adapt to drought or low-quality feed, which may threaten food security and animal welfare during heatwaves. The study revealed seasonal variations in microbial community structure and metabolic functions. During the rainy season, the microbiome exhibited an increase in acetoclastic methanogens and fibre-degraders. The dry season saw a rise in hydrogenotrophic methanogens. The latter increase reflects a decrease in acetate production, suggesting a decline in access to feed, as well as less efficient fibre breakdown. These findings bring critical insights into the metabolic adaptability and resilience of indigenous cattle microbiomes. The findings also suggest new potential targets for enhancing feed efficiency and promoting environmental sustainability. The microbiome harboured multiple antibiotic resistance genes (ARGs) throughout both seasons. The presence of ARGs exposes the risk of potential resistance spread to pathogens as well as broader ecological implications. In addition to the metagenomic study, a genomic study of Ethiopian cattle breeds highlighted significant genetic diversity and potential adaptive mechanisms to local environmental stressors. Those genetic markers open the possibility for future integration of host-genomic and microbiome analyses
Is forest conservation a socially optimal strategy for increasing forest carbon sequestration?
Get PDFPrevious studies show that the optimal rotation period would be infinitely long when carbon price is sufficiently high, indicating that forest preservation could serve as an optimal strategy for mitigating global warming. This paper examines the impact of the substitution effect of harvested wood products (HWP) and the risk of natural disturbances on the optimality of infinitely long rotation period. Our analysis shows that when the substitution effects of HWP are significant, the optimal rotation remains finite regardless of how high the carbon price is. Conversely, when the substitution effects are minimal, there exists a threshold carbon price beyond which the optimal rotation period becomes infinite. Furthermore, we demonstrate that the risk of natural disturbances can either increase or decrease the likelihood that forest preservation remains the optimal choice for climate change mitigation. A numerical example illustrates that even with conservative assumptions about the substitution effect of HWP, the optimal rotation remains finite, and the risk of forest damage further reduces the optimal rotation