Biology subjects

Stojkovic, B.

Publications and source records attributed to Stojkovic, B..

6 recordsLinked to original sources

bioRxiv2026

Experimental evolution unveils a role for structural variants and sex-specificity in the genetic architecture of lifespan

Insights into the genetic basis of lifespan evolution can link evolutionary theory with an understanding of health, disease and adaptation. We leverage the power of >200 generations of experimental evolution in a seed beetle to unveil the genomic architecture of lifespan evolution. Replicated populations evolved under regimes favoring either a short or long life, resulting in a near doubling of lifespan. Whole genome re-sequencing revealed that short- and long-lived lines were strongly differentiated (global FST = 0.41) and more than 700 genes showed consistent signs of divergent selection. Remarkably, short- and long-lived lines were consistently divergent in a large number of regions harboring copy-number variants (CNVs), involving >600 genes. The evolution of a long life involved many distinct biological processes, such as DNA fidelity, mitotic integrity, reproduction, metabolism, immunity and stress response. A pedigree-based genome scan for quantitative trait loci (QTLs) uncovered several QTLs with large effects on lifespan, but the genetic basis of a long life was dominated by a very large number of regions with medium and small effects. The genome-wide spatial association with QTL effects was, if anything, stronger for CNVs than for sequence variants. The genetic effects of QTLs on lifespan were positively correlated overall between the sexes, but four regions showed pronounced sex-differences. Our results show that structural variants play a significant role in the evolution of an extended lifespan and the highly polygenic genomic architecture is to some extent sex-specific, consistent with differences in physiology and life history tradeoffs between the sexes.

evolutionary biology↗

bioRxiv2025

A microbiome meta-transcriptomics pipeline identifies a novel human neutrophil elastase inhibitor that protects the colonic epithelial barrier

Inflammatory Bowel Diseases (IBD) are lifelong conditions. Current therapeutic approaches target inflammatory signalling rather than improving barrier permeability or repair. The gut microbiome provides an exciting opportunity for novel drug discovery to leverage its role in healthy gut homeostasis. There is a clear need to identify bioactive molecules within the microbiota that could protect the intestinal barrier. Our group has developed a systematic pipeline using metatranscriptomic data to identify, produce, purify, and test microbial proteins in IBD, pinpointing multiple novel microbiota-derived proteins linked to disease activity. We identified a new microbiota protein (BMG-1), that specifically inhibits human neutrophil elastase, a pathogenic protease in IBD. This protease inhibition allows protection of the intestinal epithelial barrier from permeability and promotes epithelial healing. BMG-1 also reduces colon damage in a mouse model of colitis. These findings demonstrate the gut microbiota can specifically regulate the balance of protease/anti-protease activity in the colon, and this represents a novel therapeutic strategy for IBD.

microbiology↗

bioRxiv2023

Coevolution of longevity and female care of male gametes

An often-overlooked aspect of life-history optimization is the allocation of resources to protect the germline and secure safe transmission of genetic information. While failure to do so renders significant fitness consequences in future generations, germline maintenance comes with substantial costs. Thus, germline allocation should trade-off with other life history decisions and be optimized in accordance with an organisms reproductive schedule. Here we tested this hypothesis by studying germline maintenance in lines of seed beetle, selected for early (E) or late (L) reproduction for 350 and 240 generations, respectively. Female animals provide maintenance and screening of male gametes in their reproductive tract and oocytes. Here, we revealed the ability of young and aged E and L-females to provide this form of germline maintenance by mating them to males with ejaculates with artificially elevated levels of protein and DNA damage. We find that germline maintenance in E-females peaks at young age and then declines, while the opposite is true for L-females, in accordance with the age of reproduction in respective regime. These findings identify the central role of allocation to secure germline integrity in life history evolution and highlight how females can play a crucial role in mitigating effects of male germline decisions on mutation rate and offspring quality.

evolutionary biology↗

bioRxiv2021

Macrophage Innate Training Induced by IL-4 Activation Enhances OXPHOS Driven Anti-Mycobacterial Responses

Macrophages are a highly adaptive population of innate immune cells. Polarization with IFN{gamma} and LPS into the "classically activated" M1 macrophage enhances pro-inflammatory and microbicidal responses, important for eradicating bacteria such as Mycobacterium tuberculosis. By contrast, "alternatively activated" M2 macrophages, polarized with IL-4, oppose bactericidal mechanisms and allow mycobacterial growth. These activation states are accompanied by distinct metabolic profiles, where M1 macrophages favor near exclusive use of glycolysis, whereas M2 macrophages up-regulate oxidative phosphorylation (OXPHOS). Here we demonstrate that activation with IL-4 and IL-13 counterintuitively induces protective innate memory against mycobacterial challenge. In human and murine models, prior activation with IL-4/13 enhances pro-inflammatory cytokine secretion in response to a secondary stimulation with mycobacterial ligands. In our murine model, enhanced killing capacity is also demonstrated. Despite this switch in phenotype, IL-4/13 trained murine macrophages do not demonstrate M1-typical metabolism, instead retaining heightened use of OXPHOS. Moreover, inhibition of OXPHOS with oligomycin, 2-deoxy glucose or BPTES all impeded heightened pro-inflammatory cytokine responses from IL-4/13 trained macrophages. Lastly, this work identifies that IL-10 attenuates protective IL-4/13 training, impeding pro-inflammatory and bactericidal mechanisms. In summary, this work provides new and unexpected insight into alternative macrophage activation states in the context of mycobacterial infection.

immunology↗

bioRxiv2020

Kinship, acquired and inherited status, and population structure at the Early Bronze Age Mokrin necropolis in northern Serbia.

Twenty-four ancient genomes with an average sequencing coverage of 0.85{+/-}0.25 X were produced from the Mokrin necropolis, an Early Bronze Age (2,100-1,800 BC) Maros culture site in Serbia, to provide unambiguous identification of biological sex, population structure, and genetic kinship between individuals. Of the 24 investigated individuals, 15 were involved in kinship relationships of varying degrees, including 3 parent-offspring relationships. All observed parent-offspring pairs were mother and son. In addition to the absence of biological daughters, we observed a number of young women and girls with no biological relatives in our sample. These observations, together with the high mitochondrial diversity in our sample, are consistent with the practice of female exogamy in the population served by Mokrin. However, moderate-to-high Y-chromosomal diversity suggests a degree of male mobility greater than that expected under strict patrilocality. Individual status differences at Mokrin, as indicated by grave goods, support the inference that females could inherit status, but could not transmit status to all their sons. The case of a son whose grave good richness outstrips that of his biological mother suggests that sons had the possibility to acquire status during their lifetimes. The Mokrin sample resembles a genetically unstructured population, suggesting that the communitys social hierarchies were not accompanied by strict marriage barriers.

genomics↗

bioRxiv2020

Cortical stiffness of keratinocytes measured by lateral indentation with optical tweezers

Keratin intermediate filaments are the principal structural element of epithelial cells. Their importance in providing bulk cellular stiffness is well recognized, but their role in the mechanics of cell cortex is less understood. In this study, we therefore compared the cortical stiffness of three keratinocyte lines: primary wild type cells (NHEK2), immortalized wild type cells (NEB1) and immortalized mutant cells (KEB7). The cortical stiffness was measured by lateral indentation of cells with AOD-steered optical tweezers without employing any moving mechanical elements. The method was validated on fixed cells and Cytochalasin-D treated cells to ensure that the observed variations in stiffness within a single cell line were not a consequence of low measurement precision. The measurements of the cortical stiffness showed that primary wild type cells were significantly stiffer than immortalized wild type cells, which was also detected in previous studies of bulk elasticity. In addition, a small difference between the mutant and the wild type cells was detected, showing that mutation of keratin impacts also the cell cortex. Thus, our results indicate that the role of keratins in cortical stiffness is not negligible and call for further investigation of the mechanical interactions between keratins and elements of the cell cortex.

biophysics↗