Biology subjects

Alberti, J.

Publications and source records attributed to Alberti, J..

5 recordsLinked to original sources

bioRxiv2026

OKN4395, a first-in-class EP2/EP4/DP1 triple antagonist reprograms prostanoid-driven immunosuppression to restore antitumor immunity

Immune checkpoint inhibitors, particularly T cell targeting anti-PD(L)1 therapies, have revolutionized the treatment landscape for solid malignancies, but challenges related to non-responsiveness and the development of treatment resistance continue to be observed. An additional immunosuppressive axis relates to prostaglandin signaling downstream of cyclooxygenase-2 (COX2), where COX2 inhibitors have shown clinical promise in re-engaging both T and non-T cell immune compartments, yet have suffered from toxicity concerns. We report here the preclinical characterization of OKN4395, a highly potent and specific first-in-class triple antagonist of EP2, EP4, and DP1, major tumor immunosuppressive receptors downstream of COX2. OKN4395 restores immune function on both T cells and NK cells in vitro. Additionally, OKN4395 acts synergistically with anti-PD1 to increase speed and depth of antitumor activity. Overall, these findings robustly support the clinical investigation of OKN4395 in an ongoing Phase 1 trial (NCT06789172) as an innovative cancer immunotherapy for solid tumors, as a single agent and in combination with anti-PD1 therapy. Statement of significanceOKN4395, a first-in-class oral EP2/EP4/DP1 antagonist, reverses prostanoid-driven immunosuppression to restore antitumor immunity. Integrated pharmacology defines mechanism, translational biomarkers as well as both monotherapy and anti-PD1 combination strategies. These data position prostanoid tri-receptor antagonism as a translatable strategy in solid tumors. A global Phase 1 study is underway (NCT06789172).

pharmacology and toxicology↗

bioRxiv2024

Long-term non-trophic effects of large herbivores on plant diversity are underestimated

The positive effects of large herbivores on plant diversity in grasslands have so far been mainly attributed to increased light availability or suppressed dominance, and thus to the consequences of aboveground biomass consumption (trophic effects). However, these insights are mainly derived from short-term experiments. Using a 46-year experiment in a salt marsh, comparing cattle grazing, mowing (as a proxy of aboveground consumption) and the ungrazed control, we found that the non-trophic effects (e.g. trampling, deposition of urine and dung) of large herbivores on plant diversity increased over time, exceeding that of the trophic effects after 23 years. This long-term accumulation of non-trophic effects through slow ecosystem-level feedback highlights the sustainability of using low to moderate densities of large herbivores to conserve plant diversity. Our results emphasize the need for the conservation and re-introduction of large herbivores, domestic or wild, to sustain long-term grassland plant diversity.

ecology↗

bioRxiv2023

Multidimensional responses of ecological stability to eutrophication in grasslands

Eutrophication usually impacts biodiversity, species composition, and functioning of grassland communities. Whether such effects propagate to influence the stability of these community aspects is unknown. Using standardized experiments across 55 global grasslands, we quantified the effects of nutrient addition on five stability facets (i.e., temporal invariability and resistance during and recovery after dry and wet growing seasons) for three community aspects (i.e., aboveground biomass, community composition, and species richness). Nutrient addition reduced the temporal invariability and resistance of species richness and community composition, but not biomass, during dry and wet growing seasons. Temporal invariability and resistance during, but not recovery after, dry and wet growing seasons were strongly positively correlated in both ambient and eutrophic conditions. This indicates that maintaining and restoring the stability of plant communities requires increasing resistance rather than recovery. Harnessing the complexity of ecological stability provides new insights for grassland ecosystem sustainability in a changing world.

ecology↗

bioRxiv2022

Nutrient addition increases grassland resistance during dry and wet climate extremes despite functional diversity loss

O_LINutrient enrichment impacts grassland plant diversity such as species richness, functional trait composition and diversity, but whether and how these changes affect ecosystem stability in the face of increasing climate extremes remains largely unknown. C_LIO_LIWe quantified the direct and diversity-mediated effects of nutrient addition (by nitrogen, phosphorus, and potassium) on the stability of aboveground biomass production in 10 long-term grassland experimental sites. We measured five facets of stability as the temporal invariability, resistance during and recovery after extreme dry and wet growing seasons. C_LIO_LILeaf traits (leaf carbon, nitrogen, phosphorus, potassium, and specific leaf area) were measured under ambient and nutrient addition conditions in the field and were used to construct the leaf economic spectrum (LES). We calculated functional trait composition and diversity of LES and of single leaf traits. We quantified the contribution of intraspecific trait shifts and species replacement to change in functional trait composition as responses to nutrient addition and its implications for ecosystem stability. C_LIO_LINutrient addition decreased functional trait diversity and drove grassland communities to the faster end of the LES primarily through intraspecific trait shifts, suggesting that intraspecific trait shifts should be included for accurately predicting ecosystem stability. Moreover, the change in functional trait diversity of the LES in turn influenced different facets of stability. That said, these diversity-mediated effects were overall weak and/or overwhelmed by the direct effects of nutrient addition on stability. As a result, nutrient addition did not strongly impact any of the stability facets. These results were generally consistent using individual leaf traits but the dominant pathways differed. Importantly, major influencing pathways differed using average trait values extracted from global trait databases (e.g. TRY). C_LIO_LISynthesis. Investigating changes in multiple facets of plant diversity and their impacts on multidimensional stability under global changes such as nutrient enrichment can improve our understanding of the processes and mechanisms maintaining ecosystem stability. C_LI

ecology↗

bioRxiv2021

Long-term cross-scale comparison of grazing and mowing on plant diversity and community composition in a salt-marsh system

O_LILand abandonment is increasing in recent decades in Europe, usually accompanied by a decline in biodiversity. Whether livestock grazing and mowing can safeguard biodiversity across spatial scales in the long term is unclear. C_LIO_LIUsing a 48-year experiment in a salt marsh, we compared land abandonment (without grazing and mowing) and seven management regimes including cattle grazing, early season mowing, late season mowing, both early and late season mowing, and grazing plus each of the mowing regimes on plant diversity at the local (i.e. plot) and landscape scales (i.e. across plots). Also, we compared their effects on community composition (both in identities and abundances) in time and space. C_LIO_LIUnder land abandonment, plant diversity declined in the local communities and this decline became more apparent at the landscape scale, particularly for graminoids and halophytes. All management regimes, except the late season mowing, maintained plant diversity at these scales. C_LIO_LILocal plant communities under all treatments underwent different successional trajectories, in the end, diverged from their initial state except for that under grazing (a cyclic succession). Interannual composition change remained stable over time under land abandonment and grazing plus early season mowing. It increased over time under grazing and late season mowing, it increased in the second half of the experiment under other treatments. Vegetation homogenized in the landscape over time under land abandonment while vegetation was heterogeneous under all management regimes. C_LIO_LISynthesis. Our experiment suggests that late season mowing may not be sustainable to conserve plant diversity in salt marshes. Other management regimes can maintain plant diversity across scales and vegetation heterogeneity in the landscape in the long term, but local community composition may change over time. C_LI

ecology↗