Biology subjects

Sanchez Ortiz, K.

Publications and source records attributed to Sanchez Ortiz, K..

3 recordsLinked to original sources

bioRxiv2026

Metabolically Activated Proteostasis Regulators Reduce Differentiation of CD4+ TH17 Cells

The differentiation of naive CD4+ T cells into effector T cell subsets such as TH1, TH2, TH17 and TREG cells is governed by tightly coordinated activation programmes dependent on T cell receptor (TCR) engagement, co-stimulation, and cytokine signalling. This differentiation process involves regulation of stress-responsive signalling pathways such as the unfolded protein response (UPR) and the oxidative stress response (OSR) to adapt to the physiologic demands specific to distinct T cell subset functions. This suggests that pharmacologically targeting stress-responsive pathways offers a unique opportunity to selectively remodel the differentiation of these different T cell subsets. We previously identified compound AA147 as a metabolically activated proteostasis regulator that can induce both the ATF6 signalling arm of the UPR and, in certain cell types, the NRF2-regulated arm of the OSR. (Paxman et al., 2018; Plate et al., 2016) Here, we show that treatment with AA147 selectively reduces differentiation of pro-inflammatory TH17 cells by promoting degradation of the lineage-specifying transcription factor RORgammat, without impacting the transcription factors of other CD4+ T cell subsets. AA147-dependent reduction in TH17 differentiation is independent of ATF6 activation and involves activation of NRF2, which reduces intracellular reactive oxygen species (ROS) to hinder TH17 cell differentiation. Apart from RORgammat, we found that AA147 decreases expression of the TCR-responsive factor IRF4, thus suppressing production of select effector cytokines across effector T cells, demonstrating additional ways in which this compound reshapes the activities of these essential T cell subsets. Our results demonstrate the potential for metabolically activated proteostasis regulators such as AA147 to selectively reshape TH17 cell identity while broadly dampening effector cytokine responses across effector T cell subsets, through both NRF2-dependent and independent mechanisms during T cell differentiation.

cell biology↗

bioRxiv2019

Effects of land-use change and related pressures on alien and native subsets of island communities

Island species and habitats are particularly vulnerable to human disturbances, and anthropogenic changes are increasingly overwriting natural island biogeographic patterns. However, quantitative comparisons of how native and alien assemblages respond to human disturbances are scarce. Using data from 6,242 species of vertebrates, invertebrates and plants, from 7,718 sites on 81 islands, we model how land-use change, human population density and distance to the nearest road affect local assemblages of alien and native species on islands. We found that land-use change reduces both richness and abundance of native species, whereas the number and abundance of alien species are high in plantation forests and agricultural or urban sites. In contrast to the long-established pattern for native species (i.e., decline in species number with island isolation), more isolated islands have more alien species across most land uses than do less isolated islands. We show that alien species play a major role in the turnover of island assemblages: our models show that aliens outnumber natives among the species present at disturbed sites but absent from minimally-disturbed primary vegetation. Finally, we found a homogenization pattern for both native and alien assemblages across sites within most land uses. The declines of native species on islands in the face of human pressures, and the particular proneness to invasions of the more remote islands, highlight the need to reduce the intensity of human pressures on islands and to prevent the introduction and establishment of alien species.

ecology↗

bioRxiv2019

Land-use and related pressures have reduced biotic integrity more on islands than on mainlands

Tracking progress towards biodiversity targets requires indicators that are sensitive to changes at policy-relevant scales, can easily be aggregated to any spatial scale and are simple to understand. The Biodiversity Intactness Index (BII), which estimates the average abundance of a diverse set of organisms in a given area relative to their reference populations, was proposed in 2005 in response to this need. A new implementation of BII was developed as part of the PREDICTS project in 2016 and has been adopted by GEO BON, IPBES and CBD. The previous global models for BII estimation could not account for pressures having different effects in different settings. Islands are a setting of particular interest: many are home to a disproportionate number of endemic species; oceanic islands may have relatively low overall species diversity because of their isolation; and the pattern and timing of human pressures can be very different from that seen on mainlands. Here, we test whether biotic integrity - as estimated by BII - has decreased more severely on islands than mainlands. We update methods previously used to estimate BII globally (Newbold et al., 2016) to allow pressure effects to differ between islands and mainlands, while also implementing some other recent improvements in modelling. We estimate BII for islands and mainlands by combining global models of how two aspects of biodiversity - overall abundance, and compositional similarity to minimally-impacted sites - have been affected by human pressures. We use these models to project high-resolution ([~]1km2) global maps of BII for the year 2005. We calculate average BII for island and mainland biomes, countries, IPBES regions and biodiversity hotspots; and repeat our analyses using a richness-based version of BII. BII on both islands and mainlands has fallen below the values proposed as safe limits across most regions, biomes and biodiversity hotspots. Our BII estimates are lower than those published in 2016, globally, within all biodiversity hotspots and within most biomes, and show greater spatial heterogeneity; detailed analysis of these differences shows that they arise mostly from a combination of improvements to the modelling framework. Average BII does not strongly differ between islands and mainlands, but richness-based BII has fallen by more on islands. It seems native species are more negatively affected by rising human population density and road development on islands than mainlands, and islands have seen more land conversion. Our results highlight the parlous state of biodiversity native to islands.

ecology↗