Fibroblast surface-associated FGF-2 promotes contact-dependent colorectal cancer cell migration and invasion through FGFR-SRC signaling and integrin αvβ5-mediated adhesion.

Carcinoma-associated fibroblasts were reported to promote colorectal cancer (CRC) invasion by secreting motility factors and extracellular matrix processing enzymes. Less is known whether fibroblasts may induce CRC cancer cell motility by contact-dependent mechanisms. To address this question we characterized the interaction between fibroblasts and SW620 and HT29 colorectal cancer cells in 2D and 3D co-culture models in vitro. Here we show that fibroblasts induce contact-dependent cancer cell elongation, motility and invasiveness independently of deposited matrix or secreted factors. These effects depend on fibroblast cell surface-associated fibroblast growth factor (FGF) -2. Inhibition of FGF-2 or FGF receptors (FGFRs) signaling abolishes these effects. FGFRs activate SRC in cancer cells and inhibition or silencing of SRC in cancer cells, but not in fibroblasts, prevents fibroblasts-mediated effects. Using an RGD-based integrin antagonist and function-blocking antibodies we demonstrate that cancer cell adhesion to fibroblasts requires integrin αvβ5. Taken together, these results demonstrate that fibroblasts induce cell-contact-dependent colorectal cancer cell migration and invasion under 2D and 3D conditions in vitro through fibroblast cell surface-associated FGF-2, FGF receptor-mediated SRC activation and αvβ5 integrin-dependent cancer cell adhesion to fibroblasts. The FGF-2-FGFRs-SRC-αvβ5 integrin loop might be explored as candidate therapeutic target to block colorectal cancer invasion

Coping with unpredictable environments: fine-tune foraging microhabitat use in relation to prey availability in an alpine species

Microhabitat utilisation holds a pivotal role in shaping a species’ ecological dynamics and stands as a crucial concern for effective conservation strategies. Despite its critical importance, microhabitat use has frequently been addressed as static, centering on microhabitat preference. Yet, a dynamic microhabitat use that allows individuals to adjust to fine-scale spatio-temporal prey fluctuations, becomes imperative for species thriving in challenging environments. High-elevation ecosystems, marked by brief growing seasons and distinct abiotic processes like snowmelt, winds, and solar radiation, feature an ephemeral distribution of key resources. To better understand species’ strategies in coping with these rapidly changing environments, we delved into the foraging behaviour of the white-winged snowfinch Montifringilla nivalis, an emblematic high-elevation passerine. Through studying microhabitat preferences during breeding while assessing invertebrate prey availability, we unveiled a highly flexible microhabitat use process. Notably, snowfinches exhibited specific microhabitat preferences, favoring grass and melting snow margins, while also responding to local invertebrate availability. This behaviour was particularly evident in snow-associated microhabitats and less pronounced amid tall grass. Moreover, our investigation underscored snowfinches’ fidelity to foraging sites, with over half located within 10 m of previous spots. This consistent use prevailed in snow-associated microhabitats and high-prey-density zones. These findings provide the first evidence of dynamic microhabitat use in high-elevation ecosystems and offer further insights into the crucial role of microhabitats for climate-sensitive species. They call for multi-faceted conservation strategies that go beyond identifying and protecting optimal thermal buffering areas in the face of global warming to also encompass locations hosting high invertebrate densities

Early-succession secondary forests following agropastoral abandonment are key winter habitats for the conservation of a priority bird in the European Alps

In contrast to old-growth forests, early-successional stands remain understudied despite potentially harbouring species of conservation interest. With this work, focused on hazel grouse Tetrastes bonasia, a cryptic and indicator species known to select for close-to-natural forests, we evaluated winter densities, home range, microhabitat selection and diet, combining DNA-based mark-recapture and metabarcoding from faecal samples. In total, 216 droppings, collected over 2 years along forest transects in the Italian Alps, were successfully genotyped and 43 individuals were identified. Density estimates were similar to values reported by other studies in the Alps with an average of 4.5 and 2.4 individuals/km2 in the first and second study year, respectively, and mean home ranges estimated at 0.95 km2. According to habitat selection models and eDNA-based diet analysis, hazel grouse selected early-succession secondary-growth forests formed after the abandonment of traditional agropastoral activities. These forests, mostly composed of hazel Corylus avellana, Norway spruce Picea abies and Sorbus spp., provided winter food resources and shelter. The diet analysis also highlighted forest arthropods as a non-negligible source of food. Birds avoided areas subject to intensive browsing by ungulates; small forest roads seasonally closed to traffic had positive influence on hazel grouse (i.e. higher abundance of droppings), while roads open to traffic had no effect. Importantly, despite the high coverage of mature forest habitats of Community Interest (53% of our study area), droppings were more abundant in non-listed early-succession secondary forests with similar plant composition. Our results suggest that forest succession after agropastoral abandonment may be beneficial for some forest birds of conservation interest, while acknowledging its negative effects on the previous grassland biodiversity. Graphical abstract: [Figure not available: see fulltext.

Identification of placental nutrient transporters associated with intrauterine growth restriction and pre-eclampsia.

Gestational disorders such as intrauterine growth restriction (IUGR) and pre-eclampsia (PE) are main causes of poor perinatal outcomes worldwide. Both diseases are related with impaired materno-fetal nutrient transfer, but the crucial transport mechanisms underlying IUGR and PE are not fully elucidated. In this study, we aimed to identify membrane transporters highly associated with transplacental nutrient deficiencies in IUGR/PE. In silico analyses on the identification of differentially expressed nutrient transporters were conducted using seven eligible microarray datasets (from Gene Expression Omnibus), encompassing control and IUGR/PE placental samples. Thereby 46 out of 434 genes were identified as potentially interesting targets. They are involved in the fetal provision with amino acids, carbohydrates, lipids, vitamins and microelements. Targets of interest were clustered into a substrate-specific interaction network by using Search Tool for the Retrieval of Interacting Genes. The subsequent wet-lab validation was performed using quantitative RT-PCR on placentas from clinically well-characterized IUGR/PE patients (IUGR, n = 8; PE, n = 5; PE+IUGR, n = 10) and controls (term, n = 13; preterm, n = 7), followed by 2D-hierarchical heatmap generation. Statistical evaluation using Kruskal-Wallis tests was then applied to detect significantly different expression patterns, while scatter plot analysis indicated which transporters were predominantly influenced by IUGR or PE, or equally affected by both diseases. Identified by both methods, three overlapping targets, SLC7A7, SLC38A5 (amino acid transporters), and ABCA1 (cholesterol transporter), were further investigated at the protein level by western blotting. Protein analyses in total placental tissue lysates and membrane fractions isolated from disease and control placentas indicated an altered functional activity of those three nutrient transporters in IUGR/PE. Combining bioinformatic analysis, molecular biological experiments and mathematical diagramming, this study has demonstrated systematic alterations of nutrient transporter expressions in IUGR/PE. Among 46 initially targeted transporters, three significantly regulated genes were further investigated based on the severity and the disease specificity for IUGR and PE. Confirmed by mRNA and protein expression, the amino acid transporters SLC7A7 and SLC38A5 showed marked differences between controls and IUGR/PE and were regulated by both diseases. In contrast, ABCA1 may play an exclusive role in the development of PE

Genetic mapping of APP and amyloid-β biology modulation by trisomy 21

Individuals who have Down syndrome (DS) frequently develop early onset Alzheimer's disease (AD), a neurodegenerative condition caused by the build-up of aggregated amyloid-β and tau proteins in the brain. Amyloid-β is produced by amyloid precursor protein (APP), a gene located on chromosome 21. People who have Down syndrome have three copies of chromosome 21 and thus also an additional copy of APP; this genetic change drives the early development of Alzheimer's disease in these individuals. Here we use a combination of next-generation mouse models of Down syndrome (Tc1, Dp3Tyb, Dp(10)2Yey and Dp(17)3Yey) and a knockin mouse model of amyloid-β accumulation (AppNL-F ) to determine how chromosome 21 genes, other than APP, modulate APP/amyloid-β in the brain when in three copies. Using both male and female mice, we demonstrate that three copies of other chromosome 21 genes are sufficient to partially ameliorate amyloid-β accumulation in the brain. We go on to identify a subregion of chromosome 21 that contains the gene/genes causing this decrease in amyloid-β accumulation and investigate the role of two lead candidate genes Dyrk1a and Bace2 Thus an additional copy of chromosome 21 genes, other than APP, can modulate APP/amyloid-β in the brain under physiological conditions. This work provides critical mechanistic insight into the development of disease and an explanation for the typically later age of onset of dementia in people who have AD-DS, compared to those who have familial AD caused by triplication of APP Significance Statement:Trisomy of chromosome 21 is a commonly occurring genetic risk factor for early-onset Alzheimer's disease, which has been previously attributed to people with Down syndrome having three copies of the APP gene, which is encoded on chromosome 21. However, we have shown that an extra copy of other chromosome 21 genes modifies AD-like phenotypes independently of APP copy number (Wiseman et al. 2018, Brain; Tosh et al. 2021 Scientific Reports). Here, we use a mapping approach to narrow-down the genetic cause of the modulation of pathology; demonstrating that gene(s) on chromosome 21 decrease amyloid-β accumulation in the brain, independently of alterations to full-length APP or C-terminal fragment abundance and that just 38 genes are sufficient to cause this