Biology subjects

Santoro, M.

Publications and source records attributed to Santoro, M..

11 recordsLinked to original sources

bioRxiv2026

Novel LRRK2 Kinase Inhibitors Enhance Phosphorylation and Restore Adapter Protein Binding in LRRK2 Variants

Autosomal dominant mutations in LRRK2 that increase kinase activity significantly increase the risk of developing Parkinson's disease (PD). Efforts to reduce the resulting hyperphosphorylation have focused mainly on small-molecule type I kinase inhibitors (KIs); however, these bind the active, closed conformation of the LRRK2 kinase domain, which affects protein tertiary structure and can alter other functions of this multi-domain protein. Because disruption of these functions may contribute to pathogenesis independently of, or in addition to, augmented kinase activity, inhibitors that engage LRRK2 differently may offer an advantage. We hypothesize that KIs, which bind distinct conformations of LRRK2 and modulate non-kinase functions differently than type I inhibitors, may be beneficial. Here we tested two series of LRRK2 inhibitors, based on hesperadin (series A) and GNF-7 (series B), which each inhibited LRRK2 kinase activity in biochemical and cellular assays while differing in effects on other LRRK2 functions. Interestingly, series B compounds enhanced phosphorylation of interdomain heterologous phosphosites and restored 14-3-3 binding in LRRK2 variants with suppressed phosphorylation. These chemotypes provide tools for dissecting the consequences of different inhibitor-bound LRRK2 conformations and support conformation-selective inhibition as a therapeutic strategy for PD.

biochemistry↗

bioRxiv2026

Biological and ecological insights from a rare underwater footage of the white shark (Carcharodon carcharias) in the Mediterranean Sea

The white shark Carcharodon carcharias (Linnaeus, 1758) is one of the most iconic and threatened marine predators globally and is listed as critically endangered by the IUCN in the Mediterranean Sea, where populations are primarily affected by fishing pressure and the degradation of critical habitats. Available information on Mediterranean white sharks mostly relies on fishing interactions and opportunistic surface records, thereby limiting evaluations on the species ecology. Here, we report an exceptionally rare underwater encounter with this species, documented by divers involved in an expedition aimed at removing ghost fishing gear from a World War II shipwreck in the Strait of Sicily (SoS), central Mediterranean. Given the exceptional nature of this observation, we analysed the video footage in detail with the aim of providing morphological information and novel insights into the species ecology. The footage analysis also allowed close observations on behavioural aspects and on interspecific and parasitic associations, thus providing information that is rarely achievable through surface sightings or from captured individuals, which historically represent the majority of records for this species in the region. To contextualize this observation within the SoS--an area suggested to function as a nursery and reproductive ground for the species--we also provide an updated compilation of records reported in the scientific literature over the last decade, adding 18 new records to existing datasets. This study highlights the value of shipwrecks as observation sites for rare and elusive species, and underscores the importance of non-invasive, video-based approaches in advancing knowledge of a species whose ecology in the Mediterranean remains poorly understood.

ecology↗

bioRxiv2026

A multi-omics map of diabetic nephropathy links c-Jun activation to tubular injury and metabolic stress

Diabetic nephropathy (DN) is a major cause of end-stage renal disease, yet the molecular mechanisms driving tubular injury and fibrosis remain poorly defined. Here, we integrated single-cell multiplexed protein imaging, spatial transcriptomics, single-nucleus and single-cell RNA sequencing and chromatin accessibility profiling to comprehensively characterize human DN pathology. Our multi-modal analysis precisely maps kidney cell types and their spatial distributions, immune-fibrotic interactions, and key transcriptional regulators. We identified eight distinct cellular neighborhoods defining the immune-fibrotic microenvironment and uncovered molecular networks driving tubular injury and fibrosis. JUN (encoding c-Jun) emerged as a central regulator of transcriptional reprogramming during tubular injury and fibrogenic remodeling. In a diabetic mouse model, c-Jun is activated in injured proximal tubules. Using an inducible c-Jun mouse model, we demonstrated that tubular-specific c-Jun activation alone is sufficient to induce tubular injury, chronic inflammation, progressive fibrosis, and systemic metabolic alterations, including impaired glucose homeostasis. We also observed reduced expression of SLC4A4, a bicarbonate transporter essential for proximal tubular function, in injured tubules. Together, our findings establish a spatially resolved framework for understanding DN pathogenesis and identify c-Jun as a key mediator of tubular injury and fibrosis in diabetic kidney disease.

pathology↗

bioRxiv2024

Characterizing features affecting local ancestry inference performance in admixed populations

In recent years, significant efforts have been made to improve methods for genomic studies of admixed populations using Local Ancestry Inference (LAI). Accurate LAI is crucial to ensure downstream analyses reflect the genetic ancestry of research participants accurately. Here, we test analytic strategies for LAI to provide guidelines for optimal accuracy, focusing on admixed populations reflective of Latin Americas primary continental ancestries - African (AFR), Amerindigenous (AMR), and European (EUR). Simulating LD-informed admixed haplotypes under a variety of 2 and 3-way admixture models, we implemented a standard LAI pipeline, testing three reference panel compositions to quantify their overall and ancestry-specific accuracy. We examined LAI miscall frequencies and true positive rates (TPR) across simulation models and continental ancestries. AMR tracts have notably reduced LAI accuracy as compared to EUR and AFR tracts in all comparisons, with TPR means for AMR ranging from 88-94%, EUR from 96-99% and AFR 98-99%. When LAI miscalls occurred, they most frequently erroneously called European ancestry in true Amerindigenous sites. Using a reference panel well-matched to the target population, even with a lower sample size, LAI produced true-positive estimates that were not statistically different from a high sample size but mismatched reference, while being more computationally efficient. While directly responsive to admixed Latin American cohort compositions, these trends are broadly useful for informing best practices for LAI across other admixed populations. Our findings reinforce the need for inclusion of more underrepresented populations in sequencing efforts to improve reference panels.

genomics↗

bioRxiv2024

Efficiency and reliability in biological neural network architectures

Simplified models of neural networks have demonstrated the importance of establishing a reasonable tradeoff between memory capacity and fault-tolerance in cortical coding schemes. The intensity of the tradeoff is mediated by the level of neuronal variability. Indeed, increased redundancy in neuronal activity enhances the robustness of the code at the cost of the its efficiency. We hypothesized that the heterogeneous architecture of biological neural networks provides a substrate to regulate this tradeoff, thereby allowing different subpopulations of the same network to optimize for different objectives. To distinguish between subpopulations, we developed a metric based on the mathematical theory of simplicial complexes that captures the complexity of their connectivity, by contrasting its higher-order structure to a random control. To confirm the relevance of our metric we analyzed several openly available connectomes, revealing that they all exhibited wider distributions of simplicial complexity across subpopulations than relevant controls. Using a biologically detailed cortical model and an electron microscopic data set of cortical connectivity with co-registered functional data, we showed that subpopulations with low simplicial complexity exhibit efficient activity. Conversely, subpopulations of high simplicial complexity play a supporting role in boosting the reliability of the network as a whole, softening the robustness-efficiency tradeoff. Crucially, we found that both types of subpopulations can and do coexist within a single connectome in biological neuronal networks, due to the heterogeneity of their connectivity. Our work thus suggests an avenue for resolving seemingly paradoxical previous results that assume homogeneous connectivity.

neuroscience↗

bioRxiv2024

Effects of excess phosphate on a coastal plankton community

Eutrophication in the Baltic Sea has caused an imbalance in the inorganic nitrogen (N) to phosphorus (P) ratio, leaving excess phosphate (PO4) after the phytoplankton spring bloom that terminates after N-depletion. Using monitoring data, we demonstrated that the PO4 concentration has continued to increase in the outermost Gulf of Finland during past decades. We further investigated the fate of such excess PO4 in a two-week mesocosm (1.2 m3) experiment. The starting concentration of PO4 was 0.66 {micro}M, and treatments included a non-treated control (control), nitrate addition (N-add; 3.6 {micro}M), glucose addition (C-add; 25 {micro}M) and combined nitrate and glucose addition (N+C-add). The addition of N both in N-add and N+C-add treatments stimulated nano- and microphytoplankton, while the picophytoplankton abundance increased only after N-depletion. Also, the copepod biomass was positively affected by the N-addition. N2-fixing cyanobacteria were present but in low abundance. Carbon addition did not enhance heterotrophic bacterial uptake of PO4 contrary to our expectations, nor did it affect the phyto- or zooplankton community composition. The PO4 concentration was reduced to [~]0.4 {micro}M in the control and C-add treatments and to 0.16 {micro}M in the two N-amended treatments, with an inorganic N:P uptake ratio of 6.7. These results underscore the role of picophytoplankton in reducing the excess PO4 pool after the spring bloom, a function traditionally ascribed to bloom-forming diazotrophic cyanobacteria in the Baltic Sea.

microbiology↗

bioRxiv2024

Microbial remineralization processes during post-spring-bloom excess phosphate in the northern Baltic Sea

In the northern Baltic, post-spring-bloom low dissolved inorganic nitrogen to phosphorus conditions, degradation of N-rich organic matter potentially supports the drawdown of excess phosphate. During a 17-day-long mesocosm experiment in the south-west Finnish archipelago, we examined nitrogen, phosphorus and carbon acquiring extracellular enzyme activities in three size fractions (<0.2 {micro}m, 0.2-3 {micro}m, and >3 {micro}m), bacterial abundance, production, community composition and its predicted metabolic functions. The mesocosms received different carbon and nitrogen amendments to test for the effect of inorganic nutrient stoichiometry on enzymatic degradation processes that ultimately determine the export potential of organic matter. Alkaline phosphatase activity occurred mainly in the dissolved form and likely contributed to the excess phosphate conditions. In the beginning of the experiment, peptidolytic and glycolytic enzymes were predicted to be produced by free-living bacteria identified within the classes Actinobacteria and Alphaproteobacteria, whereas the contribution of picocyanobacteria increased towards the end. Our results imply that heterotrophic bacteria lost the competition to picocyanobacteria due to the lack of suitable energy sources. The high hydrolytic rates in fractions <0.2 {micro}m and 0.2-3 {micro}m, found in this study, could potentially retain inorganic nutrients in the surface layer and suppress downward fluxes of organic matter and hence carbon sequestration.

microbiology↗

bioRxiv2021

Passive epidemiological surveillance in wildlife in Costa Rica identifies pathogens of zoonotic and conservation importance

Epidemiological surveillance systems for pathogens in wild species have been proposed as a preventive measure for epidemic events. These systems can minimize the detrimental effects of an outbreak, but most importantly, passive surveillance systems are the best adapted to countries with limited resources. Therefore, the present study aims to evaluate the technical and infrastructural feasibility to establish this type of scheme in Costa Rica targeting thedetection of pathogens of zoonotic and conservation importance in wildlife. Between 2018 and 2020, 85 carcasses of free-ranging vertebrates were admitted for post mortem analysis and complementary laboratory analysis, representing a solid basis for the implementation of a passive surveillance system for wildlife diseases in the country. However, we encounter during this research significant constraints that affected the availability of carcasses for analysis, mainly related to the initial identification of cases, detection biases towards events in populated- or easily accessible-areas with nearby located wildlife management centers, further associated with financial disincentives, and limited local logistics capacity. Thus resulting in the exclusion of some geographic regions of the country. This epidemiological surveillance scheme allowed us to estimate the general state of health of the countrys wildlife, establishing the cause of death of the analyzed animals as follows: (i) 46 (54.1%) traumatic events, (ii) 23 (27.1%) infectious agents, (iii) two (2.4%) degenerative illness, (iv) three (3.5%) presumably poisoning, and (v) in 11 (12.9%)undetermined. It also allowed the detection of pathogens such as, canine distemper virus, Klebsiella pneumoniae, Toxoplasma gondii, Trypanosoma spp., Angiostrongylus spp., Dirofilaria spp., Baylisascaris spp., among others. As well as recognizing the circulation of these pathogens around national territory and also on those analyzed species. This strategy is crucial in geographical regions defined as critical for the appearance of diseases due to their great biodiversity and social conditions.

pathology↗

bioRxiv2020

A global map of root biomass across the world's forests

Abstract (150 words limits)Root plays a key role in plant growth and functioning. Here we combine 10307 field measurements of forest root biomass worldwide with global observations of forest structure, climatic conditions, topography, land management and soil characteristics to derive a spatially-explicit global high-resolution (~ 1km) root biomass dataset, including fine and coarse roots. In total, 142 {+/-} 32 Pg of live dry matter biomass is stored below-ground, that is a global average root:shoot biomass ratio of 0.25 {+/-} 0.10. Our estimations of total root biomass in tropical, temperate and boreal forests are 44-226% smaller than earlier studies1-3. The smaller estimation is attributable to the updated forest area, spatially explicit above-ground biomass density used to predict the patterns of root biomass, new root measurements and upscaling methodology. We show specifically that the root shoot allometry is one underlying driver that leads to methodological overestimation of root biomass in previous estimations.

ecology↗

bioRxiv2019

The TRAPP complex mediates secretion arrest induced by stress granule assembly

The TRAnsport-Protein-Particle (TRAPP) complex controls multiple membrane trafficking steps and is thus strategically positioned to mediate cell adaptation to diverse environmental conditions, including acute stress. We have identified TRAPP as a key component of a branch of the integrated stress response that impinges on the early secretory pathway. TRAPP associates with and drives the recruitment of the COPII coat to stress granules (SGs) leading to vesiculation of the Golgi complex and an arrest of ER export. Interestingly, the relocation of TRAPP and COPII to SGs only occurs in actively proliferating cells and is CDK1/2-dependent. We show that CDK1/2 activity controls the COPII cycle at ER exit sites (ERES) and that its inhibition prevents TRAPP/COPII relocation to SGs by stabilizing them at the ERES. Importantly, TRAPP is not just a passive constituent of SGs but controls their maturation since SGs that assemble in TRAPP-depleted cells are smaller and are no longer able to recruit RACK1 and Raptor, rendering the cells more prone to undergo apoptosis upon stress exposure.

cell biology↗

bioRxiv2017

Gut microbiota of the pine weevil degrades conifer diterpenes and increases insect fitness

The pine weevil (Hylobius abietis), a major pest of conifer forests throughout Europe, feeds on the bark and cambium, tissues rich in terpenoid resins that are toxic to many insect herbivores. Here we report the ability of the pine weevil gut microbiota to degrade the diterpene acids of Norway spruce. The diterpene acid levels present in ingested bark were substantially reduced on passage through the pine weevil gut. This reduction was significantly less upon antibiotic treatment, and supplementing the diet with gut suspensions from untreated insects restored the ability to degrade diterpenes. In addition, cultured bacteria isolated from pine weevil guts were shown to degrade a Norway spruce diterpene acid. In a metagenomic survey of the insects bacterial community, we were able to annotate several genes of a previously described diterpene degradation (dit) gene cluster. Antibiotic treatment disrupted the core bacterial community of H. abietis guts and eliminated nearly all dit-genes concordant with its reduction of diterpene degradation. Pine weevils reared on an artificial diet spiked with diterpenes, but without antibiotics, were found to lay more eggs with a higher hatching rate than weevils raised on diets with antibiotics or without diterpenes. These results suggest that gut symbionts contribute towards host fitness, but not by detoxification of diterpenes, since these compounds do not show toxic effects with or without antibiotics. Rather the ability to thrive in a terpene rich environment appears to allow gut microbes to benefit the weevil in other ways, such as increasing the nutritional properties of their diet.

evolutionary biology↗