bioRxiv Science⌕ Search

Biology subjects

Sacco, M.

Publications and source records attributed to Sacco, M..

8 recordsLinked to original sources

FEATMAP: Targeted Correction of Acquisition Signatures Harmonizes Medical Foundation Model Embeddings and Enables Robust Task Generalization

AO_SCPLOWBSTRACTC_SCPLOWMedical foundation models compress biomedical data into embeddings that support diverse downstream clinical tasks. However, successful model deployment is hampered by performance degradation on external data. It is recognized that embeddings capture acquisition signatures, such as hardware and technical differences, in addition to biology. Effective harmonization must remove the acquisition signature while preserving biological signals, a trade-off that current methods fail to balance adequately. Input-level normalization fails to eliminate acquisition signatures from embeddings, whereas embedding-level methods adjust features in an untargeted manner. We present FEATMAP, a harmonization approach that models acquisition signatures as geometric distortions between manifolds of similarly arranged embeddings. Using paired data that isolate the effect of acquisition signatures, FEATMAP fits a single global affine transformation per foundation model to correct acquisition signatures directly in the embedding space. This targeted, reusable correction aims to preserve biological and demographic variation while harmonizing across acquisition signatures. Across scanner and foundation-model harmonization in digital pathology and field-strength harmonization in brain MRI, FEATMAP improves cross-condition embedding similarity, reduces performance gaps without retraining, and suggests potential for the alignment of disparate embedding spaces.

bioinformatics↗

Globally unified analysis of riverine eDNA reveals common associations of fish biodiversity with drainage characteristics

Freshwater biodiversity is declining at a pace that outstrips the capacity of existing monitoring approaches both in temporal and spatial dimensions, highlighting the urgent need for rapid and scalable assessment and attribution of biodiversity states and changes. Here, we present one of the first global assessments and unified analyses of riverine fish biodiversity using environmental DNA (eDNA) collected from 1818 sites across 113 river systems. We quantified species richness, functional redundancy, phylogenetic diversity, and genetic sequence diversity, and related them to drainage characteristics. Our results showed that eDNA effectively captured global patterns of multi-faceted riverine fish biodiversity and disentangled the roles of climate and human activities in shaping biodiversity-area relationships. Catchments in warmer climates consistently enhanced biodiversity accumulation with area, while higher human activity intensity weakened this scaling. Species richness, functional, and genetic sequence diversity exhibited stronger negative responses to human activities in larger catchments. In contrast, phylogenetic diversity showed the strongest negative effects in smaller catchments with these impacts diminishing as catchment area increased, highlighting the facet-dependent nature of biodiversity responses to environmental gradients. Our findings demonstrate the power of eDNA-based datasets for harmonized, multi-faceted biodiversity assessments, offering a scalable approach for detecting and attributing biodiversity change and informing conservation strategies under accelerating global change.

ecology↗

Integrated reanalysis of global riverine fish eDNA datasets shows robustness and congruence of biodiversity conclusions

The analysis of environmental DNA (eDNA) has revolutionized biodiversity assessments in aquatic ecosystems, enabling non-invasive monitoring of fish communities across diverse regions. However, the global comparability of these eDNA datasets remains ambiguous due heterogeneous sampling protocols and bioinformatic workflows across studies, particularly regarding the robustness of their conclusions on biodiversity assessments. Here, we conducted a meta-analysis of 58 riverine fish eDNA metabarcoding datasets, covering 1,818 sampling sites worldwide, to evaluate the robustness of eDNA-derived biodiversity patterns. We found that species richness estimates and metrics of community structure derived under a common bioinformatic workflow were overall consistent with those of original analyses, despite the relatively high variability in bioinformatic analyses in the respective original studies. Contrastingly, congruence of species identity varied more extensively across datasets, mostly reflecting different completeness and regional relevance of reference databases. Restricting taxonomic assignment to basin-specific species pools improved species identification accuracy, while datasets lacking publicly accessible or well-curated reference data were more prone to mismatches. Year of sampling had a positive effect on taxonomic congruence, such that more recent studies showed increased robustness, also reflecting improved reference database coverage and enhanced species-level identification over time and overall method congruence in more recent years. Overall, the suitability and potential of eDNA for global biodiversity monitoring is corroborating overall robust biodiversity estimates, irrespective of the bioinformatic approaches. Our study underlines the effectiveness and need of further harmonization of bioinformatic workflows and strengthened region-specific reference databases for improved taxonomic resolution and comparability across studies.

ecology↗

Natural variants of von Willebrand factor R1205 causing von Willebrand disease with accelerated von Willebrand factor clearance: in silico docking models and energetics of the interaction with both LRP1 and GpIb A1 domain

Type 1 von Willebrand disease (VWD) is often caused by variants in von Willebrand factor (VWF), including p.R1205H ("Vicenza mutation"), which accelerate VWF clearance via macrophage receptor LRP1 and impair platelet adhesion. However, the structural mechanisms underlying these phenotypes remain unclear. Here, we use integrative computational modeling (I-TASSER, HADDOCK2.4, and PRODIGY) to predict how p.R1205H/C/L/S variants alter VWF interaction with LRP1 and GPIb. Our models reveal that R1205 acts as a structural hinge: its variants disrupt polar networks in VWFs D3 domain, exposing neo-epitopes that enhance LRP1 binding ({Delta}{Delta}G up to -5.3 kcal/mol) while destabilizing the A1 domains 1-{beta}2 loop, reducing GPIb affinity (33-fold for R1205L/C). These findings explain clinical observations, p.R1205H rapid clearance yet retained platelet adhesion, and establish R1205 as a dual-functional switch regulating VWF circulatory lifetime and hemostatic activity. This analytical procedute provides a template for predicting pathogenicity of VWF variants and designing targeted therapies for VWD. Author SummaryIn our study, we explored how specific genetic changes in von Willebrand factor (VWF), a protein crucial for haemostsis, lead to a bleeding disorder called von Willebrand disease (VWD). We focused on mutations at position R1205 in VWF, known to cause rapid clearance of the protein from the bloodstream, resulting in low levels and impaired clotting. Using advanced computer modeling, we investigated how these mutations alter VWFs interactions with two key partners: LRP1, a receptor that removes VWF from circulation, and GpIb, a platelet receptor essential for clotting. Our models revealed that R1205 acts like a structural hinge. Mutations disrupt its stabilizing role, exposing regions that bind more tightly to LRP1, thus explaining the accelerated clearance seen in patients. Simultaneously, these changes can also weaken VWFs ability to interact with platelets, further impairing platelet haemostatic function. This work provides a blueprint for understanding how some VWF variants cause disease and could guide the design of targeted therapies to correct or compensate for these defects, improving treatment for VWD patients.

biochemistry↗

Metazoan diversity in Chilean hypersaline lakes unveiled by environmental DNA

Saline and hypersaline wetlands are biodiversity hotspots for metazoans such as aquatic invertebrates and wading birds. However, the survival of these habitats and their biota is increasingly threatened by a combination of pressures from climate change and extractive processes, jeopardizing the long-term ecological functioning of these ecosystems. With the goal of improving conservation efforts through state-of-the-art survey techniques in hypersaline ecosystems, this study tests the use of environmental DNA (eDNA) methods for metazoan biomonitoring. We employed a multi-assay approach utilizing three genetic markers--12S rRNA, 18S rRNA, and COI --to analyze biodiversity in two types of environmental substrates, sediment and water. These samples were collected from three hypersaline lakes situated at high altitude in Northern Chile: Salar de Atacama (Laguna Puilar), Salar de Pujsa, and Salar de Tara. In addition, we compared the eDNA outputs with results generated from aquatic macroinvertebrate assessments using kick-nets to evaluate the potential for complementary sampling approaches. Our eDNA analyses revealed a total of 21 and 22 taxa across the three hypersaline lakes in sediment and water, respectively. Within both substrates, the highest diversity was found in Salar de Tara (15 taxa within sediment and 13 taxa from water). Our multi-assay design was able to detect a range of resident hypersaline taxa with different conservation status, spanning from rotifers (Encentrum) to endangered snails (Heleobia atacamensis), to amphipods (Hyalella) and flamingos (Pheonicopterus). Macroinvertebrate presence/absence data derived from conventional kick-net surveys further validated Salar de Tara as the most biodiverse system. Compared to net-based assessments, eDNA analysis allowed more refined taxonomic assignments for copepods and ostracods, while certain taxa such as Ephydridae or Hirudinea were not detected through molecular tests. Overall, this study provides evidence that eDNA is an effective tool to elucidate fine scale taxa assemblages and can refine conservation efforts in hypersaline lakes. Given the fast pace of research developments in the field of molecular ecology, eDNA hosts great potential to become a central actor in hypersaline bioassessments in the near future.

ecology↗

Towards a global barcode reference library for subterranean fauna

Implementation of environmental DNA (eDNA) metabarcoding for biodiversity discovery and assessment offers a unique opportunity to gain new insights into subterranean communities around the world. However, for effective and meaningful identification of species from anonymous eDNA barcodes, a library of known reference sequences with associated correct taxonomic metadata -also called a barcode reference library (BRL) - is required. Here we propose an open, publicly accessible information resource for eDNA biomonitoring of subterranean fauna following findable, accessible, interoperable and reusable (FAIR) principles that can be expanded globally. While similar proposals have been made by other authors for individual taxon groups, here we have analysed a curated BRL of subterranean fauna compiled from existing GenBank and BOLD DNA sequence databases for a minimum of four genes (COI, 18S, 12S, and 16S rRNA). We demonstrate the value of such an initiative to eDNA metabarcoding where custom libraries are used to characterise entire ecosystems under examination. To examine the effectiveness of a custom BRL, we generated metabarcoding data for an exemplar system at Bungaroo Creek in the Pilbara (Australia), a globally significant location of stygofaunal diversity. We compared results of BLAST queries of eDNA Operational Taxonomic Units (OTUs) to our BRL and the GenBank nucleotide database, and observed that for all barcoding regions, the custom BRL identified subterranean ZOTUs that could not be identified using GenBank and worked better in tandem. We use the BRL presented here to propose a four-stage plan for developing data infrastructure for subterranean fauna, especially with respect to eDNA metabarcoding data. To our knowledge, this represents the first published instance of a subterranean BRL being tested against real eDNA metabarcoding data. These findings provide a step forward towards robust DNA-based bioassessments for subterranean biodiversity and further emphasise the need for the eDNA community to work together in facilitating a global BRL.

evolutionary biology↗

What are the best practices for curating eDNA custom barcode reference libraries? A case study using Australian subterranean fauna.

Identification of species for environmental assessment and monitoring is essential for understanding anthropogenic impacts on biodiversity, but for subterranean fauna this task is frequently difficult and time consuming. The implementation of environmental DNA (eDNA) metabarcoding for biodiversity discovery and assessment offers considerable promise for improving the rate, accuracy and efficiency of species detection in ecosystems both above and below the ground. Importantly, for a better understanding of the biodiversity and ecology of organisms detected using eDNA, a custom library of known reference sequences with associated correct taxonomic metadata--i.e., a barcode reference library (BRL)--is required. Yet, minimal guidance is currently available on how an effective (i.e. shareable, multi-sequence, that permits metadata and has a unified nomenclature) and accurate (i.e. verified) custom BRL can be achieved. Here, we present a detailed roadmap for curation of a BRL for subterranean fauna. To do this, we (1) curated a custom sequence database of subterranean fauna at an environmentally sensitive location, Bungaroo Creek in the Pilbara region of Western Australia, for four gene loci useful for eDNA metabarcoding (COI, 18S rRNA, 12S rRNA and 16S rRNA); (2) addressed major gaps in taxonomy and disparate nomenclature of subterranean fauna by estimating 17-29 putative new species with standard delimitation methods, including 34 Barcode Index Numbers (BINs) in BOLD, and (3) summarised a best practice workflow for curation of a custom BRL that has broad applicability and can be applied to any taxa. Scientific Significance StatementIn threatened ecosystems, environmental DNA (eDNA) metabarcoding for biodiversity discovery and assessment offers considerable promise for improvement in the rate, efficiency and accuracy of species detection. For a better understanding of the biodiversity and ecology of organisms detected using eDNA, a custom library of known reference sequences with associated correct taxonomic metadata is required. Minimal guidance is currently available on how an effective (i.e. shareable, multi-sequence, permits metadata and provides a unified nomenclature) custom barcode reference library (BRL) can be achieved for subterranean fauna. Here, we present a road map for sound and reliable curation of a BRL using subterranean fauna from Australia as a case study.

evolutionary biology↗

Discovery of SARS-CoV-2 papain-like protease inhibitors through a combination of high-throughput screening and FlipGFP-based reporter assay

The papain-like protease (PLpro) of SARS-CoV-2 is a validated antiviral drug target. PLpro is involved in the cleavage of viral polyproteins and antagonizing host innate immune response through its deubiquitinating and deISG15ylating activities, rendering it a high profile antiviral drug target. Through a FRET-based high-throughput screening, several hits were identified as PLpro inhibitors with IC50 values at the single-digit micromolar range. Subsequent lead optimization led to potent inhibitors with IC50 values ranging from 0.56 to 0.90 {micro}M. To help prioritize lead compounds for the cellular antiviral assay against SARS-CoV-2, we developed the cell-based FlipGFP assay that is suitable for quantifying the intracellular enzymatic inhibition potency of PLpro inhibitors in the BSL-2 setting. Two compounds selected from the FlipGFP-PLpro assay, Jun9-53-2 and Jun9-72-2, inhibited SARS-CoV-2 replication in Caco-2 hACE2 cells with EC50 values of 8.89 and 8.32 {micro}M, respectively, which were 3-fold more potent than GRL0617 (EC50 = 25.1 {micro}M). The X-ray crystal structures of PLpro in complex with GRL0617 showed that binding of GRL0617 to SARS-CoV-2 induced a conformational change in the BL2 loop to the more closed conformation. Overall, the PLpro inhibitors identified in this study represent promising starting points for further development as SARS-CoV-2 antivirals, and FlipGFP-PLpro assay might be a suitable surrogate for screening PLpro inhibitors in the BSL-2 setting.

pharmacology and toxicology↗