Lila Sciences

Determining a gene's functional importance within a cellular context has long been a challenge, as absolute expression level is an unreliable indicator. Here we introduce SIGnature, a framework for scoring gene importance using attributions derived from single-cell RNA-sequencing (scRNA-seq) foundation models. Attribution scores reduce technical noise, emphasize regulatory genes and facilitate cross-dataset comparison-a core challenge for scRNA-seq analyses. We developed the SIGnature package as a tool for generating and querying attributions, enabling rapid gene set searches across large scRNA-seq atlases. We demonstrate its utility using the MS1 monocyte signature, a poorly understood gene program activated in severe COVID-19 and sepsis. Searching 400 studies identified associations between the MS1 signature and multiple hyperinflammatory conditions, including Kawasaki disease. Experimental validation confirmed that serum from persons with Kawasaki disease induces the MS1 phenotype. These findings highlight that SIGnature can uncover shared mechanisms across conditions, demonstrating its power for large-scale signature scoring and cross-disease analysis.

Esophageal cancer (EC) remains an extremely lethal cancer with few prognostic biomarkers and specific therapies. Although autophagy is increasingly recognized as a key force behind tumor adaptation and resistance to therapy, its systematic role at the EC progression level for prognostics, as well as for drug target prediction, remains unclear. Here, we attempted to build a systems-wide map linking autophagy- and signaling-related genes and transcriptional dysregulation, patient survival, and druggability in EC. Hub genes were found using an integrative bioinformatics pipeline based on protein-protein interaction networks and further explored using enrichment, expression, survival, and molecular docking analyses. Functional enrichment highlighted autophagy, mitophagy, ferroptosis, and immune signaling as central processes, converging with stress- and metabolism-associated pathways. Expression profile of TCGA-ESCA data demonstrated substantial overexpression of autophagy initiators and elongation factors (ATG3, ATG5, ATG7, ATG12, ATG13), upstream regulators (AMBRA1, UVRAG), and stress/metabolic mediators (TP53, MYD88, GAPDH). Kaplan-Meier analysis indicated three genes, including ATG4A, GABARAPL2, and GAPDH, that exhibited significant expression levels correlating with less survival and emphasizing their prognostic capacities. Screening for drugs also revealed AKT1, TP53, and PIK3R4 as druggable hubs, and many drugs (e.g., Everolimus, Dabrafenib, Trabectedin) showing high-affinity interactions. These findings collectively demonstrate that the progression of EC is supported by a coordinated program that integrates autophagy and metabolic reprogramming with stress and immunological signaling. The study discovers new prognostic markers (ATG4A, GABARAPL2, GAPDH) and druggable targets, which could lead to better risk stratification and smarter drug repurposing. While restricted to in silico analyses, the integrative approach provides a basis for subsequent laboratory confirmation and translational development.

The aim of this preliminary study was to determine the effect of taurine on the expression of genes involved in glycolysis, oxidative phosphorylation, inflammation, autophagy, and regenerative activity in cultured peripheral blood mononuclear cells (PBMCs) and articular cartilage explants from patients with end-stage rheumatoid arthritis (RA). PBMCs and knee articular cartilage were obtained from 20 patients with RA (3 men and 17 women) aged 62.2 ± 10.9 years, with a mean disease duration of 17.5 years (range: 2-43), prior to arthroplasty. PBMCs and cartilage explants were cultured in the presence of 50 µM taurine. Gene expression was determined using real-time reverse transcriptase polymerase chain reaction (RT-PCR). Protein expression of the examined genes in PBMCs was quantified using ELISA. In the presence of 50 µM taurine PBMCs from patients with RA demonstrated a significant increase in the expression of genes encoding pyruvate kinase (PKM2), succinate dehydrogenase (SDHB), uncoupler of oxidation and phosphorylation (UCP2), ATP synthase (ATP5B), and unc-51-like kinase 1 (ULK1). At the same time a significant decrease in tumor necrosis factor (TNF)α and interleukin (IL)-1β expression was noted. In cartilage explants, taurine upregulated SDHB, UCP2, ULK1, and type 2 collagen gene (COL2A1), and decreased TNFα expression. We concluded that, under in vitro conditions, taurine can influence the expression of genes involved in glycolysis, oxidative phosphorylation, inflammation, autophagy, and regenerative processes in PBMCs and articular chondrocytes from patients with end-stage RA.

Hydrogels are attractive scaffolds for regenerative medicine, yet few systems combine robust mechanical performance, antimicrobial functionality, and controlled bioactivity. Here, we engineered chitosan-based hydrogels crosslinked via strain-promoted azide-alkyne cycloaddition (SPAAC) using 4-arm PEG-DBCO and functionalized with NeoNectin, a de novo-designed protein exhibiting subnanomolar affinity and high specificity for integrin α5β1. Rheological analysis confirmed stable hydrogel formation with an elastic modulus of ∼0.1 kPa, within the physiological range of bone marrow and typically associated with maintenance of mesenchymal stem cells (MSCs) in an undifferentiated state, enabling evaluation of integrin-specific biochemical cues in an inhibitory mechanical environment. Antimicrobial assays confirmed intrinsic bactericidal activity against Staphylococcus aureus and Pseudomonas aeruginosa, mitigating infection risks associated with implantation. Encapsulated human MSCs maintained high viability across all groups, validating cytocompatibility of the SPAAC crosslinking. Importantly, only covalently immobilized NeoNectin promoted sustained proliferation, increased expression of osteogenic genes, and significantly enhanced alkaline phosphatase activity, despite the low stiffness of the hydrogel matrix. These findings demonstrate that α5β1-specific signaling can override mechanical cues and drive osteogenic differentiation within ultra-soft environments. Overall, NeoNectin-functionalized SPAAC hydrogels provide a multifunctional platform that integrates antimicrobial properties, mechanical stability, and cell-instructive signaling for bone regeneration and broader tissue engineering applications.

This study evaluates the repurposed application of an expired non-sedating antihistamine drug (ENSAD), fexofenadine hydrochloride, as a high-performance "green" corrosion inhibitor for copper in 1.0 M HCl. Gravimetric results demonstrate a concentration-dependent inhibition efficiency reaching 96.4% at 120 ppm, with remarkable long-term stability (> 92.5% efficiency after 72 h). Adsorption behavior followed the Langmuir isotherm model, indicating the formation of a stable monolayer. The calculated Gibbs free energy (∆Goads =-33.8 kJ mol- 1) confirms a comprehensive physicochemical adsorption mechanism involving both electrostatic attraction and chemical coordination. Thermodynamic investigations revealed that the addition of ENSAD increased the activation energy from 30.36 to 53.89 kJ mol⁻¹, creating a substantial energy barrier against metallic dissolution. Electrochemical studies (PDP and EIS) confirmed ENSAD as a mixed-type inhibitor that significantly enhances charge transfer resistance (Rct). Quantum chemical parameters, including a low energy gap (ΔEg = 2.361 eV) and high softness (S = 0.424 eV- 1), corroborate the high reactivity and electron-donating capability of the molecule's heteroatoms (N, O) and π-systems. Surface characterization (SEM/EDX) visually and chemically confirmed the presence of a robust organic film. These findings position ENSAD as a technically viable, thermally stable, and sustainable alternative for corrosion protection in industrial acid cleaning and low-temperature desalination stages.

Bipolar II disorder (BDII) accounts for the majority of patients with bipolar disorder (BD), yet evidence supporting first-line mood stabilising treatment with lithium and lamotrigine is scarce, and the certainty of the evidence is very low. This highlights a critical evidence gap within psychiatric care. The lithium versus lamotrigine-bipolar randomised controlled trial (RCT) aims to compare lithium and lamotrigine on self-rated day-to-day mood instability (MI) and other patient-centred outcomes in BDII, hypothesising the superiority of lithium. A two-arm, single-blind, parallel-group, superiority RCT with a target sample size of 200 patients (accounting for attrition), recruiting patients with newly diagnosed BDII from specialised outpatient mood disorder clinics in the capital region of Copenhagen, Denmark. Participants are randomised in a 1:1 ratio to receive either lithium or lamotrigine for 6 months. The primary outcome is MI, assessed via daily smartphone-based mood ratings. MI is chosen as the primary outcome measure due to its internal validity as a real-life measure for patients and external validity as it reflects both illness severity and functional impairment. Secondary outcomes include the proportion of participants showing a non-response to treatment and observer-rated changes in depressive symptoms over 6 months, measured using the six-item version of the Hamilton Depression Rating Scale. Primary analyses will follow the intention-to-treat principle using linear mixed models. The trial is monitored by the good clinical practice.Recruitment commenced on 8 May 2024, and the final participant follow-up (last patient last visit) is expected on 1 December 2027. The trial has received approvals from the Danish Research Ethics Committee, the Danish Medicines Agency (EU CT No. 2023-5 09 607-32-00) and the Capital Region Data Agency (P-2023-307). Results will be published in peer-reviewed journals. Clinicaltrials.gov/NCT06184581.

In vitro fermentation models with strains of Lactiplantibacillus plantarum and Bacillus subtilis were used to track the structural changes in polyphenolic composition in wild blueberry treatments after 72 h fermentation, and to compare metabolites from exogenous fermentation to those reported to be produced by human gut-derived catabolism. Shifts in the profiles of flavonoids, anthocyanins, proanthocyanidins, phenolic acids, and phenolic acid conjugates (some putatively identified for the first time in wild blueberries) were quantified. While glucuronide and sulfate conjugates of phenolic acids (which rely on human enzymes) are not produced in vitro, exogenous fermentation can, depending on the conditions, replicate a broad range of the bioactive phenolic acids generated by endogenous fermentation of wild blueberries in the human gut. Exogenous fermentation may therefore yield more standardized and physiologically relevant phenolic profiles than an unfermented blueberry extract for use in translational preclinical research on berry health benefits.