Biology subjects

Russo, F.

Publications and source records attributed to Russo, F..

11 recordsLinked to original sources

bioRxiv2026

Protein Folding Interference Enables Selective Cyclin D1 Degradation

Cyclin D1 is a central regulator of cell-cycle progression and a compelling therapeutic target in cancer, yet its non-enzymatic function, limited ligandability, and rapid turnover have hindered direct pharmacological intervention. Here we show that these limitations can be overcome by targeting a transient conformational state populated during protein folding. Computational reconstruction of the Cyclin D1 folding landscape enabled the identification of a ligandable folding intermediate that served as the basis for structure-guided discovery of small molecules inducing selective degradation of nascent Cyclin D1. Orthogonal computational, biophysical, and cellular studies support the proposed mechanism, linking engagement of the folding intermediate to selective degradation of newly synthesized Cyclin D1. Pharmacological folding interference suppressed Cyclin D1 signaling, inhibited tumor cell proliferation, produced antitumor activity in vivo, and retained efficacy in a model of acquired resistance to CDK4/6 inhibition. Together, our findings establish a rational strategy for directly targeting Cyclin D1. More broadly, they suggest that the conformational landscape explored during protein folding represents an untapped reservoir of therapeutic opportunities, expanding small-molecule discovery beyond the native structures that have traditionally defined the druggable proteome.

biochemistry↗

bioRxiv2026

Resource Mismatch in Phototrophic Subaerial Biofilms and Resulting Phototroph/Heterotroph Ratios

Photosynthesis-driven microbial communities are frequently observed on air-exposed stone such as, for example, marble surfaces. These environments are stark, subject to varying water, temperature, UV and other stresses. As a consequence, resident microbes likely have significant maintenance requirements. Those microbes however, have access to plentiful energy when conditions are favorable for photosynthesis. High rates of photosynthesis for purposes of energy generation may also generate excess organic carbon which can be released as extracellular overflow, becoming available for heterotrophic organisms. Here we propose a simple model to explore possible consequences of this hypothesized resource mismatch. The model predicts that heterotrophs can invade purely phototrophic communities, with the resulting mixed community eventually approaching a phototroph/heterotroph ratio at steady state as a consequence of stoichiometric balance. Results from field observations at three geographically separated sites (Lincoln Memorial, Washington D.C., Merchants' Exchange, Philadelphia PA, and the Federal Hall National Memorial, New York NY), analyzed using two independent methods, are seen to match model predictions, demonstrating both cyanobacterial dominated communities as well as, mostly, mixed communities with a heterotrophs-to-cyanobacteria biovolume ratio of approximately 0.4.

microbiology↗

bioRxiv2026

Pulling water from a stone: subaerial biofilm water dynamics on porous solid materials

Subaerial biofilms (SABs) are microbial communities that colonize air exposed surfaces in both natural and engineered environments, forming an interface between the atmosphere and the substrate. Often water availability is crucial for their metabolic activity and survival. While precipitation may contribute to SAB hydration, the dynamic processes of evaporation and condensation - closely linked to fluctuating temperature and humidity conditions - can be key determinants of water availability and they constitute the main focus of this study. We present a model connecting the water-related dynamics in an SAB, its surrounding ambient air and underlying stone/masonry. A central feature of the model is the increased water affinity of the SAB in comparison to the stone pore network. Based on thermodynamic principles, the model captures changes in liquid water content and availability by accounting for the evaporation and condensation at liquid-gas interfaces through gradients in water chemical potential. It accounts for the SAB's capacity to delay water loss by drawing water from substrate material pores to compensate for atmospheric evaporation. The proposed model is compared to prior experimental observations of water transport in limestone samples with and without SAB. Additional numerical simulations under variable environmental conditions demonstrate how permeability of the substrate layer may influence SAB water activity, and how the presence or absence of an SAB might affect water content within stone/masonry.

microbiology↗

bioRxiv2026

Intra-Abdominal Bowel Dilation in Experimental Gastroschisis is Associated with a Modifiable Transcriptomic Program of Intestinal Dysfunction

STRUCTURED ABSTRACTO_ST_ABSObjectiveC_ST_ABSTo characterize intestinal transcriptional profiles in gastroschisis, their temporal evolution, and response to fetal intervention. Summary Background DataGastroschisis causes significant intestinal dysfunction, with intra-abdominal bowel dilation clinically shown to correlate with worse outcomes. While inflammation and neurovascular impairment have been implicated, genome-wide transcriptional characterization of disease severity remains lacking. MethodsUsing a fetal ovine model of complex gastroschisis, in which all gastroschisis animals demonstrated significant intra-abdominal bowel dilation at term, bulk RNA sequencing was performed on proximal small intestinal tissue from mid-gestation and term fetuses across three groups: normal, gastroschisis, and prenatally repaired gastroschisis. Differential gene expression (FDR [≤] .05, |log2 fold change| [≥] 1.5) and pathway enrichment analyses were performed, with targeted interrogation of extracellular matrix (ECM), enteric nervous system (ENS), angiogenic, and inflammatory pathways. ResultsAt mid-gestation, gastroschisis intestine showed minimal transcriptional differences (150 differentially expressed genes [DEGs]) and some bowel dilation. By term, dysregulation was substantial (2,423 DEGs) alongside significant dilation. Normal ontogenetic intestinal maturation patterns were altered, with fewer expected developmental gene changes and discordant pathway regulation. ECM pathway aberrations emerged early and persisted, while ENS, angiogenic, and inflammatory pathways were only dysregulated at term. Fetal repair was associated with normalization of gene expression at term (29 DEGs vs controls). ConclusionIntestinal transcriptional changes in experimental gastroschisis parallel progressive bowel dilation, consistent with a mechanical stress contribution to intestinal injury. Prenatal repair normalizes both dilation and gene expression, indicating a dynamic and potentially modifiable transcriptional program that supports the rationale for early fetal intervention. Mini AbstractIn a fetal ovine model, progressive bowel dilation in gastroschisis parallels transcriptomic dysregulation of ECM remodeling, neurovascular impairment, and inflammation which is normalized by prenatal repair.

developmental biology↗

bioRxiv2026

A Reproducible Fetal Lamb Model of Complex Gastroschisis with Temporal Characterization of Bowel Changes

ObjectiveTo establish a fetal lamb model of complex gastroschisis and characterize the impact on the intestines over time. Summary Background DataGastroschisis is a congenital abdominal wall defect and in its complex form is associated with serious morbidity. Robust large-animal models may help understanding are lacking. MethodsAt gestational day 75, gastroschisis was induced by creating a 1-cm abdominal wall defect reinforced by a silicone ring. Fetuses were assessed either at term or at mid-gestation (13-21 days post-induction). The primary outcome was complex gastroschisis occurrence, defined by bowel stenosis, atresia, volvulus, perforation or necrosis; otherwise classified as simple. At mid-gestation, occurrence was compared between early (13-16 days) and late (17-21 days) intervals. Secondary outcomes included prenatal ultrasound findings, in vivo bowel motility and morphology, ex-vivo bowel contractility, amniotic fluid composition, and histology across complex, simple, and normal groups. ResultsGastroschisis was induced in 32 fetuses. At term (n=14), all survivors (7/14; 50%) had complex gastroschisis, with impaired bowel motility, altered enteric neural contractile responses and smooth muscle remodeling. At mid-gestation (n=18), complex gastroschisis occurred more frequently in the late than in the early group (71% vs. 11%; p=0.035). Mid-gestation gastroschisis fetuses showed greater intra-abdominal bowel dilatation on ultrasound and higher amniotic fluid digestive enzyme levels compared with non-operated littermates, with the greatest dilation observed in complex gastroschisis. ConclusionsThis model consistently reproduces complex gastroschisis in term survivors. After induction, complex gastroschisis occurrence increases with disease duration and is accompanied by structural and functional bowel changes.

developmental biology↗

bioRxiv2024

Fiora: Local neighborhood-based prediction of compound mass spectra from single fragmentation events

Non-targeted metabolomics holds great promise for advancing precision medicine and facilitating the discovery of novel biomarkers. However, the identification of compounds from tandem mass spectra remains a non-trivial task due to the incomplete nature of spectral reference libraries. Augmenting these libraries with simulated mass spectra can provide the necessary reference to resolve unmatched mass spectra, but remains a difficult undertaking to this day. In this study, we introduce Fiora, an innovative open-source algorithm using graph neural networks to simulate tandem mass spectra in silico. Our objective is to improve fragment intensity prediction with an intricate graph model architecture that facilitates edge prediction, thereby modeling fragment ions as the result of singular bond breaks and their local molecular neighborhood. We evaluate the performance on test data from NIST (2017) and the curated MS-Dial spectral library, as well as compounds from the 2016 and 2022 CASMI challenges. Fiora not only surpasses state-of-the-art fragmentation algorithms, ICEBERG and CFM-ID, in terms of prediction quality, but also predicts additional features, such as retention time and collision cross section. In addition, Fiora demonstrates significant speed improvements through the use of GPUs. This enables rapid (re)scoring of putative compound identifications in non-targeted experiments and facilitates large-scale expansion of spectral reference libraries with accurate spectral predictions. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/590551v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@90bf99org.highwire.dtl.DTLVardef@112da33org.highwire.dtl.DTLVardef@b376eeorg.highwire.dtl.DTLVardef@450ee6_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2024

Prenatal VEGF Nano-Delivery Reverses Congenital Diaphragmatic Hernia-Associated Pulmonary Abnormalities

RationaleCongenital diaphragmatic hernia (CDH) results in lung hypoplasia. In severe cases, tracheal occlusion (TO) can be offered to promote lung growth. However the benefit is limited, and novel treatments are required to supplement TO. Vascular endothelial growth factor (VEGF) is downregulated in animal models of CDH and could be a therapeutic target, but its role in human CDH is not known. ObjectivesTo investigate whether VEGF supplementation could be a suitable treatment for CDH-associated lung pathology. MethodsFetal lungs from CDH patients were used to determine pulmonary morphology and VEGF expression. A novel human ex vivo model of fetal lung compression recapitulating CDH features was developed and used to determine the effect of exogenous VEGF supplementation (Figure 1A). A nanoparticle-based approach for intra-pulmonary delivery of VEGF was developed by conjugating it on functionalized nanodiamonds (ND-VEGF) and was tested in experimental CDH in vivo. O_FIG O_LINKSMALLFIG WIDTH=138 HEIGHT=200 SRC="FIGDIR/small/581170v1_fig1.gif" ALT="Figure 1"> View larger version (77K): org.highwire.dtl.DTLVardef@2ba882org.highwire.dtl.DTLVardef@4413d2org.highwire.dtl.DTLVardef@17155aborg.highwire.dtl.DTLVardef@1af7c73_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOFigure 1C_FLOATNO (A) Schematic of the study design based on the analysis of the early-stage CDH fetal lung sections to assess early hypoplasia and VEGF impairment. In parallel, a human compression-based CDH model will be developed to validate the CDH phenotype and test a therapeutical approach to rescue lung hypoplasia. (B) H&E analysis of 18 and 22 pcw post-mortem CDH human lung tissue reveals impaired epithelial development compared to control healthy tissue at matching developmental stages. Scale bar 100m. (C) Morphometric analysis of CDH and healthy lung tissue at 18-22 pcw reveals decreased values of volume densities of air space (Vair%) and corresponding higher values of volume densities of alveolar septa (Vsep%) in CDH tissues compared to healthy tissue at the same developmental stages. A similar trend can be observed for the mean linear intercept of air space (Lma%) and its corresponding mean linear intercept of septal thickness (Lmw%). (D) Histologic analysis of VEGFA, KDR, Ki67 and NKX2-1 markers in normal and CDH fetal lung tissue at 18 and 22 pcw. Scale bar 100m. (E) Quantification of epithelial VEGFA and KDR expression reported in D shows a significant decrease for both markers in CDH compared to healthy samples. Correspondingly, the percentage of Ki67-positive epithelial cells is significantly lower in CDH compared to healthy samples, with no significant differences in the number of NKX2-1-positive cells. ***<p=0.001. (F) Immunofluorescence analysis of ECAD in normal and CDH fetal lung tissue at 18 and 22 pcw. Scale bar 100m. (G) Quantification of epithelial nuclear density based on results in Figure F shows no significant differences between CDH and healthy tissue. C_FIG Measurements and Main ResultsVEGF expression was downregulated in distal pulmonary epithelium of human CDH fetuses in conjunction with attenuated cell proliferation. The compression model resulted in impaired branching morphogenesis similar to CDH and downregulation of VEGF expression in conjunction with reduced proliferation of terminal bud epithelial progenitors; these could be reversed by exogenous supplementation of VEGF. Prenatal delivery of VEGF with the ND-VEGF platform in CDH fetal rats resulted in lung growth and pulmonary arterial remodelling that was complementary to that achieved by TO alone with appearances comparable to healthy controls. ConclusionsThis innovative approach could have a significant impact on the treatment of CDH.

bioengineering↗

bioRxiv2022

Prioritization of driver genes in cancer-associated copy number alterations identifies B4GALT5 as a glycooncogene

Cancer is a disease resulting from aberrant communication between cells of a multicellular organism. The glycan coat that surrounds the cells is an important player in cellular communication. While altered cell surface glycans are known biomarkers for cancer, glycan biosynthesis itself has not been considered a potential oncogenic pathway. So, to understand the oncogenic potential of the glycan biosynthetic pathways we have analyzed the copy number alterations (CNA) of genes encoding for glycosylation regulators (glycogenes) in cancer genome datasets and identify novel glyco-oncogenes and glyco-tumor suppressor genes (TSGs). CNA of oncogenes and TSGs is an important cancer-associated genetic alteration that associates with worst prognosis. Nevertheless, identity of the driver genes in the copy number altered segments of the genome remains obscure in most cases. We developed a prioritization pipeline based on bioinformatic and experimental criteria to identify putative driver genes. In addition to correctly identifying several well-established oncogenes/TSGs, this pipeline discerns several novel oncogenes and TSGs, some of which are glycogenes. Further, among glyco-oncogenes there is an enrichment for glycosphingolipid biosynthetic pathway and trans-Golgi associated lysosomal sorting machinery and among glyco-TSGs there is an enrichment for early N-glycan biosynthetic enzymes. As a proof-of-principle we show that one of the identified glycooncogene B4GALT5, encoding a key enzyme in the glycosphingolipid pathway exhibits oncogenic property of promoting increased growth of hepatocellular carcinoma cells. Thus, this study identifies glycosylation pathways with oncoregulatory properties and opens up a new group of enzymes as potential therapeutic targets for cancer.

cancer biology↗

bioRxiv2021

Sphingolipid Control of Fibroblast Heterogeneity Revealed by Single-Cell Lipidomics

Human cells produce thousands of lipids that impact a wide range of biological processes in ways we are only starting to characterize. The cellular composition in lipids changes during differentiation events and also varies across individual cells of the same type. Yet, the precise differences in lipid composition that directly affect cell phenotypes remain unknown. Here we have measured the lipidomes and transcriptomes of individual human dermal fibroblasts by coupling high-resolution mass spectrometry imaging to single-cell transcriptomics. We found that the cell-to-cell variation of specific lipid metabolic pathways contributes to the establishment of cell states involved in wound repair and in skin cancer growth. Sphingolipid composition defined fibroblast subpopulations while sphingolipid metabolic rewiring drove cell state transitions. These data uncover a role for cell-to-cell lipid heterogeneity in the determination of cell states and reveal a new regulatory component to the homeostasis and self-organization of multicellular systems.

biochemistry↗

bioRxiv2020

MiREDiBase: a manually curated database of editing events in microRNAs

MicroRNAs (miRNAs) are regulatory small non-coding RNAs that function as translational repressors. MiRNAs are involved in most cellular processes, and their expression and function are presided by several factors. Amongst, miRNA editing is an epitranscriptional modification that alters the original nucleotide sequence of selected miRNAs, possibly influencing their biogenesis and target-binding ability. A-to-I and C-to-U RNA editing are recognized as the canonical types, with the A-to-I type being the predominant one. Albeit some bioinformatics resources have been implemented to collect RNA editing data, it still lacks a comprehensive resource explicitly dedicated to miRNA editing. Here, we present MiREDiBase, a manually curated catalog of editing events in miRNAs. The current version includes 3,059 unique validated and putative editing sites from 626 pre-miRNAs in humans and three primates. Editing events in mature human miRNAs are supplied with miRNA-target predictions and enrichment analysis, while minimum free energy structures are inferred for edited pre-miRNAs. MiREDiBase represents a valuable tool for cell biology and biomedical research and will be continuously updated and expanded at https://ncrnaome.osumc.edu/miredibase.

bioinformatics↗

bioRxiv2019

Whole brain delivery of an instability-prone Mecp2 transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome

Rett syndrome (RTT) is an incurable neurodevelopmental disorder caused by mutations in the gene encoding for methyl-CpG binding-protein 2 (MeCP2). Gene therapy for this disease presents inherent hurdles since MECP2 is expressed throughout the brain and its duplication leads to severe neurological conditions as well. However, the recent introduction of AAV-PHP.eB, an engineered capsid with an unprecedented efficiency in crossing the blood-brain barrier upon intravenous injection, has provided an invaluable vehicle for gene transfer in the mouse nervous system. Herein, we use AAV-PHP.eB to deliver an instability-prone Mecp2 (iMecp2) transgene cassette which, increasing RNA destabilization and inefficient protein translation of the viral Mecp2 transgene, limits supraphysiological Mecp2 protein levels in transduced neural tissues. Intravenous injections of the PHP.eB-iMecp2 virus in symptomatic male and female Mecp2 mutant mice significantly ameliorated the disease progression with improved locomotor activity, coordination, lifespan and normalization of altered gene expression and mTOR signaling. Remarkably, PHP.eB-iMecp2 administration did not result in severe toxicity effects either in female Mecp2 mutant or in wild-type animals. In contrast, we observed a strong immune response to the transgene in treated male Mecp2 mutant mice that was overcome by immunosuppression. Overall, PHP.eB-mediated delivery of the iMecp2 cassette provided widespread and efficient gene transfer maintaining physiological Mecp2 protein levels in the brain. This combination defines a novel viral system with significant therapeutic efficacy and increased safety which can contribute to overcome the hurdles that are delaying clinical applications of gene therapy for RTT.\n\nOne Sentence SummaryGlobal brain transduction of the instability-prone Mecp2 transgene by systemic AAV-PHP.eB administration is both safe and effective in protecting male and female Mecp2 mutant mice from the RTT disease phenotype.

neuroscience↗