Biology subjects

Galli, F.

Publications and source records attributed to Galli, F..

7 recordsLinked to original sources

bioRxiv2026

Primary Hyperparathyroidism Reveals Limited Adipose Remodeling in Human

BackgroundPreclinical models implicate the parathyroid hormone/parathyroid-hormone-related protein (PTH/PTHrP)-PTH1 receptor (PTH1R) axis in adipocyte lipolysis, adipose browning, and energy wasting. Whether this catabolic program is reproduced in vivo in humans remains unresolved. Primary hyperparathyroidism (PHPT), a condition of chronic endogenous PTH excess, provides a clinically relevant model to test the translational relevance of this pathway. MethodsWe combined population-scale analyses with a prospective human intervention study. PTH/PTH1R associations with body composition were evaluated in the UK Biobank and compared with PTH dynamics in cancer-associated cachexia using TRACERx proteomic data. In parallel, patients with PHPT were assessed before and after parathyroidectomy and compared with matched surgical controls. Biochemical parameters, circulating adipocytokines, DXA- and BIA-derived body composition, histology, UCP1 immunohistochemistry, and supraclavicular adipose tissue transcriptomic and proteomic profiles were integrated, with external validation in an independent supraclavicular adipose dataset. ResultsIn the UK Biobank, apparent positive associations between circulating PTH/PTH1R signals and fat or lean mass were markedly attenuated after matching for age, sex, and BMI, arguing against a disease-specific adiposity effect of PHPT. In TRACERx, circulating PTH did not increase across BMI-adjusted weight-loss grades. In the prospective cohort, parathyroidectomy normalized PTH, calcium, and phosphate but did not induce coherent changes in glucose metabolism, lipid profile, inflammatory markers, body weight, fat mass, lean mass, or thermogenic adipose signatures. Supraclavicular adipose histology, UCP1 staining, RNA-seq, proteomics, pathway analysis, and external dataset reanalysis converged on the absence of browning or thermogenic activation. By contrast, PHPT was associated with a selective adipose-related secretory phenotype: adiponectin, adipsin, and retinol-binding protein 4 were reversible after surgery, whereas lipocalin- 2 and thrombospondin-1 remained elevated. ConclusionsChronic endogenous PTH excess is not sufficient to induce a detectable thermogenic or energy- dissipating adipose program in humans under basal clinical conditions. These findings challenge direct extrapolation from rodent PTH/PTHrP models and reposition the human PTH-adipose axis as a selective secretory and remodeling pathway rather than a dominant driver of adipose browning or wasting. HighlightsO_LIPHPT provides an in vivo human model of chronic endogenous PTH excess. C_LIO_LIPTH/PTH1R associations with body composition are lost after stringent confounder control. C_LIO_LIParathyroidectomy normalizes mineral metabolism without inducing adipose browning or wasting. C_LIO_LISupraclavicular adipose histology, UCP1 staining, transcriptomics, and proteomics show no thermogenic activation. C_LIO_LIPHPT unmasks a selective adipose-related secretory signature with reversible and persistent components. C_LI

physiology↗

bioRxiv2025

Mini-agrin prevents calcium leakage and restores the dystrophin complex.

Muscle cell death in muscular dystrophies depends upon calcium ion (Ca++) leakage through sarcolemma and sarcoplasmic reticulum, triggered by muscle stretch during eccentric contraction. We show here that Ca++ spikes are detected in dystrophic myogenic cells in culture since early differentiation, before sarcomere assembly and contraction. Healthy and genetically corrected dystrophic myotubes do not display Ca++ spikes which are blocked by co-culturing DMD myogenic cells with embryonic mouse motoneurons or treating them with agrin proteoglycan. Same effect is elicited by a muscle spliced, COOH peptide of agrin (termed here mini-agrin) that interacts with dystroglycan, favouring its binding to the basal lamina. Lack of dystrophin in DMD myotubes results in decreased expression of CaV1.1 (CACNA1S), a Ca++ sensor component of the Dihydropyridine Receptor (DHPR) complex, known to regulate Ryanodine Receptor 1 (RyR1). These events explain the emergence of Ca++ spikes. Mini-agrin addition to medium, or lentivector-mediated mini-agrin expression in transplanted cells in vivo, stabilize the expression of CaV1.1 on the membrane. This leads to disappearance of Ca++ spikes and to reappearance of -dystroglycan, -sarcoglycan and n-NOS, indicating the reconstitution of the dystrophin complex in the absence of dystrophin. These findings unveil a novel regulatory mechanism and offer a new therapeutic opportunity for targeting calcium ion influx as a co-treatment strategy.

cell biology↗

bioRxiv2025

Targeting Pseudomonas aeruginosa Ventilator-associated pneumonia with a non-antibiotic and biolfilm-disrupting Live Biotherapeutic: Preclinical Safety and Efficacy study

Background.Ventilator-associated pneumonia (VAP) is the second most common hospital-acquired infection and is associated with high morbidity and mortality. The insertion of the endotracheal tube (ETT) compromises the hosts bronchial defenses and facilitates the formation of microbial biofilms and VAP. Although antibiotics remain the cornerstone treatment, their efficacy is often compromised by poor biofilm penetration and the prevalence of multidrug-resistant bacteria. This reveals the need to develop novel non-antibiotic therapeutic strategies. We engineered a non-pathogenic strain of the pulmonary bacteria Mycoplasma pneumoniae CV2 to express anti-biofilm and bactericidal enzymes (VAP platform). The therapeutic effect was validated in a murine model of Pseudomonas aeruginosa infection and ex vivo in ETTs of patients with P. aeruginosa-induced VAP. Methods.We evaluated the safety of an improved version of CV2 (CV8, Mycochassis) in a miniature pig model, and its efficacy with the VAP therapeutic platform (CV8_VAP) in a piglet model of P. aeruginosa-induced VAP. CV8_VAP was administered via intralobe instillation or nebulization. We assessed the platforms ability to degrade biofilms formed on ETTs in vivo and its impact on the airway microbiota. We evaluated bacterial load in the lungs, inflammatory responses, histopathological and the clinical outcomes to provide a comprehensive characterization of therapeutic efficacy and safety. Findings.VAP platform reduced biofilm thickness and P. aeruginosa load in ETTs and lungs, with the nebulized route showing enhanced efficacy. CV8_VAP contributed on microbiome diversity restoration. Inflammatory markers in the lung were markedly decreased, suggesting a local immunomodulatory effect. Interpretation.These findings support that CV8_VAP as a promising, non-antibiotic therapeutic strategy for treating VAP caused by P. aeruginosa. Funding.The project that gave rise to these results has received funding from "La Caixa" Foundation (HR18-00058), and the European Research Council under the European Unions Horizon 2020 research and innovation program (670216).

synthetic biology↗

bioRxiv2022

Relevance of the viral Spike protein/cellular Estrogen Receptor-α interaction for endothelial-based coagulopathy induced by SARS-CoV-2

Severe coagulopathy has been observed at the level of the microcirculation in several organs including lungs, heart and kidneys in patients with COVID-19, and in a minority of subjects receiving the SARS-CoV-2 vaccine. Various mechanisms have been implicated in these effects, including increases in circulating neutrophil extracellular traps, excessive inflammation, and endothelial dysfunction. Even if a correlation between infection by SARS-CoV-2 and upregulation of coagulation cascade components has been established in the lung, no direct proofs have been yet provided about the transcriptional machinery controlling the expression of these factors. Recent results obtained by us reported a novel transcriptional function of the SARS-CoV-2 Spike (S) viral protein involving a direct protein-protein interaction with the human Estrogen Receptor- (ER). Given the implications of ER in the control of key effectors in the coagulation cascade, we hypothesized that S-protein might increase the pro-coagulation activity of endothelial cells via the transcriptional activity of the ER, thus justifying the enhanced risk of thrombosis. To assess this, we tested the effects of S-protein on the expression of Tissue Factor (TF) and the overall procoagulation activity in a human endothelial cell line and confirmed this finding by overexpressing S-protein by gene transfer in mice. We then designed and tested two-point mutations in the S2 S-protein sequence that abolished the pro-coagulation function of S-protein in vitro and in vivo, without compromising its immunogenicity. In addition to reveal a new potential transcriptional function of S-protein, these results inspire the design of new vaccines with lower risk of thrombogenesis. Indeed, while the benefit/risk ratio remains overwhelming in favor of COVID-19 vaccination, our results shed light on the causal mechanisms of some rare anti-SARS-CoV-2 vaccine adverse events, and are thus essential for current and future vaccination and booster campaigns.

cell biology↗

bioRxiv2019

TNAP limits TGF-β-dependent cardiac and skeletal muscle fibrosis by inactivating SMAD2/3 transcription factors

Fibrosis is associated with almost all forms of chronic cardiac and skeletal muscle diseases. The accumulation of extracellular matrix impairs the contractility of muscle cells contributing to organ failure. Transforming growth factor beta (TGF-{beta}) plays a pivotal role in fibrosis, activating pro-fibrotic gene programs via phosphorylation of SMAD2/3 transcription factors. However, the mechanisms that control de-phosphorylation of SMAD2/3 have remained poorly characterized. Here we show that tissue non-specific alkaline phosphatase (TNAP) is highly upregulated in hypertrophic hearts and in dystrophic skeletal muscles, and the abrogation of TGF-{beta} signalling in TNAP positive cells reduces vascular and interstitial fibrosis. We show that TNAP co-localizes and interacts with SMAD2. TNAP inhibitor MLS-0038949 increases SMAD2/3 phosphorylation, while TNAP overexpression reduces SMAD2/3 phosphorylation and the expression of downstream fibrotic genes. Overall our data demonstrate that TNAP negatively regulates TGF-{beta} signalling and likely represents a mechanism to limit fibrosis.\n\nSummary statementThis paper shows that tissue non-specific alkaline phosphatase negatively regulates TGF-{beta} signalling and may represent a mechanism to limit fibrosis through SMAD dephosphorylation.

cell biology↗

bioRxiv2018

A seleno-hormetine protects bone marrow hematopoietic cells against ionizing radiation-induced toxicity

2,2-diselenyldibenzoic acid (DSBA) is a mild thiol peroxidase agent presently in preclinical development. This study reports that the drug has novel seleno-hormetic properties in both murine bone marrow and human liver cells. According with previous in vitro findings, mechanistic aspects of such properties were confirmed to include the activation of Nrf2 transcription factor and an increased expression of downstream stress response genes in the liver and in hematopoietic stem and progenitor cells of the myeloid lineage. These genes include glutathione S-transferase that is reported to represent a major player in the metabolism and pharmacological function of seleno-organic compounds. As a practical application, DSBA administration prevented bone marrow toxicities following acute exposure to sub-lethal doses of ionizing radiation in C57 BL/6 mice.\n\nIn conclusion, this study demonstrates for the first time the pharmacological properties of DSBA in vivo. The findings suggest applications for this selenohormetine in radioprotection and prevention protocols.

cancer biology↗

bioRxiv2018

Intellectual contributions meriting authorship:Survey results from the top cited authors across all science categories

Authorship is the currency of an academic career for which the number of papers researchers publish demonstrates creativity, productivity, and impact. To discourage coercive authorship practices and inflated publication records, journals require authors to affirm and detail their intellectual contributions but this strategy has been unsuccessful as authorship lists continue to grow. Here, we surveyed close to 6000 of the top cited authors in all science categories with a list of 25 research activities that we adapted from the National Institutes of Health (NIH) authorship guidelines. Responses varied widely from individuals in the same discipline, same level of experience, and the same geographic region. Most researchers agreed with the NIH criteria and grant authorship to individuals that draft the manuscript, analyze and interpret data, and propose ideas. However, thousands of the researchers also value supervision and contributing comments to the manuscript whereas the NIH recommends discounting these activities when attributing authorship. People value the minutiae of research beyond writing and data reduction: researchers in the humanities value it less than those in pure and applied sciences; individuals from Far East Asia and Middle East and Northern Africa value these activities more than anglophones and northern Europeans. While developing national and international collaborations, researchers must recognize differences in peoples values while assigning authorship.

scientific communication and education↗