Publications by authors named "Mario Falchi"

Article Synopsis
  • Immunoglobulin (Ig) glycosylation significantly influences immune responses and is crucial in aging and diseases, but research has primarily focused on IgG, leaving IgA glycosylation less understood.
  • Using a new liquid chromatography-mass spectrometry method, researchers created a large dataset of IgA glycosylation from 2423 twin serum samples, identifying key N- and O-glycan species.
  • The findings reveal that IgA glycosylation is highly heritable, varies with sex and age, and is largely influenced by shared genetic factors, with specific genetic loci associated with IgA and IgG glycomes linked to immune disease risk, including IgA nephropathy.
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Background: Vitamin A is essential for physiological processes like vision and immunity. Vitamin A's effect on gut microbiome composition, which affects absorption and metabolism of other vitamins, is still unknown. Here we examined the relationship between gut metagenome composition and six vitamin A-related metabolites (two retinoid: -retinol, 4 oxoretinoic acid (oxoRA) and four carotenoid metabolites, including beta-cryptoxanthin and three carotene diols).

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  • Eosinophils, when activated by the alarmin IL-33, produce extracellular vesicles (EV) that show potential anti-tumor effects, contrasting with those activated by IL-5.
  • Incorporating these IL-33-activated eosinophil-derived EV (Eo33-EV) into tumor cells leads to increased expression of genes that promote cell cycle arrest and reduces tumor growth and metastasis.
  • RNA sequencing highlights that Eo33-EV are enriched with tumor suppressor genes and pathways that enhance an epithelial phenotype, indicating their potential role in cancer therapy through cell reprogramming.
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  • The study analyzed whole genome sequencing data from 1,751 individuals in the UK and 2,587 subjects from Qatar.
  • Researchers found an association between rare variants in the sour taste gene KCNJ2 and lower levels of low-density lipoprotein cholesterol (LDL-C) and a 22% reduction in dietary trans-fat intake.
  • This discovery highlights a potential new genetic factor that could influence LDL-C levels, which is important for understanding cardiovascular disease risks.
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  • * A study involving 1,453 participants from TwinsUK found a positive link between DAL and early-stage CKD, identifying various metabolites connected to both.
  • * Certain metabolites, particularly from stool samples, showed a relationship with gut microbial species, highlighting the potential for gut microbiota interventions to mitigate the effects of DAL on CKD progression; however, further research is needed to confirm causality.
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The clinical severity of sickle cell disease (SCD) is strongly influenced by the level of fetal haemoglobin (HbF) persistent in each patient. Three major HbF loci (BCL11A, HBS1L-MYB, and Xmn1-HBG2) have been reported, but a considerable hidden heritability remains. We conducted a genome-wide association study for HbF levels in 1006 Nigerian patients with SCD (HbSS/HbSβ0), followed by a replication and meta-analysis exercise in four independent SCD cohorts (3,582 patients).

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Exosomes are among the most puzzling vehicles of intercellular communication, but several crucial aspects of their biogenesis remain elusive, primarily due to the difficulty in purifying vesicles with similar sizes and densities. Here we report an effective methodology for labelling small extracellular vesicles (sEV) using Bodipy FL C16, a fluorescent palmitic acid analogue. In this study, we present compelling evidence that the fluorescent sEV population derived from Bodipy C16-labelled cells represents a discrete subpopulation of small exosomes following an intracellular pathway.

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Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel).

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Unlabelled: Prediabetes is a metabolic condition associated with gut microbiome composition, although mechanisms remain elusive. We searched for fecal metabolites, a readout of gut microbiome function, associated with impaired fasting glucose (IFG) in 142 individuals with IFG and 1,105 healthy individuals from the UK Adult Twin Registry (TwinsUK). We used the Cooperative Health Research in the Region of Augsburg (KORA) cohort (318 IFG individuals, 689 healthy individuals) to replicate our findings.

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Short-chain fatty acids (SCFA) are involved in immune system and inflammatory responses. We comprehensively assessed the host genetic and gut microbial contribution to a panel of eight serum and stool SCFAs in two cohorts (TwinsUK,  = 2507; ZOE PREDICT-1,  = 328), examined their postprandial changes and explored their links with chronic and acute inflammatory responses in healthy individuals and trauma patients. We report low concordance between circulating and fecal SCFAs, significant postprandial changes in most circulating SCFAs, and a heritable genetic component (average : serum = 14%(SD = 14%); stool = 12%(SD = 6%)).

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Purpose: Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by systemic symptoms, cytopenias, organomegaly, and bone marrow fibrosis. JAK2 inhibitors afford symptom and spleen burden reduction but do not alter the disease course and frequently lead to thrombocytopenia. TGFβ, a pleiotropic cytokine elaborated by the MF clone, negatively regulates normal hematopoiesis, downregulates antitumor immunity, and promotes bone marrow fibrosis.

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Article Synopsis
  • Idiopathic pulmonary fibrosis (IPF) is a serious lung disease with few treatment options due to a lack of understanding of its causes and limitations in animal models.
  • Researchers hypothesized that GATA1 deficient megakaryocytes, known to worsen myelofibrosis, might also lead to lung fibrosis.
  • Their findings revealed that these megakaryocytes are present in both IPF patients and mice, and manipulating key factors like P-selectin and TGF-β1 can prevent lung fibrosis in the mice model, suggesting a new avenue for understanding and treating IPF.
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Apoptosis is a tightly controlled cell death program executed by proteases, the so-called caspases. It plays an important role in tissue homeostasis and is often dysregulated in cancer. Here, we identified FYCO1, a protein that promotes microtubule plus end-directed transport of autophagic and endosomal vesicles as a molecular interaction partner of activated CASP8 (caspase 8).

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Introduction: Hematopoietic stem cells (HSC) reside in the bone marrow (BM) in specialized niches which provide support for their self-replication and differentiation into the blood cells. Recently, numerous studies using sophisticated molecular and microscopic technology have provided snap-shots information on the identity of the BM niches in mice. In adults, HSC are localized around arterioles and sinusoids/venules whereas in juvenile mice they are in close to the osteoblasts.

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Primary and secondary bile acids (BAs) influence metabolism and inflammation, and the gut microbiome modulates levels of BAs. We systematically explore the host genetic, gut microbial, and habitual dietary contribution to a panel of 19 serum and 15 stool BAs in two population-based cohorts (TwinsUK, n = 2,382; ZOE PREDICT-1, n = 327) and assess changes post-bariatric surgery and after nutritional interventions. We report that BAs have a moderately heritable genetic component, and the gut microbiome accurately predicts their levels in serum and stool.

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Article Synopsis
  • - The study investigates chronic fatigue associated with COVID-19, particularly focusing on how pre-existing levels of the inflammatory marker IL-6 in individuals could influence this fatigue.
  • - Researchers examined a cohort of 1,274 adults, comparing chronic fatigue prevalence between COVID-19 positive and negative individuals, finding that fatigue was more common in the infected group (17% vs. 11%).
  • - While heightened IL-6 levels before the pandemic correlated with chronic fatigue in uninfected participants, this association did not hold true for those with mild COVID-19; additionally, a higher body mass index (BMI) was linked to fatigue in those infected.
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Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of melanoma and other cancers. However, no reliable biomarker of survival or response has entered the clinic to identify those patients with melanoma who are most likely to benefit from ICIs. Glycosylation affects proteins and lipids' structure and functions.

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X-chromosome inactivation (XCI) silences one X in female cells to balance sex-differences in X-dosage. A subset of X-linked genes escape XCI, but the extent to which this phenomenon occurs and how it varies across tissues and in a population is as yet unclear. To characterize incidence and variability of escape across individuals and tissues, we conducted a transcriptomic study of escape in adipose, skin, lymphoblastoid cell lines and immune cells in 248 healthy individuals exhibiting skewed XCI.

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The human microbiome is an integral component of the human body and a co-determinant of several health conditions. However, the extent to which interpersonal relations shape the individual genetic makeup of the microbiome and its transmission within and across populations remains largely unknown. Here, capitalizing on more than 9,700 human metagenomes and computational strain-level profiling, we detected extensive bacterial strain sharing across individuals (more than 10 million instances) with distinct mother-to-infant, intra-household and intra-population transmission patterns.

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Caveolin-1 (Cav-1) is a fundamental constituent of caveolae, whose functionality and structure are strictly dependent on cholesterol. In this work the U18666A inhibitor was used to study the role of cholesterol transport in the endosomal degradative-secretory system in a metastatic human melanoma cell line (WM266-4). We found that U18666A induces a shift of Cav-1 from the plasma membrane to the endolysosomal compartment, which is involved, through Multi Vesicular Bodies (MVBs), in the formation and release of small extracellular vesicles (sEVs).

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Proton pump inhibitors (PPIs) are among the most used drugs in the UK. PPI use has been associated with decreased bone mineral density (BMD) and increased fracture risk, although these results have been inconsistent. We hypothesized that PPI could modulate BMD by altering gut and/or host systemic metabolic environments.

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Garrod's concept of 'chemical individuality' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.

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The bone marrow (BM) and spleen from patients with myelofibrosis (MF), as well as those from the Gata1 mouse model of the disease contain increased number of abnormal megakaryocytes. These cells express high levels of the adhesion receptor P-selectin on their surface, which triggers a pathologic neutrophil emperipolesis, leading to increased bioavailability of transforming growth factor-β (TGF-β) in the microenvironment and disease progression. With age, Gata1 mice develop a phenotype similar to that of patients with MF, which is the most severe of the Philadelphia-negative myeloproliferative neoplasms.

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Trogocytosis is a cellular process whereby a cell acquires a membrane fragment from a donor cell in a contact-dependent manner allowing for the transfer of surface proteins with functional integrity. It is involved in various biological processes, including cell-cell communication, immune regulation, and response to pathogens and cancer cells, with poorly defined molecular mechanisms. With the exception of eosinophils, trogocytosis has been reported in most immune cells and plays diverse roles in the modulation of anti-tumor immune responses.

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Article Synopsis
  • Extracellular Vesicles (EVs) are small membrane particles released by cells that play a key role in various biological processes, including the chronic inflammation seen in psoriasis, where certain cytokines may influence their release and cargo.
  • The study examined the effects of several psoriasis-related cytokines (IL-17A, IFN-γ, TNF-α, IL-22, IL-23) on EVs release and the expression of antimicrobial peptides (AMPs) via techniques like nanoparticle tracking and gene expression analysis.
  • Results showed that IL-17A and IFN-γ enhanced EV release, while all tested cytokines altered AMPs expression; notably, EVs from treated cells prompted a specific inflammatory response (
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