Biology subjects

Carrion, C.

Publications and source records attributed to Carrion, C..

9 recordsLinked to original sources

bioRxiv2025

Preclinical characterization of AT-03, a novel Serum Amyloid P fusion protein that demonstrates pan-amyloid binding and removal

The systemic amyloidoses are progressive disorders caused by extracellular deposition of insoluble amyloid fibrils leading to organ dysfunction that often proves fatal. New therapeutics aiming at removing deposited amyloid are urgently needed to improve patient outcomes. MethodsWe developped AT-03 (originally called SAP-scFc), a fusion protein consisting of serum amyloid P-component, which binds all types of amyloid, linked to a single chain human IgG1 Fc domain. AT-03 binding to diverse types of amyloid and phagocytic activity were assessed both in vitro and in vivo. Therapeutic efficacy was evaluated in an AA mouse model. ResultsAT-03 bound with high potency to AL and ATTR human amyloid extracts. In murine models, intravenously administered AT-03 bound to AA, AL and AApoA2 amyloid, including in the heart. Ex vivo AT-03 opsonization induced phagocytosis of human AL extract by activated human THP-1 macrophages and enhanced in vivo phagocytosis in mice. A single intravenous injection of SAP-scFc induced a significant reduction of splenic amyloid in a murine model of AA amyloidosis. ConclusionsAT-03 binds many amyloid types and can promote macrophage-mediated phagocytosis of the deposits. Thus, AT-03 is a promising novel therapeutic agent for the removal of systemic amyloid.

pathology↗

bioRxiv2023

REL deregulation stands as a primary hit for AID-imprinted B-cells along the germinal center competition

In diffuse large B-cell lymphomas (DLBCLs), gains and amplifications of the 2p15-16 region, which always encompass the REL gene, are mostly restricted to the germinal center (GC) B- cell DLBCL subtype (GCB-DLBCL) for which c-Rel is the pivotal Rel/NF-{kappa}B subunit. While REL is also known to play a key role in the GC reaction, its contribution to GCB-DLBCL transformation is still unclear. To understand the role of REL in the very first steps of GCB transformation, i.e when B-cells with deregulated REL are competing with other B-cells during chronic antigenic stimulation, we have created a dual-color mouse that allows to induce REL in a limited pool of AID- imprinted B-cells after immunization and to differentially stain AID-imprinted B-cells cells that overexpress REL or not. Our results demonstrate that dysregulation of REL at the GC B-cell stage promotes GC B-cell expansion and favors both class-switch recombination and plasma cell differentiation. Additionally, although REL overexpression was neutral on post-GC memory B-cell differentiation, it did confer a long-term competitive advantage allowing for GC persistence and continuous recirculation of REL-overexpressing B-cells. Functionally, REL enhanced the protection against apoptosis in the early steps of GCB differentiation. REL- overexpressing B-cells can my occasionally transform into in an aggressive B-cell tumor. Highlighting the role of repeated immune responses, our results confirm the role of REL in the germinal center reaction and provide evidence supporting the fact that genetic deregulation of c-Rel expression is most likely a primary event in the aggressive transformation of GC B-cells. Key points- REL provides a long-term competitive advantage allowing for GC B-cell persistence and continuous recirculation of AID-imprinted B-cells - AID-imprinted B-cells overexpressing REL can occasionally transform into aggressive B-cell lymphomas Explanation of the noveltyBy showing in a new dual-color mouse model that dysregulation of REL in a very limited pool of AID-imprinted B-cells confers a strong long-term competitive advantage in the context of repeated immune responses and may occasionally lead to transformation into an aggressive B- cell lymphoma, we provide for the first time experimental evidence supporting the fact that that REL is most likely a primary event in the aggressive transformation of germinal center B-cells.

cancer biology↗

bioRxiv2023

Hospital and urban wastewaters shape the structure and active resistome of environmental biofilms

BackgroundDemonstration of the transfer, dynamics, and regulation of antibiotic resistance genes (ARGs) and mobile genetic elements (MGEs) in a complex environmental matrix is yet experimentally challenging, with many essential open questions such as how and where transfer and dissemination of ARGs happens in nature. The extent and conditions of MGEs transfer that carry ARGs is still largely unexplored in natural environments and microbial communities. Biofilms are structures that include high density multi-species bacterial communities embedded in self-produced extracellular polymeric substances (EPS) constituting a matrix that facilitates gene transfer and where bacteria exhibit high tolerance to stress and to antibiotics. In this study we implemented a sampling and analysis approach that allows phenotypic and genomic analyses of in situ and reconstituted in vitro hospital and urban wastewater (WW) biofilms. To assess the potential of hospital and urban WW biofilms to efficiently disseminate ARGs in the WW system, we explored the EPS within the biofilm matrix and assessed the expression of the resistome (ARGs) and mobilome (MGEs) by metatranscriptomics. ResultsWe first showed that a) the composition of EPS differs depending on their growth environment (in situ and in vitro) and their sampling origin (hospital vs urban WW) and that b) a low amount of ciprofloxacin impacted the composition of the EPS. Next, the metatranscriptomic approach showed that a) expression of ARGs and MGEs increase upon adding a low amount of ciprofloxacin for biofilms from hospital WW but not for those from urban WW and b) that expression of specific plasmids that carry individual or multiple ARGs varies depending on the WW origins of the biofilms. When the same plasmids were expressed in both, urban and hospital WW biofilms, they carried and expressed different ARGs. ConclusionWe show that hospital and urban wastewaters shape the structure and active resistome of environmental biofilms, and we confirmed that hospital WW is an important hot spot for the dissemination and selection of AMR. The different responses to antibiotic pressure in hospital vs urban biofilms, coupled with differences in biofilm structure helps delineate distinct characteristics of hospital and urban WW biofilms highlighting the relationships between the resistome and its expression in environmental biofilms and their surrounding ecosystems.

microbiology↗

bioRxiv2022

A dual function for the chromatin organizer Special A-T rich Binding Protein 1 in B-lineage cells

SATB1 (Special A-T rich Binding protein 1) is a cell type specific factor involved in chromatin remodelling events that participate in the regulation of the genetic network in developing T cells and neurons. In T cells, SATB1 is a key factor required for lineage commitment, VDJ recombination, development and maturation. In B cells, SATB1 is described as binding to the MARs-E{micro} regions of the IgH locus. Considering that its expression varies during differentiation, the involvement of this factor needed to be clarified in B cells. Using a KO mouse model deleting SATB1 from the pro-B cell stage, we were able to examine the consequences of SATB1 deletion in naive and activated B cell subsets. Our model indicates firstly that SATB1 is not essential for B cell development and the establishment of a broad IgH repertoire. Second, we show that this factor exhibits an ambivalent function in mature B cells, acting sequentially as a positive and negative regulator of Ig gene transcription in naive and activated cells, respectively. Third, our study indicates that the negative regulatory function of SATB1 in B cells extends to the germinal center response in which this factor limits somatic hypermutation of Ig genes. This finding suggests that SATB1 may limit the introduction of unwanted mutations into B cells.

immunology↗

bioRxiv2022

The IgH Eμ-MAR regions promote UNG-dependent error-prone repair to optimize somatic hypermutation

Two scaffold/matrix attachment regions (5- and 3-MARsE) flank the intronic core enhancer (cE) within the immunoglobulin heavy chain locus (IgH). Besides their conservation in mice and humans, the physiological role of MARsE is still unclear and their involvement in somatic hypermutation (SHM) has never been deeply evaluated. By analysing a mouse model devoid of MARsE, we observed an inverted substitution pattern: SHM being decreased upstream from cE and increased downstream of it. Strikingly, the SHM defect induced by MARsE-deletion was accompanied by an increase of sense transcription of the IgH V region, excluding a direct transcription-coupled effect. Interestingly, by breeding to DNA repair-deficient backgrounds, we showed that the SHM defect, observed upstream from cE in this model, was not due to a decrease in AID deamination but rather the consequence of a defect in base excision repair-associated unfaithful repair process. Our study pointed out an unexpected "fence" function of MARsE regions in limiting the error-prone repair machinery to the variable region of Ig gene loci.

immunology↗

bioRxiv2021

Diverse B-cell specific transcriptional contexts of the BCL2 oncogene in mouse models impacts pre-malignant development

Follicular lymphoma (FL) is the most common indolent form of non-Hodgkin lymphoma arising from malignant germinal center (GC) B-cells. The genetic hallmark that leads to the development of FL is the t(14:18) which occurs early in the bone marrow during B cell development, thereby placing the anti-apoptotic BCL2 gene under the direct control of the transcriptional enhancers in 3 of immunoglobulin heavy chain locus (IgH 3RR) and leading to the constitutive expression of the BCL2 protein. To assess the impact of the BCL2 deregulation on B-cell fate and try to reproduce FL development in mice, two models were designed: the Ig{kappa}-BCL2 (Knock in of the BCL2 in the light chain Ig kappa locus) and the 3RR-BCL2 (Transgene containing BCL2 and a micro-3RR), both containing the full BCL2 promoter region.

immunology↗

bioRxiv2020

New models to study plasma cells in mouse based on the restriction of IgJ expression to antibody secreting cells.

Plasma cells (PC) represent the last stage of B cell development and are mainly characterized by their capacity of secreting large quantities of antibodies. They can be implicated in a broad-spectrum of neoplastic disorders, including Multiple Myeloma, Waldenstrom macroglobulinemia or Monoclonal Gammopathy of Clinical Significance, all characterized by the abnormal proliferation of a PC clone. Up to date, there are only few reporter models to specifically follow PC development, migration and homing in mouse and none allowing the genetic manipulation of these cells. We created a transgenic mouse model in which a green fluorescent protein gene was placed under the control of the well-characterized regulatory elements of the murine immunoglobulin J (IgJ) chain locus. Thanks to this model, we demostrated that IgJ is an early and specific marker of antibody secreting cells (ASCs) and appears before the expression of CD138, making it a good candidate to targeted genetic modifications of plasma cells. Therefore, a conditional deletion model using a Tamoxifen-dependent Cre recombinase inserted into the IgJ locus was characterized. Using a reporter model, we showed that, in contrast with existing models of B cell lineage genetic modification, the activity of the CRE recombinase only affects ASCs after tamoxifen treatment. Additionally, we used this model in a functional in vitro assay, to show that Ig modifications directly affect plasma cell survival. These two new mouse models, IgJGFP and IgJCreERT2 represent exquisite tools to study PCs. In pathology, the IgJCreERT2model opens new frontiers for in vivo genetic modifications of PCs to better reflect the pathophysiology of PC-related diseases.

immunology↗

bioRxiv2019

Assessing the social impact of an online course on the clinical management of Cutaneous Leishmaniasis: A qualitative study

BackgroundIn conjunction with the World Health Organization (WHO), Universitat Oberta de Catalunya (UOC) has implemented training in the treatment of cutaneous leishmaniasis (CL) for health professionals in countries where the condition is highly endemic through an interactive on-line course. With three editions of the course successfully completed, we consider assessment of the courses social impact through analysis of the outcomes beyond knowledge acquisition to be of paramount importance.\n\nMethodology/Principal findingsTo this end, we have conducted a study using the Theory of Change theoretical approach, combined with an exploration of students experiences through in-depth interviews before, during and after taking the course. These testimonies have been analyzed and classified according to their type of result - outputs, outcomes and longer-term impacts - and distributed along three different levels: individual, collective (meso), and systemic change. Insights about intercultural communication in qualitative research are discussed in relation to the characteristics of UOC researchers and the class composition of faculty and students in the Middle East and North Africa countries (MENA) region.\n\nConclusions/SignificanceThis analysis fills a gap in the knowledge of social impact assessment through the establishment of a new methodological approach. The course has proven to be a valuable source of social capital and provided a space to build a network of professionals with a shared focus on how to treat CL in particular - a community of practice - and increase knowledge of other skin NTDs.\n\nAuthor summaryNeglected tropical diseases (NTDs) affecting the skin (Buruli ulcer, cutaneous leishmaniasis, post-kala-azar dermal leishmaniasis, leprosy, lymphatic filariasis, mycetoma, onchocerciasis, scabies and yaws) cause considerable disability, increase stigma and exacerbate poverty. Cutaneous leishmaniasis (CL) is one of the most neglected NTDs. It has an estimated incidence of between 900,000 and 1.3 million new cases worldwide each year. A co-venture between the World Health Organization (WHO) and Universitat Oberta de Catalunya (UOC) has developed an on-line interactive course entitled \"Clinical management of CL\" to provide health personnel with thorough and up-to-date information on the various aspects of CL. Using a new methodological approach, we have conducted a social impact assessment of this training program in order to identify the different type and level of results. The most significant impact has been the mobilizing of students and professors from the different editions of the course in a community of practice, thereby enhancing learning, knowledge sharing and effectivity.

scientific communication and education↗

bioRxiv2019

Glomerulosclerosis and kidney failure in a mouse model of monoclonal immunoglobulin light-chain deposition disease

Light chain deposition disease (LCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a monoclonal immunoglobulin (Ig) light chain (LC), leading to nodular glomerulosclerosis and nephrotic syndrome. We developed a transgenic model using site-directed insertion of the variable domain of a pathogenic human LC gene into the mouse Ig kappa locus, ensuring its production by all plasma cells. High free LC levels were achieved after backcrossing with mice presenting increased plasma cell differentiation and no Ig heavy chain (HC) production. Our mouse model recapitulates the characteristic features of LCDD, including progressive glomerulosclerosis, nephrotic-range proteinuria and finally, kidney failure. The variable domain of the LC bears alone the structural properties involved in its pathogenicity. RNA sequencing conducted on plasma cells demonstrated that LCDD LC induces endoplasmic reticulum stress, likely accounting for the high efficiency of proteasome inhibitor-based therapy. Accordingly, reduction of circulating pathogenic LC was efficiently achieved and not only preserved renal function, but partially reversed kidney lesions. Finally, transcriptome analysis of pre-sclerotic glomeruli revealed that proliferation and extracellular matrix remodelling represented the first steps of glomerulosclerosis, paving the way for future therapeutic strategies in LCDD and other kidney diseases featuring diffuse glomerulosclerosis, particularly diabetic nephropathy.

pathology↗