Biology subjects

Nacher, M.

Publications and source records attributed to Nacher, M..

6 recordsLinked to original sources

bioRxiv2026

From bats to humans: uncovering ISG15 as a new resistance factor in type 1 diabetes

Viral infections are one of the main environmental factors triggering type 1 diabetes (T1D). Pancreatic alpha cells are more resistant than beta cells to diabetogenic viruses, partially explaining their survival in T1D. Similarly, bats have enhanced viral resistance, suggesting putative convergent evolution in antiviral mechanisms. Herein, we compared global gene expression in bat fibroblasts under basal conditions or exposed to double-stranded RNA to human alpha and beta cells and found that alpha cells exhibit greater similarity than beta cells to the antiviral responses of bat cells, as well as stronger intrinsic resistance to viral infection. Interferon-stimulated gene 15 (ISG15), a key regulator of antiviral responses in humans and bats, has higher expression in alpha compared to beta cells in five single-cell RNASeq datasets from human islet cells and in human induced pluripotent stem cell (hiPSC)-derived alpha-like cells. ISG15 knockdown in human insulin-producing EndoC-{beta}H1 cells and human islets increases apoptosis under basal conditions and after IFN exposure, exacerbates IFN responses and increases cell death and viral production after infection with the diabetogenic virus coxsackievirus B1, while its overexpression protects EndoC-{beta}H1 cells from the virus. Collectively, the present results demonstrate that alpha cells but not beta cells have similarities with the virus resistance gene program present in bats and identify ISG15 as an important factor for islet cells to cope with viral and diabetogenic stresses.

immunology↗

bioRxiv2025

Spatial map of native duct cell populations in human pancreas and their representation in pancreatic cancers

BackgroundA resemblance of pancreatic tumors to their native tissue architecture remains largely unexplored, while it may reveal novel insights into the healthy and diseased tissue. ObjectiveThis study aims at generating a spatially resolved map of human pancreatic duct cell populations in the native tissue and in tumors, i.e. pancreatic ductal adenocarcinoma (PDAC) and adenosquamous cancer of the pancreas (ASCP). DesignNew datasets were acquired with several spatial transcriptomics platforms and were integrated with public single-cell RNAseq datasets and validated by multiplex immunofluorescence. Cell lines and primary human cell cultures were genetically manipulated. ResultsGroups of Keratin-5+ cells in larger ducts have a gene signature reminiscent of stem cells and (supra)basal cells from other tissues. At single cell resolution, this group comprises {Delta}Np63+ basal cells (BAS) and {Delta}Np63- supra-basally residing luminal-B cells (LUM-B). The latter express previously unreported MUC4 and MUC16. Additionally, we identified three other luminal cell populations in the ducts (LUM-A, -C, -D). In cancer, BAS and LUM-B signatures associate with basal-like (BL) PDAC, and correlate with lower survival. However, PDAC exhibits a random spatial pattern and fragmented native expression programs while ASCP preserve the identity of LUM-B and BAS in a spatially unmixed pattern. {Delta}Np63 drives cell plasticity to BAS, conserved from the native tissue to cancer. ConclusionSpatially distinct duct cell populations are revealed, and the extent of preservation of the native cell identities in pancreatic cancer underpins distinct tumor identities. This warrants a separate consideration in research and therapy. What is already known on this topicWhile tumors in the pancreas can exhibit basal-like and squamous features resembling tumors of other tissues, their resemblance to the native duct cells, and possible subpopulations thereof, had not been studied in detail. What this study addsOne basal and four luminal spatially distinct cell populations exist in human pancreatic ducts. These are best conserved in ASCP while PDAC shows loss of the native cell identity program. How this study might affect research, practice or policyOur study demonstrates fundamental differences between the tumor cells of the BL PDAC versus the rare ASCP, highlighting the necessity for a clear distinction between them in research and in tumor-specific treatments. Meanwhile, the research community should acknowledge the spatial and functional heterogeneity of human duct cells, including in their experimental models.

cancer biology↗

bioRxiv2024

Implications of noncoding regulatory functions in the development of insulinomas

Insulinomas are rare neuroendocrine tumours arising from the pancreatic {beta}-cells. While retaining the ability to produce insulin, insulinomas feature aberrant proliferation and altered hormone secretion resulting in failure to maintain glucose homeostasis. With the aim of uncovering the role of noncoding regulatory regions and their aberrations to the development of these tumors, we coupled epigenetic and gene expression profiling with whole-genome sequencing. As a result, we mapped H3K27ac sites in the tumoral tissue and unraveled overlapping somatic mutations associated with changes in regulatory functions. Critically, these regions impact insulin secretion, tumor development and epigenetic modifying genes, including key components of the polycomb complex. Chromatin remodeling is apparent as insulinoma-selective regions are mostly clustered in regulatory domains, shared across patients and containing a specific set of regulatory sequences dominated by the binding motif of the transcription factor SOX17. Moreover, a large fraction of these regions are H3K27me3-repressed in unaffected {beta}-cells, suggesting that tumoral transition is coupled with derepression of {beta}-cell polycomb-targeted domains. Our work provides a compendium of aberrant cis-regulatory elements and transcription factors that alter {beta}-cell function and fate in their progression to pancreatic neuroendocrine tumors and a framework to identify coding and noncoding driver mutations.

genomics↗

bioRxiv2023

Interferons are the key cytokines acting on pancreatic islets in type 1 diabetes

The pro-inflammatory cytokines IFN, IFN{gamma}, IL-1{beta} and TNF may contribute to innate and adaptive immune responses during islet inflammation (insulitis) in type 1 diabetes (T1D). We used deep RNA-sequencing analysis to characterize the response of human pancreatic beta cells to each cytokine individually and compared the signatures obtained with those present in islets of individuals affected by T1D. IFN and IFN{gamma} had a much greater impact on the beta cell transcriptome when compared to IL-1{beta} and TNF. The IFN-induced gene signatures have a strong correlation with those observed in beta cells from T1D patients, and the level of expression of specific IFN-stimulated genes is positively correlated with proteins present in islets of these individuals, regulating beta cell responses to "danger signals" such as viral infections. These data suggest that IFN and IFN{gamma} are the central cytokines at the islet level in T1D, contributing to the triggering and amplification of autoimmunity.

immunology↗

bioRxiv2020

What is AIDS in the Amazon and the Guianas in the 90-90-90 era?

IntroductionIn the past decade, new diagnostic methods and strategies have appeared, HIV testing efforts and the generalization of antiretroviral therapy may have influenced the number of opportunistic diagnoses and mortality of HIV-infected patients. To test this hypothesis we compiled data on the top opportunistic infections and causes of early death in the HIV cohort of French Guiana. MethodsHIV-infected persons followed in Cayenne, Kourou, and Saint Laurent du Maroni hospitals from 2010 to 2019 were studied. The annual incidence of different opportunistic infections and annual deaths were compiled. For patients with opportunistic infections we calculated the proportion of early deaths. ResultsAt the time of analysis, among 2 459 patients, (treated and untreated) 90% had a viral load <400 copies, 91% of the patients in the cohort were on antiretroviral treatment, and 94.2% of patients on treatment for over 6 months had undetectable viral loads. Only 9% of patients had CD4 counts under 200 per mm3. Disseminated histoplasmosis clearly remained the most frequent (128 cases) opportunistic infection among HIV-infected persons followed by cerebral toxoplasmosis (63 cases) and esophageal candidiasis (41 cases). Cryptococcal meningitis was ranked 5th most frequent opportunistic infection as was tuberculosis (31 cases). The trend for a sharp decline in early deaths continued (3.9% of patients). ConclusionsDespite the successes of antiretrovirals, patients presenting with advanced HIV are still common and they are still at risk of dying. Improved diagnosis, and notably systematic screening with appropriate tools are still important areas of potential progress. Author summaryIn the past decade, new diagnostic methods and strategies have appeared, HIV testing efforts and the generalization of antiretroviral therapy may have influenced the number of opportunistic diagnoses and mortality of HIV-infected patients. To test this hypothesis we compiled data on the top opportunistic infections and causes of early death in the HIV cohort of French Guiana. HIV-infected persons followed in Cayenne, Kourou, and Saint Laurent du Maroni hospitals from 2010 to 2019 were studied. The annual number of different opportunistic infections and annual deaths were compiled. For patients with opportunistic infections we calculated the proportion of early deaths. At the time of analysis, most patients were virologically controlled and had restored immunity. However, histoplasmosis clearly remained the most frequent (128 cases) opportunistic infection among HIV-infected persons followed by cerebral toxoplasmosis (63 cases) and esophageal candidiasis (41 cases). Cryptococcal meningitis was ranked 5th most frequent opportunistic infection as was tuberculosis (31 cases). The trend for a sharp decline in early deaths continued (3.9% of patients). Despite the successes of antiretroviral therapy, patients presenting with advanced HIV are still common and they are still at risk of dying. Improved diagnosis, and notably systematic screening with appropriate tools are still important areas of potential progress.

microbiology↗

bioRxiv2019

High Frequency of Enteroparasitoses in the Municipality of Oiapoque, Amapa State, Brazil, on the Border With French Guiana

IntroductionEnteroparasites represent a considerable proportion of infectious parasitic diseases worldwide. This study evaluated the frequency of enteroparasites and the correlation of enteroparasites with hemoglobin levels. This study evaluated the frequency of enteroparasites and the correlation of themwith hemoglobin levels.\n\nMethodsA cross-sectional study was performed in the municipality of Oiapoque in the state of Amapa in northern Brazil, which is located at the western border of the Amazon region. Fecal samples collected over a one-year period (2014/2015) were analyzed using direct methods and spontaneous sedimentation.\n\nResultsThe study included 446 individuals ranging in age from 7 to 61 years. Among the investigated individuals, 58.6% (261/446) were infected with some type of enteroparasites. Of these infected individuals, 45.2% (118/261) were infected only by helminth, 40.9% (107/261) were infected with protozoa, and 13.8% (36/261) had combined infections. Ascaris lumbricoides (19.9%, 52/261) was the most commonly detected helminth, followed by Entamoeba coli and Endolimax nana that were the most frequent protozoan (17.2%, 45/261). The study showed an inversely proportional correlation between the hemoglobin level and the presence of detected parasites. Conclusions: In Oiapoque, enteroparasitosis diseases may be one of the causes of anemia in the population. The high frequency of enteroparasites is a clear reflection of the lack of sanitation in the studied region, indicating an epidemiological state of concern.

epidemiology↗