Biology subjects

Mendes, D.

Publications and source records attributed to Mendes, D..

4 recordsLinked to original sources

bioRxiv2026

Distinct Progression Paths Underlie the Diversity of Pancreatic Papillary Cystic Neoplasms

Surgical decisions for intraductal papillary mucinous neoplasms (IPMNs), precursors of pancreatic cancer, depend on distinguishing low- from high-grade dysplasia, a distinction that molecular markers could refine. We microdissected 433 tumor regions from 135 patients and integrated transcriptomics, deep-learning histology, and KRAS/GNAS RNA-called variants. RNA programs and morphological motifs separated lesions by phenotype, intestinal versus others, rather than by dysplasia grade. Along gastric IPMN trajectories, low-grade lesions recapitulated the pit-chief polarity of normal gastric glands, whereas high-grade lesions were indistinguishable from pancreatobiliary lesions in morphology, RNA programs, and driver mutations. Intestinal IPMNs arose through two routes: a canonical GNAS-associated pathway and a KRAS-associated shift from low-grade gastric features, with lesions sharing driver mutations retaining common programs across phenotypes. Resolving these phenotypic trajectories clarified distinct progression paths and enabled phenotype-specific prediction of high-grade dysplasia in mucus aspirated from 94 resected lesions. These findings support a promising fluid-based assessment of IPMN status.

cancer biology↗

bioRxiv2024

Electrophysiological signatures of a developmental delay in a stem cell model of KCNQ2 developmental and epileptic encephalopathy

BackgroundKCNQ2, encoding KV7.2 ion channels, has emerged as one of the prominent genes causing early onset seizures with developmental delay (KCNQ2 developmental and epileptic encephalopathy; KCNQ2-DEE). KCNQ2 de novo loss-of-function (LOF) and associated neuronal hyperexcitability have been accepted as mechanisms contributing to seizures. To investigate the developmental impact of KCNQ2 LOF, we generated patient iPSC-derived models for two previously reported de novo variants, p.(Arg325Gly) and p.(Gly315Arg), linked to severe congenital DEE. MethodsFunctional investigation of the two variants was initially performed in Xenopus laevis oocyte system. Patient-derived iPSC lines were differentiated using NGN2- and embryoid body-based protocols yielding neurons roughly corresponding to mid- and mid-late gestational stages, respectively. KV7- mediated M-current, passive neuronal properties, action potential generation and spontaneous oscillatory network activities were analysed with whole-cell patch clamping. FindingsStudied KCNQ2 variants showed LOF with a dominant-negative effect in the heterologous system. Reduced M-currents in patient iPSC-derived neurons corroborated a LOF as the main pathomechanism. Interestingly, this led to the reduced neuronal firing of the early neurons and to a disruption of complex oscillatory activity, with significantly reduced duration and amplitude of these events in patient iPSC-derived neurons. InterpretationWe provide experimental evidence for changing roles of the M-current throughout development and place disease variant-mediated M-current reduction in the context of the neuronal maturation in the prenatal brain. Based on the reduced neuronal firing and disrupted oscillatory activity seen in patient iPSC-derived neurons, we propose that a delayed/impaired maturation of neuronal and network properties underlies KCNQ-DEE caused by LOF variants.

neuroscience↗

bioRxiv2020

Sensing soluble uric acid by Naip1-Nlrp3 platform

The immune system can recognize microbes and sterile tissue damage. Among the damage-associated molecular patterns (DAMPs), uric acid is considered a major component which can trigger inflammation. It represents a breakpoint in the evolutionary history of humans as our ancestors lost the uricase gene, the enzyme responsible for its cleavage. High soluble uric acid (sUA) concentration is able to increase IL-1{beta} in murine, but not human macrophages. We observed that sUA increased the mRNA expression of Naip1 in murine macrophages, and, therefore, we hypothesized that the recognition of sUA can be made by a Naip1-Nlrp3 inflammasome platform. Additionally, we used genome-wide transcriptome analysis, functional analyses and structural modeling predictions and observed that virus-transduction of murine Naip1 into human macrophages induced IL-1{beta} after sUA stimulus, besides leading to fatty acid production and an inflammation-related response. Moreover, pharmacologic inhibition and genetic loss of Nlrp3 led to decreased IL-1{beta} production upon sUA stimulus. Surface plasmon resonance and quartz crystal microbalance showed that sUA is able to interact with Naip1. Naip could be a lost receptor for sUA in the evolutionary process and a better understanding of the immune modulatory function of sUA could lead to design rational novel anti-hyperuricemic therapies.

immunology↗

bioRxiv2017

RSV Downregulates IL-21/IL-21R On TFH Cells Via PD-L1 Induction In APCs Impairing Protective Humoral Responses

Respiratory syncytial virus (RSV) is the major cause of hospitalization for children under two years of age. RSV vaccines are currently unavailable, and children suffering from multiple reinfections by the same viral strain, fail to develop protective memory responses. Follicular helper T (TFH) cells specialize in providing B cell help to antibody production and affinity maturation, mainly via IL-21 secretion. Although RSV-specific antibodies can be detected upon infection, how they are generated and their relevance against disease protection has not been fully examined. Here, we observed that RSV expands a functionally impaired murine TFH cell population in vitro and vivo, with downregulated IL-21R expression and IL-21 production. IL-21 treatment of RSV-infected mice, however, increased TFH cells frequency, enhanced the germinal center reaction and improved protective humoral immune responses by increasing viral protein F specific antibody avidity and neutralization capacity. In vivo, it protected from RSV infection, decreasing lung inflammation. Passive immunization with purified IgG from IL-21 treated RSV-infected mice protected against RSV infection. Both viable and UV-inactivated RSV induced PD-L1 expression on B cells and DCs, however, only in DCs a direct effect of RSV was detected. Blocking PD-L1 during infection recovered IL-21R expression in TFH and B cells and increased secretion of IL-21 by TFH cells in a DC-dependent manner. Our results unveil a novel pathway by which RSV affects TFH cells activity, reducing levels of IL-21 and its receptor, by increasing PD-L1 expression on APCs. These results highlight the PD-L1/IL-21 axis importance for the generation of protective responses to RSV infection.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=176 HEIGHT=200 SRC=\"FIGDIR/small/203133_figGA1.gif\" ALT=\"Figure 1\">\nView larger version (36K):\norg.highwire.dtl.DTLVardef@172470eorg.highwire.dtl.DTLVardef@197017eorg.highwire.dtl.DTLVardef@e31ae3org.highwire.dtl.DTLVardef@1fa4c4f_HPS_FORMAT_FIGEXP M_FIG GRAPHICAL ABSTRACTRSV infection impairing IL-21 secretion by TFH cells via PD-L1induction in dendritic cells and B cells. Low levels of IL-21 lead to poor RSV-specific humoral immune responses, low antibody titer, avidity and neutralization capacity. PD-L1 blockade can upregulate IL-21 secretion, and IL-21 treatment restores the entire immune humoral responses, resulting in protection against RSV infection.\n\nC_FIG

immunology↗