Biology subjects

Borges, T. J.

Publications and source records attributed to Borges, T. J..

5 recordsLinked to original sources

bioRxiv2026

Housekeeping Gene Expression Normalization in Transcriptomics Mitigates Data Leakage in Machine Learning Models

BackgroundInappropriate normalization can lead to data leakage and overfitting in machine learning models. Accurately identifying housekeeping genes (HKGs) can overcome this problem and is crucial for normalizing gene expression data, particularly in RNA-Seq experiments. ResultsFirst, we demonstrate that the gene expression of commonly used HKGs significantly changes over time due to immunosuppressive treatments in transplant recipients. Using large public transcriptomic datasets of kidney transplantation, we developed a pipeline based on the genes coefficient of variation, stability, and Gini coefficient, and identified nine stable and better-suitable HKG candidates. Our results demonstrate that these HKGs improve the robustness and generalizability of machine learning models by minimizing data leakage, as evidenced by superior performance compared to benchmark methods like median ratio normalization and trimmed mean of M values. ConclusionsThis approach enables more accurate comparison of gene expression datasets across different clinical scenarios, improving the reliability of biomarker identification and enhancing personalized treatment strategies.

bioinformatics↗

bioRxiv2023

Innate extracellular Hsp70 inflammatory properties are mediated by the interaction of Siglec-E and LOX-1 receptors

Innate immune responses to cell damage-associated molecular patterns induce a controlled degree of inflammation, ideally avoiding the promotion of intense unwanted inflammatory adverse events. When released by damaged cells, Hsp70 can stimulate different responses that range from immune activation to immune suppression. The effects of Hsp70 are mediated through innate receptors expressed primarily by myeloid cells, such as dendritic cells (DCs). The regulatory innate receptors that bind to extracellular mouse Hsp70 (mHsp70) are not fully characterized, and neither are their potential interactions with activating innate receptors. Here, we describe that extracellular mHsp70 interacts with a receptor complex formed by inhibitory Siglec-E and activating LOX-1 on DCs. We also find that this interaction takes place within lipid microdomains, and Siglec-E acts as a negative regulator of LOX-1-mediated innate activation upon mHsp70 or oxidized LDL binding. Thus, HSP70 can both bind to and modulate the interaction of inhibitory and activating innate receptors on the cell surface. These findings add another dimension of regulatory mechanism to how self-molecules contribute to dampening of exacerbated inflammatory responses.

immunology↗

bioRxiv2023

Immune Response of Transplanted Kidney Tissues Assembled from Organoid Building Blocks

The increasing scarcity of organs and the significant morbidity linked to dialysis requires the development of engineered kidney tissues from human-induced pluripotent stem cells. To accomplish this, integrative approaches that synergize scalable kidney organoid differentiation, tissue biomanufacturing, and comprehensive assessment of their immune response and host integration are essential. Here, we create engineered human kidney tissues composed of kidney organoid building blocks (OBBs) and transplant them into mice reconstituted with allogeneic human immune cells. We assess their host vascular integration, in vivo maturation, and their ability to trigger human immune responses. Tissue-infiltrating human immune cells are composed of effector T cells and innate cells. This immune infiltration leads to kidney tissue injury characterized by reduced microvasculature, enhanced kidney cell apoptosis, and a unique inflammatory gene signature comparable to kidney organ transplant rejection in humans. Upon treatment with the immunosuppressive agent Rapamycin, the induced immune response is greatly suppressed. Our model serves as a translational platform to study engineered kidney tissue immunogenicity and develop novel therapeutic targets for kidney rejection.

bioengineering↗

bioRxiv2021

Extracellular Hsp90α Detoxifies β-Amyloid Fibrils Through an NRF2 and Autophagy Dependent Pathway

We have investigated the role of extracellular Heat shock protein 90 alpha (eHsp90) in conferring protection of neuronal cells against fibrillary amyloid beta (f-A{beta}1-42) toxicity mediated by microglial cells. Formation of f-A{beta}1-42 plaques leads to neurotoxic inflammation, a critical pathological feature of Alzheimers Disease. We observed increased uptake and clearance of internalized f-A{beta}1-42 by microglial cells treated with eHsp90, an effect associated with activation of NRF2 (NF-E2-related factor 2) - mediated autophagy. eHsp90 thus mitigated the neuronal toxicity of f-A{beta}1-42-activated microglia. In addition, eHsp90 facilitated f-A{beta}1-42 engulfment by microglial cells in vitro. In summary, eHsp90 triggers NRF2-mediated autophagy in microglia and thus protects against the neurotoxic effects of f-A{beta}1-42.

cell biology↗

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↗