Biology subjects

Borges, C.

Publications and source records attributed to Borges, C..

6 recordsLinked to original sources

bioRxiv2026

Tipping the balance: Synthesis and evaluation of centrinone-based degraders of polo-like kinase 4

Polo-like kinase 4 (PLK4) is a serine/threonine-protein kinase that plays a pivotal role in centriole biogenesis and, as such, represents a master regulator of centriole duplication. Due to its importance in cancer development and progression, PLK4 represents an attractive target for the development of novel therapeutics. Herein, we present a series of molecular degraders of PLK4, based on the highly selective PLK4 inhibitor centrinone, with the aim of targeting PLK4 for degradation via the ubiquitin-proteasome system. While all synthesized degraders retained low nanomolar binding affinities to the kinase domain of PLK4, large differences were found with respect to their ability to change cellular PLK4 levels. We uncover a complex pharmacological profile of the most potent degraders, D6 and D10, consisting of concomitant lowering of PLK4 levels through degradation, and enhancing PLK4 levels through inhibition of its autoregulation - dependent on its localization at the centrioles.

cell biology↗

bioRxiv2026

Modular mRNA LNP design integrates RNA, lipid, and antigen engineering for protective vaccination

mRNA-lipid nanoparticle (LNP) vaccines are programmable, multi-component systems in which immune outcomes emerge from coupled control of nanoparticle chemistry, RNA regulatory architecture, and antigen design. Here we establish an integrated engineering framework that quantitatively maps how ionizable lipid identity, untranslated region (UTR) configuration, and 5' cap structure shape innate activation landscapes and thereby tune the magnitude, cellular distribution, and polarization of adaptive immunity. Benchmarking three ionizable lipids shows that lipid chemistry imprints distinct cytokine and chemokine milieus during dendritic cell-T cell priming that mirror downstream T cell activation phenotypes, identifying lipid structure as a determinant of pathway-selective activation; notably, our first-in-study lipid exhibits benchmark-comparable immunostimulatory profiles, supporting further translational evaluation. Using Crimean-Congo hemorrhagic fever virus (CCHFV) as a model high-consequence pathogen, we show that UTRs act as modular regulatory elements that redirect cytokine outputs, tuning effector versus proliferative programs and expanding helper polarization in an antigen-dependent manner. Cap structure functions primarily as a quantitative gain control, scaling cellular and humoral response magnitude without overriding antigen-defined polarization. Within this optimized platform, antigen architecture defines functional constraints on protection: structural modifications reshape immune hierarchies and antibody quality. Integrating these design axes yields an optimized mRNA-LNP vaccine encoding the CCHFV secreted glycoprotein complex (sGCs) that achieves 90% protection in an immunosuppressed murine lethal-challenge model with minimal clinical signs. Together, these data define generalizable design principles for rational, multi-parameter optimization of mRNA-LNP vaccines.

microbiology↗

bioRxiv2025

Genomic insights into ancestry and infectious disease in 17th-century colonial Brazil

During urban redevelopment in the historic district of a Brazilian metropolis, archaeologists uncovered a previously undocumented 17th-century cemetery, containing the closely spaced remains of over two dozen young adult males of military age. Historical records suggest the site once housed a makeshift hospital, raising questions about the origins and causes of death of those interred, particularly given the absence of skeletal evidence for violent or fatal trauma. The current study integrates bioarchaeological, historical, and genomic data to investigate the ancestry and putative disease-related mortality of nine individuals whose remains were recovered and subsequently sequenced. Population-genetic analyses revealed strong affinities with Northern European populations, particularly from Norway, Iceland, Estonia, and Czechoslovia, consistent with their likely roles as soldiers or laborers employed by the Dutch West India Company. To explore potential causes of death, we conducted a metagenomic screening with a novel pipeline optimized for degraded DNA, which revealed widespread presence of Klebsiella pneumoniae and Mycobacterium tuberculosis pathogens across all samples. Authenticity was confirmed through post-mortem damage patterns characteristic of historical samples. These findings, together with the absence of combat trauma and the collective burial context at the site, support the hypothesis of an epidemic-related mortality event. This study contributes to the growing field of historical pathogen genomics and offers a rare genomic perspective on life, mobility, and health during a period of colonial upheaval in South America.

evolutionary biology↗

bioRxiv2025

Bora, CEP192 and Cenexin activate different Plk1 pools and regulate distinct cell and centrosome cycle transitions

Polo-like kinase 1 (Plk1) regulates multiple steps of the cell and centrosome cycle, including mitotic entry, DNA-damage recovery, centrosome maturation and centriole disengagement. Plk1 activity depends on several independent cofactors, such as the cytoplasmic Bora, and the centrosomal proteins Cep192 and Cenexin. However, whether these Plk1 coactivators differentially regulate the Plk1-dependent processes is unknown. Here, we show that each Plk1 coactivator controls different cell cycle steps via distinct Plk1 pools in human cells. While Bora is the main driver for mitotic entry, DNA-damage recovery and centrosome maturation, centriole disengagement is mainly regulated by Cep192 and Cenexin. Moreover, we find that Plk1 and Cep192 drive S-phase progression by promoting replication origin firing. Our results thus uncover the complexity of the Plk1 activation regulatory network, in which distinct upstream activators dictate its activity in a context-dependent manner.

cell biology↗

bioRxiv2022

3D-Beacons: Decreasing the gap between protein sequences and structures through a federated network of protein structure data resources

While scientists can often infer the biological function of proteins from their 3-dimensional quaternary structures, the gap between the number of known protein sequences and their experimentally determined structures keeps increasing. A potential solution to this problem is presented by ever more sophisticated computational protein modelling approaches. While often powerful on their own, most methods have strengths and weaknesses. Therefore, it benefits researchers to examine models from various model providers and perform comparative analysis to identify what models can best address their specific use cases. To make data from a large array of model providers more easily accessible to the broader scientific community, we established 3D-Beacons, a collaborative initiative to create a federated network with unified data access mechanisms. The 3D-Beacons Network allows researchers to collate coordinate files and metadata for experimentally determined and theoretical protein models from state-of-the-art and specialist model providers and also from the Protein Data Bank.

bioinformatics↗

bioRxiv2018

The effect of plasma lipids and lipid lowering interventions on bone mineral density: a Mendelian randomization study

Statin treatment increases bone mineral density (BMD) and reduces fracture risk, but the underlying mechanism is unclear. We used Mendelian randomization (MR) to assess whether this relation is explained by a specific effect in response to statin use, or by a general effect of lipid-lowering. We utilized 400 single nucleotide polymorphisms (SNPs) robustly associated with plasma lipid levels and results from a heel BMD GWAS (derived from quantitative ultrasound) in 426,824 individuals from the UK Biobank. We performed univariate and multivariable MR analyses of low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and triglyceride levels on BMD. To test whether the effect of statins on BMD was mediated by lowering lipid levels, MR was repeated with and without SNPs in the HMGCR region, the gene targeted by statins. Univariate MR analyses provided evidence for a causal effect of LDL-C on BMD ({beta} = -0.060; -0.084 to -0.036; P = 4x10-6; standard deviation change in BMD per standard deviation change in LDL-C, with 95% CI), but not HDL or triglycerides. Multivariable MR analysis suggested that the effect of LDL-C on BMD was independent of HDL-C and triglycerides, and sensitivity analyses involving MR Egger and weighted median MR approaches suggested that the LDL-C results were robust to pleiotropy. MR analyses of LDL-C restricted to SNPs in the HMGCR region showed similar effects on BMD({beta} = -0.083; -0.132 to -0.034; P = 0.001) to those excluding these SNPs ({beta} = -0.063; -0.090 to -0.036; P = 8x10-6). Bidirectional MR analyses provided some evidence for a causal effect of BMD on plasma LDL-C levels. Our results suggest that effects of statins on BMD are at least partly due to their LDL-C lowering effect. Further studies are required to examine the potential role of modifying plasma lipid levels in treating osteoporosis.

epidemiology↗