Biology subjects

Carneiro, A.

Publications and source records attributed to Carneiro, A..

3 recordsLinked to original sources

bioRxiv2026

Sex-linked Lung Estrobolome May Contribute to Pulmonary Hypertension Penetrance of Bmpr2 R899X Mutation via an ET-1high Endoregulatory Macrophage Phenotype

Mutations in the bone morphogenetic protein receptor 2 (BMPR2) are a major genetic driver of pulmonary arterial hypertension (PAH), yet their penetrance is strikingly sex-biased: females are disproportionately affected, while males experience poorer outcomes. While hormonal and chromosomal factors have been implicated, the biological basis for this disparity remains not fully understood. Here, we investigated the role of the lung microbiome in sex-linked PAH pathogenesis. We hypothesized that increased BMPR2 mutation penetrance in females is partly driven by the accumulation of potent vasoactive molecules, such as endothelin-1 (ET-1), in response to lung microbiome dysbiosis. Using humanized Bmpr2+/R899X mice, we integrate lung metagenomics with basic functional immune profiling to show that females develop a distinct microbiome profile, characterized by increased microbial-derived lipopolysaccharide (LPS), potentially fueling the pathogenic effects of the estrogen metabolite 16-hydroxyestrone (16-OHE). These signals converge on macrophages, where co-exposure led to a hyperactivated state characterized by enhanced phagocytosis and ET-1 secretion. Tissue-level analyses confirmed immune cell infiltration and spatial association with elevated ET-1, providing evidence that these factors may contribute to the onset of sex-linked PAH. Taken together, these findings identify a previously unrecognized microbiome-estrogen-immune axis that amplifies BMPR2 dysfunction and provides a mechanistic basis for female-biased disease penetrance.

immunology↗

bioRxiv2021

Urine proteomics as a non-invasive approach to monitor exertional rhabdomyolysis during military training

Exertional rhabdomyolysis (ERM), a condition often associated with strenuous exercise, a common practice in the military activities, can be defined as the process of injury and rupture of muscle cell membranes, with leakage of its components into the blood stream. Creatine kinase (CK) has been extensively used for ERM diagnosis, albeit several studies reported the discrepancy between CK levels and clinical signs or symptoms. In this study, we analyzed the biochemical profile of the blood, and the urinary proteome of ten marine soldiers in a special training course. The samples were collected in two periods, M1 and M2, which correspond to the lowest and highest CK levels during training, respectively. Quantitative urinary proteome profile of M1 and M2 was determined showing changes with highest significance in immune system and cell adhesion-related pathways after strenuous physical exercise. Changes in the abundance of several proteins was observed in individuals carrying genetic polymorphisms related to greater risk for muscle damage. Remarkably, we identified a panel of proteins (CTSH, PIK3IP1, DEFB1, ITGB1, BCAN, and TNFRSF10C) that present high correlation with three classical blood biochemical markers of ERM and AGT MET235Thr and ACE I/D polymorphisms. These proteins represent potential urine markers of muscle damage due to intense physical conditions such as military training activities.

biochemistry↗

bioRxiv2021

Machine learning-based library design improves packaging and diversity of adeno-associated virus (AAV) libraries

Adeno-associated viruses (AAVs) hold tremendous promise as delivery vectors for clinical gene therapy, but they need improvement. AAVs with enhanced properties, such as more efficient and/or cell-type specific infection, can be engineered by creating a large, diverse starting library and screening for desired phenotypes, in some cases iteratively. Although this approach has succeeded in numerous specific cases, such as infecting cell types from the brain to the lung, the starting libraries often contain a high proportion of variants unable to assemble or package their genomes, a general prerequisite for engineering any gene delivery goal. Herein, we develop and showcase a machine learning (ML)-based method for systematically designing more effective starting libraries -- ones that have broadly good packaging capabilities while being as diverse as possible. Such carefully designed but general libraries stand to significantly increase the chance of success in engineering any property of interest. Furthermore, we use this approach to design a clinically-relevant AAV peptide insertion library that achieves 5-fold higher packaging fitness than the state-of-the-art library, with negligible reduction in diversity. We demonstrate the general utility of this designed library on a downstream task to which our approach was agnostic: infection of primary human brain tissue. The ML-designed library had approximately 10-fold more successful variants than the current state-of-the-art library. Not only should our new library serve useful for any number of other engineering goals, but our library design approach itself can also be applied to other types of libraries for AAV and beyond.

bioengineering↗