Biology subjects

Torres, P.

Publications and source records attributed to Torres, P..

10 recordsLinked to original sources

bioRxiv2026

Oral administration of dibenzoylmethane (DBM) prevents cognitive decline in a C9ORF72-mediated FTD mouse model

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related neurodegenerative disorders that display overlapping features. The hexanucleotide repeat expansion GGGGCC (G4C2) in the C9ORF72 gene is the most common cause of ALS and FTD, which results in the accumulation of dipeptide-repeat protein aggregates. Regulation of protein synthesis at the level of the initiation factor eIF2 has been suggested as a transversal event contributing to neurodegeneration in ALS and FTD. eIF2 phosphorylation blocks protein synthesis to alleviate protein misfolding overload, but conversely it can reduce the expression of synaptic proteins resulting in neuronal dysfunction. Dibenzoylmethane (DBM) is a small molecule that reverses the translational attenuation mediated by eIF2 phosphorylation which has been shown to alleviate neurodegeneration in prion-infected mice and Tau transgenic animals. Here we investigated the efficacy of the oral administration of DBM in protecting a mouse model of C9ORF72 pathogenesis. Treatment of mice with 0.5% of DBM mixture in powdered food ad libitum was sufficient to prevent cognitive impairment in C9ORF72 mice. Unexpectedly, DBM treatment did not modify the content of poly(GA) and poly(GR) protein inclusion in the hippocampus and brain cortex. Proteomic profiling of brain tissue indicated that DBM administration corrected nearly 70% of the changes in gene expression triggered by expanded G4C2, where the main pathways modified by DBM were related to cytoskeleton organization, ALS, and metabolic processes. Most proteins corrected by DBM in our C9ORF72 model were also altered in the brain of human FTD/ALS patients. Overall, our results reinforce the idea that targeting protein synthesis with small molecules in patients carrying C9ORF72 mutations may result in improved cognitive capacity.

molecular biology↗

bioRxiv2026

A Modular Platform for Purification of Organelle-associated Mitochondria Reveals Functional Specialization at Organelle Contact Sites

Mitochondria perform diverse metabolic and signaling functions, yet how these activities are spatially organized within the mitochondrial network of cells remains poorly understood. Organelle contact sites are spatially restricted hubs that regulate mitochondrial metabolism, signaling, and dynamics, and are therefore well positioned to influence mitochondrial specialization. Investigation of contact site-associated mitochondrial populations has been hindered by a lack of methods to isolate these subpopulations. Here, we develop Organelle Contact-dependent Affinity Purification (ORCA), a workflow for the isolation and analysis of subpopulations of intact mitochondria and associated proteins defined by their organelle contacts. ORCA revealed distinct proteomes for mitochondria associated with the endoplasmic reticulum, lysosomes, peroxisomes, and the Golgi apparatus, demonstrating that organelle contacts define biochemically specialized mitochondrial populations. Focused analysis of Golgi-associated mitochondria showed enrichment of mitochondrial ribosomes and increased mitochondrial translation, revealing an unexpected role for Golgi-mitochondria contacts in regulating mitochondrial protein homeostasis. ORCA also identified the previously uncharacterized Golgi protein KIAA0930/GMO1 as an evolutionarily conserved regulator of oxidative phosphorylation at Golgi-mitochondria contacts. Together, our findings establish ORCA as a broadly applicable approach for investigating the spatial organization of intracellular organelles and reveal organelle contacts as key determinants of mitochondrial specialization.

cell biology↗

bioRxiv2024

Ovalbumin-loaded mesoporous silica nanoparticles for allergen specific immunotherapy

Allergic diseases are caused by an unnecessary immune response against harmless external substances (allergens), and they pose an important economic burden for healthcare systems with a large impact on the quality of life of patients. Allergen-specific immunotherapy (AIT) is the only treatment option capable of modifying the natural history of the disease, but current AIT schemes present safety and efficacy limitations. One possible strategy to address these limitations is to encapsulate the allergen in nanoparticle carriers that can deliver it to antigen presenting cells while hiding it from effector cells responsible for the allergic reaction. In this work, we evaluate the use of allergen-loaded mesoporous silica nanoparticles (MSNs) as AIT agents. MSNs of different pore sizes were prepared and characterized, evaluating their capacity to load and release ovalbumin (OVA) as a model allergen. Extra-large pore MSNs (XL-MSNs) showed the optimal loading and release behavior, presenting also enhanced activation of the dendritic cell line DC2.4 and reduced allergenic capacity in pre-sensitized RBL-2H3 cells, both compared to free OVA. After evaluating their biodistribution following subcutaneous, sublingual or intravenous administration, their therapeutic potential in AIT was further assessed in an in vivo murine model of OVA systemic anaphylaxis. The results showed that intravenous administration of OVA-loaded XL-MSNs significantly protected the mice from anaphylaxis and induced a Th1/Treg-immune profile, while administration through other routes failed to prevent the development of an anaphylactic reaction upon provocation with OVA. These findings establish MSNs, particularly via intravenous administration, as a promising platform to develop safer and more effective AIT.

immunology↗

bioRxiv2024

Priestia megaterium ILBB592 based biofertilizer increases the efficiency of phosphorus fertilization, positively affects soybean nutrition and yield and modifies the rhizospheric bacterial community

Phosphorus (P) is needed by soybean plants to form vital molecules like ATP and nucleotides and perform plant functions like photosynthesis and Nitrogen biological fixation at nodules. Because P concentration in the soil solution is naturally low, P fertilization is applied to satisfy soybean requirements in high yielding crops. However, a small portion of added P is readily available to the plants, while most is retained by the soil matrix and eventually made available or lost through erosion and run-off to water bodies, where it promotes eutrophication. Therefore, technologies that enhance P uptake by crops could lead to lower P inputs and outputs from soybean cropping systems, improving sustainability. Priestia megaterium ILBB592 and Bacillus pumilus ILBB44 are two PGPR with P mobilization features that were single formulated as biofertilizers and co-inoculated with Bradyrhizobium elkanii on seeds of soybean Genesis 5602 in two consecutive years in the field, with and without P fertilization. Co-inoculation with ILBB592 improved plant P uptake, along with N and K, with and without P fertilization. Diversity was increased by co-inoculation with ILBB44 and ILBB592, and predicted genes related with P cycling in the rhizospheric soils were also augmented after co-inoculation with ILBB592, mostly with P fertilization. Shoot dry weight and yield were also improved although effect on yield was not statistically significant. P fertilization alone had no effect in the first year but showed some effect on nodules dry weight, P uptake and yield on the second year, suggesting a sufficient P level was obtained after repeated fertilizations. ILBB592 biofertilizer showed a positive effect on most plant parameters, including nodulation and P uptake in both years and both P fertilization regimes and is therefore considered as a useful technology to reduce P fertilization without jeopardizing plant performance.

microbiology↗

bioRxiv2024

A functional interaction between TDP-43 and USP10 reveals USP10 dysfunction in TDP-43 proteinopathies

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders characterised by the progressive degeneration of specific neurons, that are defined by the appearance of TDP-43 pathology leading to TDP-43 cytoplasmic aggregation coupled with its nuclear loss. Although the causes of TDP-43 pathology in TDP-43 proteinopathies remain unclear, stress response may play a significant role, with some TDP-43 co-localizing with stress granules (SG). The ubiquitin-specific protease 10 (USP10) is a critical inhibitor of SG assembly. Here, we identify a new functional interaction between TDP-43 and USP10, with both proteins modulating different key aspects of the biology of the other. Adding to their functional connection, we assign a new function to USP10 as a modulator of alternative splicing, sharing a subset of splicing targets with TDP-43. Critically, we found that USP10 levels can increase in postmortem tissue from ALS and FTD patients and that USP10 can ameliorate TDP-43 mediated toxicity in vivo in an animal model, overall suggesting a new role for USP10 in TDP-43 proteinopathies.

neuroscience↗

bioRxiv2023

Phenotypic and genomic characterization of Bacillus sensu lato for their biofertilization effect and plant growth promotion features in soybean plants

Bacillus sensu lato were screened for their capacity to mineralize organic phosphorus (P) and promote plant growth, improving nitrogen (N) and phosphorus nutrition of soybean plants. Isolates were first identified based on their genomic sequences through TYGS and ANII. ILBB95, ILBB510 and ILBB592 were identified as Priestia megaterium, ILBB139 as Bacillus wiedmannii, ILBB44 as a member of a sister clade of B. pumilus (together with a human pathogenic strain), ILBB15 as Peribacillus butanolivorans and ILBB64 as Lysinibacillus sp. These strains were evaluated for their capacity to mineralize organic P as sodium phytate and solubilize inorganic P forms in liquid medium. These in vitro assays allowed the strains to be ranked according to their P mobilization potential, with ILBB15 and ILBB64 showing the highest orthophosphate production from phytate, ILBB592 the lowest and ILBB510 nil. In addition, features related to their rhizocompetence and plant growth promotion were evaluated in vitro and in silico. Finally, plant bioassays were deployed to assess the effect of the co-inoculation of Bacillus s.l. strains and rhizobial inoculant on nodulation, plant growth and nutrition. In planta bioassays showed that B. pumilus ILBB44 and P. megaterium ILBB95 increased P absorbed in plants grown on a poor substrate of sand and vermiculite and also on the richer mix of sand, vermiculite and peat. Priestia megaterium ILBB592 increased rhizobial nodulation and N content in plants grown on sand, vermiculite and peat mixture only. ILBB15 reduced plant growth and nutrition on both substrates. Genomes of ILBB95 and ILBB592 were characterized by genes related with plant growth and biofertilization whereas ILBB15 was differentiated by genes related to bioremediation. Priestia megaterium ILBB592 can be described as nodule-enhancing rhizobacteria (NER) and together with ILBB95, can be envisaged as prospective PGPR with the capacity to exert a positive effect on N and P nutrition of soybean plants.

microbiology↗

bioRxiv2019

Nuclear lipidome is altered in amyotrophic lateral sclerosis: a preliminary study

In this pilot study, we show that nuclei in spinal cord from ALS patients exhibit a differential lipidomic signature. Among the differential lipid species we could annotate 41 potential identities. These comprise membrane-bound lipids such as phosphatidylethanolamines-including plasmalogens- and phosphatidylcholines but also other lipid classes such as glycosphingolipids, diacylglycerols, and triacylglycerides (potentially present as nuclear lipid droplets). These results were orthogonally validated by showing loss of alkyldihydroxyacetonephosphate synthase (AGPS), a key peroxisomal enzyme in plasmalogen synthesis, both in ALS necropsy samples, in human motor neurons derived from iPSC from ALS patients and in hSOD-G93A transgenic mice. Further, diacylglycerol content changes were associated to ALS-linked variations in related-enzymes, such as phospholipase C {beta}I (PLC{beta}I), the source of nuclear diacylglycerol, and protein kinase C{beta}II (PKC{beta}II), whose function partially depends on nuclei concentration of diacylglycerol. These results point out for not only a role of nuclear membrane lipids but also to lipids present in the nucleoplasm, suggesting an undisclosed role for this part of the subcellular lipidome in ALS pathophysiology.

neuroscience↗

bioRxiv2019

Comparative analyses of metabolic pathways in mycobacteria: Insights into the identification and characterisation of new drug targets in M. tuberculosis, M. leprae and M. abscessus

Three related mycobacteria are the cause of widespread infections in man and are the focus of intense research and drug-discovery efforts in the face of growing antimicrobial resistance. Mycobacterium tuberculosis, the causative agent of tuberculosis, is currently one of the top ten causes of death in the world according to WHO; M. abscessus, a group of non-tuberculous mycobacteria causes lung infections and other opportunistic infections in humans; and M. leprae, the causative agent of leprosy, remains endemic in tropical countries. There is an urgent need to design alternatives to conventional treatment strategies, due to the increase in resistance to standard antibacterials. In this study, we present a comparative analysis of chokepoint and essentiality datasets that will provide insight into the development of new treatment regimes. We illustrate the key metabolic pathways shared between these three organisms and identify drug targets with a wide metabolic impact that are common to the three species. We demonstrate that 72% of the chokepoint enzymes are proteins essential to Mycobacterium tuberculosis. We show also that 78% of the drug targets, prioritized based on their presence in multiple paths on the metabolic network, are present in pathways shared by M. tuberculosis, M. leprae and M. abscessus, including biosynthesis of amino acids, carbohydrates, cell structures, fatty acid and lipid biosynthesis. A further 17% is found in the prioritised pathways shared between M. tuberculosis and M. abscessus. We have performed comparative structure modelling of potential drug targets identified using our analysis in order to assess druggability and demonstrate the importance of chokepoint analysis in terms of drug target identification. AUTHOR SUMMARYComputer simulation studies to design new drugs against mycobacteria

bioinformatics↗

bioRxiv2018

Exposure to a Healthy Gut Microbiome Protects Against Reproductive and Metabolic Dysregulation in a PCOS Mouse Model

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting approximately 10% of reproductive-aged women worldwide. Diagnosis requires two of the following: hyperandrogenism, oligo/anovulation and polycystic ovaries. In addition to reproductive dysfunction, many women with PCOS display metabolic abnormalities associated with hyperandrogenism. Recent studies have reported that the gut microbiome is altered in women with PCOS and rodent models of the disorder. However, it is unknown whether the gut microbiome plays a causal role in the development and pathology of PCOS. Given its potential role, we hypothesized that exposure to a healthy gut microbiome would protect against development of PCOS. A co-housing study was performed using a letrozole-induced PCOS mouse model that recapitulates many reproductive and metabolic characteristics of PCOS. Since mice are coprophagic, co-housing results in repeated, non-invasive inoculation of gut microbes in co-housed mice via the fecal-oral route. In contrast to letrozole-treated mice housed together, letrozole-treated mice co-housed with placebo mice showed significant improvement in both reproductive and metabolic PCOS phenotypes. Using 16S rRNA gene sequencing, we observed that the gut microbial composition of letrozole-treated mice co-housed with placebo mice differed from letrozole mice housed together. In addition, our analyses identified several bacterial taxa including Coprobacillus, Dorea and Adlercreutzia associated with the improved PCOS phenotype in letrozole-treated mice co-housed with placebo mice. These results indicate that disruption of the gut microbiome may play a causal role in PCOS and that manipulation of the gut microbiome may be a potential treatment option for PCOS.\n\nSignificancePCOS is a common cause of female infertility and ~80% of women with PCOS have metabolic dysregulation that predisposes them to type 2 diabetes and cardiovascular disease. Since treatment options for the metabolic symptoms of PCOS are limited, there is a need to develop novel therapeutic options. The gut microbiome has emerged as an important player in human health and has been shown to play a causal role in obesity. In this study, we found that exposure to a healthy gut microbiome through co-housing protected against the development of reproductive and metabolic dysregulation in a PCOS mouse model. These results suggest that manipulation of the gut microbiome may be a potential treatment option for women with PCOS.

physiology↗

bioRxiv2017

ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup

The most commonly mutated genes in pancreatic neuroendocrine tumors (PanNETs) are ATRX, DAXX, and MEN1. Little is known about the cells-of-origin for non-functional neuroendocrine tumors. Here, we genotyped 64 PanNETs for mutations in ATRX, DAXX, and MEN1 and found 37 tumors (58%) carry mutations in these three genes (A-D-M mutant PanNETs) and this correlates with a worse clinical outcome than tumors carrying the wild-type alleles of all three genes (A-D-M WT PanNETs). We performed RNA sequencing and DNA-methylation analysis on 33 randomly selected cases to reveal two distinct subgroups with one group consisting entirely of A-D-M mutant PanNETs. Two biomarkers differentiating A-D-M mutant from A-D-M WT PanNETs were high ARX gene expression and low PDX1 gene expression with PDX1 promoter hyper-methylation in the A-D-M mutant PanNETs. Moreover, A-D-M mutant PanNETs had a gene expression signature related to that of alpha cells (pval < 0.009) of pancreatic islets including increased expression of HNF1A and its transcriptional target genes. This gene expression profile suggests that A-D-M mutant PanNETs originate from or transdifferentiate into a distinct cell type similar to alpha cells.

cancer biology↗