Instituto de Neurociencias

Tissue damage activates immediate responses to restrict further harm and initiate repair. How injury sensing is coupled to regeneration is still not well understood. Here, we study regenerative responses in the adult Drosophila brain, where proliferation is normally strongly restricted. We show that localized brain damage triggers oxidative stress and diverse brain protective programs. We find that ROS generation by the NADPH Oxidase Duox in glial cells is responsible for injury-induced oxidative stress. Both genetic and chemical suppression of ROS in injured brains impairs regeneration. In particular, selective knockdown of calcium-sensitive Duox in glia, which show elevated calcium after injury, reduces injury-induced proliferation. We further provide evidence that diffusing ROS can sustain the activity of pro-regenerative signaling, which is required to stimulate cell divisions. Although oxidative stress is generally considered as harmful in the brain, we uncover here an unanticipated beneficial role of transient ROS release by glia to promote brain repair.

To evaluate clinical outcomes, treatment response and predictors of seizure freedom after vagus nerve stimulation in patients with drug-resistant epilepsy in a Mexican cohort. We conducted a retrospective multicenter cohort across 13 epilepsy centers in Mexico (2003-2024) including patients aged ≥4 years with drug-resistant epilepsy or epileptic encephalopathy. Treatment response was defined as at least 50% seizure reduction and Engel outcomes. Logistic regression identified predictors of seizure freedom. Model performance was assessed with receiver operating characteristic analysis, area under the curve, Hosmer-Lemeshow test, and a confusion matrix. Ninety-three patients (51 children, 42 adults) were included. At 1 year, median monthly seizure frequency decreased by 82.5% (40-7; p < .001). The incidence of status epilepticus declined by 92.8%, acute prolonged seizures by 80.9%, the burden of antiseizure medications by 25%, and epilepsy-related hospitalizations by 100% (all p < .001). Overall, 68.8% achieved ≥50% reduction and 11.8% became seizure-free. On univariate analysis, comorbidities, multiple seizure types, higher baseline seizure frequency, greater number of antiseizure medications, and magnet use were inversely related to seizure freedom, while normal brain MRI showed a direct relationship. On multivariable analysis, only baseline seizure frequency ≥30/month independently predicted seizure freedom (p = .047), corresponding to 97.7% lower odds. A predictive model incorporating comorbidities and number of antiseizure medications improved discrimination (p < .001) with 86.6% sensitivity and 81.8% specificity. Vagus nerve stimulation was associated with substantial seizure frequency reduction, lower morbidity, and less healthcare utilization, with a favorable safety profile. Baseline seizure burden emerged as the key predictor of seizure freedom and may guide patient selection, supporting earlier vagus nerve stimulation consideration in drug-resistant epilepsy.

Radiopharmaceuticals that combine diagnostic and therapeutic isotopes are at the forefront of novel cancer treatments. A crucial element is the method of attaching radioisotopes to biomolecules using chelator-based techniques that are widely used clinically. Selection from available chelators is essential because this choice influences the physicochemical and biological characteristics of the final radiopharmaceutical. Numerous chelators exist because none fulfill all ideal conditions: rapid and complete binding to radiometals at low concentrations and with metallic impurities, high thermodynamic and kinetic stability in vivo, easy bioconjugation, and, key for this work, achieving these for many radiometals from the growing list of medical isotopes. We demonstrate how nanotechnology may change this. Ten nano-radiotracers were synthesized, incorporating radiometals such as 68Ga, 64Cu, 89Zr, 99mTc, 201Tl, 111In, 67Ga, 177Lu, 223Ra, and 225Ac into the nanoparticle core. The versatility of the platform was demonstrated through proof-of-concept experiments, including passive targeting in glioblastoma, active targeting of thrombosis, intratumoral radiotherapy in glioblastoma, and renal clearance optimization. This nanotracer addresses traditional challenges in radiopharmaceutical development, offering a single platform with consistent physicochemical and biological properties regardless of the radioisotope used for robust diagnostic and therapeutic applications.

Asymmetric cell division (ACD) is a fundamental process to balance cell proliferation and differentiation during development and in the adult. Cancer stem cells (CSCs), a very small but highly malignant population within many human tumors, are able to provide differentiated progeny by ACD that contribute to the intratumoral heterogeneity, as well as to proliferate without control by symmetric, self-renewing divisions. Thus, ACD dysregulation in CSCs could trigger cancer progression. Here, we consistently find low expression levels of RAP2A, the human homolog of the Drosophila ACD regulator Rap2l, in glioblastoma (GBM) patient samples, and observe that scarce levels of RAP2A are associated with poor clinical prognosis in GBM. Additionally, we show that restitution of RAP2A in GBM neurosphere cultures increases the ACD of glioblastoma stem cells (GSCs), decreasing their proliferation and expression of stem cell markers. Our results support that ACD failures in GSCs increase their spread and ACD amendment could contribute to reduce the expansion of GBM.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most prevalent genetic kidney disorder. Animal preclinical studies are one of the main tools to study this disease, often through either 2D histology imaging for high-resolution analysis or CT or MRI for full kidney segmentation. As an alternative to these modalities, we propose the use of Light Sheet Fluorescence Microscopy (LSFM) for high-resolution 3D imaging of healthy and ADPKD-induced mouse kidneys, enabling a detailed volumetric morphological analysis of the disease’s effects. In a mouse ADPKD model, ex vivo imaging of the kidneys was performed through LSFM, after which a combination of machine learning and other processing techniques allowed us to perform an in-depth image analysis. This includes the segmentation of key structures, such as the full kidney volume and, within it, its internal cavities, cortex, glomeruli, and cysts, complemented by texture analysis of tubular structures in the cortical area. Pathological kidneys exhibited significant volume enlargement and increased internal cavities due to cystogenesis. While glomerular count remained stable, their spatial distribution was altered, showing increased interglomerular distances and showcasing the deformations produced by the disease. The texture analysis of tubules from the cortex region identified Local Binary Pattern (LBP) uniformity and porosity as key biomarkers of tissue deformation, which could be used as markers to further evaluate the development of the disease. These findings underscore the potential of LSFM imaging as a powerful tool for detailed ADPKD characterization and treatment assessment.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-24473-y.