Biology subjects

Costa, E.

Publications and source records attributed to Costa, E..

11 recordsLinked to original sources

bioRxiv2026

SMARCA4, STK11, and KEAP1 co-inactivation associates with poor prognosis and upregulation of the TGF-β pathway in lung adenocarcinoma

BackgroundLung adenocarcinoma (LUAD) is clinically and molecularly defined by oncogenic driver mutations, identification of which has led to the development of driver-targeted therapies and substantial improvements in prognosis for subsets of LUAD patients. Recent studies assessing clinical outcomes in the context of multigenic alterations have identified secondary mutations that might explain differential responses to targeted therapies, chemotherapies and immunotherapies. Genetic inactivation or loss of SMARCA4, which frequently co-occurs with loss-of-function mutations in STK11 and KEAP1, is especially predictive of poor prognosis and shorter overall survival in LUAD patients, regardless of driver status. We sought to examine the clinical and functional associations of SMARCA4 deficiency in LUAD, with or without co-associated STK11/KEAP1 loss-of-function. MethodsWe examined correlation between SMARCA4 loss, gene expression and prognosis through genomic and transcriptomic profiling of clinically annotated LUAD samples. We generated isogenic cell line models with genetic knockouts of SMARCA4 with or without concomitant STK11 and KEAP1 to profile mutationally-defined genotypes of interest in vitro and in vivo. Lastly, we interrogated the functional dependency of SMARCA4/STK11/KEAP1 triple mutant models on TGF-{beta} signaling to assess its potential as a therapeutic target. ResultsSMARCA4/STK11/KEAP1 triple mutant LUAD is associated with poor survival and high frequency of multisite metastasis. SMARCA4/STK11/KEAP1 triple knockout models showed enhanced migration and invasion in vitro, and diversified organotropism in an in vivo intracardiac xenograft metastasis assay. RNA-Seq and DNaseI-Seq of these in vitro models and clinical samples identified upregulation of TGF-{beta} signaling and EMT gene expression signatures, and corresponding changes in chromatin accessibility, in SMARCA4/STK11/KEAP1 triple mutant LUAD. ConclusionsWe identify SMARCA4/STK11/KEAP1 triple mutant LUAD as a prognostically significant disease subset and nominate TGF-{beta} signaling as a potential therapeutic target.

cancer biology↗

bioRxiv2024

Attention and working memory investigated through the P300 component in children practicing Karate at different stages of biological maturation

AimTo investigate attention and working memory, comparing children practice Karate and non-Karate practitioners at different stages of biological maturation through the amplitude and latency of the P300 component during the execution of a Go/No-Go paradigm. Material and MethodsThe P300 was analyzed for Fz, Cz, and Pz electrodes in 80 participants separated in two groups: an Karate practitioners group comprising Karate practitioners and comprising non-Karate practitioners. Each group was further subdivided according to the biological maturation range defined by Peak Height Velocity. In addition, the participants performed a Go/No-Go paradigm to measure amplitude and latency. ResultsThe EEG analysis showed Ffr electrodes Pz and Cz, an interaction was found between group and Peak Height Velocity for the amplitude variable (respectively: F = 45.858; d = 0.38; p < 0.001 / F = 10.411; d = 0.17; p = 0.004). For the Fz electrode, a main effect was found between group and Peak Height Velocity (respectively: F = 40.330; d = 0.34; p = 0.010 / F = 36.730; d = 0.30; p = 0.012) for the variable amplitude and latency. main effect between group and Peak Height Velocity (respectively: F = 7.719; d = 0.14; p = 0.012 / F = 38.370; d = 0.31; p = 0.010). ConclusionsIn general, it is possible to conclude that participants in the Karate practitioners group exhibited electrocortical measures corresponding to greater efficiency in decision-making and attention processes, motor planning, working memory, attention allocation, motor execution, and greater attentional engagement. It was also demonstrated that, despite the children being at very close chronological ages, their biological maturation differed.

neuroscience↗

bioRxiv2024

Dense, Continuous Membrane Labeling and Expansion Microscopy Visualization of Ultrastructure in Tissues

Lipid membranes are key to the nanoscale compartmentalization of biological systems, but fluorescent visualization of them in intact tissues, with nanoscale precision, is challenging to do with high labeling density. Here, we report ultrastructural membrane expansion microscopy (umExM), which combines a novel membrane label and optimized expansion microscopy protocol, to support dense labeling of membranes in tissues for nanoscale visualization. We validated the high signal-to-background ratio, and uniformity and continuity, of umExM membrane labeling in brain slices, which supported the imaging of membranes and proteins at a resolution of [~]60 nm on a confocal microscope. We demonstrated the utility of umExM for the segmentation and tracing of neuronal processes, such as axons, in mouse brain tissue. Combining umExM with optical fluctuation imaging, or iterating the expansion process, yielded [~]35 nm resolution imaging, pointing towards the potential for electron microscopy resolution visualization of brain membranes on ordinary light microscopes.

bioengineering↗

bioRxiv2023

Mosquitoes do not like bitter: new perspectives for biorational repellents

Chemical repellents play a crucial role in personal protection, serving as essential elements in reducing the transmission of vector-borne diseases. A biorational perspective that extends beyond the olfactory system as the classical target may be a promising direction to move. The taste system provides reliable information regarding food quality, helping animals discriminate between nutritious and potentially harmful food sources, often associated with a bitter taste. Understanding how bitter compounds affect feeding in blood-sucking insects could unveil novel molecules with the potential to reduce biting and feeding. Here, we investigated the impact of two naturally occurring bitter compounds, caffeine and quinine, on the feeding decisions in female Aedes aegypti mosquitoes at two distinctive phases: (1) when the mosquito explores the biting substrate using external taste sensors and (2) when the mosquito takes a sip of food and tastes it using internal taste receptors. We assessed the aversiveness of bitter compounds through both an artificial feeding condition (artificial feeder test) and a real host (arm-in-cage test). Our findings revealed different sensitivities in the external and internal sensory pathways responsible for detecting bitter taste in Ae. aegypti. Internal detectors exhibited responsiveness to lower doses compared to the external sensors. Quinine exerted a more pronounced negative impact on biting and feeding activity than caffeine. The implications of our findings are discussed in the context of mosquito food recognition and the potential practical implications for personal protection.

zoology↗

bioRxiv2023

Decrease in reaction time for volleyball athletes during saccadic eye movement task: An associative analysis with evoked potentials

AimThe current study investigated the differences to event-related potential and reaction time under two groups (athletes vs. non-athletes). Material and MethodsThe P300 was analyzed for Fz, Cz and Pz electrodes in thirty-one healthy volunteers divided into two groups (volleyball athletes and non-athletes). In addition, the participants performed a saccadic eye movement task to measure reaction time. ResultsThe EEG analysis showed that the athletes in comparison to the no-athletes has differences of the P300 in the frontal area (p=0.021). In relation to reaction time, the results show lower reaction time for athletes (p=0.001). ConclusionsThe volleyball athletes may present a greater allocation of attention during the execution of the inhibition task, since they have a lower reaction time for responses when compared to non-athletes.

neuroscience↗

bioRxiv2022

Global Protein-Turnover Quantification in Escherichia coli Reveals Cytoplasmic Recycling under Nitrogen-Limitation

Protein turnover is critical for proteostasis, but turnover quantification is challenging, and even in well-studied E. coli, proteome-wide measurements remain scarce. Here, we quantify the degradation rates of [~]3.2k E. coli proteins under 12 conditions by combining heavy isotope labeling with complement reporter ion quantification and find that cytoplasmic proteins are recycled when nitrogen is limited. We use knockout experiments to assign substrates to the known cytoplasmic ATP-dependent proteases. Surprisingly, none of these proteases are responsible for the observed cytoplasmic protein degradation in nitrogen limitation, suggesting that a major proteolysis pathway in E. coli remains to be discovered. Lastly, we show that protein degradation rates are generally independent of cell division rates. Thus, we introduce broadly applicable technology for protein turnover measurements and provide a rich resource for protein half-lives and protease substrates in E. coli, complementary to genomics data, that will allow researchers to decipher the control of proteostasis.

systems biology↗

bioRxiv2021

Improving behavior monitoring of free moving dairy cows using noninvasive wireless EEG approach and digital signal processing techniques.

BackgroundElectroencephalography (EEG) is the most common method to access brain information. Techniques to monitor and to extract brain signal characteristics in farm animals are not as developed as in humans and laboratory animals. New methodThe method comprised two steps. In the first step, the signals were acquired after the telemetric equipment was developed, the electrodes were positioned and fixed, the sample frequency was defined, the equipment was positioned, and artifacts and other acquisition problems were dealt with. Brain signals from six Holstein heifers that could move freely in free stalls were acquired. The control group consisted in the same number of bovines, contained in a climatic chamber (restrained group). In the second step, the signals were characterized by Power Spectral Density, Short-Time Fourier Transform, and Lempel-Ziv complexity. ResultsThe results indicated that there was an ideal position to attach the electrodes to the front of the bovines head, so that longer artifact-free signal sections were acquired. The signals showed typical EEG frequency bands, like the bands found in humans. The Lempel-Ziv complexity values indicated that the bovine brain signals contained random and chaotic components. As expected, the signals acquired from the retained bovine group displayed sections with a larger number of artifacts. Comparison with existing methodsWe present the first method that helps to monitor and to extract brain signal features in unrestrained bovines. ConclusionsThe method could be applied to investigate changes in brain electrical activity during animal farming, to monitor brain activity related with animal behavior. HighlightsO_LIA method that allows brain signals to be monitored in freely moving dairy cows is described C_LIO_LIThe method uses noninvasive electrodes to minimize stress during EEG monitoring and allows bovines to behave normally during the process C_LIO_LIThe method establishes the frequency sampling rate, electrodes positioning and fixation, equipment holding, artifact extraction, and signal characterization C_LIO_LIThe brain signals are characterized by PSD, STFT, and Lempel-Ziv normalized complexity C_LIO_LIThe method can be applied to relate EEG to animal behavior under normal handling conditions C_LI

animal behavior and cognition↗

bioRxiv2021

Differential nuclear import sets the timing of protein access to the embryonic genome

The development of a fertilized egg to an embryo requires the proper temporal control of gene expression1-6. During cell differentiation, timing is often controlled via cascades of transcription factors (TFs)7,8. However, in early development, transcription is often inactive, and many TF levels are constant, suggesting that unknown mechanisms govern the observed rapid and ordered onset of gene expression9. Here, we find that in early embryonic development, access of maternally deposited nuclear proteins to the genome is temporally ordered via importin affinities, thereby timing the expression of downstream targets. We quantify changes in the nuclear proteome during early development and find that nuclear proteins, such as TFs and RNA polymerases, enter nuclei sequentially. Moreover, we find that the timing of the access of nuclear proteins to the genome corresponds to the timing of downstream gene activation. We show that the affinity of proteins to importin is a major determinant in the timing of protein entry into embryonic nuclei. Thus, we propose a mechanism by which embryos encode the timing of gene expression in early development via biochemical affinities. This process could be critical for embryos to organize themselves before deploying the regulatory cascades that control cell identities. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=196 HEIGHT=200 SRC="FIGDIR/small/464816v1_ufig1.gif" ALT="Figure 1"> View larger version (85K): org.highwire.dtl.DTLVardef@1e9438org.highwire.dtl.DTLVardef@1950f92org.highwire.dtl.DTLVardef@131716corg.highwire.dtl.DTLVardef@10d6d24_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2021

Decellularized Normal and Tumor Scaffolds for Cancer Organoid Cultures as a Model of Colorectal Peritoneal Metastases

Peritoneal metastases (PM) from colorectal cancer (CRC) are associated with poor survival. The extracellular matrix (ECM) plays a fundamental role in modulating the homing of CRC metastases to the peritoneum. The mechanisms underlying the interactions between metastatic cells and the ECM, however, remain poorly understood and the number of in vitro models available for the study of the peritoneal metastatic process is limited. Here, we show that decellularized ECM of the peritoneal cavity allows the growth of organoids obtained from PM, favoring the development of three-dimensional nodules that maintain the characteristics of in vivo PM. Organoids preferentially grow on scaffolds obtained from neoplastic peritoneum, which are characterized by greater stiffness than normal scaffolds. A gene expression analysis of organoids grown on different substrates reflected faithfully the clinical and biological characteristics of the organoids. An impact of the ECM on the response to standard chemotherapy treatment for PM was also observed. SignificanceEvidence of the value of ex vivo 3D models obtained by combining patient-derived extracellular matrices depleted of cellular components and organoids to mimic the metastatic niche, to be used as a tool to develop new therapeutic strategies in a biologically relevant context, to personalize treatments and increase their efficacy.

cancer biology↗

bioRxiv2019

In-Depth Characterization and Validation in BRG1-Mutant Lung Cancers Define Novel Catalytic Inhibitors of SWI/SNF Chromatin Remodeling

Members of the ATP-dependent SWI/SNF chromatin remodeling complexes are among the most frequently mutated genes in cancer, suggesting their dysregulation plays a critical role. The synthetic lethality between SWI/SNF catalytic subunits BRM/SMARCA2 and BRG1/SMARCA4 has instigated great interest in targeting BRM. Here we have performed a critical and in-depth investigation of novel dual inhibitors (BRM011 and BRM014) of BRM and BRG1 in order to validate their utility as chemical probes of SWI/SNF catalytic function, while obtaining insights into the therapeutic potential of SWI/SNF inhibition. In corroboration of on-target activity, we discovered compound resistant mutations through pooled screening of BRM variants in BRG1-mut cancer cells. Strikingly, genome-wide transcriptional and chromatin profiling (ATAC-Seq) provided further evidence of pharmacological perturbation of SWI/SNF chromatin remodeling as BRM011 treatment induced specific changes in chromatin accessibility and gene expression similar to genetic depletion of BRM. Finally, these compounds have the capacity to inhibit the growth of tumor-xenografts, yielding important insights into the feasibility of developing BRM/BRG1 ATPase inhibitors for the treatment of BRG1-mut lung cancers. Overall, our studies not only establish the feasibility of inhibiting SWI/SNF catalytic function, providing a framework for SWI/SNF therapeutic targeting, but have also yielded successful elucidation of small-molecule inhibitors that will be of importance in probing SWI/SNF function in various disease contexts.

cancer biology↗

bioRxiv2019

Population imaging of neural activity in awake behaving mice in multiple brain regions

A longstanding goal in neuroscience has been to image membrane voltage, with high temporal precision and sensitivity, in awake behaving mammals. Here, we report a genetically encoded voltage indicator, SomArchon, which exhibits millisecond response times and compatibility with optogenetic control, and which increases the sensitivity, signal-to-noise ratio, and number of neurons observable, by manyfold over previous reagents. SomArchon only requires conventional one-photon microscopy to achieve these high performance characteristics. These improvements enable population analysis of neural activity, both at the subthreshold and spiking levels, in multiple brain regions - cortex, hippocampus, and striatum - of awake behaving mice. Using SomArchon, we detect both positive and negative responses of striatal neurons during movement, highlighting the power of voltage imaging to reveal bidirectional modulation. We also examine how the intracellular subthreshold theta oscillations of hippocampal neurons govern spike output, finding that nearby cells can exhibit highly correlated subthreshold activities, even as they generate highly divergent spiking patterns.

neuroscience↗