Biology subjects

Varela, N.

Publications and source records attributed to Varela, N..

5 recordsLinked to original sources

bioRxiv2024

Systemic autoimmune disease patients' blood immunome reveals specificities and commonalities among different diagnostic entities

1BackgroundSystemic autoimmune diseases (SADs) are characterized by internal heterogeneity, overlapping clinical symptoms, and shared molecular pathways. Therefore, they are difficult to diagnose and new tools allowing precise diagnosis are needed. Molecular-based reclassification studies enable to find patterns in a diagnosis-independent way. ObjectiveTo evaluate the possibility of using high-content immunophenotyping for detecting patient subgroups in the context of precise treatment. MethodsWhole blood high-content immunophenotyping of 101 patients with 7 systemic autoimmune diseases and 22 controls was performed using 36-plex mass cytometry panel. Patients were compared across diagnostic entities and re-classified using Monte Carlo reference-based consensus clustering. Levels of 45-plex multiplexed cytokine were measured and used for cluster characterization. ResultsDifferential analysis by diagnosis did not reveal any disease-specific pattern in the cellular compositions and phenotypes but rather their relative similarities. Accordingly, patients were classified into phenotypically distinct groups composed of different diagnostic entities sharing common immunophenotypes and cytokine signatures. These features were mainly based on granulocyte activation and CD38 expression in discrete lymphocyte populations and were related to Th17 or IFN-dependent cytokines. ConclusionsOur data indicate that specific individuals could potentially benefit from the same line of treatment independently of their diagnosis and emphasize the possibility of using immunophenotyping as a stratification tool in precision rheumatology. 2 Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=84 SRC="FIGDIR/small/594621v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1098351org.highwire.dtl.DTLVardef@18c45a1org.highwire.dtl.DTLVardef@2f5f42org.highwire.dtl.DTLVardef@170e28_HPS_FORMAT_FIGEXP M_FIG C_FIG Key messagesO_LIWhole blood immmunophenotyping could be used to stratify systemic autoimmune patients, thus it is a useful tool in precision medicine. C_LIO_LIPatients groups could benefit from the same line of treatment. C_LI

immunology↗

bioRxiv2023

A competitive disinhibitory network for robust optic flow processing in Drosophila

Many animals rely on optic flow for navigation, using differences in eye image velocity to detect deviations from their intended direction of travel. However, asymmetries in image velocity between the eyes are often overshadowed by strong, symmetric translational optic flow during navigation. Yet, the brain efficiently extracts these asymmetries for course control. While optic flow sensitive-neurons have been found in many animal species, far less is known about the postsynaptic circuits that support such robust optic flow processing. In the fly Drosophila melanogaster, a group of neurons called the horizontal system (HS) are involved in course control during high-speed translation. To understand how HS cells facilitate robust optic flow processing, we identified central networks that connect to HS cells using full brain electron microscopy datasets. These networks comprise three layers: convergent inputs from different, optic flow-sensitive cells, a middle layer with reciprocal, and lateral inhibitory interactions among different interneuron classes, and divergent output projecting to both the ventral nerve cord (equivalent to the vertebrate spinal cord), and to deeper regions of the fly brain. By combining two-photon optical imaging to monitor free calcium dynamics, manipulating GABA receptors and modeling, we found that lateral disinhibition between brain hemispheres enhance the selectivity to rotational visual flow at the output layer of the network. Moreover, asymmetric manipulations of interneurons and their descending outputs induce drifts during high-speed walking, confirming their contribution to steering control. Together, these findings highlight the importance of competitive disinhibition as a critical circuit mechanism for robust processing of optic flow, which likely influences course control and heading perception, both critical functions supporting navigation.

neuroscience↗

bioRxiv2020

Metastatic signaling of hypoxia-related genes across TCGA Pan-Cancer types

Many primary-tumor subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis. Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Here we focused on elucidating the molecular hallmarks of tumor hypoxia that remains poorly defined. To fill this gap, we analyzed the genomic alterations and hypoxia score of 233 hypoxia-related genes of 6,343 individuals across 17 TCGA Pan-Cancer types. In addition, we analyzed a protein-protein interactome (PPi) network and the shortest paths from hypoxic proteins to metastasis. As results, mRNA high alteration was prevalent in all cancer types. Genomic alterations and hypoxia score presented a highest frequency in tumor stage 4 and positive metastasis status in all cancer types. The most significant signaling pathways were HIF-1, ErbB, PI3K-Akt, FoxO, mTOR, Ras and VEGF. The PPi network revealed a strong association among hypoxic proteins, cancer driver proteins and metastasis driver proteins. The analysis of shortest paths revealed 99 ways to spread metastasis signaling from hypoxic proteins. Additionally, we proposed 62 hypoxic genes strongly associated with metastasis and 27 of them with high amount of genomic alterations. Overall, tumor hypoxia may drive aggressive molecular features across cancer types. Hence, we identified potential biomarkers and therapeutic targets regulated by hypoxia that could be incorporated into strategies aimed at improving novel drug development and treating metastasis.

cancer biology↗

bioRxiv2019

Motor context coordinates visually guided walking in Drosophila

Course control is critical for the acquisition of spatial information during exploration and navigation, and it is thought to rely on neural circuits that process locomotive-related multimodal signals. However, which circuits underlie this control, and how multimodal information contributes to the control system are questions poorly understood. We used Virtual Reality to examine the role of self-generated visual signals (visual feedback) on the control of exploratory walking in flies. Exploratory flies display two distinct motor contexts, characterized by low speed and fast rotations, or by high speed and slow rotations, respectively. Flies use visual feedback to control body rotations, but in a motor-context specific manner, primarily when walking at high speed. Different populations of visual motion-sensitive cells estimate body rotations via congruent, multimodal inputs, and drive compensatory rotations. However, their effective contribution to course control is dynamically tuned by a speed-related signal. Our data identifies visual networks with a multimodal circuit mechanism for adaptive course control and suggests models for how visual feedback is combined with internal signals to guide exploratory course control.

neuroscience↗

bioRxiv2018

Avoidance response to CO2 in the lateral horn

In flies, the olfactory information is carried from the first relay in the brain, the antennal lobe, to the mushroom body (MB) and the lateral horn (LH). Olfactory associations are formed in the MB. The LH was ascribed a role in innate responses based on the stereotyped connectivity with the antennal lobe, stereotyped physiological responses to odors and MB silencing experiments. Direct evidence for the functional role of the LH is still missing. Here we investigate the behavioral role of the LH neurons directly, using the CO2 response as a paradigm. Our results show the involvement of the LH in innate responses. Specifically, we demonstrate that activity in two sets of neurons is required for the full behavioral response to CO2. Using calcium imaging we observe that the two sets of neurons respond to CO2 in different manners. Using independent manipulation and recording of the two sets of neurons we find that the one that projects to the SIP also outputs to the local neurons within the LH. The design of simultaneous output at the LH and the SIP, an output of the MB, allows for coordination between innate and learned responses.

neuroscience↗