Biology subjects

Gomez, C.

Publications and source records attributed to Gomez, C..

At least 19 recordsLinked to original sources

bioRxiv2026

Concomitant ablation of SOS1 and SOS2 triggers a lethal phenotype involving compromised intestinal integrity and widespread septicemia

The RAS guanine nucleotide exchange factors Son of Sevenless 1 and 2 (SOS1 and SOS2) are key regulators of RAS signaling pathways controlling cellular proliferation, differentiation, and survival processes that are essential for correct tissue homeostasis. While mice lacking both SOS1 and SOS2 die precipitously, we demonstrate herein that the combined genetic ablation of SOS1 and SOS2 triggers spontaneous, gut-derived, lethal bacteremia. Double-knockout (DKO) SOS1/2 mice exhibit extensive intestinal tissue damage, massive bacterial leakage out of the gut, and rapid progression to multi-organ failure and death. At the cellular level, loss of both SOS1 and SOS2 leads to profound immune cell depletion and a marked reduction in intestinal stem cell abundance and proliferative capacity, which is accompanied by severe disruption of intestinal architecture and increased epithelial permeability, indicating a breakdown of gut barrier integrity. Notably, therapeutic interventions aimed at enhancing cellular stemness significantly improve survival in SOS1/2 DKO mice, restoring intestinal proliferation and tissue organization. Collectively, our findings identify SOS1 and SOS2 as critical regulators of intestinal homeostasis and regenerative capacity during systemic infection and reveal stemness reinforcement as a potential strategy to overcome lethal susceptibility to sepsis.

cell biology↗

bioRxiv2026

Chemical Probing of Diacylglycerol Dynamics at Lipid Droplets

Diacylglycerols (DAGs) are central intermediates in lipid metabolism and signaling, yet their trafficking and persistence within lipid droplets (LDs) remain incompletely understood due to the lack of chemically stable, DAG-mimetic imaging tools. Here, we report the development of a family of solvatochromic fluorescent lipid analogs, termed DONDI, designed to probe DAG-associated dynamics at LDs. These probes are based on a 1,8-naphthalimide scaffold conjugated to modified aminoglycerol backbones bearing oleoyl chains to mimic native glycerolipids. Biophysical characterization and atomistic molecular dynamics simulations revealed probe-specific membrane insertion and hydrogen-bonding behaviors consistent with distinct lipid-mimetic properties. Live-cell imaging in NIH 3T3 fibroblasts demonstrated that DONDI probes were efficiently internalized and selectively accumulated within lipid droplets. Structure-function analysis identified DONDI-5 as the closest mimic of 1,2-diacylglycerol, displaying rapid uptake, strong LD enrichment, and prolonged intracellular retention without detectable relocalization to other cellular membranes. These properties enabled sustained visualization of LD-associated DAG pools over extended time scales. Collectively, this work establishes DONDI-5 as a chemically stable DAG-mimetic probe and provides direct experimental support that DAGs can be transported to and transiently stored within lipid droplets without prior conversion to triacylglycerols.

biochemistry↗

bioRxiv2026

Estimating Gait Kinematics from Muscle Activity Using Deep Learning in Typically Developing Children

Instrumented gait assessment in pediatric populations is often constrained by the complexity and lack of portability of traditional motion capture systems. In this article, we propose a deep learning approach utilizing a one-dimensional (1D) U-Net architecture to accurately estimate ankle and knee joint angles in the sagittal plane from surface electromyography (sEMG) signals. We analyzed data from the tibialis anterior and medial gastrocnemius of 25 typically developing children (ages 4-16) to evaluate the models performance and the influence of age-related gait maturation. The proposed 1D U-Net achieved high predictive accuracy for the ankle joint (RMSE: 3.6{degrees}) and the knee joint (RMSE: 4.1{circ}). Experimental results demonstrated that incorporating the toe-off event as a temporal marker significantly enhanced prediction stability during transitional gait phases. Furthermore, Statistical Parametric Mapping (SPM) was employed to identify systematic errors, which were primarily localized during initial contact and pre-swing but remained below clinically relevant thresholds. The findings reveal that prediction accuracy increases with age, reflecting more stable neuromotor patterns. This study demonstrates that a 1D U-Net can reliably decode lower-limb kinematics from sEMG alone, enabling the development of simplified, non-invasive, and portable pediatric gait assessment tools that can be integrated into the control strategies of assistive devices.

bioengineering↗

bioRxiv2026

Neurophysiological excitation/inhibition imbalance in young adults burdened with childhood interpersonal trauma

Adverse childhood experiences, such as violence, abuse, and neglect, are increasingly recognized as significant modifiers of brain development. Here, we tested whether adults with histories of childhood trauma, but without psychiatric comorbidities exhibit altered excitation/inhibition (E/I) balance, as indicated by electroencephalography (EEG) signatures. Participants, divided into low- trauma and high-trauma groups, underwent two experimental conditions: eyes-closed resting-state recording and a reaction-time task with visual stimuli. From these data, we computed 1/f spectral slopes, a widely used electrophysiological marker of E/I balance; we complemented these analyses with a leaky integrate-and-fire (LIF) microcircuit model combined with a biophysically grounded forward-modeling approach to simulate realistic brain signals and derive E/I balance estimates. Group comparisons for both slopes and E/I estimates revealed significant resting-state differences, characterized by a shift toward increased neuronal excitation in the high-trauma group. The high- trauma group exhibited altered stimulus-related 1/f slope dynamics relative to the pre-stimulus baseline, reflecting attenuated neuronal inhibition. E/I ratio measures were not significantly correlated with participants transient affective states. Together, these findings suggest that childhood trauma is associated with enduring, trait-like alterations in cortical E/I balance that extend beyond affective state and manifest across both resting and task-related brain dynamics. Significance StatementChildhood trauma is a major risk factor for mental illness, yet its lasting effects on basic brain physiology remain poorly understood. Using electroencephalography combined with biophysically grounded neural circuit modeling, we show that young adults with a history of childhood interpersonal trauma exhibit a persistent shift toward cortical hyperexcitation at rest and a reduced ability to engage inhibitory control during cognitive processing. These effects occur even in individuals without psychiatric diagnoses and are independent of current anxiety or depression, indicating a trait-like neurophysiological footprint of early adversity. This excitation-inhibition imbalance may represent a transdiagnostic vulnerability linking childhood trauma to later psychopathology.

neuroscience↗

bioRxiv2025

Glycolysis and hexosamine biosynthesis pathways are key for inflammatory protein maturation and leukocyte adhesion to human aortic valve cells

Inflammation and metabolism reprogramming are hallmarks of calcific aortic valve disease (CAVD). Recent studies link inflammation to hyperglycolysis and calcification in valve interstitial cells (VICs). The metabolism of valve endothelial cells (VECs) has received less attention despite both resident valve cells are exposed to alike inflammatory clues involved in the biosynthesis of pathologically relevant glycoproteins during the early stages of CAVD. On this basis, we investigated the outcomes of glucose metabolism rewiring on glycoprotein maturation and immune cell adhesion in human resident valve cells. Real-time metabolic analysis revealed that basal VECs are more glycolytic than VICs. Also, VECs and VICs exposed to inflammatory stimuli exhibited a distinct rewiring, with VECs shifting to a more energetic metabolism, despite a similar upregulation of glycolytic genes. Blunting glucose metabolism in VICs and VECs inhibited inflammatory routes canonically associated with glycolysis, and the expression of proteins associated to the inflammatory response like interleukin-6 and cyclooxigenase-2. Moreover, Western blot and adhesion assays revealed that glycolysis is necessary for the expression and post-translational modifications of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, and the ensuing process of monocyte-VECs adhesion. Notably, inhibition of the hexosamine biosynthetic pathway using DON and of N-glycosylation by tunicamycin, further disrupted adhesion molecule maturation and monocyte-VECs adhesion. In conclusion, glycolysis and its side-branch route the hexosamine biosynthesis pathway are necessary for nutrient-driven post-translational modifications of inflammatory proteins in inflamed valve cells and the subsequent process of monocyte-VECs adhesion that plays a key role in the initial stages of CAVD pathogenesis. NEW & NOTEWORTHYThe study uncovers a relevant role of glycolysis and its side-branch route the hexosamine biosynthesis pathway in sugar-driven post-translational modifications that are critical for the proper function of leukocyte adhesion molecules and other relevant proinflammatory molecules in aortic valve cells. These events are essential for the recruitment of cells of the monocytic lineage to aortic valve leaflets in the initial stages of calcific aortic valve disease. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=166 SRC="FIGDIR/small/693904v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@1211b22org.highwire.dtl.DTLVardef@7c5df7org.highwire.dtl.DTLVardef@fd0da2org.highwire.dtl.DTLVardef@18a40a1_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

Restoring signatures of consciousness by thalamic stimulation in a whole-brain model of an anesthetized nonhuman primate

Treatment options for Disorders of Consciousness (DoC) are limited due to insufficient understanding of the underlying neurobiological mechanisms. Two primary strategies for characterizing DoC and assessing treatment efficacy are in vivo experiments with animal models, and in silico computational models. We combined both approaches by creating a whole-brain model tailored to the experimental functional magnetic resonance imaging (fMRI) data of a single anesthetized macaque. It was previously reported in an in vivo experiment that anesthesia-induced loss of consciousness was partially reversed by specific electrical stimulation of the thalamic central nuclei. The in silico model reproduced the brain dynamics underlying the restoration of consciousness, providing a potential explanation for the transition between these brain states as continuous trajectories unfolding in a low-dimensional space. Our results demonstrate that whole-brain computational models reproduce the spatiotemporal properties of fMRI recordings during loss of consciousness and during its recovery induced by electrical stimulation, enabling computational exploration of perturbation-based interventions to potentially personalize treatment and aid recovery of consciousness in DoC patients.

neuroscience↗

bioRxiv2025

Targeting SOS1 synergistically enhances efficacy of BCR/ABL tyrosine kinase inhibitors and overcomes resistance in chronic myeloid leukemia

ABSTRACTDisease persistence and therapeutic resistance remain a significant challenge in chronic myelogenous leukemia (CML). Here, we evaluated the therapeutic impact of SOS1 inhibition by its specific pharmacological inhibitor BI-3406 as single-agent or in combination with BCR/ABL tyrosine kinase inhibitors (TKI) like imatinib in preclinical models of CML including p210BCR/ABL mice, human CML cell lines, and patient-derived bone marrow cells. In p210BCR/ABL mice, treatment with BI-3406 or imatinib was well-tolerated in vivo after single or combined use of the drugs. Treatment with imatinib alone significantly improved survival and corrected various hematological parameters of disease burden, while the combination with BI-3406 therapy yielded even more pronounced benefits, including a substantial increase in median survival, marked reductions in peripheral white blood cell and neutrophil counts, and a notable decrease in leukemia stem cells within the bone marrow. Additionally, the combination led to further spleen size reduction and restoration of normal splenic architecture. Human CML cell lines and primary cells from CML patients subjected to combined treatment with BI-3406 and imatinib or later-generation TKI drugs showed significantly reduced proliferation and enhanced apoptosis as compared to single-agent-treated cultures, revealing a strong synergistic therapeutic behavior of the BI-3406 +TKI combinations. Remarkably, the combined treatments including BI-3406 significantly restored imatinib sensitivity in CML patient cells harboring imatinib-resistant mutations. Cellular signaling and transcriptomics profiling suggested coordinated attenuation of RAS and RAC downstream signals as a mechanistic basis for the observed therapeutic responses. Our findings highlight the synergistic therapeutic behavior of BI-3406 and underscore the benefit of SOS1 pharmacological targeting as a novel strategy enhancing efficacy and overcoming resistance to TKIs in CML.

cancer biology↗

bioRxiv2025

Alterations in glucocorticoid homeostasis following sleeve gastrectomy

Elevated intra-tissue levels of active glucocorticoids in obese patients are associated with insulin resistance, diabetes, impaired immune regulation, and other adverse effects. Sleeve gastrectomy (SG) induces significant weight loss and improves metabolic outcomes, including insulin resistance and hyperlipidemia. Among the enzymes controlling intracellular concentrations of active glucocorticoids, 11{beta}-hydroxysteroid dehydrogenase type 1 (HSD11B1, SDR26C1) has been extensively studied concerning obesity and post-gastric surgery interventions. However, most studies focused on either a single tissue, circulating glucocorticoid levels, or HSD11B1 activity. In this work, we showed that circulating active/inactive glucocorticoid ratio (corticosterone (B)/11-dehydrocorticosterone (A)) negatively correlated with glucose tolerance; SG in male C57BL/6 mice slightly reduced circulating mineralocorticoids and reversed the elevated ratio of B/A seen in sham-operated mice after high-fat diet, while improving glucose tolerance. This change was likely due to increased renal 11{beta}-hydroxysteroid dehydrogenase type 2 (HSD11B2, SDR9C3) activity after SG. To provide a comprehensive overview of the systemic effects post-surgery, we evaluated enzymes involved in glucocorticoid homeostasis across tissues on mRNA, protein, and activity level. Moreover, mRNA expression of transcription factors CCAAT enhancer binding protein alpha (Cebpa), Cebpb and nuclear factor kappa b (Nf{kappa}b (p50)), as well as cytokines influencing Hsd11b1 and Hsd11b2 gene expression were analyzed. The results emphasize stronger influence of renal HSD11B2 than hepatic HSD11B1 activity on the circulating B/A ratio, supported by intrarenal and intrahepatic B/A ratios. The improved glucocorticoid homeostasis following SG, indicated by decreased B/A ratios, proposes a lower risk for glucocorticoid-mediated adverse health effects, including chronic kidney disease, hypertension, and metabolic disturbances. NEW & NOTEWORTHYThis study revealed improved glucocorticoid homeostasis after sleeve gastrectomy (SG), with lower circulating ratios of active (corticosterone, B)/inactive (11-dehydrocorticosterone, A) glucocorticoids and a better glucose tolerance compared to Sham mice. SG enhanced renal HSD11B2 activity, while hepatic HSD11B1 oxoreductase activity was unchanged. These findings suggest that SG reverses some adverse metabolic effects of high-fat diet by enhancing renal HSD11B2 activity, potentially lowering the risk of chronic kidney disease, hypertension, and metabolic disease.

physiology↗

bioRxiv2025

Comparative proteomic analysis of the ECM composition of the human omentum and mesentery, the main sites of ovarian cancer metastasis

Due to its limited symptoms, high-grade serous ovarian cancer (HGSOC) has frequently metastasized extensively throughout the peritoneal cavity prior to its diagnosis, resulting in an overall five-year survival rate of less than 50%. The greater omentum and the small bowel mesentery are two of the most common metastatic sites in advanced HGSOC. However, the mechanisms underlying HGSOC metastatic tropism remain unknown. The extracellular matrix is a complex and dynamic meshwork of proteins that provides biochemical and mechanical signals to surrounding cells and has been shown to drive the dissemination of several cancer types to preferential distant sites. Here, using histological assessment and proteomics, we examined the composition of the extracellular matrix of paired omentum and mesentery samples from disease-free adult females. We found that the fibrillar collagen content of the mesothelial layer of the omentum was significantly higher than that of the mesentery. Using ECM-focused proteomics, we further defined the ECM composition - or matrisome - of these two tissues. We found that over 90% of the proteins detected were shared between the omentum and mesentery. Our analysis also revealed small subsets of tissue-specific ECM proteins. Future work will aim to test the possible functional contributions of these ECM proteins to HGSOC metastatic tropism. To facilitate the reuse of our dataset, we have deposited the raw mass spectrometry data and accompanying metadata files to the ProteomeXchange Consortium with the dataset identifier PXD061586.

cancer biology↗

bioRxiv2024

Surviving Medical School During a Pandemic: Experiences of New York Medical Students During the Height of SARS-CoV-2

BackgroundThe COVID-19 pandemic dramatically altered the landscape of medical education. While patients overwhelmed hospital systems, lockdowns and social distancing recommendations took priority, and medical education was pushed online. Early in 2020, New York State (NYS) was hit especially hard by COVID-19. ObjectiveThis study sought to understand the effect of the COVID-19 pandemic on medical students well-being and education. MethodsNYS medical students responded to a six-question survey during April and May 2020. Questions assessed self-reported changes in stress levels, academic performance, and board preparation efforts. Open-ended data was analyzed using a modified grounded theory approach. Results488 responses across 11 medical schools were included (response rate of 5.8%). Major themes included: standardized test-related stressors (23%), study-related changes (19%), education and training concerns (17%), financial stressors (12%), and additional family obligations (12%). Second year students reported more stress/anxiety than students in other years (95.9%, p-value< 0.00001). Reported stress/anxiety, effects on exam preparation, and anticipated academic effect varied by geographics. ConclusionsWhile all NYS medical students reported being greatly affected, those closest to the NY City pandemic epi-center and closest to taking the Step 1 exam were the most distressed. Lack of flexibility of the medical education system during this public health emergency contributed to worsened student well-being. It is time to make plans for supporting the long-term mental health needs of these physicians-in-training and to examine ways the academic medical community can better adapt to the needs of students affected by a large public health emergency in the future.

scientific communication and education↗

bioRxiv2024

CDK4 and CDK6 upregulation promotes DNA replication stress, genomic instability and resistance to EGFR targeted therapy in lung cancer

Epidermal growth factor receptor (EGFR) mutant lung adenocarcinomas (LUAD) harbor a complex landscape of genetic co-alterations and potential oncogenic interactions. Among them are recurrent amplifications of the cell cycle regulatory genes CDK4 and CDK6, which have been clinically implicated in resistance to EGFR tyrosine kinase inhibitors (TKIs). However, the mechanisms by which CDK4/6 upregulation promotes therapy resistance remain poorly defined. Here, we demonstrate that CDK4 or CDK6 overexpression limits EGFR inhibitor-induced proliferative arrest, promoting continued cell cycle progression. This is accompanied by elevated replication stress, increased TPX2 expression, DNA damage leading to ATM activation, and ultimately genomic instability. Integrative transcriptomic and copy number analyses of EGFR-mutant LUAD tumors from both patients and preclinical models revealed that CDK4 or CDK6 amplification is associated with the upregulation of genes linked to tumor progression, including AGR2, ASNS, and STEAP1. CDK4 amplification was also highly correlated with gene expression changes associated with epithelial-to-mesenchymal transition (EMT) in a single-cell RNA sequencing dataset from patient biopsies. In preclinical models, co-treatment with CDK4/6 and EGFR inhibitors restored proliferative arrest, induced tumor cell apoptosis, and reduced replication stress, DNA damage, and genomic instability. Our findings uncover a mechanistic basis for EGFR inhibitor resistance of CDK4 and CDK6 amplified EGFR-mutant LUAD. They also provide a rationale for the biomarker-driven clinical development of combination EGFR and CDK4/6-targeted therapies for the treatment of a subset of EGFR-mutant LUAD patients.

cancer biology↗

bioRxiv2024

Changes in bird migration phenology over one century: a perspective from the Neotropical non-breeding grounds

Changes in the migration phenology of birds linked to global change are extensively documented. Longitudinal studies from temperate breeding grounds have mostly shown earlier arrivals in the spring and a variety of patterns during fall migration 1,2, yet no studies have addressed whether and how migration phenology has changed using data from the tropical non-breeding grounds. Understanding whether changes in migratory phenology are also evident in non-breeding sites is essential to determine the underlying causes of patterns documented in breeding areas. Using data from historical scientific collections and modern repositories of community-science records, we assessed changes in migration phenology of 12 Nearctic-Neotropical long-distance migratory birds in Colombia over six decades. We also explored whether shared breeding and non-breeding climatic niches explained variation in phenological patterns observed among species. All species showed shifts in spring (range -37 - 9 days from peak passage date) or fall (range -26 - 36 days) migration, but patterns differed among species in ways partly attributable to shared breeding or wintering climatic niches. Our results, although not yet broadly generalizable, suggest that birds use cues to time their migration at their non-breeding grounds which are most likely different to those they use on their breeding grounds. To better understand the effects of global change on biodiversity, exploring the underlying drivers of phenological changes with further research integrating more long-term datasets available through scientific collections and community science platforms should be a priority.

ecology↗

bioRxiv2023

Low-usage splice junctions underpin immune-mediated disease risk

The majority of immune-mediated disease (IMD) risk loci are located in non-coding regions of the genome, making it difficult to decipher their functional effects. To assess the extent to which alternative splicing contributes to IMD risk, we mapped genetic variants associated with alternative splicing (splicing quantitative trait loci or sQTL) in macrophages exposed to 24 cellular conditions. We found that genes involved in innate immune response pathways undergo extensive differential splicing in response to stimulation and detected significant sQTL effects for 5,734 genes across all conditions. We colocalised sQTL signals for over 700 genes with IMD-associated risk loci from 21 IMDs with high confidence (PP4 [≥] 0.75). Approximately half of the colocalisations implicate lowly-used splice junctions (mean usage ratio < 0.1). Finally, we demonstrate how an inflammatory bowel disease (IBD) risk allele increases the usage of a lowly-used isoform of PTPN2, a negative regulator of inflammation. Together, our findings highlight the role alternative splicing plays in IMD risk, and suggest that lowly-used splicing events significantly contribute to complex disease risk.

genomics↗

bioRxiv2023

Gene expression QTL mapping in stimulated iPSC-derived macrophages provides insights into common complex diseases.

Many disease-associated variants are thought to be regulatory but are not present in existing catalogues of expression quantitative trait loci (eQTL). We hypothesise that these variants may regulate expression in specific biological contexts, such as stimulated immune cells. Here, we used human iPSC-derived macrophages to map eQTLs across 24 cellular conditions. We found that 76% of eQTLs detected in at least one stimulated condition were also found in naive cells. The percentage of response eQTLs (reQTLs) varied widely across conditions (3.7% - 28.4%), with reQTLs specific to a single condition being rare (1.11%). Despite their relative rarity, reQTLs were overrepresented among disease-colocalizing eQTLs. We nominated an additional 21.7% of disease effector genes at GWAS loci via colocalization of reQTLs, with 38.6% of these not found in the Genotype-Tissue Expression (GTEx) catalogue. Our study highlights the diversity of genetic effects on expression and demonstrates how condition-specific regulatory variation can enhance our understanding of common disease risk alleles.

genomics↗

bioRxiv2023

A Machine Learning One-Class Logistic Regression Model to Predict Stemness in Single Cell Transcriptomics and Spatial Omics Datasets

Cell annotation is a crucial methodological component to interpreting single cell and spatial omics data. These approaches are often biased and manually curated. Here we harness an existing stemness model for assessing oncogenic states to transform its application to single cell and spatial omic datasets. This one-class logistic regression machine learning algorithm is used to extract transcriptomic or proteomic features from non-transformed stem cells to identify dedifferentiated cell states. We found this method identifies single cell states in metastatic tumor cell populations without the requirement of cell annotation. Finally these stemness indices are applicable across a variety of spatial transcriptomic and proteomic technologies for the identification of oncogenic cell types in the tumor microenvironment. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=162 SRC="FIGDIR/small/539461v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@f2973forg.highwire.dtl.DTLVardef@a7aa9corg.highwire.dtl.DTLVardef@1b1ea27org.highwire.dtl.DTLVardef@183b4a5_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2023

Connectivity-based Meta-Bands: A new approach for automatic frequency band identification in connectivity analyses

The majority of electroencephalographic (EEG) and magnetoencephalographic (MEG) studies filter and analyse neural signals in specific frequency ranges, known as "canonical" frequency bands. However, this segmentation, is not exempt from limitations, mainly due to the lack of adaptation to the neural idiosyncrasies of each individual. In this study, we introduce a new data-driven method to automatically identify frequency ranges based on the topological similarity of the frequency-dependent functional neural network. The resting-state neural activity of 195 cognitively healthy subjects from three different databases (MEG: 123 subjects; EEG1: 27 subjects; EEG2: 45 subjects) was analysed. In a first step, MEG and EEG signals were filtered with a narrow-band filter bank (1 Hz bandwidth) from 1 to 70 Hz with a 0.5 Hz step. Next, the connectivity in each of these filtered signals was estimated using the orthogonalized version of the amplitude envelope correlation to obtain the frequency-dependent functional neural network. Finally, a community detection algorithm was used to identify communities in the frequency domain showing a similar network topology. We have called this approach the "Connectivity-based Meta-Bands" (CMB) algorithm. Additionally, two types of synthetic signals were used to configure the hyper-parameters of the CMB algorithm. We observed that the classical approaches to band segmentation reflect the underlying network topologies at group level for the MEG signals, but they fail to adapt to the individual differentiating patterns revealed by our methodology. On the other hand, the sensitivity of EEG signals to reflect this underlying frequency-dependent network structure is limited. To the best of our knowledge, this is the first study that proposes an unsupervised band segmentation method based on the topological similarity of functional neural network across frequencies. This methodology fully accounts for subject-specific patterns, providing more robust and personalized analyses, and paving the way for new studies focused on exploring the frequency-dependent structure of brain connectivity.

bioinformatics↗

bioRxiv2021

A focal adhesion kinase-YAP signaling axis drives drug tolerant persister cells and residual disease in lung cancer

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant tumor cells which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.

cancer biology↗

bioRxiv2021

Multi-modal profiling of the extracellular matrix of human fallopian tubes and serous tubal Intraepithelial carcinomas

Recent evidence supports the fimbriae of the fallopian tube as a potential origin site for high-grade serous ovarian cancer (HGSOC). The progression of many solid tumors is accompanied by changes in the microenvironment, including alterations of the extracellular matrix (ECM). The ECM of fallopian tube and HGSOC has not been well characterized. Therefore, we sought to determine the ECM composition of the benign fallopian tube and how it changes with the onset of serous intraepithelial carcinomas (STICs), precursor of HGSOC. The ECM composition of benign human fallopian tube was first defined from a meta-analysis of published proteomic datasets and identified 190 ECM proteins. We then conducted de novo proteomics using ECM enrichment and identified 88 proteins, 7 of which were not identified in prior studies. We further investigated the levels and localization of seven of these ECM proteins (type I, III, and IV collagens, fibronectin, laminin, versican, perlecan) and hyaluronic acid using multi-spectral immunohistochemical staining of fimbriae from patients with benign conditions or STICs. Quantification revealed an increase in stromal fibronectin and a decrease in epithelial versican in STICs. Our results provide an in-depth picture of the ECM in the benign fallopian tube and identified ECM changes that accompany STIC formation.

cancer biology↗