Biology subjects

Silva, B.

Publications and source records attributed to Silva, B..

9 recordsLinked to original sources

bioRxiv2026

Multilevel sex-specific neurobiological signatures of early life adversity

Stress exposure early in life is an established risk factor for adult psychiatric illness, yet these disorders - including anxiety disorders and depression - show significant sex-dependence in prevalence, symptomatology, and treatment response. The biology underlying these differences remains largely unexplored and may contribute to the clinical heterogeneity in anxiety and depression. Here, we characterize the lasting impact of developmental stress on adulthood neurobiology and behavior in mice by combining analyses of multiple levels of brain function, including whole-brain c-Fos mapping, manganese-enhanced MRI and transcriptomics with advanced behavioral phenotyping. Across levels of investigation, we find distinct and often opposite effects of developmental stress depending on sex. These results together showcase the strong influence of sex on how early life adversity affects the onset of stress-related disorders. This work emphasizes the necessity of considering sex when investigating developmental and neurobiological underpinnings of stress-related disorders and displays a vast range of lasting effects of developmental stress on the brain, which provides a valuable resource for future studies aiming to improve psychiatric treatments.

neuroscience↗

bioRxiv2026

Genetic sex of enteric neurons enables ovarian relaxin togate maternal gut plasticity

Animals must align intestinal plasticity and feeding with reproductive state, yet the checkpoint that gates these adaptations is unknown. Here we show that an ovary-to-enteric-neuron axis gates the onset of maternal gut plasticity in Drosophila. Genetic sex establishes endocrine competence in a subset of enteric neurons via the sex determination pathway, enabling female-specific expression of the relaxin-family receptor Lgr3. After mating, steroid signalling increases Lgr3 receptor expression, priming these neurons for reproductive adaptation. Once oocytes mature fully, follicle cells secrete the relaxin-like hormone dILP8, which activates Lgr3 to trigger gut enlargement and increased feeding. Disrupting the sex determination pathway in enteric neurons, Lgr3, or ovarian dILP8 prevents gut enlargement and reduces feeding. Thus, genetic sex establishes competence, steroid signalling primes it, and ovarian relaxin triggers it, defining a maternal intestinal plasticity checkpoint that ensures gut adaptations initiate only once reproduction is underway and energy demands peak. Our findings delineate an ovary-to-enteric-neuron axis that couples reproductive state to maternal gut plasticity.

physiology↗

bioRxiv2025

Inactivation of peptidoglycan remodeling promotes antibiotic susceptibility in vancomycin-resistant Enterococcus faecium

Vancomycin-resistant Enterococcus faecium (VREfm) is a leading cause of healthcare-associated infections globally and demands new approaches for treatment. Here we show that genetic and pharmacological inactivation of a highly conserved NlpC/P60 peptidoglycan hydrolase, secreted antigen A (SagA), enhanced vancomycin susceptibility of VREfm ex vivo and in vivo. Notably, genetic deletion of sagA impaired VREfm peptidoglycan remodeling, growth and increased the activity of vancomycin. We then identified first-in-class covalent NlpC/P60 peptidoglycan hydrolase inhibitors and demonstrated that pharmacological inactivation of SagA activity also impaired peptidoglycan remodeling and increased the efficacy of vancomycin across genetically distinct VREfm clinical isolates. Our study reveals peptidoglycan hydrolases are druggable targets whose inactivation improves the efficacy of vancomycin against VREfm.

microbiology↗

bioRxiv2025

The Innexin 7 gap junction protein contributes to synchronized activity in the Drosophila antennal lobe and regulates olfactory function

In the mammalian olfactory bulb (OB), gap junctions coordinate synchronous activity among mitral and tufted cells to process olfactory information. In insects, gap junctions are also present in the Antennal Lobe (AL), a structure homologous to the mammalian OB. The invertebrate gap junction protein ShakB contributes to electrical synapses between AL Projections Neurons (PNs) in Drosophila. Other gap junction proteins, including Innexin 7 (Inx7), are also expressed in the Drosophila AL, but little is known about their contribution to intercellular communication during olfactory information processing. Here we report spontaneous calcium transients in PNs grown in cell culture that are highly synchronous when these neurons are physically connected. RNAi-mediated knock down of Inx7 in cultured PNs blocks calcium transient neuronal synchronization. In vivo, downregulation of Inx7 in the AL impairs both vinegar-induced electrophysiological calcium responses and behavioral responses to this appetitive stimulus. These results demonstrate that Inx7-encoded gap junctions functionally coordinate PN activity and modulate olfactory information processing in the adult Drosophila AL.

neuroscience↗

bioRxiv2024

Neuronal fatty acid oxidation fuels memory after intensive learning

Metabolic flexibility allows cells to adapt to different fuel sources, which is particularly important for cells with high metabolic demands. In contrast, neurons, which are major energy consumers, are considered to rely almost solely on glucose and its derivatives to support their metabolism1-3. Here, using Drosophila melanogaster, we show memory formed after intensive massed training is dependent on mitochondrial fatty acid (FA) {beta}-oxidation to produce ATP in neurons of the mushroom bodies (MB), a major integrative center in insects brain. We identify neuronal lipid droplets as the main source of FAs for this type of memory. Furthermore, we demonstrate that this intensive massed training is associated with mitochondria network remodeling in the soma of MB neurons, resulting in increased mitochondrial size. Artificially increasing mitochondria size in adult MB neurons increases ATP production in their soma and, at the behavioral level, strikingly results in improved memory performance after massed training. These findings challenge the prevailing view that neurons are unable to use FAs for energy production, and importantly revealing on the contrary that in vivo neuronal FA oxidation has an essential role in cognitive function, including memory formation.

neuroscience↗

bioRxiv2024

Pan-cancer N-glycoproteomic atlas of patient derived xenografts uncovers FAT2 as a therapeutic target for head and neck cancers

Cell surface proteins offer significant cancer therapeutic potential attributable to their accessible membrane localization and central role in cellular signaling. Despite this, their promise remains largely untapped due to the technical challenges inherent to profiling cell surface proteins. Here, we employed N-glycoproteomics to analyze 85 patient-derived xenografts (PDX), constructing Glyco PDXplorer - an in vivo pan-cancer atlas of cancer-derived cell surface proteins. We developed a target discovery pipeline to prioritize proteins with favorable expression profiles for immunotherapeutic targeting and validated FAT2 as a head and neck squamous cancer (HNSC) enriched surface protein with limited expression in normal tissue. Functional studies revealed that FAT2 is essential for HNSC growth and adhesion through regulation of surface architecture and integrin-PI3K signaling. Chimeric antigen receptor (CAR) T cells targeting FAT2 demonstrated potent anti-tumor activity in HNSC models. This work lays the foundation for developing FAT2-targeted therapies and represents a pivotal resource to inform therapeutic target discovery for multiple cancers. HIGHLIGHTSO_LIPan-cancer landscape of cancer-derived cell surface proteins detected in vivo C_LIO_LIDevelopment of a multi-omic discovery pipeline to prioritize proteins with optimal expression profiles as immunotherapy targets C_LIO_LIIdentification and validation of FAT2 as a head and neck squamous cancer enriched surface protein with minimal expression in normal tissues C_LIO_LIFAT2 coordinates cell surface organization, adhesion, growth and survival through the integrin-PI3K-AKT pathway C_LIO_LIFAT2 CAR T cells demonstrate anti-tumour activity in pre-clinical models C_LI

cancer biology↗

bioRxiv2024

Multi-Temporal Remote Sensing of Inland Surface Waters: A Fusion of Sentinel-1 Data Applied to Small Seasonal Ponds in Semiarid Environments

Inland freshwater resources in semiarid environments play a key role in maintaining ecological systems and supporting human development. Space-based remote sensing spatiotemporal data have emerged as a new paradigm for understanding ecohydrological processes and trends, particularly in water-stressed areas. However, comprehensive cataloging is still lacking, especially in semi-arid regions and for small-sized water bodies (i.e., ponds), which are often overlooked despite their ecological relevance. In this study, high-resolution optical and radar Sentinel data (Sentinel-1 and Sentinel-2) were used to construct Sentinel-1&2-based local surface water (SLSW) models, to infer surface water occurrence and extent. To assess the reliability of this model, the results were compared with verification data, and separately with Landsat-based global water (LGSW) models. Three distinct semiarid regions were selected in SW Iberia, within a Mediterranean climate, each encompassing special protection areas for conservation and subjected to marked seasonality and bioclimatic changes. Surface water attributes were modeled using Random Forests for SLSW time series forecasting, which included the period from January 1, 2020, to December 31, 2021. During this period, the completeness of the archived information was compared between SLSW and LGSW, considering both intra-annual and inter-annual variations. The predictive performance of these models was then compared for specific periods (dry and wet), and each was independently validated with verification data. The results showed that SLWM achieved satisfactory predictive performances in detecting surface water occurrence ({approx}72%), with far greater completeness and reconstructed seasonality patterns compared to LGSW. The relatedness between SLSW and LGSW was stronger during wet periods (R2=0.38) than dry periods (R2=0.05), and SLSW related much better with the verification data (R2=0.66) than when compared to LGSW (R2=0.24). The proposed SLSW approach may therefore provide advantages in the delineation of dynamic surface water characteristics (occurrence and extent) in very small-sized water bodies (i.e., <0.5 ha), allowing for uninterrupted surface water time series forecasting at high spatiotemporal detail, and over extensive areas. Given the water constraints in semiarid regions and water resources vulnerability to climate change, our results show high potential for supporting a variety of activities underlying rural development and biodiversity conservation. Additionally, the socio-ecological applications of this research may help identify surface water anomalies (e.g., drought events) and enhance sustainable water supply governance, a particular priority in climate change hotspots. HighlightsO_LISurface water occurrence and extent was modeled across three semiarid regions C_LIO_LISentinel-1&2 data was compared with Landsat for characterizing very small water bodies C_LIO_LIModels based on Sentinel-1&2 resulted in a satisfactory classification precision C_LIO_LIVery high series completeness across seasons was found using Sentinel-1&2 data C_LIO_LISentinel-1&2 data was more reliable than Landsat when compared to verification data C_LI

ecology↗

bioRxiv2023

The effect of estradiol during the early stages of osteoclast differentiation is associated with the accumulation of phosphorylated p53 in mitochondria and the inhibition of mitochondrial metabolism.

Estrogen deficiency increases bone resorption and is a major contributor to osteoporosis. However, the molecular mechanisms mediating the effects of estrogen on osteoclasts remain unclear. This study aimed at elucidating the early metabolic effects of RANKL - the essential cytokine for osteoclastogenesis - and 17-beta-estradiol (E2) on osteoclast progenitor cells, using RAW 264.7 macrophage cell line and bone marrow-derived macrophages as biological models. RANKL stimulated complex I activity, oxidative phosphorylation (OXPHOS), and mitochondria-derived ATP production, as early as 3 to 6 h. This up-regulation of mitochondrial bioenergetics was associated with an increased capacity to oxidize TCA cycle substrates, fatty acids, and amino-acids. E2 inhibited all effects of RANKL on mitochondria metabolism. In the presence of RANKL, E2 also decreased cell number and stimulated the mitochondrial-mediated apoptotic pathway, detected as early as 3h. Surprisingly, the pro-apoptotic effects of E2 were associated with an accumulation of p392S-p53 in mitochondria. These findings elucidate early effects of RANKL on osteoclast progenitor metabolism and suggest novel p53-mediated mechanisms that contribute to postmenopausal osteoporosis.

cell biology↗

bioRxiv2021

TERRA transcription destabilizes telomere integrity to initiate break-induced replication in human ALT cells.

Alternative Lengthening of Telomeres (ALT) is a Break-Induced Replication (BIR)-based mechanism elongating telomeres in a subset of human cancer cells. While the notion that spontaneous DNA damage at telomeres is required for ALT to occur, the molecular triggers of this physiological telomere instability are largely unknown. We previously proposed that the telomeric long noncoding RNA TERRA may represent one such trigger; however, given the lack of tools to suppress TERRA transcription in cells, our hypothesis remained speculative. We have now developed Transcription Activator-Like Effectors able to rapidly inhibit TERRA transcription from multiple chromosome ends in an ALT cell line. TERRA transcription inhibition decreases marks of DNA replication stress and DNA damage at telomeres and impairs ALT activity and telomere length maintenance. We conclude that TERRA transcription actively destabilizes telomere integrity in ALT cells, thereby initiating BIR and supporting telomere elongation. Our data point to TERRA transcription manipulation as a potentially useful target for therapy.

cell biology↗