Biology subjects

Palma, M.

Publications and source records attributed to Palma, M..

9 recordsLinked to original sources

bioRxiv2026

A mouse model of metastasis-induced breast cancer cachexia with non-cachectic controls bearing isogenic primary tumors

Background Patients with advanced cancer frequently develop cachexia, an involuntary weight-loss condition that correlates strongly with metastatic burden. Despite this clinical association, metastasis is rarely considered in preclinical research of cancer cachexia, which is in part due to the lack of rigorously established animal models to investigate metastasis-associated cancer cachexia. Methods To establish an animal model of metastasis-associated cancer cachexia, here we focused on syngeneic mouse models of breast cancer. Using the metastatic 4T1 murine breast cancer cell line and its isogenic non-metastatic 67NR cell line, we generated primary tumors via orthotopic injection into the mammary fat pad and surgically resected the primary tumor to allow sufficient time for spontaneous metastatic outgrowth, or generated experimental lung metastases by direct intravenous injection into the tail vein. Across these tumor-bearing groups, we systematically characterized the metastatic burden and cachectic phenotypes of the mice, including body weight, food intake, body composition, muscle mass, grip strength, locomotor activity, energy expenditure, and respiratory exchange ratio. To isolate the contribution of reduced food intake to the cachectic phenotypes, we pair-fed orthotopic 4T1 tumor-bearing mice (which were non-cachectic) to mice with 4T1 lung metastases (which were cachectic). We further measured muscle atrophy gene expression and profiled circulating cytokines and metabolic hormones for the mouse groups. Results Body weight loss occurred exclusively in mice bearing lung metastases from 4T1 tumors, with no weight loss observed in mice bearing either primary 4T1 tumors or 67NR lung tumors, thus presenting a model of cancer cachexia that is driven by 4T1 lung metastasis. Comprehensive cachexia characterization demonstrated that the 4T1 metastasis model recapitulates all key features of cachexia, manifesting as reduced food intake (or anorexia), depletion of adipose tissues, loss of lean mass including muscle mass loss, and reduced grip strength. Pair-feeding non-cachectic primary 4T1 tumor-bearing mice to 4T1 metastatic mice led to the same losses in body weight, fat, and lean mass as in cachectic mice, but no change in grip strength, indicating that anorexia is the primary driver of tissue wasting whereas muscle weakness arises through a food intake-independent mechanism. Moreover, we identified distinct circulating cytokines and metabolic hormones associated with the metastasis-driven cachexia. Conclusions Our results establish a metastasis-induced breast cancer cachexia model with a tightly matched control group, providing a platform for the field to identify metastasis-derived cachectic mediators and pathways.

cancer biology↗

bioRxiv2025

Plasma plasmalogen levels and risk of lymph node positive breast cancer

Lymph node involvement is a key predictor of poor breast cancer prognosis. Systemic lipid alterations can contribute to cancer cell survival in lymph nodes, but their relevance in humans remains unclear. Here, we combine human epidemiologic analyses from the Nurses Health Study 2 and complementary mechanistic studies in mouse models to investigate how systemic lipid profiles relate to lymph node positive breast cancer. We show that in pre-diagnostic human plasma (n=511), lower levels of phosphatidylethanolamine (PE) and phosphatidylcholine (PC)-enriched plasmalogens are associated with increased risk of lymph node positivity, with stronger associations in samples collected closer to diagnosis. Consistent with the human data, lower levels of PE and PC-enriched plasma plasmalogens are found in mice with nodal involvement. Furthermore, in mice, dietary PUFA depletion reduces lipid oxidation in breast cancer cells in lymph nodes and promotes their survival and metastatic spread. These findings suggest that reduced levels of PE and PC-plasmalogens and decreased PUFA availability creates a lipid environment that enables breast cancer lymph node involvement.

cancer biology↗

bioRxiv2023

Optimising CNT-FET Biosensor Design: Predictive Modelling of Biomolecular Electrostatic Gating and its Application to Beta-Lactamase Detection

Carbon nanotube field effect transistor (CNT-FET) setups hold great promise for constructing next generation miniaturised biosensors whereby a biomolecular event gates conductance. The main issue is predicting how proteins, with their innate mosaic and distinctive electrostatic surfaces, interact with and thus modulate conductance of the CNT-FET. To overcome this barrier, we used advanced sampling molecular dynamics combined with non-canonical amino acid chemistry, to model the protein electrostatic potential imparted on SWCNTs. Here, we focused our efforts using {beta}-lactamase binding protein (BLIP2) as the receptor due to its potential as a biosensor for the most common antibiotic degrading enzymes, the {beta}-lactamases (BLs). Modelling was confirmed experimentally by attaching BLIP2 at single designed residues positions directly to SWCNTs using genetically encoded phenyl azide photochemistry. Our devices were able to successfully detect the two different BLs, TEM-1 and KPC-2, with each BL generating distinct conductance profiles due to differences in their unique surface electrostatic profiles presented close to the SWCNT surface. The changes in conductance closely matched the predicted electrostatic profile sampled by the SWCNTs on BL binding. Thus, our modelling approach combined with new and straight-forward residue-specific receptor attachment techniques, provides a general approach for more effective and optimal CNT-FET biosensor construction.

bioengineering↗

bioRxiv2023

HTLV-1 Rex hijacks UPF1 in a CRM1 dependent manner, leading to NMD inhibition and revealing unexpected proviral roles of UPF1

The hijacking of CRM1 export is an important step of the retroviral replication cycle. Here, we investigated the consequences of this hijacking for the host. During HTLV-1 infection, we identified that this hijacking by the viral protein Rex favours the association between CRM1 and the RNA helicase UPF1, leading to a decreased affinity of UPF1 for cellular RNA and its nuclear retention. As a consequence, we found that the nonsense mediated mRNA decay (NMD), known to have an antiviral function, was inhibited. Corroborating these results, we described a similar process with Rev, the functional homolog of Rex from HIV-1. Unexpectedly, we also found that, for HTLV-1, this process is coupled with the specific loading of UPF1 onto vRNA, independently of NMD. In this latter context, UPF1 positively regulates several steps of the viral replication cycle, from the nuclear export of vRNA to the production of mature viral particles. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/545693v2_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1e91e61org.highwire.dtl.DTLVardef@1c9951borg.highwire.dtl.DTLVardef@15c6021org.highwire.dtl.DTLVardef@1ab35ff_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO During retroviral replication, the nuclear export unspliced vRNA is conducted via the hijacking of the exportin CRM1 by the viral protein Rex. In parallel, the RNA helicase UPF1 is naturally exported in a CRM1 dependent manner. In the cytoplasm it drives NMD, whose substrates include vRNA. Here we demonstrated that HTLV-1 Rex dependent hijacking of CRM1 is associated with the nuclear accumulation of UPF1 and the stabilization of the interaction between CRM1 and UPF1 (1). In this complex, UPF1 shows a decreased affinity for cellular RNA associated to NMD inhibition (2). We also observed that UPF1 is selectively loaded onto vRNA and stimulates vRNA export (3). In this context, UPF1 is driven in the viral particles (without NMD cofactors) where it plays critical role in virion assembly, maturation (4) and ultimately viral infection (5). Created in BioRender. PROCHASSON, L. (2025) https://BioRender.com/urj0cvo". C_FIG

molecular biology↗

bioRxiv2022

Graphene-based thin film microelectrode technology for in vivo high resolution neural recording and stimulation

Neuroprosthetic technology aims to restore nervous system functionality in cases of severe damage or degeneration by recording and stimulating the electrical activity of the neural tissue. One of the key factors determining the quality of the neuroprostheses is the electrode material used to establish electrical communication with the neural tissue, which is subject to strict electrical, electrochemical, and mechanical specifications as well as biological and microfabrication compatibility requirements. This work presents a nanoporous graphene-based thin film technology and its engineering to form flexible neural implants. Bench measurements show that the developed microelectrodes offer low impedance and high charge injection capacity throughout millions of pulses. In vivo electrode performance was assessed in rodents both from brain surface and intracortically showing high-fidelity recording performance, while stimulation performance was assessed with an intrafascicular implant that demonstrated low current thresholds and high selectivity for activating subsets of axons within the sciatic nerve. Furthermore, the tissue biocompatibility of the devices was validated by chronic epicortical and intraneural implantation. Overall, this works describes a novel graphene-based thin film microelectrode technology and demonstrates its potential for high-precision neural interfacing in both recording and stimulation applications.

bioengineering↗

bioRxiv2022

Regulation of Cardiomyocyte Adhesion and Mechanosignalling Through Distinct Nanoscale Behaviour of Integrin Ligands Mimicking Healthy or Fibrotic ECM

The stiffness of the cardiovascular environment changes during ageing and in disease and contributes to disease incidence and progression. Changing collagen expression and crosslinking regulate the rigidity of the cardiac ECM. Additionally, basal lamina glycoproteins, especially laminin and fibronectin regulate cardiomyocyte adhesion formation, mechanics and mechano-signalling. Laminin is abundant in the healthy heart, but fibronectin is increasingly expressed in the fibrotic heart. ECM receptors are co-regulated with the changing ECM. Due to differences in integrin dynamics, clustering, and downstream adhesion formation this is expected to ultimately influence cardiomyocyte mechanosignalling; however details remain elusive. Here we sought to investigate how different cardiomyocyte ligand/integrin combinations are affecting adhesion formation, traction forces and mechanosignalling, using a combination of uniformly coated surfaces with defined stiffness, PDMS nanopillars, micropatterning and specifically designed bionanoarrays for precise ligand presentation. Thereby we find that neonatal rat cardiomyocytes (which express both laminin and fibronectin binding integrins) adhesion nanoscale organisation, signalling and traction force generation are strongly dependent on the integrin/ligand combination. Together our data indicates that the presence of fibronectin in combination with the enhanced stiffness in fibrotic areas will strongly impact on the cardiomyocyte behaviour and influence disease progression.

cell biology↗

bioRxiv2020

Self-powered piezo-bioelectronic device mediates tendon repair through modulation of mechanosensitive ion channels.

Tendon disease constitutes an unmet clinical need and remains a critical challenge in the field of orthopaedic surgery. Innovative solutions are required to overcome the limitations of current tendon grafting approaches, and bioelectronic therapies are showing promise in the treatment of musculoskeletal disease, accelerating functional recovery through the activation of tissue regeneration signalling pathways (guided regeneration). Self-powered bioelectronic devices, and in particular piezoelectric materials represent a paradigm shift in biomedicine, negating the need for battery or external powering and complementing existing mechanotherapy to accelerate the repair processes. Here, we show the dynamic response of tendon cells to a piezoelectric collagen-analogue scaffold comprised of aligned nanoscale fibres made of the ferroelectric material poly(vinylidenefluoride-co-trifluoroethylene), (PVDF-TrFE). We demonstrate that electromechanical stimulation of tendon tissue results in guided regeneration by ion channel modulation. Finally, we show the potential of the bioelectronic device in regulating the progression of tendinopathy associated processes using a rat Achilles tendinopathy model. This study indicates that body motion-powered electromechanical stimulation can control the expression of TRPA1 and PIEZO2 receptors and stimulate tendon-specific tissue repair processes.

bioengineering↗

bioRxiv2019

Quantifying uncertainty in brain-predicted age using scalar-on-image quantile regression

Prediction of subject age from brain anatomical MRI has the potential to provide a sensitive summary of brain changes, indicative of different neurodegenerative diseases. However, existing studies typically neglect the uncertainty of these predictions. In this work we take into account this uncertainty by applying methods of functional data analysis. We propose a penalised functional quantile regression model of age on brain structure with cognitively normal (CN) subjects in the Alzheimers Disease Neuroimaging Initiative (ADNI), and use it to predict brain age in Mild Cognitive Impairment (MCI) and Alzheimers Disease (AD) subjects. Unlike the machine learning approaches available in the literature of brain age prediction, which provide only point predictions, the outcome of our model is a prediction interval for each subject.

neuroscience↗

bioRxiv2019

Acoustic contamination of electrophysiological brain signals during speech production and sound perception

A current challenge of neurotechnologies is the development of speech brain-computer interfaces to restore communication in people unable to speak. To achieve a proof of concept of such system, neural activity of patients implanted for clinical reasons can be recorded while they speak. Using such simultaneously recorded audio and neural data, decoders can be built to predict speech features using features extracted from brain signals. A typical neural feature is the spectral power of field potentials in the high-gamma frequency band (between 70 and 200 Hz), a range that happens to overlap the fundamental frequency of speech. Here, we analyzed human electrocorticographic (ECoG) and intracortical recordings during speech production and perception as well as rat microelectrocorticographic ({micro}-ECoG) recordings during sound perception. We observed that electrophysiological signals, recorded with different recording setups, often contain spectrotemporal features highly correlated with those of the sound, especially within the high-gamma band. The characteristics of these correlated spectrotemporal features support a contamination of electrophysiological recordings by sound. In a recording showing high contamination, using neural features within the high-gamma frequency band dramatically increased the performance of linear decoding of acoustic speech features, while such improvement was very limited for another recording showing weak contamination. Further analysis and in vitro replication suggest that the contamination is caused by a mechanical action of the sound waves onto the cables and connectors along the recording chain, transforming sound vibrations into an undesired electrical noise that contaminates the biopotential measurements. This study does not question the existence of relevant physiological neural information underlying speech production or sound perception in the high-gamma frequency band, but alerts on the fact that care should be taken to evaluate and eliminate any possible acoustic contamination of neural signals in order to investigate the cortical dynamics of these processes.

neuroscience↗