Publications

Prostate cancer remains one of the leading causes of cancer-related mortality. Although there were advances in cancer therapy, there is a need for advanced drug delivery strategies to improve the spatiotemporal control of therapeutic action. Here, we developed conductive, redox-responsive hybrid sponges based on glutathione-extended waterborne polyurethane (WPU-GSSG) and the electroactive polymer poly(3,4-ethylenedioxythiophene) (PEDOT) for dual-stimuli-triggered release of anticancer peptide in locoregional tumor therapy. WPU/PEDOT porous scaffolds presented lightweight and mechanically resilient structures with homogeneous loading of the pentapeptide Cys-Arg-N-methyl-Glu-Lys-Ala (CR(NMe)EKA). PEDOT incorporation significantly enhanced the electrochemical properties of the sponges, providing reversible redox activity, reduced impedance, and near-ideal capacitive behavior. The sponges supported cell adhesion and high cell viability within the three-dimensional architecture. In vitro release studies demonstrated that peptide delivery is regulated by a synergistic combination of redox and electrical stimuli. A mimetic tumor microenvironment accelerated peptide release relative to physiological conditions. Electrostimulation (+0.5 V chronoamperometry) further enhanced release kinetics, and the combined application of redox and electrical triggers enabled peptide release of up to similar to 94%, demonstrating tunable stimulus-responsive delivery. Functional assays on cancer cells supported the therapeutic potential of this platform. While WPU alone was fully cytocompatible and PEDOT-containing sponges exhibited moderate electrostimulation-dependent effects, CR(NMe)EKA-loaded conductive sponges induced a pronounced reduction in cancer cell viability under electrostimulation, decreasing survival to similar to 20%. Although further in vivo validation is required, these findings highlight the potential of multifunctional WPU/PEDOT sponges for localized, stimuli-responsive peptide delivery.

JTD Keywords: Cancer, Cell-line, Citrate transport, Design, Electrostimulation, Locoregional drugdelivery, Nanoparticle, Pedot, Ph, Polyurethane, Porosity, Prostate cancer, Redox, Scaffolds

Bioelectrical cues are essential for cardiac function and regeneration, yet current electrostimulation strategies rely on invasive electrodes that limit spatial control and clinical translation. Here, we report magnetoelectric nanocomposite hydrogels that combine core-shell CoFe2O4@BiFeO3 magnetoelectric nanoparticles (ME NPs) with a photo-cross-linked methacrylated gelatin (GelMA) network, enabling wireless electroactivity through externally applied magnetic fields within a soft, biomimetic three-dimensional scaffold. Structural and physicochemical analyses confirmed the successful synthesis of crystalline core-shell ME NPs with strong interfacial coupling, as demonstrated by transmission electron microscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and magnetic hysteresis measurements showing exchange bias effects. Homogeneous incorporation of ME NPs within GelMA produced highly porous and interconnected hydrogels, as revealed by scanning electron microscopy and microcomputed tomography. The presence of nanoparticles reduced equilibrium swelling and refined pore architecture, suggesting increased effective cross-linking density and nanoparticle-polymer interactions. Mechanical testing showed soft elastomeric behavior with compressive moduli compatible with cardiac tissue. Under dynamic magnetic stimulation, magnetoelectric hydrogels significantly enhanced cardiac cell viability, proliferation, and morphological organization compared with pristine GelMA controls. After 10 days, the metabolic activity of cells cultured on GelMA-ME NP hydrogels under stimulation was approximately 3-fold higher than that of unstimulated GelMA. These results demonstrate that magnetoelectric hydrogels provide an effective platform for wireless electrostimulation, offering promising opportunities for cardiac tissue engineering and implantable bioelectronic therapies without wired electrodes.

JTD Keywords: Cardiac tissue engineering, Core-shell nanoparticles, Fields, Gelma hydrogels, Magnetoelectric nanocomposites, Tissue, Wireless electrostimulation

Helping behavior in rodents provides a powerful model for studying neurobiological underpinnings of prosocial motivation. Previously, rats allowed to release a trapped conspecific demonstrated prosocial motivation selectively toward ingroup members. Here, a refined version of the helping behavior test (HBT) allowed trapped rats to be freed without ensuing social contact, dissociating social from prosocial reward. In this "separated" HBT (SHBT), helping was not biased, as rats equally released ingroup and outgroup members. Whole brain c-Fos mapping revealed a subset of the standard HBT prosocial brain network engaged in the SHBT. Observed absence of activity in the nucleus accumbens (NAc) instigated a chemogenetic investigation of this region. NAc activity was not necessary for helping, but significantly reduced affiliative behavior. The recruitment of Oxtr+ cells in sensory cortices suggests modulated sensory processing. Together, these findings dissociate neural circuits underlying social and prosocial motivation and provide a mechanistic framework for studying mammalian prosocial behavior.

JTD Keywords: Basolateral amygdala, Brain, Cingulate, Cognition, Empathy, Involvement, Maternal-behavior, Nucleus-accumbens core, Orbitofrontal cortex, Oxytocin

Although an increasing number of micro/nanomotors have been designed for environmental remediation in the past decade, the construction of contaminants-fueled nanomotors for synergistically degrading multiple pollutants simultaneously remains a challenge. Herein, laccase-powered Fe3O4@silica nanomotors are fabricated, assisted with lipase enzyme for the enhanced degradation of multiple contaminants using the contaminants themselves as fuels. Notably, we demonstrate that representative industrial phenols and polycyclic aromatic pollutants possess the ability of triggering the enhanced Brownian motion of laccase nanomotors (De of 1.16 mu m(2)/s in 220 mu M biphenol A (BPA), 1.40 mu m(2)/s in 375 mu M Congo red (CR)). Additionally, the k(cat) value of lipase-assisted laccase-powered nanomotors increased over 1.4 times, enhancing their Brownian motion, while leading to the efficient degradation of multiple contaminants such as BPA, CR, and triacetin droplets within 40 min, simultaneously. Ultimately, the lipase-assisted laccase nanomotors exhibit great advantages over free laccase, free lipase, lipase nanomotors, or laccase nanomotors in K-m, k(cat), catalytic stability, recycling property, and the degradation efficiency of contaminants. Therefore, our work further broadens the library of enzyme-powered nanomotors and provides deep insights in synergistical enzymatic catalysis, thus paving avenues for environmental remediation based on enzyme-powered micro/nanomotors. (C) 2022 Elsevier Ltd. All rights reserved.

JTD Keywords: core, dye, environmental remediation, enzyme catalysis, hybrid, light, microspheres, motors, pollutants removal, propulsion, removal, self-propulsion, shell, Core, Dye, Environmental remediation, Enzyme catalysis, Hybrid, Light, Micro/nanomotors, Micromotors, Microspheres, Motors, Pollutants removal, Propulsion, Removal, Self-propulsion, Shell

The histone demethylase KDM1A is a multi- faceted regulator of vital developmental processes, including mesodermal and cardiac tube formation during gastrulation. However, it is unknown whether the fine-tuning of KDM1A splicing isoforms, already shown to regulate neuronal maturation, is crucial for the specification and maintenance of cell identity during cardiogenesis. Here, we discovered a temporal modulation of ubKDM1A and KDM1A+2a during human and mice fetal cardiac development and evaluated their impact on the regulation of cardiac differentiation. We revealed a severely impaired cardiac differentiation in KDM1A(-/-) hESCs that can be rescued by re-expressing ubKDM1A or catalytically impaired ubKDM1A-K661A, but not by KDM1A+2a or KDM1A+2a-K661A. Conversely, KDM1A+2a(-/-) hESCs give rise to functional cardiac cells, displaying increased beating amplitude and frequency and enhanced expression of critical cardiogenic markers. Our findings prove the existence of a divergent scaffolding role of KDM1A splice variants, independent of their enzymatic activity, during hESC differentiation into cardiac cells.

JTD Keywords: cell biology, molecular mechanism of gene regulation, omics, Bhlh transcription factor, Cell biology, Corest, Differentiation, Dna, Embryonic stem-cells, Heart, Lsd1, Molecular mechanism of gene regulation, Omics, Phosphorylation, Proteins, Stem cells research, Swirm domain

Moderate exercise has well-founded benefits in cardiovascular health. However, increasing, yet controversial, evidence suggests that extremely trained athletes may not be protected from cardiovascular events as much as moderately trained individuals. In our rodent model, intensive but not moderate training promoted aorta and carotid stiffening and elastic lamina ruptures, tunica media thickening of intramyocardial arteries, and an imbalance between vasoconstrictor and relaxation agents. An up-regulation of angiotensin-converter enzyme, miR-212, miR-132, and miR-146b might account for this deleterious remodeling. Most changes remained after a 4-week detraining. In conclusion, our results suggest that intensive training blunts the benefits of moderate exercise. (C) 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

JTD Keywords: atherosclerosis, cacs, coronary artery calcium score, cad, coronary artery disease, coronary artery disease, cv, cardiovascular, endurance exercise, extreme sport, mmp9, matrix metalloproteinase 9, no, nitric oxide, phe, phenylephrine, vsmc, vascular smooth muscle cell, Age, Atherosclerosis, Cacs, coronary artery calcium score, Cad, coronary artery disease, Coronary artery disease, Coronary atherosclerosis, Cv, cardiovascular, Disease, Endurance exercise, Extreme sport, Metalloproteinases, Micrornas, Mmp9, matrix metalloproteinase 9, No, nitric oxide, Phe, phenylephrine, Physical-activity, Prevalence, Rats, Relevance, Risk, Vascular stiffening, Vsmc, vascular smooth muscle cell

Formalin-fixed paraffin embedding (FFPE) is the most widespread long-term tissue preservation approach. Here, we report a procedure to perform genome-wide spatial analysis of mRNA in FFPE-fixed tissue sections, using well-established, commercially available methods for imaging and spatial barcoding using slides spotted with barcoded oligo(dT) probes to capture the 3' end of mRNA molecules in tissue sections. We applied this method for expression profiling and cell type mapping in coronal sections from the mouse brain to demonstrate the method's capability to delineate anatomical regions from a molecular perspective. We also profiled the spatial composition of transcriptomic signatures in two ovarian carcinosarcoma samples, exemplifying the method's potential to elucidate molecular mechanisms in heterogeneous clinical samples. Finally, we demonstrate the applicability of the assay to characterize human lung and kidney organoids and a human lung biopsy specimen infected with SARS-CoV-2. We anticipate that genome-wide spatial gene expression profiling in FFPE biospecimens will be used for retrospective analysis of biobank samples, which will facilitate longitudinal studies of biological processes and biomarker discovery.© 2021 The Authors.

JTD Keywords: colonic transit, gut, intestinal motility, ld score regression, metaanalysis, nervous-system, neurotrophic factor, population, severity, Covid-19, Ffpe, Genome-wide, Irritable-bowel-syndrome, Mouse brain, Organoids, Ovarian carcinosarcoma, Pfa, Sars-cov-2, Spatial transcriptomics, Visium

Background & Aims: Prognostic models of cirrhosis underestimate disease severity for patients with cirrhosis and ascites. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein linked to hepatic neoangiogenesis and fibrogenesis. We investigated ascites MFAP4 as a predictor of transplant-free survival in patients with cirrhosis and ascites. Methods: A dual-centre observational study of patients with cirrhosis and ascites recruited consecutively in relation to a paracentesis was carried out. Patients were followed up for 1 year, until death or liver transplantation (LTx). Ascites MFAP4 was tested with the model for end-stage liver disease (MELD-Na), CLIF Consortium Acute Decompensation (CLIF-C AD), and Child-Pugh score in Cox regression models. Results: Ninety-three patients requiring paracentesis were included. Median ascites MFAP4 was 29.7 U/L [22.3–41.3], and MELD-Na was 19 [16–23]. A low MELD-Na score (<20) was observed in 49 patients (53%). During follow-up, 20 patients died (22%), and 6 received LTx (6%). High ascites MFAP4 (>29.7 U/L) was associated with 1-year transplant-free survival (p = 0.002). In Cox regression, ascites MFAP4 and MELD-Na independently predicted 1-year transplant-free survival (hazard ratio [HR] = 0.97, p = 0.03, and HR = 1.08, p = 0.01, respectively). Ascites MFAP4 and CLIF-C AD also predicted survival independently (HR = 0.96, p = 0.02, and HR = 1.05, p = 0.03, respectively), whereas only ascites MFAP4 did, controlling for the Child-Pugh score (HR = 0.97, p = 0.03, and HR = 1.18, p = 0.16, respectively). For patients with MELD-Na <20, ascites MFAP4 but not ascites protein predicted 1-year transplant-free survival (HR 0.91, p = 0.02, and HR = 0.94, p = 0.17, respectively). Conclusions: Ascites MFAP4 predicts 1-year transplant-free survival in patients with cirrhosis and ascites. In patients with low MELD-Na scores, ascites MFAP4, but not total ascites protein, significantly predicted 1-year transplant-free survival. Lay summary: Patients with cirrhosis who have fluid in the abdomen, ascites, are at an increased risk of death and in need for liver transplantation. Our study identified patients with ascites and a poor prognosis by measuring microfibrillar associated protein 4 (MFAP4), a protein present in the abdominal fluid. Patients with low levels of the MFAP4 protein are at particularly increased risk of death or liver transplantation, suggesting that clinical care should be intensified in this group of patients. © 2021 The Authors

JTD Keywords: biomarker, clif-c ad, clif consortium acute decompensation, cps, child-pugh score, crp, c-reactive protein, ct, computed tomography, decompensated, ecm, extracellular matrix, fibrosis, fluid protein, gfr, glomerular filtration rate, hr, hazard ratio, inr, internationalised normal ratio, liver disease, liver-cirrhosis, ltx, liver transplantation, markers, meld-na, model for end-stage liver disease, mfap4, microfibrillar associated protein 4, mortality, nash, non-alcoholic steatohepatitis, natural-history, prognosis, risk-factors, sbp, spontaneous bacterial peritonitis, scores, stage, Biomarker, Decompensated, Egfr, estimated gfr, Fibrosis, Liver disease, Mortality, Prognosis, Spontaneous bacterial peritonitis

Poor sleep quality is a risk factor for multiple mental, cardiovascular, and cerebrovascular diseases. Certain sleep positions or excessive position changes can be related to some diseases and poor sleep quality. Nevertheless, sleep position is usually classified into four discrete values: supine, prone, left and right. An increase in sleep position resolution is necessary to better assess sleep position dynamics and to interpret more accurately intermediate sleep positions. This research aims to study the feasibility of smartphones as sleep position monitors by (1) developing algorithms to retrieve the sleep position angle from smartphone accelerometry; (2) monitoring the sleep position angle in patients with obstructive sleep apnea (OSA); (3) comparing the discretized sleep angle versus the four classic sleep positions obtained by the video-validated polysomnography (PSG); and (4) analyzing the presence of positional OSA (pOSA) related to its sleep angle of occurrence. Results from 19 OSA patients reveal that a higher resolution sleep position would help to better diagnose and treat patients with position-dependent diseases such as pOSA. They also show that smartphones are promising mHealth tools for enhanced position monitoring at hospitals and home, as they can provide sleep position with higher resolution than the gold-standard video-validated PSG.

JTD Keywords: accelerometry, actigraphy, association, biomedical signal processing, index, latency, mhealth, monitoring, pathophysiology, quality, questionnaire, score, sleep apnea, sleep position, smartphone, time, Accelerometry, Biomedical signal processing, Mhealth, Monitoring, Sleep apnea, Sleep position, Smartphone, Supine position