Activity-driven synaptic translocation of LGI1 controls excitatory neurotransmission.

The fine control of synaptic function requires robust trans-synaptic molecular interactions. However, it remains poorly understood how trans-synaptic bridges change to reflect the functional states of the synapse. Here, we develop optical tools to visualize in firing synapses the molecular behavior of two trans-synaptic proteins, LGI1 and ADAM23, and find that neuronal activity acutely rearranges their abundance at the synaptic cleft. Surprisingly, synaptic LGI1 is primarily not secreted, as described elsewhere, but exo- and endocytosed through its interaction with ADAM23. Activity-driven translocation of LGI1 facilitates the formation of trans-synaptic connections proportionally to the history of activity of the synapse, adjusting excitatory transmission to synaptic firing rates. Accordingly, we find that patient-derived autoantibodies against LGI1 reduce its surface fraction and cause increased glutamate release. Our findings suggest that LGI1 abundance at the synaptic cleft can be acutely remodeled and serves as a critical control point for synaptic function.

Smart Design of ZnFe and ZnFe@Fe Nanoparticles for MRI-Tracked Magnetic Hyperthermia Therapy: Challenging Classical Theories of Nanoparticles Growth and Nanomagnetism.

Iron Oxide Nanoparticles (IONPs) hold the potential to exert significant influence on fighting cancer through their theranostics capabilities as contrast agents (CAs) for magnetic resonance imaging (MRI) and as mediators for magnetic hyperthermia (MH). In addition, these capabilities can be improved by doping IONPs with other elements. In this work, the synthesis and characterization of single-core and alloy ZnFe novel magnetic nanoparticles (MNPs), with improved magnetic properties and more efficient magnetic-to-heat conversion, are reported. Remarkably, the results challenge classical nucleation and growth theories, which cannot fully predict the final size/shape of these nanoparticles and, consequently, their magnetic properties, implying the need for further studies to better understand the nanomagnetism phenomenon. On the other hand, leveraging the enhanced properties of these new NPs, successful tumor therapy by MH is achieved following their intravenous administration and tumor accumulation via the enhanced permeability and retention (EPR) effect. Notably, these results are obtained using a single low dose of MNPs and a single exposure to clinically suitable alternating magnetic fields (AMF). Therefore, as far as the authors are aware, for the first time, the successful application of intravenously administered MNPs for MRI-tracked MH tumor therapy in passively targeted tumor xenografts using clinically suitable conditions is demonstrated.

Ribonucleotide reductase inhibition improves the symptoms of a Caenorhabditis elegans model of Alzheimer's disease.

Alzheimer's disease is the main cause of aging-associated dementia, for which there is no effective treatment. In this work, we reanalyze the information of a previous genome wide association study, using a new pipeline design to identify novel potential drugs. With this approach, ribonucleoside-diphosphate reductase gene (RRM2B) emerged as a candidate target and its inhibitor, 2', 2'-difluoro 2'deoxycytidine (gemcitabine), as a potential pharmaceutical drug against Alzheimer's disease. We functionally verified the effect of inhibiting the RRM2B homolog, rnr-2, in an Alzheimer's model of Caenorhabditis elegans, which accumulates human Aß1-42 peptide to an irreversible paralysis. RNA interference against rnr-2 and also treatment with 200 ng/ml of gemcitabine, showed an improvement of the phenotype. Gemcitabine treatment increased the intracellular ATP level 3.03 times, which may point to its mechanism of action. Gemcitabine has been extensively used in humans for cancer treatment but at higher concentrations. The 200 ng/ml concentration did not exert a significant effect over cell cycle, or affected cell viability when assayed in the microglia N13 cell line. Thus, the inhibitory drug of the RRM2B activity could be of potential use to treat Alzheimer's disease and particularly gemcitabine might be considered as a promising candidate to be repurposed for its treatment.

Light-to-Heat Conversion of Optically Trapped Hot Brownian Particles.

Anisotropic hybrid nanostructures stand out as promising therapeutic agents in photothermal conversion-based treatments. Accordingly, understanding local heat generation mediated by light-to-heat conversion of absorbing multicomponent nanoparticles at the single-particle level has forthwith become a subject of broad and current interest. Nonetheless, evaluating reliable temperature profiles around a single trapped nanoparticle is challenging from all of the experimental, computational, and fundamental viewpoints. Committed to filling this gap, the heat generation of an anisotropic hybrid nanostructure is explored by means of two different experimental approaches from which the local temperature is measured in a direct or indirect way, all in the context of hot Brownian motion theory. The results were compared with analytical results supported by the numerical computation of the wavelength-dependent absorption efficiencies in the discrete dipole approximation for scattering calculations, which has been extended to inhomogeneous nanostructures. Overall, we provide a consistent and comprehensive view of the heat generation in optical traps of highly absorbing particles from the viewpoint of the hot Brownian motion theory.

Tumor infiltrating lymphocytes (TILs) are a prognosis biomarker in Colombian patients with triple negative breast cancer.

Triple negative breast cancer (TNBC) is highly immunogenic and high levels of tumor infiltrating lymphocytes (TILs) have been associated with a better prognosis and higher probability to achieve pathological complete response. Here, we explore the potential role of stromal TILs level and composition as a prognostic and predictive biomarker in TNBC. 195 Tumor biospecimens from patients diagnosed with TNBC were included. Stromal TILs (sTILs), positive CD4/CD8 cells were evaluated. Differences in clinic-pathological characteristics according to immune infiltration were assessed. The predictive and prognostic value of immune infiltration was analyzed by multivariate models. Higher immune infiltration was observed in patients with favorable clinical-pathological features. Survival analysis showed that longer overall survival times were observed in patients with a higher infiltration of sTILs (p = 0.00043), CD4 + (p = 0.0074) and CD8 + (p = 0.008). In the multivariate analysis, low levels of sTILs were found to be associated with a higher mortality hazard (HR: 1.59, 95% CI 1.01-2.48). CD4 and CD8 immune infiltration were associated with higher odds for pathological complete response (OR: 1.20, 95% CI 1.00-1.46, OR: 1.28, 1.02-1.65, respectively). Our results suggest that immune infiltration could be used as a prognostic marker for overall survival in TNBC patients.

Optimization of iron oxide nanoparticles for MRI-guided magnetic hyperthermia tumor therapy: reassessing the role of shape in their magnetocaloric effect.

Superparamagnetic iron oxide nanoparticles have hogged the limelight in different fields of nanotechnology. Surprisingly, notwithstanding the prominent role played as agents in magnetic hyperthermia treatments, the effects of nanoparticle size and shape on the magnetic hyperthermia performance have not been entirely elucidated yet. Here, spherical or cubical magnetic nanoparticles synthesized by a thermal decomposition method with the same magnetic and hyperthermia properties are evaluated. Interestingly, spherical nanoparticles displayed significantly higher magnetic relaxivity than cubic nanoparticles; however, comparable differences were not observed in specific absorption rate (SAR), pointing out the need for additional research to better understand the connection between these two parameters. Additionally, the as-synthetized spherical nanoparticles showed negligible cytotoxicity and, therefore, were tested in vivo in tumor-bearing mice. Following intratumoral administration of these spherical nanoparticles and a single exposure to alternating magnetic fields (AMF) closely mimicking clinical conditions, a significant delay in tumor growth was observed. Although further in vivo experiments are warranted to optimize the magnetic hyperthermia conditions, our findings support the great potential of these nanoparticles as magnetic hyperthermia mediators for tumor therapy.

New insights in the targets of action of dimethyl fumarate in endothelial cells: effects on energetic metabolism and serine synthesis in vitro and in vivo.

Dimethyl fumarate is an ester from the Krebs cycle intermediate fumarate. This drug is approved and currently used for the treatment of psoriasis and multiple sclerosis, and its anti-angiogenic activity was reported some years ago. Due to the current clinical relevance of this compound and the recently manifested importance of endothelial cell metabolism on the angiogenic switch, we wanted to elucidate whether dimethyl fumarate has an effect on energetic metabolism of endothelial cells. Different experimental approximations were performed in endothelial cells, including proteomics, isotope tracing and metabolomics experimental approaches, in this work we studied the possible role of dimethyl fumarate in endothelial cell energetic metabolism. We demonstrate for the first time that dimethyl fumarate promotes glycolysis and diminishes cell respiration in endothelial cells, which could be a consequence of a down-regulation of serine and glycine synthesis through inhibition of PHGDH activity in these cells. Dimethyl fumarate alters the energetic metabolism of endothelial cells in vitro and in vivo through an unknown mechanism, which could be the cause or the consequence of its pharmacological activity. This new discovery on the targets of this compound could open a new field of study regarding the mechanism of action of dimethyl fumarate.

Soluble HLA-G (sHLA-G) measurement might be useful as an early diagnostic biomarker and screening test for gastric cancer.

Gastric cancer (GC) is the fifth most frequent malignancy worldwide and has a high mortality rate related to late diagnosis. Although the gold standard for the GC diagnosis is endoscopy with biopsy, nonetheless, it is not cost-effective and is invasive for the patient. The Human leukocyte antigen G (HLA-G) molecule is a checkpoint of the immune response. Its overexpression in cancer is associated with immune evasion, metastasis, poor prognosis, and lower overall survival. We evaluate the plasma levels of soluble HLA-G, (sHLA-G) in patients with GC and benign gastric pathologies using an ELISA test. A higher concentration of sHLA-G in patients with GC than in those with benign pathologies, higher levels of plasma sHLA-G in women with GC compared with men and significant differences in the sHLA-G levels between the benign gastric pathologies evaluated, was our main findings. As no significant differences were found between the GC assessed stages in our study population, we suggest that sHLA-G is not an adequate marker for staging GC, but it does have diagnostic potential. In addition to providing information on the potential of sHLA-G as a diagnostic marker for GC, our study demonstrate that HLA-G molecules can be found in the membrane of exosomes, which highlights the need to perform studies with a larger number of samples to explore the functional implications of HLA-G positive exosomes in the context of gastric cancer, and to determine the clinical significance and possible applications of these findings in the development of non-invasive diagnostic methods.

Multi-stimuli-responsive chitosan-functionalized magnetite/poly(ε-caprolactone) nanoparticles as theranostic platforms for combined tumor magnetic resonance imaging and chemotherapy.

Chitosan-functionalized magnetite/poly(ε-caprolactone) nanoparticles were formulated by interfacial polymer disposition plus coacervation, and loaded with gemcitabine. That (core/shell)/shell nanostructure was confirmed by electron microscopy, elemental analysis, electrophoretic, and Fourier transform infrared characterizations. A short-term stability study proved the protection against particle aggregation provided by the chitosan shell. Superparamagnetic properties of the nanoparticles were characterized in vitro, while the definition of the longitudinal and transverse relaxivities was an initial indication of their capacity as T2 contrast agents. Safety of the particles was demonstrated in vitro on HFF-1 human fibroblasts, and ex vivo on SCID mice. The nanoparticles demonstrated in vitro pH- and heat-responsive gemcitabine release capabilities. In vivo magnetic resonance imaging studies and Prussian blue visualization of iron deposits in tissue samples defined the improvement in nanoparticle targeting into the tumor when using a magnetic field. This tri-stimuli (magnetite/poly(ε-caprolactone))/chitosan nanostructure could find theranostic applications (biomedical imaging & chemotherapy) against tumors.

Developmental transcriptional control of mitochondrial homeostasis is required for activity-dependent synaptic connectivity.

During neuronal circuit formation, local control of axonal organelles ensures proper synaptic connectivity. Whether this process is genetically encoded is unclear and if so, its developmental regulatory mechanisms remain to be identified. We hypothesized that developmental transcription factors regulate critical parameters of organelle homeostasis that contribute to circuit wiring. We combined cell type-specific transcriptomics with a genetic screen to discover such factors. We identified Telomeric Zinc finger-Associated Protein (TZAP) as a temporal developmental regulator of neuronal mitochondrial homeostasis genes, including Pink1 . In Drosophila , loss of dTzap function during visual circuit development leads to loss of activity-dependent synaptic connectivity, that can be rescued by Pink1 expression. At the cellular level, loss of dTzap/TZAP leads to defects in mitochondrial morphology, attenuated calcium uptake and reduced synaptic vesicle release in fly and mammalian neurons. Our findings highlight developmental transcriptional regulation of mitochondrial homeostasis as a key factor in activity-dependent synaptic connectivity.

Hot Brownian Motion of Thermoresponsive Microgels in Optical Tweezers Shows Discontinuous Volume Phase Transition and Bistability.

Microgels are soft microparticles that often exhibit thermoresponsiveness and feature a transformation at a critical temperature, referred to as the volume phase transition temperature. Whether this transformation occurs as a smooth or as a discontinuous one is still a matter of debate. This question can be addressed by studying individual microgels trapped in optical tweezers. For this aim, composite particles are obtained by decorating  Poly-N-isopropylacrylamide (pNIPAM) microgels with iron oxide nanocubes. These composites become self-heating when illuminated by the infrared trapping laser, performing hot Brownian motion within the trap. Above a certain laser power, a single decorated microgel features a volume phase transition that is discontinuous, while the usual continuous sigmoidal-like dependence is recovered after averaging over different microgels. The collective sigmoidal behavior enables the application of a power-to-temperature calibration and provides the effective drag coefficient of the self-heating microgels, thus establishing these composite particles as potential micro-thermometers and micro-heaters. Moreover, the self-heating microgels also exhibit an unexpected and intriguing bistability behavior above the critical temperature, probably due to partial collapses of the microgel. These results set the stage for further studies and the development of applications based on the hot Brownian motion of soft particles.

Lanthanide vanadate-based trimodal probes for near-infrared luminescent bioimaging, high-field magnetic resonance imaging, and X-ray computed tomography.

We have developed a trimodal bioimaging probe for near-infrared luminescent imaging, high-field magnetic resonance imaging, and X-ray computed tomography using Dy3+ as the paramagnetic component and Nd3+ as the luminescent cation, both of them incorporated in a vanadate matrix. Among different essayed architectures (single phase and core-shell nanoparticles) the one showing the best luminescent properties is that consisting of uniform DyVO4 nanoparticles coated with a first uniform layer of LaVO4 and a second layer of Nd3+-doped LaVO4. The magnetic relaxivity (r2) at high field (9.4 T) of these nanoparticles was among the highest values ever reported for this kind of probes and their X-ray attenuation properties, due to the presence of lanthanide cations, were also better than those of a commercial contrast agent (iohexol) commonly used for X-ray computed tomography. In addition, they were chemically stable in a physiological medium in which they could be easily dispersed owing to their one-pot functionalization with polyacrylic acid, and, finally, they were non-toxic for human fibroblast cells. Such a probe is, therefore, an excellent multimodal contrast agent for near-infrared luminescent imaging, high-field magnetic resonance imaging, and X-ray computed tomography.

Exploring the mechanistic pathways of how social network influences social norms in adolescent smoking prevention interventions.

We know little about how smoking prevention interventions might leverage social network structures to enhance protective social norms. In this study we combined statistical and network science methods to explore how social networks influence social norms related to adolescent smoking in school-specific settings in Northern Ireland and Colombia. Pupils (12-15 years old) participated in two smoking prevention interventions in both countries (n = 1344). A Latent Transition Analysis identified three groups characterized by descriptive and injunctive norms towards smoking. We employed a Separable Temporal Random Graph Model to analyze homophily in social norms and conducted a descriptive analysis of the changes in the students' and their friends' social norms over time to account for social influence. The results showed that students were more likely to be friends with others who had social norms against smoking. However, students with social norms favorable towards smoking had more friends with similar views than the students with perceived norms against smoking, underlining the importance of network thresholds. Our results support the notation that the ASSIST intervention takes advantage of friendship networks to leverage greater change in the students' smoking social norms than the Dead Cool intervention, reiterating that social norms are subject to social influence.

Carboxylate functionalized NaDy(MoO4)2 nanoparticles with tunable size and shape as high magnetic field MRI contrast agents.

Uniform sodium-dysprosium double molybdate (NaDy(MoO4)2) nanoparticles having different morphologies (spheres and ellipsoids) and tunable size have been synthesized for the first time in literature. The procedure is based on a homogeneous precipitation process at moderated temperatures (≤220 °C) from solutions containing appropriated precursors dissolved in ethylene glycol-water mixtures, in the absence (spheres) or the presence (ellipsoids) of tartrate anions. The effects of the morphological characteristics (size and shape) of the nanoparticles on the magnetic relaxivity at high field (9.4 T) have been evaluated finding that the latter magnitude was higher for the spheres than for the ellipsoids, indicating their better suitability as contrast agents for high-field magnetic resonance imaging. Such nanoparticles have been successfully coated with polymers bearing carboxylate functional groups through a layer-by-layer process, which improves the colloidal stability of the nanoparticles in physiological media. It has been also found that the coating layer had no significant effects on the nanoparticles relaxivity and that such coated nanoparticles exhibited a high biocompatibility and a high chemical stability. In summary, we have developed NaDy(MoO4)2 based bioprobes which meet the required criteria for their use as contrast agents for high-field magnetic resonance imaging.

Does Carbon Footprint Play a Relevant Role in Food Consumer Behaviour? A Focus on Spanish Beef.

Carbon footprint has become a reference indicator of the environmental impact of food production. Governments are increasingly demanding a trend towards low-carbon-footprint production in order to reduce the impact on climate change. In this sense, the study of consumers' preferences and assessment of products from the perspective of their carbon footprint is crucial to achieve a green and circular economy. This paper specifically attempted to assess consumer preference and willingness to pay for beef that has been carbon-footprint-labelled as an attribute. In order to attain this objective, a choice experiment was designed and applied to a total of 362 Spanish consumers. The results revealed a positive preference towards beef produced in low-carbon-footprint systems. In addition, the segmentation of these consumers revealed the existence of a group of consumers who prioritise environmental impact over product price.

Enantioselective synthesis of 4-amino-3,4-dihydrocoumarins and their non-cyclic hydroxyester precursors: Biological evaluation for the treatment of glioblastoma multiforme.

The stereoselective addition of ethyl acetate enolate to the C═N bond of N-tert-butylsulfinylimines has been investigated in depth. A significant effect of the LHMDS amount and the N-sulfinylimine nature on the stereoselectivity of the process was observed. Conditions were found where sulfinylimines of differently substituted salicylaldehydes derivatives, ethyl acetate, and LHMDS afforded the corresponding addition products as a single diastereomer in good yields. The developed protocol was successfully applied to the first stereoselective synthesis of differently substituted 4-amino-3,4-dihydrocoumarin derivatives. Computational models confirmed the prominent role of the ortho aryl substituent in the stereoselectivity of the process. A significant and selective cytotoxic activity against Glioblastoma Multiforme (GBM) cancer line has been determined for the noncyclic hydroxy ester derivative.

Immune Lymphocyte Infiltrate and its Prognostic Value in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) occurs more frequently in young (<50 years) non-Hispanic black and Hispanic/Latina women. It is considered the most aggressive subtype of breast cancer, although, recently, immune infiltrate has been associated with long-term survival, lower risk of death and recurrence, and response to neoadjuvant chemotherapy. The aim of this review was to evaluate the clinical impact of the immune infiltrate in TNBC by discussing whether its prognostic value varies across different populations. A comprehensive systematic search in databases such as PubMed and Web of Science was conducted to include papers focused on tumor-infiltrating lymphocytes (TILs) in TNBC in different population groups and that were published before January 2021. TNBC patients with higher levels of TILs had longer overall survival and disease-free survival times compared with TNBC patients with low TIL levels. Similar results were observed for CD4+, CD8+ TIL populations. On the other hand, patients with high TIL levels showed a higher rate of pathological complete response regardless of the population group (Asian, European, and American). These results altogether suggest that TIL subpopulations might have a prognostic role in TNBC, but the underlying mechanism needs to be elucidated. Although the prognosis value of TILs was not found different between the population groups analyzed in the revised literature, further studies including underrepresented populations with different genetic ancestries are still necessary to conclude in this regard.

Outstanding MRI contrast with dysprosium phosphate nanoparticles of tuneable size.

The use of high-field magnets for magnetic resonance imaging (MRI) is expected to experience the fastest growth rate during the present decade. Although several CAs for MRI scanners using high magnetic fields have been reported, they are mostly based on fluoride matrices, which are known for their low chemical stability in aqueous suspensions. Chemically stable MRI CAs for high-field magnets are therefore needed to enable the advances in MRI technique. Herein, we synthesized uniform DyPO4 nanoparticles (NPs) with tuneable sizes between 23 and 57 nm using homogeneous precipitation in butanol. The NPs were successfully functionalized with polyacrylic acid (PAA) and showed good colloidal stability in aqueous suspensions. Chemical stability was also assessed in PBS, showing negligible solubility. The effect of particle size on the transversal relaxivity value (r2) was further explored at 9.4 T, finding a clear increase in r2 with particle size. The r2 value found for the largest NPs was 516 mM-1 s-1, which is, to the best of our knowledge, the highest r2 value ever reported at 9.4 T for any Dy-based nanometric particles in the literature. Finally, the latter NPs were submitted to biosafety studies after polyethylene glycol (PEG) functionalization. Cell morphology, induction of necrotic/late apoptotic cells, and mitochondrial activity were thoroughly analyzed. The results clearly indicated negligible toxicity effects under the assayed conditions. Short- and long-term in vivo pharmacokinetics of the intravenously injected NPs were assessed by dynamic T2-weighted MRI and quantitative T2 mapping, revealing faster liver than spleen uptake, while no accumulation was observed in the kidneys. Finally, no histopathological changes were observed in any of the studied organs, including the liver, kidney, spleen, and lung, which provide further evidence of the biocompatibility of DyPO4 NPs and, therefore, their suitability as bioimaging probes.

Iron-Gold Nanoflowers: A Promising Tool for Multimodal Imaging and Hyperthermia Therapy.

The development of nanoplatforms prepared to perform both multimodal imaging and combined therapies in a single entity is a fast-growing field. These systems are able to improve diagnostic accuracy and therapy success. Multicomponent Nanoparticles (MCNPs), composed of iron oxide and gold, offer new opportunities for Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) diagnosis, as well as combined therapies based on Magnetic Hyperthermia (MH) and Photothermal Therapy (PT). In this work, we describe a new seed-assisted method for the synthesis of Au@Fe Nanoparticles (NPs) with a flower-like structure. For biomedical purposes, Au@Fe NPs were functionalized with a PEGylated ligand, leading to high colloidal stability. Moreover, the as-obtained Au@Fe-PEG NPs exhibited excellent features as both MRI and CT Contrast Agents (CAs), with high r2 relaxivity (60.5 mM-1⋅s-1) and X-ray attenuation properties (8.8 HU mM-1⋅HU). In addition, these nanoflowers presented considerable energy-to-heat conversion under both Alternating Magnetic Fields (AMFs) (∆T ≈ 2.5 °C) and Near-Infrared (NIR) light (∆T ≈ 17 °C). Finally, Au@Fe-PEG NPs exhibited very low cytotoxicity, confirming their potential for theranostics applications.

What effect does the presence of sustainability and traceability certifications have on consumers of traditional meat products? The case of Iberian cured products in Spain.

The objective of this study was to determine the differences in the behaviour and perception of consumers from three regions in Spain with different levels of Iberian ham consumption (high, medium and low) on the attributes related to traceability and differentiated quality certifications. The study was carried out with a sample of 1501 consumers using an online questionnaire in which respondents were asked about their consumption habits regarding cured products and a choice experiment for Iberian ham was performed. The results showed that consumers give greater utility to the attributes of mandatory certification established for Iberian products (quality standards) and to the price, followed by nonmandatory quality certifications (organic, animal welfare, carbon footprint, and PDO). Specifically, animal welfare certification has been the most valued in all areas, especially in the areas with the lowest consumption.