Complutense University of Madrid

Objective. Clinical implementation of in-beam positron emission tomography (PET) monitoring in proton therapy (PT) requires the integration of an online fast and reliable dose calculation engine. This manuscript reports on the achievement of real-time reconstruction of 3D dose and activity maps with proton range verification from experimental in-beam PET measurements. Approach. Several cylindrical homogeneous PMMA phantoms were irradiated with a monoenergetic 70 MeV proton beam in a clinical facility. Additionally, PMMA range-shifting foils of varying thicknesses were placed at the proximal surface of the phantom to investigate range shift prediction capabilities. PET activity was measured using a state-of-the-art in-house developed six-module PET scanner equipped with online PET reconstruction capabilities. For real-time dose estimation, we integrated this system with an in-beam dose estimation algorithm, which combines a graphical processing unit-based 3D reconstruction algorithm with a dictionary-based software, capable of estimating deposited doses from the 3D PET activity images. The range shift prediction performance has been quantitatively studied in terms of the minimum dose to be delivered and the maximum acquisition time. Main results. With this framework, 3D dose maps were accurately reconstructed and displayed with a delay as short as one second. For a dose fraction of 8.4 Gy at the Bragg peak maximum, range shifts as small as 1 mm could be detected. The quantitative analysis shows that accumulating 20 s of statistics from the start of the irradiation, doses down to 1 Gy could be estimated online with total uncertainties smaller than 2 mm. Significance. The hardware and software combination employed in this work can deliver dose maps and accurately predict range shifts after short acquisition times and small doses, suggesting that real-time monitoring and dose reconstruction during PT are within reach. Future work will focus on testing the methodology in more complex clinical scenarios and on upgrading the PET prototype for increased sensitivity.

In this work, we compare the structural and dynamic behavior of active filaments in two dimensions using tangential and push–pull models, including a variant with passive end monomers, to bridge the two frameworks. These models serve as valuable frameworks for understanding self-organization in biological polymers and synthetic materials. At low activity, all models exhibit similar behavior; as activity increases, subtle differences emerge in intermediate regimes, but at high activity, their behaviors converge. Adjusting for differences in mean active force reveals nearly identical behavior across models, even across varying filament configurations and bending rigidities. Our results highlight the importance of force definitions in active polymer simulations and provide insights into phase transitions across varying filament configurations.

El objetivo del presente estudio aborda los retos del futuro del trabajo y las implicaciones que tiene en las empresas y las personas, utilizando un método de investigación mixta, que incluyó un cuestionario en línea dirigido a trabajadores y entrevistas semiestructuradas a directivos en Monterrey y Ciudad de México. Los resultados cuantitativos revelan un incremento en la adopción de esquemas de trabajo híbrido, que pasó de un 21.7% en 2020 a un 39.9% en 2022. De acuerdo con los hallazgos encontrados se destacan las principales categorías que se consideran relevantes considerar como el trabajo remoto, las modalidades híbridas, la tecnología y la automatización como elementos clave para la adaptación organizacional de los nuevos modelos de negocios, destacando así la originalidad de la investigación. Así mismo se concluye que las modalidades de trabajo han dejado de ser una solución temporal para convertirse en una estrategia clave a largo plazo y que estarán impactando en las formas de realizar el trabajo y en la cultura de las organizaciones, algunas limitaciones se relacionan con el contexto metodológico de la investigación.

Polyhalides are molecular systems that defy conventional views of chemical bonding, being infinite linear halide chains the most challenging systems. By studying CsI3 under compression, we show how I3‒ polyanions, with electron-rich multicenter bonds, polymerize giving rise to infinite linear iodine chains, I∞, and demonstrate that these chains, and, by extension, infinite linear halide chains, feature electron-deficient multicenter bonds. This result is in sharp contrast with previous assumptions that considered this type of bond to be impossible in valence electron-rich elements as halogens. Importantly, the process of formation of electron-deficient multicenter bonds in CsI3 at high pressure agrees with the recently proposed unified theory of multicenter bonding.

Toll‐like receptor 2 (TLR2) is involved in infectious diseases, inflammatory processes and carcinogenesis. Soluble TLR2 (sTLR2) can be released into circulation stream acting as an endogenous negative regulator of TLR2 signaling, essential for the prevention of chronic inflammation and tissue destruction. In this context, we propose pioneering electrochemical biotechnology for the determination of sTLR2 in plasma of colorectal cancer (CRC) patients. The method involves the use of magnetic particles as micro‐supports for the implementation of a sandwich immunoassay using a pair of specific antibodies and horseradish peroxidase as enzymatic tracer to carry out the amperometric transduction on screen‐printed carbon electrodes in the presence of H2O2 and hydroquinone. The proposed immunoplatform shows attractive operational and analytical characteristics, reaching a low limit of detection of 241 pg mL⁻¹ for TLR2 standards in buffered solutions, and showing an excellent reproducibility (RSD 1.4 %), and a wide dynamic range (804 to 25000 pg mL⁻¹). It has been applied to the analysis of a cohort of 21 plasma samples from healthy individuals and CRC patients at different stages of the disease, demonstrating precise quantitative determinations, in just 45 min and requiring minimal sample amount and pre‐treatments. The results demonstrate the promising utility of TRL2 plasma levels for minimally invasive monitoring of CRC progression.

The ethical obligation of psychiatrist includes acting in the best interest of the patient, doing no harm, and observing justice, i.e. acting with regard to the limited resources of the community. Psychiatrist can perform this best if it is sensitive on the one hand to the consequences of the determination that an illness value is a disorder, if it is consider not only the medical but also the psychic and social consequences of a diagnosis, and, on the other hand, if the diagnostic competence not only to apply the standardised diagnostic algorithms for assessing the illness of the patient but also for the patient's personal experience of ill being. Furthermore, the moral valuation of our language (and of our scientific instruments expressed in language) should be recognized and its influence should be reflected in the diagnostic assessment of a disorder; it should be considered particularly in assessing the individuality of the patient as a sick person and should be used in dealing with him and optimizing treatment.

Photoacoustic (PA) imaging, by integrating optical and ultrasound (US) modalities, combines high spatial resolution with deep tissue penetration, making it a transformative tool in biomedical research. This review presents a comprehensive analysis of the current status of dual PA/US imaging technologies, emphasising their applications in preclinical research. It details advancements in light excitation strategies, including tomographic and microscopic modalities, innovations in pulsed laser and alternative light sources, and US instrumentation. The review further explores preclinical methodologies, encompassing dedicated instrumentation, signal processing, and data analysis techniques essential for PA/US systems. Key applications discussed include the visualisation of blood vessels, micro-circulation, and tissue perfusion; diagnosis and monitoring of inflammation; evaluation of infections, atherosclerosis, burn injuries, healing, and scar formation; assessment of liver and renal diseases; monitoring of epilepsy and neurodegenerative conditions; studies on brain disorders and preeclampsia; cell therapy monitoring; and tumour detection, staging, and recurrence monitoring. Challenges related to imaging depth, resolution, cost, and the translation of contrast agents to clinical practice are analysed, alongside advancements in high-speed acquisition, artificial intelligence-driven reconstruction, and innovative light-delivery methods. While clinical translation remains complex, this review underscores the crucial role of preclinical studies in unravelling fundamental biomedical questions and assessing novel imaging strategies. Ultimately, this review delves into the future trends of dual PA/US imaging, highlighting its potential to bridge preclinical discoveries with clinical applications and drive advances in diagnostics, therapeutic monitoring, and personalised medicine.

During meiosis, homologous chromosomes exchange genetic material through crossing over. The main crossover pathway relies on ZMM proteins, including ZIP4 and HEI10, and is typically resolved by the MLH1/MLH3 heterodimer, MutLγ. Our analysis shows that while MUS81 may partially compensate for MutLγ loss, its role remains uncertain. However, our multiple mutant analysis shows that MUS81 is unlikely to be the sole resolvase of ZMM-protected recombination intermediates when MutLγ is absent. Comparing genome-wide crossover maps of mlh1 mutants with ZMM-deficient mutants and lines with varying HEI10 levels reveals that crossover interference persists in mlh1 but is weakened. The significant crossover reduction in mlh1 also increases aneuploidy in offspring. The loss of MutLγ can be suppressed by eliminating the FANCM helicase. Combined with the lower-than-expected chiasma frequency, this suggests that in MutLγ absence, some ZMM-protected intermediates are ultimately resolved by DNA helicases and/or their complexes with Top3α. Elevated MLH1 or MLH3 expression moderately increases crossover frequency, while their misregulation drastically reduces crossover numbers and plant fertility, highlighting the importance for tight control of MLH1/MLH3 levels. By contrast, PMS1, a component of the MutLα endonuclease, appears uninvolved in crossing over. Together, these findings demonstrate the unique role of MutLγ in ZMM-dependent crossover regulation.

Graphene has attracted significant attention in dentistry due to its structural and adhesive properties, enhancing the mechanical performance of dental composites. This study investigates the behavior and interaction of monomers and graphene-based adhesives using molecular docking and molecular dynamics (MD) simulations. Binding energies and interactions between monomers and graphene derivatives were assessed using molecular docking, while MD simulations with the Forcite module and COMPASS II force field provided insights into the mechanical properties of the composites. The simulations involved energy minimization, NVT/NPT ensembles, and equilibration for 50 ns. The binding energies of the monomer-graphene complexes ranged from − 16.27 to -18.55 kcal/mol, with the Bis-GMA-Graphene Quantum Dot complex showing the most stable interaction. Mechanical properties such as Young’s modulus, shear modulus, and flexural strength were calculated for selected complexes: Bis-GMA-Graphene Quantum Dot (14.74 GPa, 9.32 GPa, 120.51 MPa), EBPADMA-Graphene Quantum Dot (14.28 GPa, 9.13 GPa, 118.22 MPa), HEMA-Nitrogen-doped Graphene (9.85 GPa, 6.86 GPa, 95.7 MPa), TEGDMA-Graphene Oxide (11.96 GPa, 8.12 GPa, 110.23 MPa), and UDMA-CCOOH Functionalized Graphene (13.82 GPa, 8.43 GPa, 115.4 MPa). The Bis-GMA-Graphene Quantum Dot complex showed the highest stability with 20 hydrogen bonds. These results highlight graphene quantum dots and functionalized graphene derivatives as promising candidates for high-performance dental composites, offering strong adhesive properties and improved mechanical strength. Future research may focus on further optimizing these interactions and exploring additional graphene modifications.

We introduce the notion of the realifications of an arbitrary holomorphic partial differential relation R$\mathcal {R}$, that are partial differential relations associated with the restrictions of R$\mathcal {R}$ to totally real submanifolds of maximal dimension. Our main result states that if any realification of an open holomorphic partial differential relation over a Stein manifold satisfies a relative to domain hh‐principle, then it is possible to deform any formal solution into one that is holonomic in a neighborhood of a Lagrangian skeleton of the Stein manifold. If the Stein manifold is an open Riemann surface or it has finite type, then that skeleton is independent of the formal solution. This yields the existence of local hh‐principles over that skeleton. These results broaden those obtained by Forstnerič and Slapar on holomorphic immersions, submersions, and complex contact structures for instance to holomorphic local hh‐principles for the corresponding version in the complex category of some other classical examples of distributions and structures in the smooth category such as complex even contact, complex Engel, and complex twisted locally conformal symplectic structures.

A multifunctional cerium oxide nanoparticles (CeO2NPs)-based nanolabel is exploited to implement an electrochemical sandwich-type immunoplatform for the determination of T-cell immunoglobulin and mucin domain 1 (TIM-1) biomarker, a mucin-like class I membrane glycoprotein associated with cancer angiogenesis. The immunoplatform is constructed using screen-printed electrodes where capture antibody is immobilized through the chemistry of diazonium salts. CeO2NPs exhibit robust pseudo-peroxidase activity even at high substrate concentrations. They are covalently functionalized in a simple manner after carboxylation with a detector antibody (dAb), acting dually as a nanozyme and nanocarrier for sensing bioreceptors. This allows the development of immunoplatforms with improved robustness and performance (in terms of a moderate enhancement in sensitivity, a significant expansion in the linear range, and a reduction in the background current) compared with the immunoplatforms prepared using nanolabels also decorated with the natural enzyme (horseradish peroxidase, HRP) or the conventional enzymatic labeling involving the dAb and an HRP-secondary antibody. Under the optimized experimental conditions, the developed electrochemical immunoplatform allows the highly sensitive detection of the TIM-1 glycoprotein, with a detection limit of 9.9 pg mL⁻¹ and a linear working range of 33–600 pg mL⁻¹. This performance permits biomarker quantification within clinically relevant ranges. This innovative configuration enables the precise diagnosis and stratification of colorectal cancer patients by analyzing plasma samples without pretreatment beyond a sample dilution and allows establishment of the first cut-off values reported for this purpose. Graphical abstract

Cattle ( Bos taurus ) play an important role in the life of humans in the Iberian Peninsula not just as a food source but also in cultural events. When domestic cattle were first introduced to Iberia, wild aurochs ( Bos primigenius ) were still present, leaving ample opportunity for mating (whether intended by farmers or not). Using a temporal bioarchaeological dataset covering eight millennia, we trace gene flow between the two groups. Our results show frequent hybridisation during the Neolithic and Chalcolithic, likely reflecting a mix of hunting and herding or relatively unmanaged herds, with mostly male aurochs and female domestic cattle involved. This is supported by isotopic evidence consistent with ecological niche sharing, with only a few domestic cattle possibly being managed. The proportion of aurochs ancestry in domestic cattle remains relatively constant from about 4000 years ago, probably due to herd management and selection against first generation hybrids, coinciding with other cultural transitions. The constant level of wild ancestry (~20%) continues into modern Western European breeds including Iberian cattle selected for aggressiveness and fighting ability. This study illuminates the genomic impact of human actions and wild introgression in the establishment of cattle as one of the most important domestic species today.

Background Recently, magnetic composite biomaterials have raised attention in bone tissue engineering as the application of dynamic magnetic fields proved to modulate the proliferation and differentiation of several cell types. Methods This study presents a novel method to fabricate biofunctional magnetic scaffolds by the deposition of superparamagnetic iron oxide nanoparticles (SPIONs) through thermal Drop-On-Demand inkjet printing on three-dimensional (3D) printed scaffolds. Firstly, 3D scaffolds based on thermoplastic polymeric composed by poly-L-lactic acid/poly-caprolactone/poly(3-hydroxybutyrate-co-3-hydroxyvalerate) were fabricated by Fused Deposition Modelling. Then, in a second step, SPIONs were incorporated onto the surface of the scaffolds by inkjet printing following a designed 2D pattern. Results A complete characterization of the resulting magnetic scaffolds was carried out attending to the surface SPIONs deposits, demonstrating the accuracy and versatility of the production technique, as well as the stability under physiological conditions and the magnetic properties. Biological evaluation with human bone marrow mesenchymal stems cells demonstrated biocompatibility of the scaffolds and increased osteogenic capability under the application of a magnetic field, due to the activation of mechanotransduction processes. Conclusion These results show that the developed 3D magnetic biofunctional scaffolds can be a very promising tool for advanced and personalised bone regeneration treatments. Graphical abstract