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Abstract Disorders of consciousness (DoC) represent a challenging and complex group of neurological conditions characterised by profound disturbances in consciousness. The current range of treatments for DoC is limited. This has sparked growing interest in developing new treatments, including the use of psychedelic drugs. Nevertheless, clinical investigations and the mechanisms behind them are methodologically and ethically constrained. To tackle these limitations, we combined biologically plausible whole-brain models with deep learning techniques to characterise the low-dimensional space of DoC patients. We investigated the effects of model pharmacological interventions by including the whole-brain dynamical consequences of the enhanced neuromodulatory level of different neurotransmitters, and providing geometrical interpretation in the low-dimensional space. Our findings show that serotonergic and opioid receptors effectively shifted the DoC models towards a dynamical behaviour associated with a healthier state, and that these improvements correlated with the mean density of the activated receptors throughout the brain. These findings mark an important step towards the development of treatments not only for DoC but also for a broader spectrum of brain diseases. Our method offers a promising avenue for exploring the therapeutic potential of pharmacological interventions within the ethical and methodological confines of clinical research.

Abstract A new lithostrotian titanosaur, Qunkasaura pintiquiniestra gen. et sp. nov., is described based on a single partial skeleton from the late Campanian-early Maastrichtian fossil-site of Lo Hueco (Cuenca, Spain). This new taxon is supported by an exclusive combination of characters that highlights strong convergences with members of the South American Aeolosaurini. Qunkasaura allows to reorganise the complex phylogenetic relationships of the increasingly diverse finicretaceous sauropods of Europe. Phylogenetic analyses places Qunkasaura within Saltasauridae and possibly Opisthocoelicaudiinae, together with Abditosaurus. A new clade is established, Lohuecosauria, including Saltasaurus, Lohuecotitan, their most recent common ancestor and all its descendants. Two distinct Ibero-Armorican Campanian-Maastrichtian saltasauroid lineages are recognised: (i) Lirainosaurinae that is exclusive from Europe, and (ii) a saltasaurid lineage with possible opisthocoelicaudiine affinities, with a Laurasian distribution. Lirainosaurinae was a relict lineage including possible dwarf forms that evolved in isolation after reaching Europe before the Late Cretaceous through the Apulian route. The occurrence of opisthocoelicaudiines in Europe may be the result of a Late Cretaceous interchange between Europe and Asia. No evidence of insular dwarfism is found in the Ibero-Armorican opisthocoelicaudiines suggesting that they may have been newcomers to the area that arrived before the ‘Maastrichtian Dinosaur Turnover’ in southwestern Europe.

Abstract Brain damage triggers diverse cellular and molecular events, with astrocytes playing a crucial role in activating local neuroprotective and reparative signaling within damaged neuronal circuits. Here, we investigated reactive astrocytes using a multidimensional approach to categorize their responses into different subtypes based on morphology. This approach utilized the StarTrack lineage tracer, single-cell imaging reconstruction and multivariate data analysis. Our findings identified three profiles of reactive astrocyte responses, categorized by their effects on cell size- and shape- related morphological parameters: “moderate”, “strong,” and “very strong”. We also examined the heterogeneity of astrocyte reactivity, focusing on spatial and clonal distribution. Our research revealed a notable enrichment of protoplasmic and fibrous astrocytes within the “strong” and “very strong” response subtypes. Overall, our study contributes to a better understanding of astrocyte heterogeneity in response to an injury. By characterizing the diverse reactive responses among astrocyte subpopulations, we provide insights that could guide future research aimed at identifying novel therapeutic targets to mitigate brain damage and promote neural repair. Graphical Abstract

Abstract Background The gut microbiota controls broad aspects of human metabolism and feeding behavior, but the basis for this control remains largely unclear. Given the key role of human dipeptidyl peptidase 4 (DPP4) in host metabolism, we investigate whether microbiota DPP4-like counterparts perform the same function. Results We identify novel functional homologs of human DPP4 in several bacterial species inhabiting the human gut, and specific associations between Parabacteroides and Porphyromonas DPP4-like genes and type 2 diabetes (T2D). We also find that the DPP4-like enzyme from the gut symbiont Parabacteroides merdae mimics the proteolytic activity of the human enzyme on peptide YY, neuropeptide Y, gastric inhibitory polypeptide (GIP), and glucagon-like peptide 1 (GLP-1) hormones in vitro. Importantly, administration of E. coli overexpressing the P. merdae DPP4-like enzyme to lipopolysaccharide-treated mice with impaired gut barrier function reduces active GIP and GLP-1 levels, which is attributed to increased DPP4 activity in the portal circulation and the cecal content. Finally, we observe that linagliptin, saxagliptin, sitagliptin, and vildagliptin, antidiabetic drugs with DPP4 inhibitory activity, differentially inhibit the activity of the DPP4-like enzyme from P. merdae. Conclusions Our findings confirm that proteolytic enzymes produced by the gut microbiota are likely to contribute to the glucose metabolic dysfunction that underlies T2D by inactivating incretins, which might inspire the development of improved antidiabetic therapies.

To enable transmission of information in the brain, synaptic vesicles fuse to presynaptic membranes, liberating their content and exposing transiently a myriad of vesicular transmembrane proteins. However, versatile methods for quantifying the synaptic translocation of endogenous proteins during neuronal activity remain unavailable, as the fast dynamics of synaptic vesicle cycling difficult specific isolation of trafficking proteins during such a transient surface exposure. Here, we developed a novel approach using synaptic cleft proximity labeling to capture and quantify activity-driven trafficking of endogenous synaptic proteins at the synapse. We show that accelerating cleft biotinylation times to match the fast dynamics of vesicle exocytosis allows capturing endogenous proteins transiently exposed at the synaptic surface during neural activity, enabling for the first time the study of the translocation of nearly every endogenous synaptic protein. As proof-of-concept, we further applied this technology to obtain direct evidence of the surface translocation of noncanonical trafficking proteins, such as ATG9A and NPTX1, which had been proposed to traffic during activity but for which direct proof had not yet been shown. The technological advancement presented here will facilitate future studies dissecting the molecular identity of proteins exocytosed at the synapse during activity, helping to define the molecular machinery that sustains neurotransmission in the mammalian brain.

We analyzed here how formin-like 1 β (FMNL1β), an actin cytoskeleton-regulatory protein, regulates microtubule-organizing center (MTOC) and multivesicular bodies (MVB) polarization and exosome secretion at an immune synapse (IS) model in a phosphorylation-dependent manner. IS formation was associated with transient recruitment of FMNL1β to the IS, which was independent of protein kinase C δ (PKCδ). Simultaneous RNA interference of all FMNL1 isoforms prevented MTOC/MVB polarization and exosome secretion, which were restored by FMNL1βWT expression. However, expression of the non-phosphorylatable mutant FMNL1βS1086A did not restore neither MTOC/MVB polarization nor exosome secretion to control levels, supporting the crucial role of S1086 phosphorylation in MTOC/MVB polarization and exosome secretion. In contrast, the phosphomimetic mutant, FMNL1βS1086D, restored MTOC/MVB polarization and exosome secretion. Conversely, FMNL1βS1086D mutant did not recover the deficient MTOC/MVB polarization occurring in PKCδ-interfered clones, indicating that S1086 FMNL1β phosphorylation alone is not sufficient for MTOC/MVB polarization and exosome secretion. FMNL1 interference inhibited the depletion of F-actin at the central region of the immune synapse (cIS), which is necessary for MTOC/MVB polarization. FMNL1βWT and FMNL1βS1086D, but not FMNL1βS1086A expression, restored F-actin depletion at the cIS. Thus, actin cytoskeleton reorganization at the IS underlies the effects of all these FMNL1β variants on polarized secretory traffic. FMNL1 was found in the IS made by primary T lymphocytes, both in T cell receptor (TCR) and chimeric antigen receptor (CAR)-evoked synapses. Taken together, these results point out a crucial role of S1086 phosphorylation in FMNL1β activation, leading to cortical actin reorganization and subsequent control of MTOC/MVB polarization and exosome secretion.

Friedreich ataxia (FA) is a rare neurodegenerative disease caused by decreased levels of the mitochondrial protein frataxin. Frataxin has been related in iron homeostasis, energy metabolism, and oxidative stress. Ferroptosis has recently been shown to be involved in FA cellular degeneration; however, its role in dorsal root ganglion (DRG) sensory neurons, the cells that are affected the most and the earliest, is mostly unknown. In this study, we used primary cultures of frataxin-deficient DRG neurons as well as DRG from the FXNI151F mouse model to study ferroptosis and its regulatory pathways. A lack of frataxin induced upregulation of transferrin receptor 1 and decreased ferritin and mitochondrial iron accumulation, a source of oxidative stress. However, there was impaired activation of NRF2, a key transcription factor involved in the antioxidant response pathway. Decreased total and nuclear NRF2 explains the downregulation of both SLC7A11 (a member of the system Xc, which transports cystine required for glutathione synthesis) and glutathione peroxidase 4, responsible for increased lipid peroxidation, the main markers of ferroptosis. Such dysregulation could be due to the increase in KEAP1 and the activation of GSK3β, which promote cytosolic localization and degradation of NRF2. Moreover, there was a deficiency in the LKB1/AMPK pathway, which would also impair NRF2 activity. AMPK acts as a positive regulator of NRF2 and it is activated by the upstream kinase LKB1. The levels of LKB1 were reduced when frataxin decreased, in agreement with reduced pAMPK (Thr172), the active form of AMPK. SIRT1, a known activator of LKB1, was also reduced when frataxin decreased. MT-6378, an AMPK activator, restored NRF2 levels, increased GPX4 levels and reduced lipid peroxidation. In conclusion, this study demonstrated that frataxin deficiency in DRG neurons disrupts iron homeostasis and the intricate regulation of molecular pathways affecting NRF2 activation and the cellular response to oxidative stress, leading to ferroptosis.

Extensive efforts have been conducted in the search for new targetable drivers of lung squamous cell carcinoma (LUSC); to date, however, candidates remain mostly unsuccessful. One of the oncogenic pathways frequently found to be active in LUSC is NFE2L2 (NRF2 transcription factor), the levels of which are regulated by KEAP1. Mutations in NFE2L2 or KEAP1 trigger NRF2 activation, an essential protector against reactive oxygen species (ROS). We hypothesized that the frequency of NRF2 activation in LUSC (∼35 %) may reflect a sensitivity of LUSC to ROS. Results from this study reveal that whereas tumors containing active forms of NRF2 were protected, ROS induction in wild-type NFE2L2/KEAP1 LUSC cells triggered ferroptosis. The mechanism of ROS action in normal-NRF2 LUSC cells involved transient NRF2 activation, miR-126-3p/miR-126-5p upregulation, and reduction of p85β and SETD5 levels. SETD5 levels reduction triggered pentose pathway gene levels increase to toxic values. Simultaneous depletion of p85βPI3K and SETD5 triggered LUSC cell death, while p85βPI3K and SETD5 overexpression rescued survival of ROS-treated normal-NRF2 LUSC cells. This shows that the cascade involving NRF2 > miR-126-3p, miR-126-5p > p85βPI3K and SETD5 is responsible for ROS-induced cell death in normal-NRF2 LUSC. Transient ROS-induced cell death is shown in 3D spheroids, patient-derived organoids, and in xenografts of wild-type NFE2L2/KEAP1 LUSC cells, supporting the potential of acute local ROS induction as a therapeutic strategy for LUSC patients with normal-NRF2.

The dynamics of tissue wound healing associated with dental implants placed in fresh extraction sockets or in healed alveolar ridges are not fully understood. Therefore, the aim of this preclinical in vivo investigation was to evaluate soft tissue healing and osseointegration after immediate implant placement, compared with delayed implant placement, using histomorphometric and immunohistochemical analyses. Methods: In 8 dogs, immediate postextraction implants and delayed implants were evaluated. After 2 and 8 weeks of healing, dissected tissue blocks were processed for calcified and decalcified histological analysis. Histometric measurements for soft tissue height and width were performed. Immunohistochemical analysis for the evaluation of bone metabolism, immune response and angiogenesis was performed. Results: At 2 weeks, histometric analysis showed that peri-implant soft tissue height was significantly greater in the immediate implant group (4.47 mm ± 0.78) compared to the delayed implant group (2.92 mm ± 0.51, p = 0.028), primarily due to the connective tissue height. Immunohistochemical analysis indicated significantly higher alkaline phosphatase (ALP) (6.85 ± 5.17 vs. 3.56 ± 2.31, p < 0.05) and matrix metalloproteinase (MMP2) activity (1.59 ± 1.64 vs. 0.58 ± 0.48, p < 0.05) in immediate implants, suggesting increased osteogenic and matrix metalloproteinase activity. At 8 weeks, the peri-implant soft tissue height remained higher in the immediate implant group (3.43 mm ± 0.83) compared to the delayed implant group (2.4 mm ± 0.37, p = 0.088), although the difference was less pronounced. Immunohistochemical differences between groups diminished in late healing stages. Conclusions: Soft tissue dimensions around immediate implants differ from those established around staged implants placed on healed alveolar ridges. Moreover, osseointegration dynamics around immediate implants may occur at a different rate compared with staged implants.

Summary: Cell cycle progression is regulated by the orderly balance between kinase and phosphatase activities. PP2A phosphatase holoenzymes containing the B55 family of regulatory B subunits function as major CDK1-counteracting phosphatases during mitotic exit in mammals. However, the identification of the specific mitotic roles of these PP2A-B55 complexes has been hindered by the existence of multiple B55 isoforms. Here, through the generation of loss-of-function genetic mouse models for the two ubiquitous B55 isoforms (B55α and B55δ), we report that PP2A-B55α and PP2A-B55δ complexes display overlapping roles in controlling the dynamics of proper chromosome individualization and clustering during mitosis. In the absence of PP2A-B55 activity, mitotic cells display increased chromosome individualization in the presence of enhanced phosphorylation and perichromosomal loading of Ki-67. These data provide experimental evidence for a regulatory mechanism by which the balance between kinase and PP2A-B55 phosphatase activity controls the Ki-67-mediated spatial organization of the mass of chromosomes during mitosis.

Abstract Recent evidence suggests a role of sensory neurons expressing the sodium channel Nav1.8 on the energy homeostasis control. Using a murine diphtheria toxin ablation strategy and ad libitum and time-restricted feeding regimens of control or high-fat high-sugar diets, here we further explore the function of these neurons on food intake and on the regulation of gastrointestinal elements transmitting immune and nutrient sensing. The Nav1.8+ neuron ablation increases food intake in ad libitum and time-restricted feeding, and exacerbates daily body weight variations. Mice lacking Nav1.8+ neurons show impaired prandial regulation of gut hormone secretion and gut microbiota composition, and altered intestinal immunity. Our study demonstrates that Nav1.8+ neurons are required to control food intake and daily body weight changes, as well as to maintain physiological enteroendocrine and immune responses and the rhythmicity of the gut microbiota, which highlights the potential of Nav1.8+ neurons to restore energy balance in metabolic disorders.

This paper explores the potential use of fused deposition modeling (FDM) technology for manufacturing microwave and millimeter-wave dielectric resonator antennas (DRAs) for 5G and beyond communication systems. DRAs operating at microwave and millimeter-wave (mmWave) frequency bands were simulated, fabricated, and analyzed in terms of manufacturing quality and radio frequency (RF) performance. Samples were manufactured using a 3D printer and PREPERM® ABS1000 filament, which offers a stable dielectric constant (εr = 10 ± 0.35) and low losses (tan δ = 0.003) over wide frequency and temperature ranges. Surface profile tests and microscope measurements revealed discrepancies in the dimensions in the xy-plane and along the z-axis, consistent with the observed shift in resonant frequency. Despite these variations, reasonably good agreement between RF-simulated and measured results was achieved, and the DRA array successfully covered the intended mmWave band. However, challenges in achieving high precision may restrict applications at higher mmWave bands. Nevertheless, compared with conventional methods, FDM techniques offer a highly accessible and flexible solution with a wide range of materials for home and micro-manufacturing of mmWave DRAs for modern 5G systems.

Falls are a major health hazard for older adults; therefore, in the context of an aging population, predicting the risk of a patient suffering falls in the near future is of great impact for health care systems. Currently, the standard prospective fall risk assessment instrument relies on a set of clinical and functional mobility assessment tools, one of them being the Timed Up and Go (TUG) test. Recently, wearable inertial measurement units (IMUs) have been proposed to capture motion data that would allow for the building of estimates of fall risk. The hypothesis of this study is that the data gathered from IMU readings while the patient is performing the TUG test can be used to build a predictive model that would provide an estimate of the probability of suffering a fall in the near future, i.e., assessing prospective fall risk. This study applies deep learning convolutional neural networks (CNN) and recurrent neural networks (RNN) to build such predictive models based on features extracted from IMU data acquired during TUG test realizations. Data were obtained from a cohort of 106 older adults wearing wireless IMU sensors with sampling frequencies of 100 Hz while performing the TUG test. The dependent variable is a binary variable that is true if the patient suffered a fall in the six-month follow-up period. This variable was used as the output variable for the supervised training and validations of the deep learning architectures and competing machine learning approaches. A hold-out validation process using 75 subjects for training and 31 subjects for testing was repeated one hundred times to obtain robust estimations of model performances At each repetition, 5-fold cross-validation was carried out to select the best model over the training subset. Best results were achieved by a bidirectional long short-term memory (BLSTM), obtaining an accuracy of 0.83 and AUC of 0.73 with good sensitivity and specificity values.

The TaqIA polymorphism is a marker of both the Ankyrin Repeat and Kinase Domain containing I gene (ANKK1) encoding a RIP-kinase, and the DRD2 gene for the dopamine receptor D2. Despite a large number of studies of TaqIA in addictions and other psychiatric disorders, there is difficulty in interpreting this genetic phenomenon due to the lack of knowledge about ANKK1 function. In SH-SY5Y neuroblastoma models, we show that ANKK1 interacts with the synapse protein FERM ARH/RhoGEF and Pleckstrin Domain 1 (FARP1), which is a guanine nucleotide exchange factor (GEF) of the RhoGTPases RAC1 and RhoA. ANKK1–FARP1 colocalized in F-ACTIN-rich structures for neuronal maturation and migration, and both proteins activate the Wnt/PCP pathway. ANKK1, but not FARP1, promotes neuritogenesis, and both proteins are involved in neuritic spine outgrowth. Notably, the knockdown of ANKK1 or FARP1 affects RhoGTPases expression and neural differentiation. Additionally, ANKK1 binds WGEF, another GEF of Wnt/PCP, regulating its interaction with RhoA. During neuronal differentiation, ANKK1–WGEF interaction is downregulated, while ANKK1–FARP1 interaction is increased, suggesting that ANKK1 recruits Wnt/PCP components for bidirectional control of F-ACTIN assembly. Our results suggest a brain structural basis in TaqIA-associated phenotypes.

The Mediterranean diet (MD) has beneficial effects on the intestinal microbiota by the promotion of bacteria associated with a healthy gut. However, its impact on intestinal fungi, among others, is still unknown, and how it affects digestive symptoms and different biomarkers in patients with gastrointestinal (GI) disorders has hardly been explored. The present study evaluated the effect of the MD on gut microbial diversity and structure and intestinal symptoms and biomarkers after 6 weeks of dietary intervention in 46 patients with GI disorders. Dysbiosis in fungal composition and diversity was observed, with a significantly lower abundance of Sordariomycetes, Leotiomycetes, and Orbiliomycetes; a significantly higher abundance of Saccharomycetes; the Chytridiomycota and Mucoromycota phyla were significantly reduced; and the bacterial microbiota remained unchanged. In addition, various GI disorders decreased and associations between stool consistency and intestinal permeability were found with the bacterial genera Alistipes and Roseburia. Thus, the data suggest that MD can alter the fungal intestinal microbiota and improve GI disorders.

Peripheral neurons are heterogeneous and functionally diverse, but all share the capability to switch to a pro-regenerative state after nerve injury. Despite the assumption that the injury response is similar among neuronal subtypes, functional recovery may differ. Understanding the distinct intrinsic regenerative properties between neurons may help to improve the quality of regeneration, prioritizing the growth of axon subpopulations to their targets. Here, we present a comparative analysis of regeneration across four key peripheral neuron populations: motoneurons, proprioceptors, cutaneous mechanoreceptors, and nociceptors. Using Cre/Ai9 mice that allow fluorescent labeling of neuronal subtypes, we found that nociceptors showed the greater regeneration after a sciatic crush, followed by motoneurons, mechanoreceptors, and, finally, proprioceptors. By breeding these Cre mice with Ribotag mice, we isolated specific translatomes and defined the regenerative response of these neuronal subtypes after axotomy. Only 20% of the regulated genes were common, revealing a diverse response to injury among neurons, which was also supported by the differential influence of neurotrophins among neuron subtypes. Among differentially regulated genes, we proposed MED12 as a specific regulator of the regeneration of proprioceptors. Altogether, we demonstrate that the intrinsic regenerative capacity differs between peripheral neuron subtypes, opening the door to selectively modulate these responses.

A fundamental challenge in neuroscience is accurately defining brain states and predicting how and where to perturb the brain to force a transition. Here, we investigated resting-state fMRI data of patients suffering from disorders of consciousness (DoC) after coma (minimally conscious and unresponsive wakefulness states) and healthy controls. We applied model-free and model-based approaches to help elucidate the underlying brain mechanisms of patients with DoC. The model-free approach allowed us to characterize brain states in DoC and healthy controls as a probabilistic metastable substate (PMS) space. The PMS of each group was defined by a repertoire of unique patterns (i.e., metastable substates) with different probabilities of occurrence. In the model-based approach, we adjusted the PMS of each DoC group to a causal whole-brain model. This allowed us to explore optimal strategies for promoting transitions by applying off-line in silico probing. Furthermore, this approach enabled us to evaluate the impact of local perturbations in terms of their global effects and sensitivity to stimulation, which is a model-based biomarker providing a deeper understanding of the mechanisms underlying DoC. Our results show that transitions were obtained in a synchronous protocol, in which the somatomotor network, thalamus, precuneus and insula were the most sensitive areas to perturbation. This motivates further work to continue understanding brain function and treatments of disorders of consciousness.

Background Previous research in nursing has found favorable results from the use of teaching methodologies alternative to lectures. One of the complementary methodologies used for university teaching is gamification, or the inclusion of game elements, creating a dynamic learning environment that allows the acquisition of knowledge and the development of other skills necessary for nursing students. The purpose of this study was to evaluate the effect of a gamification session on student satisfaction and knowledge scores in nursing students in simulated laboratory practice. Methods A pre-post quasi-experimental study was conducted with 122 students from the nursing degree program who participated in the research. The evaluation consisted of four sessions of three hours each. In two sessions, participants were trained through a vertical methodology, by means of theoretical training provided by teaching staff, and two hours of clinical simulation, where the students were able to practice the techniques on professional simulators. At the other two sessions, participants received an explanation of the theoretical aspects of the session, one hour of clinical simulation, and one hour of gamification, in which they had to pass tests based on the performance of practical activities on the subject of the session. At the end of the gamification session, all the participants received a certificate as winners of the “nursing game”. Results There was an improvement in the satisfaction and the knowledge level in the gamification sessions. Both were statistically significant (P < 0.001). There was an improvement in the items related to the development of critical thinking and the mobilizing concepts from theory to practice in the gamification sessions. Conclusion The intervention was effective in improving the satisfaction of the sessions received and in knowledge development.

Summary: Nitric oxide (NO) is a gasotransmitter required in a broad range of mechanisms controlling plant development and stress conditions. However, little is known about the specific role of this signaling molecule during lipid storage in the seeds. Here, we show that NO is accumulated in developing embryos and regulates the fatty acid profile through the stabilization of the basic/leucine zipper transcription factor bZIP67. NO and nitro-linolenic acid target and accumulate bZIP67 to induce the downstream expression of FAD3 desaturase, which is misregulated in a non-nitrosylable version of the protein. Moreover, the post-translational modification of bZIP67 is reversible by the trans-denitrosylation activity of peroxiredoxin IIE and defines a feedback mechanism for bZIP67 redox regulation. These findings provide a molecular framework to control the seed fatty acid profile caused by NO, and evidence of the in vivo functionality of nitro-fatty acids during plant developmental signaling.

Introduction: Aging induces functional and structural changes in the lung, characterized by a decline in elasticity and diminished pulmonary remodeling and regenerative capacity. Emerging evidence suggests that most biomechanical alterations in the lung result from changes in the composition of the lung extracellular matrix (ECM), potentially modulating the behavior of pulmonary cells and increasing the susceptibility to chronic lung diseases. Therefore, it is crucial to investigate the mechanical properties of the aged lung. This study aims to assess the mechanical alterations in the lung ECM due to aging at both residual (RV) and functional (FV) lung volumes and to evaluate their effects on the survival and proliferation of mesenchymal stromal cells (MSCs).Methods: The lungs from young (4-6-month-old) and aged (20-24-month-old) mice were inflated with optimal cutting temperature compound to reach FV or non-inflated (RV). ECM proteins laminin, collagen I and fibronectin were quantified by immunofluorescence and the mechanical properties of the decellularized lung sections were assessed using atomic force microscopy. To investigate whether changes in ECM composition by aging and/or mechanical properties at RV and FV volumes affects MSCs, their viability and proliferation were evaluated after 72 h.Results: Laminin presence was significantly reduced in aged mice compared to young mice, while fibronectin and collagen I were significantly increased in aged mice. In RV conditions, the acellular lungs from aged mice were significantly softer than from young mice. By contrast, in FV conditions, the aged lung ECM becomes stiffer than that of in young mice, revealing that strain hardening significantly depends on aging. Results after MSCs recellularization showed similar viability and proliferation rate in all conditions.Discussion: This data strongly suggests that biomechanical measurements, especially in aging models, should be carried out in physiomimetic conditions rather than following the conventional non-inflated lung (RV) approach. The use of decellularized lung scaffolds from aged and/or other lung disease murine/human models at physiomimetic conditions will help to better understand the potential role of mechanotransduction on the susceptibility and progression of chronic lung diseases, lung regeneration and cancer.

Summary: The posttranslational modification of proteins critically influences many biological processes and is a key mechanism that regulates the function of the RNA-binding protein Hu antigen R (HuR), a hub in liver cancer. Here, we show that HuR is SUMOylated in the tumor sections of patients with hepatocellular carcinoma in contrast to the surrounding tissue, as well as in human cell line and mouse models of the disease. SUMOylation of HuR promotes major cancer hallmarks, namely proliferation and invasion, whereas the absence of HuR SUMOylation results in a senescent phenotype with dysfunctional mitochondria and endoplasmic reticulum. Mechanistically, SUMOylation induces a structural rearrangement of the RNA recognition motifs that modulates HuR binding affinity to its target RNAs, further modifying the transcriptomic profile toward hepatic tumor progression. Overall, SUMOylation constitutes a mechanism of HuR regulation that could be potentially exploited as a therapeutic strategy for liver cancer.

Despite remarkable improvement in the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) care continuum, the rate of late diagnosis of HIV and HCV in high-income countries remains unacceptably high. Testing relies mainly on primary care physicians’ identification of risk factors. We aimed to adapt an analogic to an online questionnaire to help HIV and HCV screening and perform a pilot study to assess its accuracy and acceptability. We used the Delphi method to adapt a previously validated analogical questionnaire to a user-friendly online tool. It aimed to identify participants who should be screened for HIV or HCV and those who should be referred for pre-exposure prophylaxis (PrEP). We then designed a proof-of-concept pilot study from July to October 2022 to test its feasibility and suitability for use on a larger scale and to assess its accuracy in identifying patients at risk for HIV or HCV or with indication for PrEP. The final questionnaire consisted of 37 questions. A total of 142 participants provided informed consent, and 102 completed the questionnaire: 41 random patients recruited at the primary care level, 10 participants recently diagnosed with HIV, 20 participants with HIV on follow-up, 21 participants from the PrEP program, and 10 patients diagnosed with HCV. The tool adequately indicated the need for testing in more than 98% of participants with confirmed HIV/HCV infections or in the PrEP program. Furthermore, it adequately assessed PrEP referral in 94% of participants already on PrEP or with known HIV infection. Participants were highly satisfied with the tool, and 98% of them recommended its use. A self-administered web-based tool to identify patients who should be tested for HIV or HCV or referred to PrEP could simplify patient selection and help reduce late diagnosis.

The aim of this study was to evaluate a newly formulated mouth rinse containing cymenol in patients undergoing supportive periodontal care in terms of safety (primary outcome) and the impact on dental biofilm and gingival inflammation (secondary outcomes). This research was designed as a pilot, controlled, randomized, parallel, triple-blinded, single-center, clinical trial of a 12-week duration. Adverse events and product perception were assessed by a questionnaire. Clinical, patient-reported outcomes (PROs), compliance, tooth staining, dentin hypersensitivity and microbiological variables were also evaluated. Student T, Mann–Whitney-U and Chi-square tests were applied. Thirty participants (15 per group) were included, randomized and followed for 12 weeks. No adverse events were reported. The questionnaire showed an overall rating of 7.2 (out of 10) in the experimental group and of 8.2 in the control group (p = 0.165) at 12 weeks. No statistically significant differences were observed in terms of gingival health, tooth staining, dentin hypersensitivity or microbiological outcomes between groups at baseline, 6- and 12-week visits. The adjuvant use of the new mouth rinse formulation proved to be as safe as the control product and no significant differences were observed in terms of clinical efficacy.

In recent years, there has been growing interest in understanding the potential role of microbiota dysbiosis or alterations in the composition and function of human microbiota in the development of chronic rhinosinusitis with nasal polyposis (CRSwNP). This systematic review evaluated the literature on CRSwNP and host microbiota for the last ten years, including mainly nasal bacteria, viruses, and fungi, following the PRISMA guidelines and using the major scientific publication databases. Seventy original papers, mainly from Asia and Europe, met the inclusion criteria, providing a comprehensive overview of the microbiota composition in CRSwNP patients and its implications for inflammatory processes in nasal polyps. This review also explores the potential impact of microbiota-modulating therapies for the CRSwNP treatment. Despite variability in study populations and methodologies, findings suggest that fluctuations in specific taxa abundance and reduced bacterial diversity can be accepted as critical factors influencing the onset or severity of CRSwNP. These microbiota alterations appear to be implicated in triggering cell-mediated immune responses, cytokine cascade changes, and defects in the epithelial barrier. Although further human studies are required, microbiota-modulating strategies could become integral to future combined CRSwNP treatments, complementing current therapies that mainly target inflammatory mediators and potentially improving patient outcomes.

Knowledge of the molecular mechanisms that underlie the regulation of major adaptive responses to an unbalanced oxygen tension is central to understanding tissue homeostasis and disease. Hypoxia-inducible transcription factors (HIFs) coordinate changes in the transcriptome that control these adaptive responses. Here, we focused on the functional role of the transcriptional repressor basic-helix-loop-helix family member e40 (Bhlhe40), which we previously identified in a meta-analysis as one of the most consistently upregulated genes in response to hypoxia across various cell types. We investigated the role of Bhlhe40 in controlling proliferation and angiogenesis using a gene editing strategy in mouse embryonic stem cells (mESCs) that we differentiated in embryoid bodies (EBs). We observed that hypoxia-induced Bhlhe40 expression was compatible with the rapid proliferation of pluripotent mESCs under low oxygen tension. However, in EBs, hypoxia triggered a Bhlhe40-dependent cell cycle arrest in most progenitor cells and endothelial cells within vascular structures. Furthermore, Bhlhe40 knockout increased the basal vascularization of the EBs in normoxia and exacerbated the hypoxia-induced vascularization, supporting a novel role for Bhlhe40 as a negative regulator of blood vessel formation. Our findings implicate Bhlhe40 in mediating key functional adaptive responses to hypoxia, such as proliferation arrest and angiogenesis.

The beekeeping sector is increasingly focused on creating optimal and natural environments for honeybees to reduce dependence on external factors, especially given progressively hotter summers. Improving hive thermal conditions can enhance bee wellbeing and production. While pinewood hives are predominant, some have started using insulating materials like polystyrene. However, many synthetic materials, despite their excellent insulation properties, are incompatible with organic food production, requiring alternative solutions. This study compares the thermal insulation properties of various natural materials, including white and black agglomerated cork, wood fibres, and rock mineral wool. These materials are potentially compatible with organic food production. Additionally, the research evaluates cost-effective sensor networks to monitor bioclimatic variables in real time. Lab tests using a Langstroth-type hive with a controlled heat source were conducted, monitoring temperature and humidity inside and outside the hive. The results revealed that all selected materials provided similar thermal insulation, superior to a hive without insulation. This finding suggests that using natural materials can enhance hive thermal comfort (i.e., the material’s ability to maintain a stable internal temperature), thereby improving honeybee wellbeing and productivity in a manner compatible with organic food production.

A new family of antifibrinolytic drugs has been recently discovered, combining a triazole moiety, an oxadiazolone, and a terminal amine. Two of the molecules of this family have shown activity that is greater than or similar to that of tranexamic acid (TXA), the current antifibrinolytic gold standard, which has been associated with several side effects and whose use is limited in patients with renal impairment. The aim of this work was to thoroughly examine the mechanism of action of the two ideal candidates of the 1,2,3-triazole family and compare them with TXA, to identify an antifibrinolytic alternative active at lower dosages. Specifically, the antifibrinolytic activity of the two compounds (1 and 5) and TXA was assessed in fibrinolytic isolated systems and in whole blood. Results revealed that despite having an activity pathway comparable to that of TXA, both compounds showed greater activity in blood. These differences could be attributed to a more stable ligand–target binding to the pocket of plasminogen for compounds 1 and 5, as suggested by molecular dynamic simulations. This work presents further evidence of the antifibrinolytic activity of the two best candidates of the 1,2,3-triazole family and paves the way for incorporating these molecules as new antifibrinolytic therapies.

The International Civil Aviation Organization (ICAO) specifies that in the design phase of instrument flight procedures, an additional clearance may be added to an obstacle when flights are over mountainous terrain. This clearance increase can be up to 100 per cent of the minimum obstacle clearance (MOC). Airspace and instrument flight procedure designers usually face the problem of determining what value should be applied, since setting the maximum value of 100% often implies operational penalties, but there are no standardized criteria to determine lower values. The ICAO PANS-OPS indicates that the additional clearance over obstacles in mountainous areas is caused by two effects, both related to orography and wind speed. The first effect is due to the altimeter indication error. The second one is related to the loss of altitude when an aircraft is exposed to turbulence produced by mountain waves. This paper presents a methodology for determining the additional clearance to be applied over obstacles when, in the flight procedure design phase, the overflight of mountainous terrain is expected. Through this methodology, results have been achieved for the proposal of an appropriate additional clearance. The development of graphs and tables allows us to identify which additional value should be considered in each case.

Anthropogenic activities cause the introduction of nitrogen (N) into aquatic environments where these N inputs drive the biological synthesis of nitrous oxide (N2O), a potent and ozone-depleting greenhouse gas. To assess the significance of N2O emissions to climate change, the Intergovernmental Panel on Climate Change (IPCC) estimates indirect N2O emissions from rivers, lakes, and estuaries by multiplying the amounts of N received by these ecosystems with specific emission factors. Interestingly, the IPCC recently increased the N2O emission factor associated with wastewater discharge into “nutrient-impacted (eutrophic) aquatic receiving environments” nearly four times based on experimental evidence of high N2O emissions from N-receiving eutrophic ecosystems. As microalgae can produce N2O, these organisms may contribute to the N2O emissions frequently reported in eutrophic aquatic bodies. If that is the case, estimating N2O emissions solely based on nitrogen inputs to water bodies might lead to inaccurate N2O budgeting as microalgae growth is often limited by phosphorus in these environments. Establishing the significance of microalgal N2O synthesis in eutrophic environments is, therefore, critical and may lead to considerable changes on how to budget and mitigate N2O emissions and eutrophication.

Abstract Background The rapid expansion of Whole-Genome Sequencing has revolutionized the fields of clinical and food microbiology. However, its implementation as a routine laboratory technique remains challenging due to the growth of data at a faster rate than can be effectively analyzed and critical gaps in bioinformatics knowledge. Results To address both issues, CamPype was developed as a new bioinformatics workflow for the genomics analysis of sequencing data of bacteria, especially Campylobacter, which is the main cause of gastroenteritis worldwide making a negative impact on the economy of the public health systems. CamPype allows fully customization of stages to run and tools to use, including read quality control filtering, read contamination, reads extension and assembly, bacterial typing, genome annotation, searching for antibiotic resistance genes, virulence genes and plasmids, pangenome construction and identification of nucleotide variants. All results are processed and resumed in an interactive HTML report for best data visualization and interpretation. Conclusions The minimal user intervention of CamPype makes of this workflow an attractive resource for microbiology laboratories with no expertise in bioinformatics as a first line method for bacterial typing and epidemiological analyses, that would help to reduce the costs of disease outbreaks, or for comparative genomic analyses. CamPype is publicly available at https://github.com/JoseBarbero/CamPype .

Summary: Nerve growth factor receptor (NGFR) is expressed by follicular dendritic cells (FDCs). However, the role of NGFR in the humoral response is not well defined. Here, we study the effect of Ngfr loss on lymph node organization and function, demonstrating that Ngfr depletion leads to spontaneous germinal center (GC) formation and an expansion of the GC B cell compartment. In accordance with this effect, stromal cells are altered in Ngfr−/− mice with a higher frequency of FDCs, characterized by CD21/35, MAdCAM-1, and VCAM-1 overexpression. GCs are located ectopically in Ngfr−/− mice, with lost polarization together with impaired high-affinity antibody production and an increase in circulating autoantibodies. We observe higher levels of autoantibodies in Bcl2 Tg/Ngfr−/− mice, concomitant with a higher incidence of autoimmunity and lower overall survival. Our work shows that NGFR is involved in maintaining GC structure and function, participating in GC activation, antibody production, and immune tolerance.

Brain signal irreversibility has been shown to be a promising approach to study neural dynamics. Nevertheless, the relation with cortical hierarchy and the influence of different electrophysiological features is not completely understood. In this study, we recorded local field potentials (LFPs) during spontaneous behavior, including awake and sleep periods, using custom micro-electrocorticographic (μECoG) arrays implanted in ferrets. In contrast to humans, ferrets remain less time in each state across the sleep-wake cycle. We deployed a diverse set of metrics in order to measure the levels of complexity of the different behavioral states. In particular, brain irreversibility, which is a signature of non-equilibrium dynamics, captured by the arrow of time of the signal, revealed the hierarchical organization of the ferret's cortex. We found different signatures of irreversibility and functional hierarchy of large-scale dynamics in three different brain states (active awake, quiet awake, and deep sleep), showing a lower level of irreversibility in the deep sleep stage, compared to the other. Irreversibility also allowed us to disentangle the influence of different cortical areas and frequency bands in this process, showing a predominance of the parietal cortex and the theta band. Furthermore, when inspecting the embedded dynamic through a Hidden Markov Model, the deep sleep stage was revealed to have a lower switching rate and lower entropy production. These results suggest functional hierarchies in organization that can be revealed through thermodynamic features and information theory metrics.

Genes involved in gonadal sex differentiation have been traditionally thought to be fairly conserved across vertebrates, but this has been lately questioned. Here, we performed the first comparative analysis of gonadal transcriptomes across vertebrates, from fish to mammals. Our results unambiguously show an extraordinary overall variability in gene activation and repression programs without a phylogenetic pattern. During sex differentiation, genes such as dmrt1, sox9, amh, cyp19a and foxl2 were consistently either male- or female-enriched across species while many genes with the greatest expression change within each sex were not. We also found that downregulation in the opposite sex, which had only been quantified in the mouse model, was also prominent in the rest of vertebrates. Finally, we report 16 novel conserved markers (e.g., fshr and dazl) and 11 signaling pathways. We propose viewing vertebrate gonadal sex differentiation as a hierarchical network, with conserved hub genes such as sox9 and amh alongside less connected and less conserved nodes. This proposed framework implies that evolutionary pressures may impact genes based on their level of connectivity.

Malignant human B cells express autocrine prolactin (PRL), which has the potential to engage the long isoform and intermediate form of the PRL receptor to promote proliferation and/or survival.

The role of the gut microbiota and its interplay with host metabolic health, particularly in the context of type 2 diabetes mellitus (T2DM) management, is garnering increasing attention. Dipeptidyl peptidase 4 (DPP4) inhibitors, commonly known as gliptins, constitute a class of drugs extensively used in T2DM treatment. However, their potential interactions with gut microbiota remain poorly understood. In this study, we employed computational methodologies to investigate the binding affinities of various gliptins to DPP4-like homologs produced by intestinal bacteria. The 3D structures of DPP4 homologs from gut microbiota species, including Segatella copri, Phocaeicola vulgatus, Bacteroides uniformis, Parabacteroides merdae, and Alistipes sp., were predicted using computational modeling techniques. Subsequently, molecular dynamics simulations were conducted for 200 ns to ensure the stability of the predicted structures. Stable structures were then utilized to predict the binding interactions with known gliptins through molecular docking algorithms. Our results revealed binding similarities of gliptins toward bacterial DPP4 homologs compared to human DPP4. Specifically, certain gliptins exhibited similar binding scores to bacterial DPP4 homologs as they did with human DPP4, suggesting a potential interaction of these drugs with gut microbiota. These findings could help in understanding the interplay between gliptins and gut microbiota DPP4 homologs, considering the intricate relationship between the host metabolism and microbial communities in the gut.

The present research proposes the implementation of an architecture for industrial process monitoring and control for a manufacturing execution system (MES) using an immersive digital twin (DT). For the design of the proposal, cyber–physical systems (CPS), MES, robotics, the Internet of Things, augmented reality, virtual reality, and open platform communication-unified architecture (OPC UA) communication protocols were used to integrate these technologies and enhance the functionalities of the DT by providing greater performance. The proposed work is implemented in an Industry 4.0 laboratory that is composed of Festo Cyber–Physical Factory and CP-Lab stations. The implementation of the architecture is based on ISO 23247, where the following requirements were considered for the design of DTs: (1) observable attributes and 3D design and visualization of all physical production lines in all of their stages, (2) a communication entity through the OPC UA protocol for the collection of state changes of manufacturing elements, (3) a DT entity where digital models are modeled and updated based on the collected data, and (4) user entities through the use of AR and VR to make manufacturing more efficient. The experimental results showed that the architecture enables interoperability between different platforms and control subsystems. It allows for the detection and diagnosis of problems during the execution of the production line; in addition, the high-fidelity simulation and AR and VR environments provided by the DT with data obtained in real time can improve the accuracy and efficiency of manufacturing through a more detailed analysis of the process, providing advantages such as interactive creation for customized products and continuous innovation.

Digital twin (DT) technology provides a path for implementing cyber–physical systems (CPS) and developing smart manufacturing because they are essential tools for monitoring and controlling manufacturing processes. It is considered a vital technology in smart manufacturing and is being widely researched in academia and industry. Furthermore, the combination of DTs and immersive environments has shown great potential for integrating novel capabilities into the new generation of CPS. This research presents an architecture for implementing immersive digital twins under ISO 23247 in flexible manufacturing processes. The proposed system is based on the integration of DT technologies in conjunction with augmented reality (AR) and gesture tracking, and validation was performed in the sorting station of the MPS 500 to increase the interaction and flexibility between physical and virtual environments in real time, thus enhancing the capabilities of the DT. The methodology used for the design and implementation of the DT includes (1) general principles and requirements; (2) models with functional views based on domains and entities; (3) attributes of the observable manufacturing elements; and (4) protocols for the exchange of information between entities. The results show that the integration of these technologies improves the monitoring, control, and simulation capabilities of processes using 3D resources and immersive environments, achieving a higher level of interactivity. In addition, error detection tests were carried out, where a reduction of time was observed in the resolution of errors that may be caused by internal or external disturbances of the process, thus avoiding production delays.

The search for natural food additives makes propolis an exciting alternative due to its known antimicrobial activity. This work aims to investigate propolis’ behavior as a nitrite substitute ingredient in cooked ham (a ready-to-eat product) when confronted with pathogenic microorganisms of food interest. The microbial evolution of Listeria monocytogenes, Staphylococcus aureus, Bacillus cereus, and Clostridium sporogenes inoculated at known doses was examined in different batches of cooked ham. The design of a challenge test according to their shelf life (45 days), pH values, and water activity allowed the determination of the mesophilic aerobic flora, psychotropic, and acid lactic bacteria viability. The test was completed with an organoleptic analysis of the samples, considering possible alterations in color and texture. The cooked ham formulation containing propolis instead of nitrites limited the potential growth (δ < 0.5 log10) of all the inoculated microorganisms until day 45, except for L. monocytogenes, which in turn exhibited a bacteriostatic effect between day 7 and 30 of the storage time. The sensory analysis revealed the consumer’s acceptance of cooked ham batches including propolis as a natural additive. These findings suggest the functionality of propolis as a promising alternative to artificial preservatives for ensuring food safety and reducing the proliferation risk of foodborne pathogens in ready-to-eat products.

The platelet-rich plasma (PRP) approach may be an effective treatment for joint and cartilage pathologies. However, the rationale for its effectiveness on joint instability is limited. This study aimed to assess the safety and effectiveness of PRP injections in patients with chronic lateral ankle instability (CLAI). This retrospective study was performed at a single-center outpatient clinic between January 2015 and February 2023 and included pre-intervention assessment and short-term follow-up. Patients were excluded if they had received previous surgical treatment or had constitutional hyperlaxity, systemic diseases, or grade II or III osteoarthritis. The clinical and functional evaluation consisted of the Karlsson score, the Cumberland Ankle Instability Tool (CAIT), Good’s grading system, the patient’s subjective satisfaction level, and the time required to return to exercise. The entire PRP therapy regime consisted of three PRP administrations at 7-day intervals and follow-up appointments. PRP was administered both intraarticularly and into talofibular ligaments. A total of 47 consecutive patients with CLAI were included, 11 were female (23.4%), with a mean age at intervention of 31.19 ± 9.74 years. A statistically significant improvement was found in the CAIT and Karlsson scores at 3 months (27.74 ± 1.68 and 96.45 ± 4.28, respectively) relative to the pre-intervention status (10.26 ± 4.33 and 42.26 ± 14.9, respectively, p < 0.000). The mean follow-up of patients with CLAI was 17.94 ± 3.25 weeks. This study represents successful short-term functional and clinical outcomes in patients with CLAI after PRP treatment, with no adverse effects. It demonstrates the feasibility of a randomized controlled trial to further assess this therapy.

The high demand for aesthetic treatments among the population has resulted in a wide array of bleaching products available on the market. It is imperative to investigate the potential adverse effects these products may have on dental health. The objective of this systematic review is to assess, based on available experimental in vitro studies in the scientific literature, whether bleaching products exhibit cytotoxic properties against pulp stem cells and fibroblasts. A comprehensive literature search was conducted across the Medline, Scopus, and Lilacs databases using the search formula ((Tooth whitening) OR (bleaching agent)) AND cytotoxicity AND ((stem cell*) OR fibroblast). Following the application of inclusion and exclusion criteria, 14 articles were deemed suitable for full analysis. The most utilized assay in the evaluated studies was the MTT cell viability assay. Fibroblasts emerged as the most scrutinized cell type due to the potential adverse effects of bleaching, such as invasive cervical resorption, which primarily affects the periodontal ligament where fibroblasts are located. It was observed that as the concentration of hydrogen peroxide increases, so does the cytotoxicity of the product. Additionally, other factors such as application time, activation methods, and the type of peroxide used also play a significant role. Bleaching products have been shown to exert cytotoxic effects on fibroblasts. Further exploration of the impact of bleaching agents on dental pulp stem cells is warranted to better understand their implications for these cells.

A major challenge for the Air Traffic Management system is the need to boost airspace capacity, which is near saturation in some situations. Separation minima are one of the factors related to airspace capacity, and the SESAR program promotes research into advanced separation modes. Ad Hoc separation, a novel separation mode, involves applying different pairwise separation minima in the same volume of airspace depending on a set of factors, such as encounter geometry, aircraft models, and flight level, among others. This research examines the impact of implementing this concept in different en-route scenarios. The goal is to determine whether applying this concept proves advantageous or, conversely, results in an increase in the complexity of the system without significant benefits in the key performance areas of capacity, environment, and cost-efficiency. Fast Time Simulations are conducted in RAMS software, with the concept being implemented in the LECMZMU, LECMTLU, and LECMDGU sectors of the Madrid ACC. The results reveal favorable capacity outcomes with increases of around 2% and the LECMZMU sector exhibits the most significant environmental and cost-efficiency benefits. Furthermore, implementing the Ad Hoc concept in a larger scenario could yield even greater environmental and cost-efficiency benefits.

Neointimal hyperplasia is the main cause of vascular graft failure in the medium term. Vitamin D receptor activation modulates the biology of vascular smooth muscle cells and has been reported to protect from neointimal hyperplasia following endothelial injury. However, the molecular mechanisms are poorly understood. We have now explored the impact of the selective vitamin D receptor activator, paricalcitol, on neointimal hyperplasia, following guidewire-induced endothelial cell injury in rats, and we have assessed the impact of paricalcitol or vehicle on the expression of key cell stress factors. Guidewire-induced endothelial cell injury caused neointimal hyperplasia and luminal stenosis and upregulated the expression of the growth factor growth/differentiation factor-15 (GDF-15), the cytokine receptor CD74, NFκB-inducing kinase (NIK, an upstream regulator of the proinflammatory transcription factor NFκB) and the chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2). Immunohistochemistry confirmed the increased expression of the cellular proteins CD74 and NIK. Paricalcitol (administered in doses of 750 ng/kg of body weight, every other day) had a non-significant impact on neointimal hyperplasia and luminal stenosis. However, it significantly decreased GDF-15, CD74, NIK and MCP-1/CCL2 mRNA expression, which in paricalcitol-injured arteries remained within the levels found in control vehicle sham arteries. In conclusion, paricalcitol had a dramatic effect, suppressing the stress response to guidewire-induced endothelial cell injury, despite a limited impact on neointimal hyperplasia and luminal stenosis. This observation identifies novel molecular targets of paricalcitol in the vascular system, whose differential expression cannot be justified as a consequence of improved tissue injury.

Neuroinflammation and epilepsy are different pathologies, but, in some cases, they are so closely related that the activation of one of the pathologies leads to the development of the other. In this work, we discuss the three main cell types involved in neuroinflammation, namely (i) reactive astrocytes, (ii) activated microglia, and infiltration of (iii) peripheral immune cells in the central nervous system. Then, we discuss how neuroinflammation and epilepsy are interconnected and describe the use of different repurposing drugs with anti-inflammatory properties that have been shown to have a beneficial effect in different epilepsy models. This review reinforces the idea that compounds designed to alleviate seizures need to target not only the neuroinflammation caused by reactive astrocytes and microglia but also the interaction of these cells with infiltrated peripheral immune cells.

Dental pulp infections are common buccal diseases. When this happens, endodontic treatments are needed to disinfect and prepare the root canal for subsequent procedures. However, the lack of suitable in vitro models representing the anatomy of an immature root canal hinders research on regenerative events crucial in endodontics, such as regenerative procedures. This study aimed to develop a 3D microphysiological system (MPS) to mimic an immature root canal and assess the cytotoxicity of various irrigating solutions on stem cells. Utilizing the Dental Stem Cells SV40 (DSCS) cell line derived from human apical papilla stem cells, we analyzed the effects of different irrigants, including etidronic acid. The results indicated that irrigating solutions diminished cell viability in 2D cultures and influenced cell adhesion within the microphysiological device. Notably, in our 3D studies in the MPS, 17% EDTA and 9% 1-hydroxyethylidene-1, 1-bisphosphonate (HEBP) irrigating solutions demonstrated superior outcomes in terms of DSCS viability and adherence compared to the control. This study highlights the utility of the developed MPS for translational studies in root canal treatments and suggests comparable efficacy between 9% HEBP and 17% EDTA irrigating solutions, offering potential alternatives for clinical applications.

During the 2021 La Palma strombolian and fissure eruption, two faults were identified that controlled the spatial distribution of earthquake hypocenters and effusive eruptive vents. One of these faults has a NW-SE trend (Tazacorte Fault: TZF) and the other one shows an ENE-WSW trend (Mazo Fault: MZF). Previous works on fault structural analysis in La Palma indicated that the eruption zone was compatible with an extensional tectonic strain ellipsoid which activated normal-strike-slip directional faults at the confluence of TZF and MZF. These fractures were activated during the 2021 Tajogaite eruption, determining the NW-SE and WSW-ENE spatial distribution of vents. Both faults were mapped in real time during the volcanic eruption from fieldwork and remote sensing imagery (aerial drone images). We have collected more than 300 fracture data associated with the effusive vents and post-eruption seismic creep. Since the affected area was densely inhabited, most of these fractures affect houses and infrastructures. Some of the houses affected by the TZF were damaged 9 months after the eruption, although they were not damaged during the eruption. Surprisingly, these houses already had repairs made to the same fractures since 1980, giving information of previous fault creep movement. During the 2021 Tajogaite eruption, shallow seismicity was spatially related to both faults, suggesting a seismic behavior instead of the precedent creep movement. However, the lack of seismicity after the eruption indicates that the faults went back to creep aseismic behavior, similarly to 1980. The mapping and monitoring of these faults (TZF and MZF) is relevant bearing in mind that they have been active since 1980 and the post-eruptive phase of the 2021 volcanic eruption, which has to be included in the land use planning in areas affected by the volcanic eruption and creep movement. Furthermore, both faults could act as seismogenic sources triggering volcanic earthquakes with potential high macroseismic intensities and mass movements. The data presented here show the importance of having this type of study before the onset of the eruption, thus allowing a better interpretation of seismic data during volcanic unrest.

The present study focused on the effects of a physical training program on physical- and psychological-related variables in professional esports players. Five professional League of Legends (LOL) players belonging to the highest national category participated in this study. Data were obtained before and after a 5 h virtual training session (acute), as well as before and after an 8-week intervention period, focused on decreasing the impact of fatigue on players’ health and performance. The results showed that a complete virtual training session influences their performance, decreasing jump height and joint mobility (p < 0.01), as well as increasing perceived physical and cognitive exertion by 76.9% (p < 0.01) and 166.67% on the “Rating of Fatigue” scale (p = 0.002). Moreover, the intervention was able to reduce the impact of fatigue (30.8% and 43.3% reduction in cognitive and overall fatigue, respectively, p < 0.05), improving, at the same time, the amount of muscle mass by 2%, jumping ability by 9.8% to 21%, and strength levels in various exercises by 63% to 173% (p < 0.01). The implementation of a physical training program is capable of reducing the players’ fatigue perception, improving their physical conditioning and health status, and decreasing the injury risk.

Beach handball (BH) is characterized by high-intensity actions, such as accelerations and short rest times, in combination with long periods of low-intensity activity during a match. The purpose of this study was to establish a comparative analysis between the effect of a hard surface vs. sandy surface on the properties of the sprint Force–Velocity–Power Profile (FVP) of female beach handball top-level players. Fourteen female BH players participated in this research. A cross-sectional investigation was performed in order to evaluate the determining variables of the FVP profile for different surfaces. After a specific warm-up, two maximal 20–30 m sprints (4 min resting between trials) were performed in two conditions (hard surface and sand) within 10 min. The female BH players showed higher mean values for all the FVP profile variables (p < 0.001) on the hard surface compared to sand, in addition to lower values for the 5 m (ES = 2.29 to 3.89) and 20 m sprinting times (ES = 2.39 to 3.99) (p < 0.001). However, the decrease in the ratio of force over acceleration was not discriminant between the surfaces. Positive correlations were found for the speed variables (0.691–0.807, p < 0.01), as well as the Pmax (0.520, p = 0.035), between the surfaces. A prior knowledge of the FVP profile for hard–sandy surfaces could offer an important reference value about the sprint properties of this population, and be useful for evaluating the efficiency, as well as the effect on the sprint and gaming performance, of specifically oriented training programs based on those reference values.

The electric vehicle deployment, due to the plans defined according to the energy transition objectives, produces new challenges for the electrical system. These challenges are associated with the charging infrastructure of these vehicles since they require a high current during specific periods, which can increase losses in the network, overload the lines, or cause voltage drops that affect the system’s stability. To solve these challenges, one of the possible solutions is the investment in new network infrastructure to face the increase in demand, such as the construction of new transformation centers or new medium and low-voltage lines. However, in the case of rural networks with a small number of users, these investments may not be viable. This article analyzes the possible impacts of connecting electric vehicles in a rural low-voltage network located in a Spanish municipality, as well as possible implementable solutions that do not require investment in new infrastructure. The number of connected vehicles has been calculated based on the national plan for 2030, and the network model used is based on actual data provided by the distribution company that operates in the area.

This study aimed to evaluate the impact of Candida albicans on subgingival biofilm formation on dental implant surfaces. Scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) were used to compare biofilm structure and microbial biomass in the presence and absence of the fungus after periods of 24, 48, and 72 h. Quantitative polymerase chain reaction (qPCR) was used to quantify the number of viable and total micro-organisms for each of the biofilm-forming strains. A general linear model was applied to compare CLSM and qPCR results between the control and test conditions. The biofilm developed with C. albicans at 72 h had a higher bacterial biomass and a significantly higher cell viability (p < 0.05). After both 48 and 72 h of incubation, in the presence of C. albicans, there was a significant increase in counts of Fusobacterium nucleatum and Porphyromonas gingivalis and in the cell viability of Streptococcus oralis, Aggregatibacter actinomycetemcomitans, F. nucleatum, and P. gingivalis. Using a dynamic in vitro multispecies biofilm model, C. albicans exacerbated the development of the biofilm grown on dental implant surfaces, significantly increasing the number and cell viability of periodontal bacteria.

Cardiorenal syndrome (CRS) involves joint dysfunction of the heart and kidney. Acute forms share biochemical alterations like hyperuricaemia (HU) with tumour lysis syndrome (TLS). The mainstay treatment of acute CRS with systemic overload is diuretics, but rasburicase is used in TLS to prevent and treat hyperuricaemia. An observational, retrospective study was performed to assess the effectiveness and safety of a single dose of rasburicase in hospitalized patients with cardiorenal syndrome, worsening renal function and uric acid levels above 9 mg/dL. Rasburicase improved diuresis and systemic congestion in the 35 patients included. A total of 86% of patients did not need to undergo RRT, and early withdrawal was possible in the remaining five. Creatinine (Cr) decreased after treatment with rasburicase from a peak of 3.6 ± 1.27 to 1.79 ± 0.83 mg/dL, and the estimated glomerular filtration rate (eGFR) improved from 17 ± 8 to 41 ± 20 mL/min/1.73 m2 (p = 0.0001). The levels of N-terminal type B Brain Natriuretic Peptide (Nt-ProBNP) and C-reactive protein (CRP) were also significantly reduced. No relevant adverse events were detected. Our results show that early treatment with a dose of rasburicase in patients with CRS and severe HU is effective to improve renal function and systemic congestion, avoiding the need for sustained extrarenal clearance, regardless of comorbidities and ventricular function.