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Phosphoryl transfer is a fundamental reaction in cellular signaling and metabolism that requires Mg2+ as an essential cofactor. While the primary function of Mg2+ is electrostatic activation of substrates, such as ATP, the full spectrum of catalytic mechanisms exerted by Mg2+ is not known. In this study, we integrate structural biology methods, molecular dynamic (MD) simulations, phylogeny, and enzymology assays to provide molecular insights into Mg2+-dependent structural reorganization in the active site of the metabolic enzyme adenylate kinase. Our results demonstrate that Mg2+ induces a conformational rearrangement of the substrates (ATP and ADP), resulting in a 30° adjustment of the angle essential for reversible phosphoryl transfer, thereby optimizing it for catalysis. MD simulations revealed transitions between conformational substates that link the fluctuation of the angle to large-scale enzyme dynamics. The findings contribute detailed insight into Mg2+ activation of enzymes and may be relevant for reversible and irreversible phosphoryl transfer reactions.
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Adenilato Quinasa , Dominio Catalítico , Magnesio , Simulación de Dinámica Molecular , Magnesio/metabolismo , Magnesio/química , Adenilato Quinasa/metabolismo , Adenilato Quinasa/química , Adenosina Trifosfato/metabolismo , Adenosina Trifosfato/química , Conformación Proteica , Adenosina Difosfato/metabolismo , Adenosina Difosfato/químicaRESUMEN
Human metapneumovirus (HMPV) is an important cause of acute respiratory tract infection and causes significant morbidity and mortality. There is no specific antiviral drug to treat HMPV or vaccine to prevent HMPV. This study determined if probenecid, a host-targeting antiviral drug, had prophylactic (pre-virus) or therapeutic (post-virus) efficacy to inhibit HMPV replication in LLC-MK2 cells in vitro and in the lungs of BALB/c mice. This study showed that ≥0.5 µM probenecid significantly inhibited HMPV replication in vitro, and 2-200 mg/kg probenecid prophylaxis or treatment reduced HMPV replication in BALB/c mice.
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Antivirales , Metapneumovirus , Ratones Endogámicos BALB C , Infecciones por Paramyxoviridae , Probenecid , Replicación Viral , Animales , Metapneumovirus/efectos de los fármacos , Metapneumovirus/fisiología , Replicación Viral/efectos de los fármacos , Ratones , Probenecid/farmacología , Infecciones por Paramyxoviridae/tratamiento farmacológico , Infecciones por Paramyxoviridae/virología , Antivirales/farmacología , Línea Celular , Pulmón/virología , Humanos , Infecciones del Sistema Respiratorio/virología , Infecciones del Sistema Respiratorio/tratamiento farmacológico , FemeninoRESUMEN
While the involvement of actin polymerization in cell migration is well-established, much less is known about the role of transmembrane water flow in cell motility. Here, we investigate the role of water influx in a prototypical migrating cell, the neutrophil, which undergoes rapid, directed movement to sites of injury, and infection. Chemoattractant exposure both increases cell volume and potentiates migration, but the causal link between these processes are not known. We combine single-cell volume measurements and a genome-wide CRISPR screen to identify the regulators of chemoattractant-induced neutrophil swelling, including NHE1, AE2, PI3K-gamma, and CA2. Through NHE1 inhibition in primary human neutrophils, we show that cell swelling is both necessary and sufficient for the potentiation of migration following chemoattractant stimulation. Our data demonstrate that chemoattractant-driven cell swelling complements cytoskeletal rearrangements to enhance migration speed.
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Movimiento Celular , Neutrófilos , Humanos , Neutrófilos/metabolismo , Tamaño de la Célula , Intercambiador 1 de Sodio-Hidrógeno/metabolismo , Intercambiador 1 de Sodio-Hidrógeno/genética , Factores Quimiotácticos/metabolismoRESUMEN
BACKGROUND: Comprehensive management of multimorbidity can significantly benefit from advanced health risk assessment tools that facilitate value-based interventions, allowing for the assessment and prediction of disease progression. Our study proposes a novel methodology, the Multimorbidity-Adjusted Disability Score (MADS), which integrates disease trajectory methodologies with advanced techniques for assessing interdependencies among concurrent diseases. This approach is designed to better assess the clinical burden of clusters of interrelated diseases and enhance our ability to anticipate disease progression, thereby potentially informing targeted preventive care interventions. OBJECTIVE: This study aims to evaluate the effectiveness of the MADS in stratifying patients into clinically relevant risk groups based on their multimorbidity profiles, which accurately reflect their clinical complexity and the probabilities of developing new associated disease conditions. METHODS: In a retrospective multicentric cohort study, we developed the MADS by analyzing disease trajectories and applying Bayesian statistics to determine disease-disease probabilities combined with well-established disability weights. We used major depressive disorder (MDD) as a primary case study for this evaluation. We stratified patients into different risk levels corresponding to different percentiles of MADS distribution. We statistically assessed the association of MADS risk strata with mortality, health care resource use, and disease progression across 1 million individuals from Spain, the United Kingdom, and Finland. RESULTS: The results revealed significantly different distributions of the assessed outcomes across the MADS risk tiers, including mortality rates; primary care visits; specialized care outpatient consultations; visits in mental health specialized centers; emergency room visits; hospitalizations; pharmacological and nonpharmacological expenditures; and dispensation of antipsychotics, anxiolytics, sedatives, and antidepressants (P<.001 in all cases). Moreover, the results of the pairwise comparisons between adjacent risk tiers illustrate a substantial and gradual pattern of increased mortality rate, heightened health care use, increased health care expenditures, and a raised pharmacological burden as individuals progress from lower MADS risk tiers to higher-risk tiers. The analysis also revealed an augmented risk of multimorbidity progression within the high-risk groups, aligned with a higher incidence of new onsets of MDD-related diseases. CONCLUSIONS: The MADS seems to be a promising approach for predicting health risks associated with multimorbidity. It might complement current risk assessment state-of-the-art tools by providing valuable insights for tailored epidemiological impact analyses of clusters of interrelated diseases and by accurately assessing multimorbidity progression risks. This study paves the way for innovative digital developments to support advanced health risk assessment strategies. Further validation is required to generalize its use beyond the initial case study of MDD.
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Multimorbilidad , Humanos , Estudios Retrospectivos , Femenino , Masculino , Persona de Mediana Edad , Medición de Riesgo/métodos , Adulto , Anciano , España , Trastorno Depresivo Mayor/epidemiología , Teorema de Bayes , Progresión de la Enfermedad , Reino Unido , Depresión/epidemiología , Finlandia/epidemiologíaRESUMEN
Temporal cleaning of high-power infrared (IR) pulses generated by a Ti:Sapphire system is demonstrated by the use of the Nonlinear Fourier Filtering (NFF) method. In a proof-of-principle experiment suppression of up to 1000 is achieved for the temporal pedestal prior to the main pulse, with a moderate (20-25%) overall throughput. This includes the same suppression ratio for the picosecond coherent pedestal in the direct vicinity of the main pulse. Based on the instantaneous, intensity-dependent and high-order switching characteristics of NFF, excellent pulse cleaning performance is observed. The efficient, high-contrast removal of the coherent pedestal from the foot of the main pulse even if its duration is shorter than 100 fs is compared with the capability of the plasma mirror technique. Calculations are also performed, supporting the experimentally observed sharp intensity dependence of the switching process, pointing out the dominant role of the ionization-based refractive index change.
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Reactive inhibitory control plays an important role in phenotype of different diseases/different phases of a disease. One candidate electrophysiological marker of inhibitory control is frontal alpha asymmetry (FAA). FAA reflects the relative difference in contralateral frontal brain activity. However, the relationship between FAA and potential behavioral/brain activity indices of reactive inhibitory control is not yet clear. We assessed the relationship between resting-state FAA and indicators of reactive inhibitory control. Additionally, we investigated the effect of modulation of FAA via transcranial direct current stimulation (tDCS). We implemented a randomized sham-controlled design with 65 healthy humans (Mage = 23.93, SDage = 6.08; 46 female). Before and after 2-mA anodal tDCS of the right frontal site (with the cathode at the contralateral site) for 20 min, we collected EEG data and reactive inhibitory performance in neutral and food-reward conditions, using the stop signal task (SST). There was no support for the effect of tDCS on FAA or any indices of reactive inhibitory control. Our correlation analysis revealed an association between inhibitory brain activity in the food-reward condition and (pre-tDCS) asymmetry. Higher right relative to left frontal brain activity was correlated with reduced early-onset inhibitory activity and, in contrast, linked with higher late-onset inhibitory control in the food-reward condition. Similarly, event-related potential analyses showed reduced early-onset and enhanced late-onset inhibitory brain activity over time, particularly in the food-reward condition. These results suggest that there can be a dissociation regarding the lateralization of frontal brain activity and early- and late-onset inhibitory brain activity.NEW & NOTEWORTHY This research reveals dissociation between baseline frontal alpha asymmetry and the timing of reactive inhibitory brain activities in food-reward contexts. Whereas inhibitory control performance decreases over time in a stop signal task, electrophysiological indices show reduced early- and heightened late-onset inhibitory brain activity, especially in the reward condition. Additionally, greater right frontal activity correlates with reduced early-onset and increased late-onset inhibitory brain activity.
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Ritmo alfa , Lóbulo Frontal , Inhibición Psicológica , Estimulación Transcraneal de Corriente Directa , Humanos , Femenino , Masculino , Ritmo alfa/fisiología , Adulto , Adulto Joven , Lóbulo Frontal/fisiología , Lateralidad Funcional/fisiología , Recompensa , Función Ejecutiva/fisiología , ElectroencefalografíaRESUMEN
This study aimed to develop a novel radiotracer using trastuzumab and the long-lived [52Mn]Mn isotope for HER2-targeted therapy selection and monitoring. A new Mn(II) chelator, BPPA, synthesized from a rigid bispyclen platform possessing a picolinate pendant arm, formed a stable and inert Mn(II) complex with favorable relaxation properties. BPPA was converted into a bifunctional chelator (BFC), conjugated to trastuzumab, and labeled with [52Mn]Mn isotope. In comparison to DOTA-GA-trastuzumab, the BPPA-trastuzumab conjugate exhibits a labeling efficiency with [52Mn]Mn approximately 2 orders of magnitude higher. In female CB17 SCID mice bearing 4T1 (HER2-) and MDA-MB-HER2+ (HER2+) xenografts, [52Mn]Mn-BPPA-trastuzumab demonstrated superior uptake in HER2+ cells on day 3, with a 3-4 fold difference observed on day 7. Overall, the hexadentate BPPA chelator proves to be exceptional in binding Mn(II). Upon coupling with trastuzumab as a BFC ligand, it becomes an excellent imaging probe for HER2-positive tumors. [52Mn]Mn-BPPA-trastuzumab enables an extended imaging time window and earlier detection of HER2-positive tumors with superior tumor-to-background contrast.
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Manganeso , Ratones SCID , Tomografía de Emisión de Positrones , Receptor ErbB-2 , Trastuzumab , Animales , Femenino , Ratones , Línea Celular Tumoral , Quelantes/química , Quelantes/síntesis química , Manganeso/química , Manganeso/metabolismo , Ratones Endogámicos BALB C , Ácidos Picolínicos/química , Tomografía de Emisión de Positrones/métodos , Radiofármacos/química , Radiofármacos/síntesis química , Radiofármacos/farmacocinética , Receptor ErbB-2/metabolismo , Distribución Tisular , Trastuzumab/químicaRESUMEN
Most current approaches to establish subgroups of depressed patients for precision medicine aim to rely on biomarkers that require highly specialized assessment. Our present aim was to stratify participants of the UK Biobank cohort based on three readily measurable common independent risk factors, and to investigate depression genomics in each group to discover common and separate biological etiology. Two-step cluster analysis was run separately in males (n = 149,879) and females (n = 174,572), with neuroticism (a tendency to experience negative emotions), body fat percentage, and years spent in education as input variables. Genome-wide association analyses were implemented within each of the resulting clusters, for the lifetime occurrence of either a depressive episode or recurrent depressive disorder as the outcome. Variant-based, gene-based, gene set-based, and tissue-specific gene expression test were applied. Phenotypically distinct clusters with high genetic intercorrelations in depression genomics were found. A two-cluster solution was the best model in each sex with some differences including the less important role of neuroticism in males. In females, in case of a protective pattern of low neuroticism, low body fat percentage, and high level of education, depression was associated with pathways related to olfactory function. While also in females but in a risk pattern of high neuroticism, high body fat percentage, and less years spent in education, depression showed association with complement system genes. Our results, on one hand, indicate that alteration of olfactory pathways, that can be paralleled to the well-known rodent depression models of olfactory bulbectomy, might be a novel target towards precision psychiatry in females with less other risk factors for depression. On the other hand, our results in multi-risk females may provide a special case of immunometabolic depression.
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Trastorno Depresivo Mayor , Masculino , Animales , Humanos , Femenino , Trastorno Depresivo Mayor/psicología , Depresión/genética , Estudio de Asociación del Genoma Completo , Medicina de Precisión , Modelos AnimalesRESUMEN
Despite the long-term contributions of the spiny mouse (Acomys cahirinus) to research, basic knowledge of appropriate nutrition is lacking for this species. In the wild, spiny mice eat a high-fiber, high-protein food source. In the research setting, spiny mice are prone to obesity that can lead to diabetes mellitus. Common dietary modifications for weight control in humans with diabetes mellitus consist of increased fiber and protein. We hypothesized that increasing the dietary protein or fiber of spiny mice would reduce weight gain and improve their glycemic control, whereas the combination of protein and fiber in the diet would achieve optimal weight management and glycemic control without diet-related pathologic changes. We randomly assigned cages of young adult spiny mice (n = 34) to one of 4 diets: high protein (HP), high fiber (HF), a combination of both high protein and high fiber (HPF), or the base (control) diet (BD). Over the 8-wk study, spiny mice given HF diets maintained baseline weights despite the elevated dietary protein. None of the diets altered blood glucose levels; all diet groups maintained mean blood glucose levels within normal ranges. Spiny mice seem particularly sensitive to changes within their environment, as seen by increased food waste and transient elevated blood glucose levels when the spiny mice were transitioned to novel diets. The short-term elevations in protein and fiber that we tested were well tolerated by spiny mice. Although HF was effective in controlling weight, the ideal percentage of fiber still needs to be determined. The combination diet (HPF) maintained weight and body condition scores and showed a nonsignificant elevation of blood glucose that warrants a longer diet trial before our recommending this specific combination.
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Glucemia , Fibras de la Dieta , Murinae , Animales , Fibras de la Dieta/administración & dosificación , Glucemia/análisis , Masculino , Murinae/fisiología , Dieta Rica en Proteínas , Femenino , Peso Corporal , Alimentación Animal/análisis , Proteínas en la Dieta/administración & dosificación , Distribución AleatoriaRESUMEN
Previous studies have shown that the human capacity to gauge one's own physiological state is notoriously flawed. The cause for the mismatch between perceived and physiological stress has not yet been properly identified. In this study, we assumed that cardioceptive accuracy (CAc) is positively associated with cardiovascular reactivity, and CAc and expectation about stress might account for the discrepancy between perceived and physiological stress. In a crossover experiment, we assessed cardioceptive accuracy in two ways (mental heartbeat tracking task and perception of heart rate), and induced physiological (handgrip exercise) and mental (N-back task) stress in 64 university students (51 % male, mean age 22.2). We assessed cardiac and electrodermal activity, and expected and perceived stress. We found that indicators of cardioceptive accuracy were not associated with cardiovascular reactivity. However, heart rate perception moderated the association between the change in heart rate and perceived stress in the physical but not in the mental task. Whereas heartbeat tracking accuracy was not associated with perceived stress. Moreover, perceived stress was predicted by the expected stress but not by the change in heart rate and electrodermal activity in the mental stress task. In conclusion, heart rate perception and expectation of stress may shape perceived stress more than actual physiological changes in moderate acute stress.
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Fuerza de la Mano , Interocepción , Humanos , Masculino , Adulto Joven , Adulto , Femenino , Frecuencia Cardíaca/fisiología , Motivación , Percepción/fisiología , Estrés Psicológico , Interocepción/fisiologíaRESUMEN
BACKGROUND/AIM: Since the use of anaesthetics has the drawback of altering radiotracer distribution, preclinical positron emission tomography (PET) imaging findings of anaesthetised animals must be carefully handled. This study aimed at assessing the cerebral [18F]F-FDG uptake pattern in healthy Wistar rats under four different anaesthesia protocols using microPET/magnetic resonance imaging (MRI) examinations. MATERIALS AND METHODS: Post-injection of 15±1.2 MBq of [18F]F-FDG, either while awake or during the isoflurane-induced incubation phase was applied. Prior to microPET/MRI imaging, one group of the rats was subjected to forane-only anaesthesia while the other group was anaesthetised with the co-administration of forane and dexmedetomidine/Dexdor® Results: While as for the whole brain it was the addition of dexmedetomidine/Dexdor® to the anaesthesia protocol that generated the differences between the radiotracer concentrations of the investigated groups, regarding the cortex, the [18F]F-FDG accumulation was rather affected by the way of incubation. To ensure the most consistent and highest uptake, forane-induced anaesthesia coupled with an awake uptake condition seemed to be most suitable method of anaesthetisation for cerebral metabolic assessment. Diminished whole brain and cortical tracer accumulation detected upon dexmedetomidine/Dexdor® administration highlights the significance of the mechanism of action of different anaesthetics on radiotracer pharmacokinetics. CONCLUSION: Overall, the standardization of PET protocols is of utmost importance to avoid the confounding factors derived from anaesthesia.
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Anestesia , Anestésicos , Dexmedetomidina , Isoflurano , Ratas , Animales , Fluorodesoxiglucosa F18/metabolismo , Dexmedetomidina/farmacología , Dexmedetomidina/metabolismo , Ratas Wistar , Encéfalo , Tomografía de Emisión de Positrones/métodos , Anestésicos/farmacología , Anestésicos/metabolismo , Isoflurano/farmacología , Isoflurano/metabolismo , Radiofármacos/farmacologíaRESUMEN
Functionally graded materials have broad engineering applications including mechanical engineering, electronics, chemistry, and biomedical engineering. One notable advantage of such materials is that their stiffness distribution can be optimized to avoid stress concentration. A novel approach for solving the equations describing the longitudinal vibration of functionally graded rods with viscous and elastic boundary conditions is proposed. The characteristic equation of the system is derived for the solution of the undamped case for the constant stiffness rod. Then, a homotopy method is applied to compute the eigenvalues and mode shapes of graded rods for viscoelastic boundary conditions. The changes of the eigenvalues and mode shapes as function of the damping parameters are investigated. The optimal damping of the system is computed. It is shown that the qualitative behavior depends on the relation between the actual damping and the optimal damping of the system. The energy density distribution of graded rods is also discussed. An energy measure, the mean scaled energy density distribution is introduced to characterize the energy distribution along the rod in the asymptotic time limit. The significance of such a measure is that it reveals how the energy tends to distribute along the rod. It is shown that the energy distribution can be manipulated by changing the damping parameters. Qualitative changes depending on the relation between the actual damping and the optimal damping are highlighted.
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The ability to perform attosecond-pump attosecond-probe spectroscopy (APAPS) is a longstanding goal in ultrafast science. While first pioneering experiments demonstrated the feasibility of APAPS, the low repetition rates (10 to 120 Hz) and the large footprints of existing setups have so far hindered the widespread exploitation of APAPS. Here, we demonstrate two-color APAPS using a commercial laser system at 1 kHz, straightforward post-compression in a hollow-core fiber, and a compact high-harmonic generation (HHG) setup. The latter enables the generation of intense extreme-ultraviolet (XUV) pulses by using an out-of-focus HHG geometry and by exploiting a transient blueshift of the driving laser in the HHG medium. Near-isolated attosecond pulses are generated, as demonstrated by one-color and two-color XUV-pump XUV-probe experiments. Our concept allows selective pumping and probing on extremely short timescales in many laboratories and permits investigations of fundamental processes that are not accessible by other pump-probe techniques.
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BACKGROUND: The aim of our cross-sectional study was to evaluate the current situation and curriculum of nontechnical skills (NTS) training in the undergraduate education of health care professionals in Hungary. METHODS: All institutes with relevant NTS training in Hungarian faculties of medicine and faculties of health sciences were asked to fill out a 19-item questionnaire. Descriptive statistics were performed, and the characteristics of NTS teaching and non-NTS teaching institutes were compared. The independent predictors of teaching NTS in a particular institute were identified with multiple logistic regression. RESULTS: Seventy-seven institutes responded (52% response rate), of which 66% trained NTS. The most frequent method of NTS training is talking about them during a practice or lecture, and less than half of NTS respondents use simulation. The most frequent cause of not teaching NTS is a lack of human or technical resources. The type of faculty (p = 0.025), academic year (p = 0.001), field of medicine (p = 0.025), and importance of teamwork (p = 0.021) differed between NTS and noNTS institutes. Teaching students in academic year two represented the only independent predictor of NTS education (p = 0.012). CONCLUSIONS: Our findings show that the undergraduate curriculum of Hungarian universities includes some type of NTS education; however, this education requires further development.
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Curriculum , Estudiantes , Humanos , Estudios Transversales , Hungría , Personal de SaludRESUMEN
Ionophores are antibacterial compounds that affect bacterial growth by changing intracellular concentrations of the essential cations, sodium and potassium. They are extensively used in animal husbandry to increase productivity and reduce infectious diseases, but our understanding of the potential for and effects of resistance development to ionophores is poorly known. Thus, given their widespread global usage, it is important to determine the potential negative consequences of ionophore use on human and animal health. In this study, we demonstrate that exposure to the ionophore monensin can select for resistant mutants in the human and animal pathogen Staphylococcus aureus, with a majority of the resistant mutants showing increased growth rates in vitro and/or in mice. Whole-genome sequencing and proteomic analysis of the resistant mutants show that the resistance phenotype is associated with de-repression of de novo purine synthesis, which could be achieved through mutations in different transcriptional regulators including mutations in the gene purR, the repressor of the purine de novo synthesis pathway. This study shows that mutants with reduced susceptibility to the ionophore monensin can be readily selected and highlights an unexplored link between ionophore resistance, purine metabolism, and fitness in pathogenic bacteria.IMPORTANCEThis study demonstrates a novel link between ionophore resistance, purine metabolism, and virulence/fitness in the key human and animal pathogen Staphylococcus aureus. The results show that mutants with reduced susceptibility to the commonly used ionophore monensin can be readily selected and that the reduced susceptibility observed is associated with an increased expression of the de novo purine synthesis pathway. This study increases our understanding of the impact of the use of animal feed additives on both human and veterinary medicine.
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Monensina , Infecciones Estafilocócicas , Humanos , Animales , Ratones , Monensina/farmacología , Virulencia , Staphylococcus aureus , Proteómica , Infecciones Estafilocócicas/veterinaria , Infecciones Estafilocócicas/microbiología , Antibacterianos/farmacología , Antibacterianos/metabolismo , Ionóforos/farmacología , Ionóforos/metabolismo , PurinasRESUMEN
Anxiety disorders are the most prevalent mental health issues in childhood, yet most children do not receive treatment. With recent advances in technology, a growing number of digital anxiety interventions are becoming accessible. This study is the first meta-analysis to evaluate the effectiveness and usefulness of digital cognitive-behavioral anxiety interventions for individuals under the age of 18. Five electronic databases (PsycNET, Web of Science, Science Direct, Pub Med, SAGE Journals.) were systematically searched in 2021. Inclusion criteria were: randomized control trials with a wait list no treatment control, standalone to blended care with minimal therapist involvement, diagnosed anxiety disorder or elevated levels of anxiety, outcome anxiety levels had to be assessed by a clinician, or the patients themselves by a validated anxiety measure. We assessed and controlled for publication bias, and considered the risk of bias using the Cochrane risk-of-bias tool. Eighteen studies were found eligible, which examined 1290 participants in total. Pooled effect sizes using a random-effects model yielded low overall effect for self-ratings (g = 0.28, k = 18, p < 0.001, 95% CI [0.14; 0.41]), and medium effect for ratings of clinicians (g = 0.66, k = 13, p < 0.001, 95% CI [0.50; 0.80]) as well as for parental report (g = 0.49, k = 16, p < 0.001, 95% CI [0.29; 0.69]). We found that the effects were homogenous across studies. Further examining potential moderating factors of treatment efficacy is needed in future research, as well as conducting studies that compare traditional methods of care to their digital counterparts. Digital interventions could contribute to the well-being of children regardless of age, minimizing therapist involvement. We conclude that digital cognitive-behavioral interventions may provide an accessible, cost-effective, and scalable anxiety treatment option for children and adolescents.
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Terapia Cognitivo-Conductual , Niño , Humanos , Adolescente , Terapia Cognitivo-Conductual/métodos , Ansiedad/terapia , Trastornos de Ansiedad/terapia , Resultado del Tratamiento , CogniciónRESUMEN
While the involvement of actin polymerization in cell migration is well-established, much less is known about the role of transmembrane water flow in cell motility. Here, we investigate the role of water influx in a prototypical migrating cell, the neutrophil, which undergoes rapid, directed movement to sites of injury and infection. Chemoattractant exposure both increases cell volume and potentiates migration, but the causal link between these processes is not known. We combine single cell volume measurements and a genome-wide CRISPR screen to identify the regulators of chemoattractant-induced neutrophil swelling, including NHE1, AE2, PI3K-gamma, and CA2. Through NHE1 inhibition in primary human neutrophils, we show that cell swelling is both necessary and sufficient for the potentiation of migration following chemoattractant stimulation. Our data demonstrate that chemoattractant-driven cell swelling complements cytoskeletal rearrangements to enhance migration speed.
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The co-existence of gaming disorder (GD) with other mental health problems has been widely reported. Despite the growing research interest in the comorbidity of GD with attention-deficit/hyperactivity disorder (ADHD), to date, no quantitative synthesis has been performed. The present study comprised a systematic literature search using Scopus, Science Direct, Web of Science, and PubMed databases. Three types of studies were included in the analyses: studies reporting (i) correlation coefficients between the symptoms of GD and ADHD, (ii) means, and standard deviations for comparison of GD severity between ADHD/non-ADHD individuals, and (iii) comparison of ADHD severity between GD/non-GD individuals. The results indicated a moderate relationship between GD and ADHD symptom severity when both subdomains of ADHD were combined (r = 0.296), and also when only inattention (r = 0.306) or hyperactivity (r = 0.266) symptoms were analyzed, which was also confirmed in a structural equation model meta-analysis. Studies showed a large average difference comparing the GD symptom severity of ADHD and non-ADHD individuals (g = 0.693), or ADHD symptom severity of GD and non-GD individuals (g = 0.854). In some cases, higher estimates of association were reported among studies that (i) had a higher proportion of males, (ii) assessed problematic internet use among predominantly videogame player samples rather than assessing only GD, and (iii) had been more recently published. The present review shows that this is an emerging field demonstrating significant results in cross-sectional correlational studies. However, future research should apply more rigorous methodologies to investigate the relationship further (e.g., longitudinal studies and studies using professional/clinical ratings and diagnosis). These results suggest that screening and treatment for ADHD among individuals with gaming disorder is necessary, and individuals with ADHD should be made aware of their higher susceptibility to gaming disorder.
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Trastorno por Déficit de Atención con Hiperactividad , Conducta Adictiva , Masculino , Humanos , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Estudios Transversales , Comorbilidad , CogniciónRESUMEN
INTRODUCTION: Discrepancy between measured HbA1c and HbA1c calculated from plasma glucose is associated with higher risk for diabetic complications. However, quantification of this difference is inaccurate due to the imperfect linear conversion models. We propose to introduce a mathematical formula that correlates with the observational data and supports individualized glycemic control. METHODS: We analysed 175,437 simultaneous plasma glucose and HbA1c records stored in our laboratory database. Employing the Michaelis-Menten (MM) equation, we compared the calculated HbA1c levels to the measured HbA1c levels. Data from patients with multiple records were used to establish the patients' glycemic status and to assess the predictive power of our MM model. RESULTS: HbA1c levels calculated with the MM equation closely matched the population's average HbA1c levels. The Michaelis constant (Km) had a negative correlation with HbA1c (r2 = 0.403). Using personalized Km values in the MM equation, 85.1% of HbA1c predictions were within 20% error (ADAG calculation: 78.4%). MM prediction also performed better in predicting pathologic HbA1c levels (0.904 AUC vs. 0.849 AUC for ADAG). CONCLUSION: MM equation is an improvement over linear models and could be readily employed in routine diabetes management. Km is a reliable and quantifiable marker to characterize variations in glucose tolerance.
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Glucemia , Control Glucémico , Humanos , Pruebas Hematológicas , Hemoglobina GlucadaRESUMEN
Dietary lutein can be naturally metabolized to 3'-epilutein and 3'-oxolutein in the human body. The epimerization of lutein can happen in acidic pH, and through cooking, 3'-epilutein can be the product of the direct oxidation of lutein in the retina, which is also present in human serum. The 3'-oxolutein is the main oxidation product of lutein. Thus, the allylic oxidation of dietary lutein can result in the formation of 3'-oxolutein, which may undergo reduction either to revert to dietary lutein or epimerize to form 3'-epilutein. We focused on the effects of 3'-epilutein and 3'-oxolutein itself and on glutamate-induced neurotoxicity on SH-SY5Y human neuroblastoma cells to identify the possible alterations in oxidative stress, inflammation, antioxidant capacity, and iron metabolism that affect neurological function. ROS measurements were performed in the differently treated cells. The inflammatory state of cells was followed by TNFα, IL-6, and IL-8 cytokine ELISA measurements. The antioxidant status of the cells was determined by the total antioxidant capacity kit assay. The alterations of genes related to ferroptosis and lipid peroxidation were followed by gene expression measurements; then, thiol measurements were performed. Lutein metabolites 3'-epilutein and 3'-oxolutein differently modulated the effect of glutamate on ROS, inflammation, ferroptosis-related iron metabolism, and lipid peroxidation in SH-SY5Y cells. Our results revealed the antioxidant and anti-inflammatory features of 3'-epilutein and 3'-oxolutein as possible protective agents against glutamate-induced oxidative stress in SH-SY5Y cells, with greater efficacy in the case of 3'-epilutein.