Olfactory genes affect major depression in highly educated, emotionally stable, lean women: a bridge between animal models and precision medicine.

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.

Heart rate perception and expectation impact laboratory-induced perceived stress.

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.

Effects of High-protein and High-fiber Diets on Weight and Glucose Regulation in Spiny Mice (Acomys cahirinus).

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.

In Vivo Evaluation of Brain [18F]F-FDG Uptake Pattern Under Different Anaesthesia Protocols.

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.

Vibrations and energy distribution in inhomogeneous rods with elastic and viscous boundary conditions.

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.

Teaching nontechnical skills in the undergraduate education of health care professionals: a nationwide cross-sectional study in Hungary.

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.

Compact realization of all-attosecond pump-probe spectroscopy.

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.

Staphylococcus aureus mutants resistant to the feed-additive monensin show increased virulence and altered purine metabolism.

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.

Cognitive Behavioral Digital Interventions are Effective in Reducing Anxiety in Children and Adolescents: A Systematic Review and Meta-analysis.

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.

The emerging evidence on the association between symptoms of ADHD and gaming disorder: A systematic review and meta-analysis.

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.

Michaelis-Menten kinetic modeling of hemoglobin A1c status facilitates personalized glycemic control.

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.

Physical exercise induces mental flow related to catecholamine levels in noncompetitive, but not competitive conditions in men.

The study aimed to reveal physical exercise conditions and catecholamine response-dependent differences while an individual experiences a flow state (FS) following noncompetitive and competitive running drills. Urine laboratory catecholamine levels were measured using a standard clinical method during pre- and post-physical exercises. The noncompetitive task involved intermittent running drills, from an absolute beginning up through exhaustion. Initially, the drill is performed individually then later competing alongside other runners. Twenty-two males (mean age: 40.27; SD: 5.4; min-max: 31-49 years) were selected in accordance to the following criterion: healthy status without using medication, routine forms of training (running, cycling or swimming) ideally performed with regularity, at least three times per week, 45 min per session. During the noncompetitive task, a high FS experience was associated with a low level of catecholamines, (noradrenaline and adrenaline) while in parallel, the high FS was associated with a low concentration of homovallinic acid. During competitive conditions, the FS-related catecholamine level changes have not yet been found. In conclusion, the low concentration of the circulating catecholamines supports the transient hypofrontality hypothesis regarding the FS experiences. Furthermore, synchronized noradrenaline and adrenaline neurosecretion play an essential role in the manifestation and the prolongation of FS in noncompetitive exercise conditions.

Protective Effects of 3'-Epilutein and 3'-Oxolutein against Glutamate-Induced Neuronal Damage.

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.

Neutrophils actively swell to potentiate rapid migration.

While the involvement of actin polymerization in membrane protrusion is well-established, we have a more limited understanding of the role of transmembrane water flow in cell motility. Here we investigate the role of water influx in neutrophil migration. These cells undergo directed movement to sites of injury and infection. Chemoattractant exposure increases cell volume and potentiates neutrophil migration, but the causal link between these processes is not known. Using a genome-wide CRISPR screen, we identify the regulators of the 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 rapid migration following chemoattractant stimulation. Our data demonstrate that cell swelling complements cytoskeletal inputs for chemoattractant-induced potentiation of migration.

Serum Progranulin Level Might Differentiate Non-IPF ILD from IPF.

Diagnosing interstitial lung disease (ILD) can be a challenging process. New biomarkers may support diagnostic decisions. Elevated serum progranulin (PGRN) levels have been reported in liver fibrosis and dermatomyositis-associated acute interstitial pneumonia. Our aim was to assess the role of PGRN in the differential diagnosis of idiopathic pulmonary fibrosis (IPF) and other ILDs. Serum levels of PGRN were measured by enzyme-linked immunosorbent assay in stable IPF (n = 40), non-IPF ILD (n = 48) and healthy controls (n = 17). Patient characteristics, lung function, CO diffusion (DLCO), arterial blood gases, 6-min walk test, laboratory parameters and high-resolution (HR)CT pattern were assessed. In stable IPF, PGRN levels did not differ from healthy controls; however, serum PGRN levels were significantly higher in non-IPF ILD patients compared to healthy subjects and IPF (53.47 ± 15.38 vs. 40.99 ± 5.33 vs. 44.66 ± 7.77 ng/mL respectively; p < 0.01). The HRCT pattern of usual interstitial pneumonia (UIP) was associated with normal PGRN level, while for non-UIP patterns, significantly elevated PGRN level was measured. Elevated serum PGRN levels may be associated with non-IPF ILD, especially non-UIP patterns and might be helpful in cases of unclear radiological patterns in the differentiation between IPF and other ILDs.

Morphological and Functional Remodeling of the Ischemic Heart Correlates with Homocysteine Levels.

BACKGROUND: Homocysteine (Hcy) is involved in various methylation processes, and its plasma level is increased in cardiac ischemia. Thus, we hypothesized that levels of homocysteine correlate with the morphological and functional remodeling of ischemic hearts. Thus, we aimed to measure the Hcy levels in the plasma and pericardial fluid (PF) and correlate them with morphological and functional changes in the ischemic hearts of humans. METHODS: Concentration of total homocysteine (tHcy) and cardiac troponin-I (cTn-I) of plasma and PF were measured in patients undergoing coronary artery bypass graft (CABG) surgery (n = 14). Left-ventricular (LV) end-diastolic diameter (LVED), LV end-systolic diameter (LVES), right atrial, left atrial (LA) area, thickness of interventricular septum (IVS) and posterior wall, LV ejection fraction (LVEF), and right ventricular outflow tract end-diastolic area (RVOT EDA) of CABG and non-cardiac patients (NCP; n = 10) were determined by echocardiography, and LV mass was calculated (cLVM). RESULTS: Positive correlations were found between Hcy levels of plasma and PF, tHcy levels and LVED, LVES and LA, and an inverse correlation was found between tHcy levels and LVEF. cLVM, IVS, and RVOT EDA were higher in CABG with elevated tHcy (>12 µM/L) compared to NCP. In addition, we found a higher cTn-I level in the PF compared to the plasma of CABG patients (0.08 ± 0.02 vs. 0.01 ± 0.003 ng/mL, p < 0.001), which was ~10 fold higher than the normal level. CONCLUSIONS: We propose that homocysteine is an important cardiac biomarker and may have an important role in the development of cardiac remodeling and dysfunction in chronic myocardial ischemia in humans.

The Effect of Environmental Factors on Mould Counts and AFB1 Toxin Production by Aspergillus flavus in Maize.

The toxins produced by Aspergillus flavus can significantly inhibit the use of maize. As a result of climate change, toxin production is a problem not only in tropical and subtropical areas but in an increasing number of European countries, including Hungary. The effect of meteorological factors and irrigation on mould colonization and aflatoxin B1 (AFB1) mycotoxin production by A. flavus were investigated in natural conditions, as well as the inoculation with a toxigenic isolate in a complex field experiment for three years. As a result of irrigation, the occurrence of fungi increased, and toxin production decreased. The mould count of fungi and toxin accumulation showed differences during the examined growing seasons. The highest AFB1 content was found in 2021. The main environmental factors in predicting mould count were temperature (Tavg, Tmax ≥ 30 °C, Tmax ≥ 32 °C, Tmax ≥ 35 °C) and atmospheric drought (RHmin ≤ 40%). Toxin production was determined by extremely high daily maximum temperatures (Tmax ≥ 35 °C). At natural contamination, the effect of Tmax ≥ 35 °C on AFB1 was maximal (r = 0.560-0.569) in the R4 stage. In the case of artificial inoculation, correlations with environmental factors were stronger (r = 0.665-0.834) during the R2-R6 stages.

Alternatively spliced exon regulates context-dependent MEF2D higher-order assembly during myogenesis.

During muscle cell differentiation, the alternatively spliced, acidic ß-domain potentiates transcription of Myocyte-specific Enhancer Factor 2 (Mef2D). Sequence analysis by the FuzDrop method indicates that the ß-domain can serve as an interaction element for Mef2D higher-order assembly. In accord, we observed Mef2D mobile nuclear condensates in C2C12 cells, similar to those formed through liquid-liquid phase separation. In addition, we found Mef2D solid-like aggregates in the cytosol, the presence of which correlated with higher transcriptional activity. In parallel, we observed a progress in the early phase of myotube development, and higher MyoD and desmin expression. In accord with our predictions, the formation of aggregates was promoted by rigid ß-domain variants, as well as by a disordered ß-domain variant, capable of switching between liquid-like and solid-like higher-order states. Along these lines, NMR and molecular dynamics simulations corroborated that the ß-domain can sample both ordered and disordered interactions leading to compact and extended conformations. These results suggest that ß-domain fine-tunes Mef2D higher-order assembly to the cellular context, which provides a platform for myogenic regulatory factors and the transcriptional apparatus during the developmental process.

Oral Non-absorbable Polymer-Deferoxamine Conjugates for Reducing Dietary Iron Absorption.

Hereditary hemochromatosis (HH) is a non-transfusional genetic iron overload (IO) disease wherein patients are not able to regulate dietary iron absorption, which ultimately leads to excess cellular iron accumulation. Preventative measures for HH mainly include phlebotomy and asking patients to minimize dietary iron intake. To investigate alternative iron reduction strategies, we report on prophylactic non-absorbable polymer-deferoxamine (DFO) conjugates capable of chelating and reducing excessive gut uptake of dietary iron. Three different sizes of the conjugates (56 nm, 256 nm, and 7.4 µm) were prepared, and their physicochemical properties, transit times in the gut under fed/fasted conditions, acute safety, and efficacy at reducing iron absorption in a dietary iron-overload mouse model were investigated. The conjugates were synthesized through reverse phase water-in-oil (w/o) emulsions, followed by conjugation of DFO to the resulting polymer scaffolds. In vitro studies using Caco-2 transwell assays showed that the conjugates could not permeate across the monolayer, were poorly endocytosed, and did not induce cellular toxicity. In vivo mouse studies via oral gavage demonstrated that polymer-DFO conjugates remained in the gastrointestinal (GI) tract for up to 12 h and significantly prevented escalation of serum ferritin levels and excess liver iron accumulation. Ex vivo images of the duodenum suggest that nanometer-sized conjugates (56 and 246 nm) perform better at chelating dietary iron based on longer retention times (i.e., entrapment in the villi of the duodenum) and an overall slower transit from the GI tract compared to larger micron-sized (7.4 µm) conjugates. Overall, nanometer-sized polymer-DFO conjugates were orally non-absorbable, appeared safe, and were more efficacious at reducing dietary iron absorption when taken with non-heme containing food.

A sound mind in a sound body: a novel concept unravelling heterogeneity of depression.

Depression is a highly prevalent and debilitating condition, yet we still lack both in-depth knowledge concerning its etiopathology and sufficiently efficacious treatment options. With approximately one third of patients resistant to currently available antidepressants there is a pressing need for a better understanding of depression, identifying subgroups within the highly heterogeneous illness category and to understand the divergent underlying biology of such subtypes, to help develop and personalise treatments. The TRAJECTOME project aims to address such challenges by (1) identifying depression-related multimorbidity subgroups and shared molecular pathways based on temporal disease profiles from healthcare systems and biobank data using machine learning approaches, and by (2) characterising these subgroups from multiple aspects including genetic variants, metabolic processes, lifestyle and environmental factors. Following the identification of multimorbidity trajectories, a disease burden score related to depression and adjusted for multimorbidity was established summarising the current state of the patient to weigh the molecular mechanisms associated with depression. In addition, the role of genetic and environmental factors, and also their interactions were identified for all subgroups. The project also attempted to identify potential metabolomic markers for the early diagnostics of these multimorbidity conditions. Finally, we prioritized molecular drug candidates matching the multimorbidity pathways indicated for the individual subgroups which would potentially offer personalised treatment simultaneously for the observable multimorbid conditions yet minimising polypharmacy and related side effects. The present paper overviews the TRAJECTOME project including its aims, tasks, procedures and accomplishments. (Neuropsychopharmacol Hung 2023; 25(4): 183-193)