Lipoamino bundle LNPs for efficient mRNA transfection of dendritic cells and macrophages show high spleen selectivity.

Messenger RNA (mRNA) is a powerful tool for nucleic acid-based therapies and vaccination, but efficient and specific delivery to target tissues remains a significant challenge. In this study, we demonstrate lipoamino xenopeptide carriers as components of highly efficient mRNA LNPs. These lipo-xenopeptides are defined as 2D sequences in different 3D topologies (bundles or different U-shapes). The polar artificial amino acid tetraethylene pentamino succinic acid (Stp) and various lipophilic tertiary lipoamino fatty acids (LAFs) act as ionizable amphiphilic units, connected in different ratios via bisamidated lysines as branching units. A series of more lipophilic LAF4-Stp1 carriers with bundle topology is especially well suited for efficient encapsulation of mRNA into LNPs, facilitated cellular uptake and strongly enhanced endosomal escape. These LNPs display improved, faster transfection kinetics compared to standard LNP formulations, with high potency in a variety of tumor cell lines (including N2a neuroblastoma, HepG2 and Huh7 hepatocellular, and HeLa cervical carcinoma cells), J774A.1 macrophages, and DC2.4 dendritic cells. High transfection levels were obtained even in the presence of serum at very low sub-microgram mRNA doses. Upon intravenous application of only 3 µg mRNA per mouse, in vivo mRNA expression is found with a high selectivity for dendritic cells and macrophages, resulting in a particularly high overall preferred expression in the spleen.

Training matters: Heading incidence and characteristics in children's and youth football (soccer) players.

OBJECTIVE: Concerns about short- and long-term consequences of repetitive heading contributed to heading restrictions in youth football in some countries. This prospective longitudinal cohort study aims to describe heading exposure in children's and youth football over two seasons using standardized video analysis. METHODS: All matches and training sessions of a male Under-11 (n = 29), Under-15 (n = 28), Under-19 (n = 38), and female Under-17 (n = 39) team were videotaped during the seasons 2019-2020 and 2020-2021. Heading frequencies and characteristics were analyzed. Individual heading exposure is presented as average incidence rates (IR) per 1000 match/training hours. RESULTS: In 275 matches and 673 training sessions, 22 921 headers were observed. Heading IR per player in matches was 1256 (Under-11 m), 1608 (Under-15 m), 1050 (Under-17 f), and 1966 (Under-19 m). In training sessions, IR per player was 739 (Under-11 m), 2206 (Under-15 m), 1661 (Under-17 f), and 1419 (Under-19 m). Five Under-15 males headed the ball five to eight times per training on average. Most headers were performed without heading duels. Flight distance was predominantly 5-20 m (54%) in matches and <5 m (65%) in training. While head impact location most frequently was at frontal areas, one-third of all headers in Under-11 in matches hit temporal, parietal, and occipital parts of the head. CONCLUSION: Heading incidence was low in the youngest age group, whereas (predominantly five) Under-15 males showed very high heading exposures in training. In assessment and regulation of heading burden, training sessions and individual heading behavior should specifically be addressed. Recommendations for heading the ball in practice should account for individual and age-related differences.

Cortical thickness and neurocognitive performance in former high-level female soccer and non-contact sport athletes.

BACKGROUND: Long-term effects of playing soccer (football) on the brain structure and function of the brain are vividly debated. While some studies showed differences in neurocognitive performance and structural brain changes in retired male players, data on female players are scarce. The present study compares cortical thickness and neurocognitive performance in former high-level female soccer (SOC) and non-contact sport athletes (CON). METHODS: 3 T T1-weighted 3D MPRAGE MRI was performed, and vertex-wise cortical thickness was analyzed using FreeSurfer (v. 6.0.0). Neurocognitive performance in seven domains of SOC and CON was assessed. A multivariate linear model was used to analyze interactions with respect to heading frequency and a history of concussion. RESULTS: SOC (n = 15, mean age 38.3 ± 5.1 years) and CON (n = 16, mean age 36.6 ± 5.8 years) had a similar cortical thickness and performed similarly in the neurocognitive tests except for verbal memory and psychomotor speed, where SOC performed significantly worse than CON. Moderate headers had a significantly larger cortical thickness than rare headers in the right inferior parietal region. Visual memory and cortical thickness were positively correlated in the group of frequent headers and negatively correlated in CON, but not in the other header groups. PERSPECTIVE: In contrast to previous reports in male soccer players, female players did not reveal cortical thinning in comparison with control athletes, whereas neurocognitive profiles of female soccer players might not significantly differ from male athletes. Small sample sizes, subjective header assessment, and the case-control study design require a cautious interpretation.

Electrophysiological signatures of dedifferentiation differ between fit and less fit older adults.

Cardiorespiratory fitness was found to influence age-related changes of resting state brain network organization. However, the influence on dedifferentiated involvement of wider and more unspecialized brain regions during task completion is barely understood. We analyzed EEG data recorded during rest and different tasks (sensory, motor, cognitive) with dynamic mode decomposition, which accounts for topological characteristics as well as temporal dynamics of brain networks. As a main feature the dominant spatio-temporal EEG pattern was extracted in multiple frequency bands per participant. To deduce a pattern's stability, we calculated its proportion of total variance among all activation patterns over time for each task. By comparing fit (N = 15) and less fit older adults (N = 16) characterized by their performance on a 6-min walking test, we found signs of a lower task specificity of the obtained network features for the less fit compared to the fit group. This was indicated by fewer significant differences between tasks in the theta and high beta frequency band in the less fit group. Repeated measures ANOVA revealed that a significantly lower proportion of total variance can be explained by the main pattern in high beta frequency range for the less fit compared to the fit group [F(1,29) = 12.572, p = .001, partial η2 = .300]. Our results indicate that the dedifferentiation in task-related brain activation is lower in fit compared to less fit older adults. Thus, our study supports the idea that cardiorespiratory fitness influences task-related brain network organization in different task domains. SUPPLEMENTARY INFORMATION: The online version of this article (10.1007/s11571-020-09656-9) contains supplementary material, which is available to authorized users.

Effects of force level and task difficulty on force control performance in elderly people.

As the proportion of people over 60 years of age rises continuously in westernized societies, it becomes increasingly important to better understand aging processes and how to maintain independence in old age. Fine motor tasks are essential in daily living and, therefore, necessary to maintain. This paper extends the existing literature on fine motor control by manipulating the difficulty of a force maintenance task to characterize performance optima for elderly. Thirty-seven elderly (M = 68.00, SD = 4.65) performed a force control task at dynamically varying force levels, i.e. randomly changing every 3 s between 10%, 20%, and 30% of the individual's maximum voluntary contraction (MVC). This task was performed alone or with one or two additional tasks to increase task difficulty. The force control characteristics accuracy, variability, and complexity were analyzed. Lowest variability was observed at 20%. Accuracy and complexity increased with increasing force level. Overall, increased task difficulty had a negative impact on task performance. Results support the assumption, that attention control has a major impact on force control performance in elderly people. We assume different parameters to have their optimum at different force levels, which remain comparably stable when additional tasks are performed. The study contributes to a better understanding of how force control is affected in real-life situations when it is performed simultaneously to other cognitive and sensory active and passive tasks.