Mendelian disorders of cholesterol biosynthesis typically result in multi-system clinical phenotypes, underlining the importance of cholesterol in embryogenesis and development. FDFT1 encodes for an evolutionarily conserved enzyme, squalene synthase (SS, farnesyl-pyrophosphate farnesyl-transferase 1), which catalyzes the first committed step in cholesterol biosynthesis. We report three individuals with profound developmental delay, brain abnormalities, 2-3 syndactyly of the toes, and facial dysmorphisms, resembling Smith-Lemli-Opitz syndrome, the most common cholesterol biogenesis defect. The metabolite profile in plasma and urine suggested that their defect was at the level of squalene synthase. Whole-exome sequencing was used to identify recessive disease-causing variants in FDFT1. Functional characterization of one variant demonstrated a partial splicing defect and altered promoter and/or enhancer activity, reflecting essential mechanisms for regulating cholesterol biosynthesis/uptake in steady state.

Mutations in PLA2G6 (PARK14) cause neurodegenerative disorders in humans, including autosomal recessive neuroaxonal dystrophy and early-onset parkinsonism. We show that loss of iPLA2-VIA, the fly homolog of PLA2G6, reduces lifespan, impairs synaptic transmission, and causes neurodegeneration. Phospholipases typically hydrolyze glycerol phospholipids, but loss of iPLA2-VIA does not affect the phospholipid composition of brain tissue but rather causes an elevation in ceramides. Reducing ceramides with drugs, including myriocin or desipramine, alleviates lysosomal stress and suppresses neurodegeneration. iPLA2-VIA binds the retromer subunits Vps35 and Vps26 and enhances retromer function to promote protein and lipid recycling. Loss of iPLA2-VIA impairs retromer function, leading to a progressive increase in ceramide. This induces a positive feedback loop that affects membrane fluidity and impairs retromer function and neuronal function. Similar defects are observed upon loss of vps26 or vps35 or overexpression of α-synuclein, indicating that these defects may be common in Parkinson disease.

Human studies suggest that a meal elevates glucose uptake in brown adipose tissue (BAT). However, in postprandial state the thermogenic activity and the metabolism of non-esterified fatty acids (NEFAs) in BAT remain unclear. Using indirect calorimetry combined with positron emission tomography and computed tomography (PET/CT), we showed that whole-body and BAT thermogenesis (oxygen consumption) increases after the ingestion of a mixed carbohydrate-rich meal, to the same extent as in cold stress. Postprandial NEFA uptake into BAT is minimal, possibly due to elevated plasma insulin inhibiting lipolysis. However, the variation in postprandial NEFA uptake is linked to BAT thermogenesis. We identified several genes participating in lipid metabolism to be expressed at higher levels in BAT compared with white fat in postprandial state, and to be positively correlated with BAT UCP1 expression. These findings suggest that substrates preferred by BAT in postprandial state are glucose or LPL-released NEFAs due to insulin stimulation.

Heterogeneity is a hallmark feature of the adaptive immune system in vertebrates. Following infection, naive T cells differentiate into various subsets of effector and memory T cells, which help to eliminate pathogens and maintain long-term immunity. The current model suggests there is a single lineage of naive T cells that give rise to different populations of effector and memory T cells depending on the type and amounts of stimulation they encounter during infection. Here, we have discovered that multiple sub-populations of cells exist in the naive CD8+ T cell pool that are distinguished by their developmental origin, unique transcriptional profiles, distinct chromatin landscapes, and different kinetics and phenotypes after microbial challenge. These data demonstrate that the naive CD8+ T cell pool is not as homogeneous as previously thought and offers a new framework for explaining the remarkable heterogeneity in the effector and memory T cell subsets that arise after infection.

Nearly all prostate cancer deaths are from metastatic castration-resistant prostate cancer (mCRPC), but there have been few whole-genome sequencing (WGS) studies of this disease state. We performed linked-read WGS on 23 mCRPC biopsy specimens and analyzed cell-free DNA sequencing data from 86 patients with mCRPC. In addition to frequent rearrangements affecting known prostate cancer genes, we observed complex rearrangements of the AR locus in most cases. Unexpectedly, these rearrangements include highly recurrent tandem duplications involving an upstream enhancer of AR in 70%-87% of cases compared with <2% of primary prostate cancers. A subset of cases displayed AR or MYC enhancer duplication in the context of a genome-wide tandem duplicator phenotype associated with CDK12 inactivation. Our findings highlight the complex genomic structure of mCRPC, nominate alterations that may inform prostate cancer treatment, and suggest that additional recurrent events in the non-coding mCRPC genome remain to be discovered.

A human variant in the BDNF gene (Val66Met; rs6265) is associated with impaired fear extinction. Using super-resolution imaging, we demonstrate that the BDNF Met prodomain disassembles dendritic spines and eliminates synapses in hippocampal neurons. In vivo, ventral CA1 (vCA1) hippocampal neurons undergo similar morphological changes dependent on their transient co-expression of a SorCS2/p75NTR receptor complex during peri-adolescence. BDNF Met prodomain infusion into the vCA1 during this developmental time frame reduces dendritic spine density and prelimbic (PL) projections, impairing cued fear extinction. Adolescent BdnfMet/Met mice display similar spine and PL innervation deficits. Using fiber photometry, we found that, in wild-type mice, vCA1 neurons projecting to the PL encode extinction by enhancing neural activity in threat anticipation and rapidly subsiding their response. This adaptation is absent in BDNFMet/Met mice. We conclude that the BDNF Met prodomain renders vCA1-PL projection neurons underdeveloped, preventing their capacity for subsequent circuit modulation necessary for fear extinction. VIDEO ABSTRACT.

The ability to remember and to navigate to safe places is necessary for survival. Place navigation is known to involve medial entorhinal cortex (MEC)-hippocampal connections. However, learning-dependent changes in neuronal activity in the distinct circuits remain unknown. Here, by using optic fiber photometry in freely behaving mice, we discovered the experience-dependent induction of a persistent-task-associated (PTA) activity. This PTA activity critically depends on learned visual cues and builds up selectively in the MEC layer II-dentate gyrus, but not in the MEC layer III-CA1 pathway, and its optogenetic suppression disrupts navigation to the target location. The findings suggest that the visual system, the MEC layer II, and the dentate gyrus are essential hubs of a memory circuit for visually guided navigation.

Clinical application of stem cell derivatives requires clinical-grade cells and sufficient preclinical proof of safety and efficacy, preferably in primates. We previously successfully established a clinical-grade human parthenogenetic embryonic stem cell (hPESC) line, but the suitability of its subtype-specific progenies for therapy is not clear. Here, we compared the function of clinical-grade hPESC-derived midbrain dopaminergic (DA) neurons in two canonical protocols in a primate Parkinson's disease (PD) model. We found that the grafts did not form tumors and produced variable but apparent behavioral improvement for at least 24 months in most monkeys in both groups. In addition, a slight DA increase in the striatum correlates with significant functional improvement. These results demonstrated that clinical-grade hPESCs can serve as a reliable source of cells for PD treatment. Our proof-of-concept findings provide preclinical data for China's first ESC-based phase I/IIa clinical study of PD (ClinicalTrials.gov number NCT03119636).

Influenza A virus (IAV) remains a major worldwide health threat, especially to high-risk populations, including the young and elderly. There is an unmet clinical need for therapy that will protect the lungs from damage caused by lower respiratory infection. Here, we analyzed the role of EMAPII, a stress- and virus-induced pro-inflammatory and pro-apoptotic factor, in IAV-induced lung injury. First, we demonstrated that IAV induces EMAPII surface translocation, release, and apoptosis in cultured endothelial and epithelial cells. Next, we showed that IAV induces EMAPII surface translocation and release to bronchoalveolar lavage fluid (BALF) in mouse lungs, concomitant with increases in caspase 3 activity. Injection of monoclonal antibody (mAb) against EMAPII attenuated IAV-induced EMAPII levels, weight loss, reduction of blood oxygenation, lung edema, and increase of the pro-inflammatory cytokine TNF alpha. In accordance with the pro-apoptotic properties of EMAPII, levels of caspase 3 activity in BALF were also decreased by mAb treatment. Moreover, we detected EMAPII mAb-induced increase in lung levels of M2-like macrophage markers YM1 and CD206. All together, these data strongly suggest that EMAPII mAb ameliorates IAV-induced lung injury by limiting lung cell apoptosis and shifting the host inflammatory setting toward resolution of inflammation.

Dyslipidemia is the most common lipid metabolism disorder in humans, and its etiology remains elusive. Hypertriglyceridemia (HTG) is a type of dyslipidemia that contributes to atherosclerosis and coronary heart disease. Previous studies have demonstrated that mutations in lipoprotein lipase (LPL), apolipoprotein CII (APOC2), apolipoprotein AV (APOA5), glycosylphosphatidylinositol anchored high-density lipoprotein-binding protein 1 (GPIHBP1), lipase maturation factor 1(LMF1), and glycerol-3 phosphate dehydrogenase 1 (GPD1) are responsible for HTG by using genomic microarrays and next-generation sequencing. The aim of this study was to identify genetic lesions in patients with HTG.

Cardiac natriuretic peptides (NPs) play an important role in the regulation of energy expenditure in skeletal muscle and adipose tissue. A systematic review on the effects of exercise on NPs in patients with heart failure reported that aerobic and resistance training reduced NPs; however, the effects of exercise on NPs and the underlying mechanism of exercise-induced NP secretion in subjects without heart failure remain unknown. In athletes and young, healthy subjects, the NP concentration at rest is not elevated, but strenuous endurance exercise significantly increases NPs. The exercise-induced increase in NPs may be caused by transient myocardial wall stress, cardiomyocyte metabolic changes, or neuroendocrinological response, which may have cytoprotective and growth-regulating effects on the heart. On the other hand, in elderly, overweight/obese subjects, and patients with hypertension, NP concentrations also increase during exercise; however, NP secretion may be more susceptible to cardiac stress compared to young, healthy individuals. Recent studies have shown that NPs are associated with thermogenesis in fat tissue and oxidative capacity in skeletal muscles. NPs may also have a protective role for skeletal muscle in humans, although further studies are warranted to elucidate the physiological mechanism of exercise-induced NP secretion.

Targeting the weekend to promote physical activity (PA) in children seems to be promising given that they tend to be less physically active and, particularly, as the age-related decline in PA is more marked during weekends. Considering the ambiguity of why children are not able to maintain their PA level on weekends, the aim of the present study was to objectively investigate differences in children's spatial PA patterns between week and weekend days using the combination of Global Positioning System (GPS) and accelerometry. Seventy-four second graders (aged 7⁻9 years) and 98 sixth graders (aged 11⁻14 years) wore an accelerometer and GPS sensor for seven consecutive days to determine where children spend time and engage in PA. Time-matched accelerometer and GPS data was mapped with a geographic information system and multilevel analyses accounting for the hierarchical structure of the data were conducted. Differences between weekdays and weekends regarding the total time spent and the absolute and relative level of PA in various settings were found in both age groups. The findings support previous research pointing to the importance of targeting weekend PA, especially when children grow older. Future interventions should encourage children to use outdoor spaces more frequently on weekends, rather than stay at home, and to commute actively to destinations other than school.

The Star Excursion Balance Test (SEBT) is effective in measuring dynamic postural control (DPC). This research aimed to determine whether DPC measured by the SEBT in young athletes (YA) with back pain (BP) is different from those without BP (NBP). 53 BP YA and 53 NBP YA matched for age, height, weight, training years, training sessions/week and training minutes/session were studied. Participants performed 4 practice trials after which 3 measurements in the anterior, posteromedial and posterolateral SEBT reach directions were recorded. Normalized reach distance was analyzed using the mean of all 3 measurements. There was no statistical significant difference (p > 0.05) between the reach distance of BP (87.2 ± 5.3, 82.4 ± 8.2, 78.7 ± 8.1) and NBP (87.8 ± 5.6, 82.4 ± 8.0, 80.0 ± 8.8) in the anterior, posteromedial and posterolateral directions respectively. DPC in YA with BP, as assessed by the SEBT, was not different from NBP YA.

Background: The present study evaluated the effects of resistance training (RT) following a non-linear periodization model in the physical fitness of young soccer athletes. Methods: Young soccer players (n = 23) were allocated into two groups: an RT group (RTG), and the control group (CON). The RTG underwent 15 weeks of non-linear RT periodization in three weekly sessions in addition to their specific soccer training. The CON continued performing the specific soccer training. Before and after the training period, all of the subjects performed one-repetition maximum (RM) tests for speed, agility, and power (vertical and horizontal jump). Results: The RTG obtained significant gains in one-RM tests (before 64.1 ± 5.8 kg, after 79.1 ± 3.3 kg) and power (vertical jump (before 56 ± 2.7 cm, after 61.3 ± 1.7 cm) and horizontal jump (before 184.5 ± 5.5 cm, after 213.6 ± 3.2 cm)). In contrast, the CON group presented a non-significant increase in one-RM tests and horizontal jump, and a significant reduction in vertical jump (before 55.4 ± 2.2 cm, after 51.3 ± 1.5 cm). Neither group presented significant gains in speed (CON: p = 0.27; RTG: p = 0.72) and agility (CON: p = 0.19; RTG: p = 0.58). Conclusion: Our data suggest that non-linear RT should be inserted into the routine of young soccer athletes for improving strength and power without impairing speed and agility.

The primary purpose of this study was to investigate gender differences in the dynamic strength index (DSI): an assessment of upper-body dynamic strength relative to maximal isometric strength. The secondary purpose was to investigate gender differences in the dynamic skill deficit (DSD): an assessment of sports-specific dynamic strength relative to maximal isometric strength, and its association with a sports-specific performance measure in surfers. Nine male (age = 30.3 ± 7.3 yrs) and eight female (age = 25.5 ± 5.2 yrs) surfers undertook three upper-body assessments: isometric push-up, dynamic push-up, and a force plate pop-up to determine the DSI and DSD. The performance measure of time taken to pop-up (TTP) was recorded. No gender differences for the DSI (d = 0.48, p = 0.33) or DSD (d = 0.69, p = 0.32) were observed. Normalized peak force (PF) of the isometric push-up, dynamic push-up, and force plate pop-up were significantly greater in males (p ≤ 0.05), with males recording significantly quicker TTP (d = 1.35, p < 0.05). The results suggest that male and female surfers apply a similar proportion of their maximal strength in sports-specific movements. However, greater normalized isometric and dynamic strength in males resulted in greater sports-specific PF application and a faster TTP. It would appear favorable that female surfers improve their maximal strength to facilitate sports-specific pop-up performance.

The identification of football talent is a critical issue both for clubs and the families of players. However, despite its importance in a sporting, economic and social sense, there appears to be a lack of instruments that can reliably measure talent performance. The aim of this study was to design and validate the Nomination Scale for Identifying Football Talent (NSIFT), with the aim of optimising the processes for identifying said talent. The scale was first validated through expert judgment, and then statistically, by means of an exploratory factor analysis (EFA), confirmatory factor analysis (CFA), internal reliability and convergent validity. The results reveal the presence of three factors in the scale's factor matrix, with these results being confirmed by the CFA. The scale revealed suitable internal reliability and homogeneity indices. Convergent validity showed that it is teammates who are best able to identify football talent, followed by coaches and parents. It can be concluded that the NSIFT is suitable for use in the football world. Future studies should seek to confirm these results in different contexts by means of further CFAs.

Grouping people according to chronological age is popular in fields such as education and sport. Athletes who are born in the first months of the year usually have cognitive and physical development differences in contrast to those born in the last months of the same year. That is why competitive teams tend to select older players more often than youngsters. Age differences between athletes born in the same year as well as an over-representation of older players are known as the Relative Age Effect. This effect is extensively described in young and elite team sports such as basketball, volleyball or, ice-hockey, as well as in soccer. The purpose of this study is to examine the state-of-the-art of the Relative Age Effect in youth and elite soccer players. This review summarizes recent research articles on the Relative Age Effect related to competitive soccer from 2010 to 2016. The systematic literature search was conducted in four databases: SPORTDiscus, Medline, EBSCO host and Google Scholar. Although causes and final solutions have not been clearly achieved yet, it is necessary to continue investigating this phenomenon in order to provide a starting point for future research.

Observational methodology provides a rigorous yet flexible framework for capturing behaviors over time to allow for the performance of subsequent diachronic analyses of the data captured. Theme is a specialized software program that detects hidden temporal behavioral patterns (T-patterns) within data sets. It is increasingly being used to analyze performance in soccer and other sports. The aim of this study was to show how to select and interpret T-patterns generated by the application of three "quantitative" sort options in Theme and three "qualitative" filters established by the researchers. These will be used to investigate whether 7-a-side (F7) or 8-a-side (F8) soccer is best suited to the learning and skills development needs of 7- and 8-year-old male soccer players. The information contained in the T-patterns generated allowed us to characterize patterns of play in children in this age group. For both formats, we detected technical-tactical behaviors showing that children of this age have difficulty with first-touch actions and controlling the ball after a throw-in. We also found that ball control followed by a pass or a shot at the goal are common in the central corridor of the pitch. Further, depth of play is achieved by ball control, followed by dribbling and a pass or shot. In F8, we saw that depth of play was achieved through ball control, followed by dribbling and passing of one or more opponents leading to a pass or shot. However, in F7, we saw that players succeeded in advancing from their goal area to the rival goal area through a sequence of actions.

A four-year retrospective analysis of injury data was conducted on a collegiate (NCAA Division I) women's volleyball team. Twenty athletes (Year 1: age = 19.4 ± 0.9 y, height = 175.2 ± 5.1 cm, body mass = 70.5 ± 10.2 kg; Year 2: age = 20.1 ± 1.0 y, height = 175.7 ± 4.7 cm, body mass = 69.5 ± 10.1 kg; Year 3: age = 20.1 ± 1.4 y, height = 173.8 ± 6.3 cm, body mass = 69.9 ± 10.8 kg; Year 4: age = 19.5 ± 1.4 y, height = 174.4 ± 8.6 cm, body mass = 72.7 ± 10.8 kg) participated in this study, accounting for 1483 total training exposures. Injury was defined as any damage to a body part, incurred during volleyball or strength and conditioning-related activities, which interfered with training and/or competition. Injury rate was normalized to the number of athletes and exposure and expressed as injuries per 1000 exposures. A total of 133 injuries were recorded. The most common injury was to the knee (left = 7.5%, right = 12.0%). Injuries occurred most often in volleyball practice (75.2%), followed by competition (20.3%), and strength and conditioning-related activities (4.5%). Non-contact injuries (upper body = 26.3%, lower body = 53.4%) were more common than contact injuries (upper-body = 13.5%, lower-body = 6.8%). An examination of injury rates relative to the training year revealed patterns in injury occurrence. Specifically, spikes in injury rate were consistently observed during periods of increased training volume that were preceded by breaks in organized training, such as the early pre-season and off-season training periods.

The field hockey coaching process across both Malaysia and India favours a traditional, coach-centred approach of mastering technical skills in terms of game play parameters, fitness, intensity, and load training, whereas a tactical- and player-centred pedagogical approach still takes a backseat. On the other hand, the Teaching Games for Understanding (TGfU) model offers tactical-cognitive instruction and is gaining international recognition for its ability to produce intelligent players via a problem-solving approach in game play. Therefore, the purpose of this quasi-experimental study was to investigate the effect of TGfU compared to skill mastery instruction, termed as Skill Drill Technical (SDT), among Malaysian and Indian elite junior hockey players in term of the game play attributes of adjust and cover in 5 vs. 5 small-sided game play and game play intensity via heart rate (HR) at different points of game play. A total of n = 60 players with an average age of 15 ± 1.03 was selected via simple random sampling from both countries involved in this study and assigned equally to groups, with 15 per group for TGfU and for SDT across Malaysia and India. Gathered data were analysed using the ANOVA and ANCOVA techniques. Findings indicated that there were no significant differences for adjust in 5 vs. 5 game play between TGfU and SDT across Malaysia and India after the intervention. For cover, there was significant improvement for Malaysian players using the TGfU model compared to SDT. In contrast, there was no significant difference between these two models among the Indian players after the intervention. There was significant difference between these two models in terms of warm-up HR across the two countries, and HR was higher via TGfU. For HR immediately after the 5 vs. 5 game play intervention and HR after three minutes' recovery, Indian players with TGfU recorded a higher and significant difference compared to SDT. However, findings indicated no significant difference between these two instruction types among Malaysians, although TGfU proved to have higher HR intensity. Therefore, these findings reiterated that TGfU is a useful approach for game play to enhance intensity and cardiac output. In conclusion, for TGfU to be more relevant to the coaching environment, future research should link game play and physiological parameters. TGfU should able to overcome the barriers of tradition and cultural background that may hinder its momentum.