Blood vessel occlusion by Cryptococcus neoformans is a mechanism for haemorrhagic dissemination of infection.

Meningitis caused by infectious pathogens is associated with vessel damage and infarct formation, however the physiological cause is often unknown. Cryptococcus neoformans is a human fungal pathogen and causative agent of cryptococcal meningitis, where vascular events are observed in up to 30% of patients, predominantly in severe infection. Therefore, we aimed to investigate how infection may lead to vessel damage and associated pathogen dissemination using a zebrafish model that permitted noninvasive in vivo imaging. We find that cryptococcal cells become trapped within the vasculature (dependent on their size) and proliferate there resulting in vasodilation. Localised cryptococcal growth, originating from a small number of cryptococcal cells in the vasculature was associated with sites of dissemination and simultaneously with loss of blood vessel integrity. Using a cell-cell junction tension reporter we identified dissemination from intact blood vessels and where vessel rupture occurred. Finally, we manipulated blood vessel tension via cell junctions and found increased tension resulted in increased dissemination. Our data suggest that global vascular vasodilation occurs following infection, resulting in increased vessel tension which subsequently increases dissemination events, representing a positive feedback loop. Thus, we identify a mechanism for blood vessel damage during cryptococcal infection that may represent a cause of vascular damage and cortical infarction during cryptococcal meningitis.

Genetics of Exercise and Diet-Induced Fat Loss Efficiency: A Systematic Review.

Physical exercise and dieting are well-known and effective methods for fat loss and improving cardiovascular health. However, different individuals often react differently to the same exercise regimen or dietary plan. While specific individuals may undergo substantial fat loss, others may observe only limited effects. A wide range of inter-individual variability in weight gain and changes in body composition induced by physical exercises and diets led to an investigation into the genetic factors that may contribute to the individual variations in such responses. This systematic review aimed at identifying the genetic markers associated with fat loss resulting from diet or exercise. A search of the current literature was performed using the PubMed database. Forty-seven articles met the inclusion criteria when assessing genetic markers associated with weight loss efficiency in response to different types of exercises and diets. Overall, we identified 30 genetic markers of fat-loss efficiency in response to different kinds of diets and 24 in response to exercise. Most studies (n = 46) used the candidate gene approach. We should aspire to the customized selection of exercise and dietary plans for each individual to prevent and treat obesity.

Ethical Aspects of Human Genome Research in Sports-A Narrative Review.

Human genome research in sports raises complex ethical considerations regarding the intersection of genetics and athletic performance. Pursuing genetic enhancements must uphold fairness, equality, and respect for human dignity. This narrative review explores the ethical dimensions of human genome research in sports, its potential implications on athletes, and the integrity of sports. As a narrative review, this study synthesizes the existing literature and expert insights to examine the ethical aspects of human genome research in sports. This study extensively examined the current literature on genetics, sports performance, ethical concerns, human rights, and legal regulations within the European context. The literature was searched using the SPORTDiscus, Scopus, Google Scholar, and PubMed databases. Exploring human genome research in sports reveals significant ethical implications, including potential genetic discrimination, impacts on human rights, and creating a genetic underclass of athletes. There are also definite benefits surrounding genetic testing. In conclusion, this review contends that integrating ethical considerations into developing and applying genetic technologies in sports is crucial to upholding fundamental principles of fairness, equality, and respect for human dignity. It stresses the importance of open and inclusive dialogue about the potential consequences of genetic advancements on athletic performance, future generations, and the integrity of sports.

Changes of Anaerobic Power and Lactate Concentration following Intense Glycolytic Efforts in Elite and Sub-Elite 400-meter Sprinters.

400-m races are based on anaerobic energy metabolism, they induce significant muscle fatigue, muscle fiber damage, and high blood lactate (LA) concentration. Despite extensive research on sprint training, our understanding of the training process that leads to world-class sprint performance is rather limited. This study aimed to determine differences in LA concentration and anaerobic power using jumping tests after an intense glycolytic effort in a group of elite and sub-elite 400-m runners. One hundred thirty male runners were divided into two groups: elite (n = 66, body mass = 73.4 ± 7.8 kg, body height = 182.1 ± 6.2 cm, age = 20.8 ± 4.0 y) running the 400-m dash below 50 s and sub-elite (n = 64, body mass = 72.0 ± 7.1 kg, body height = 182.1 ± 5.2 cm, age = 20.8 ± 4.0 y) with a 400-m personal best above 50 s. The power of the countermovement and the sequential squat jumps was measured in two sets after a warm-up, followed by two intermittent 30-s Wingate tests. LA concentration was measured eight times. It was observed that elite athletes achieved significantly higher power in both types of jumps. The maximum post-exercise LA concentration was significantly lower in the sub-elite group after the 3rd, the 6th, the 9th, and the 20th min after the cessation of two Wingate tests (p < 0.001). The rate of LA accumulation after exercise and the rate of LA utilization did not differ between the groups. It can be concluded that elite and non-elite runners differ in higher LA production but not in LA utilization. Anaerobic power and LA concentration seem to differentiate between 400 elite and sub-elite performance.

Analysis of Industrial Bacillus Species as Potential Probiotics for Dietary Supplements.

So far, Bacillus species bacteria are being used as bacteria concentrates, supplementing cleaning preparations in order to reduce odor and expel pathogenic bacteria. Here, we discuss the potential of Bacillus species as 'natural' probiotics and evaluate their microbiological characteristics. An industrially used microbiological concentrates and their components of mixed Bacillus species cultures were tested, which may be a promising bacteria source for food probiotic preparation for supplementary diet. In this study, antagonistic activities and probiotic potential of Bacillus species, derived from an industrial microbiological concentrate, were demonstrated. The cell free supernatants (CFS) from Bacillus licheniformis mostly inhibited the growth of foodborne pathogenic bacteria, such as Escherichia coli O157:H7 ATCC 35150, Salmonella Enteritidis KCCM 12021, and Staphylococcus aureus KCCM 11335, while some of Bacillus strains showed synergistic effect with foodborne pathogenic bacteria. Moreover, Bacillus strains identified by the MALDI TOF-MS method were found sensitive to chloramphenicol, kanamycin, and rifampicin. B. licheniformis and B. cereus displayed the least sensitivity to the other tested antibiotics, such as ampicillin, ampicillin and sulfbactam, streptomycin, and oxacillin and bacitracin. Furthermore, some of the bacterial species detected extended their growth range from the mesophilic to moderately thermophilic range, up to 54 °C. Thus, their potential sensitivity to thermophilic TP-84 bacteriophage, infecting thermophilic Bacilli, was tested for the purpose of isolation a new bacterial host for engineered bionanoparticles construction. We reason that the natural environmental microflora of non-pathogenic Bacillus species, especially B. licheniformis, can become a present probiotic remedy for many contemporary issues related to gastrointestinal tract health, especially for individuals under metabolic strain or for the increasingly growing group of lactose-intolerant people.

Correction: Lubkowska et al. Analysis of Industrial Bacillus Species as Potential Probiotics for Dietary Supplements. Microorganisms 2023, 11, 488.

There was an error in the original publication [...].

Association Between the rs4680 Polymorphism of the COMT Gene and Personality Traits among Combat Sports Athletes.

Physical performance has been the focus of studies examining genetic influences in martial arts. There has been little quantitative analysis of the interaction between psychological traits and gene variants in athletes. This study aimed to determine whether the rs4680 polymorphism of the COMT gene (catechol-O-methyltransferase) was linked to other sports phenotypes such as temperament, mental toughness, and stress tolerance. In our study, we concentrated on the case-control analysis of athletes in the aspect of their personality traits in association with the COMT gene polymorphism. Participants comprised 258 combat sports athletes and 278 healthy male individuals as a control group. Psychometric properties were assessed with the Revised Temperament and Character Inventory (TCI-R). COMT polymorphism testing was performed using real-time PCR. We found a statistically significant effect of a complex factor COMT rs4680 genotype with combat athletes/controls and novelty seeking (F2,530 = 5.958, p = 0.0028, η2 = 0.022), self-management (F2,530 = 6.772, p = 0.0012, η2 = 0.025), and with self-transcendence skills (F2,530 = 9.387, p = 0.00009, η2 = 0.034). The results are important for encouraging further studies on the genetic makeup of athletes in conjunction with personality traits. Due to the multigene and multifactorial nature of determinants of sports predispositions, we propose to take into account also other features, especially when studying genes related to cerebral neurotransmission. It is a holistic departure, and it clearly illustrates the relationship between the given characteristics of an athlete.

Polyphenol Supplementation and Antioxidant Status in Athletes: A Narrative Review.

Antioxidants in sports exercise training remain a debated research topic. Plant-derived polyphenol supplements are frequently used by athletes to reduce the negative effects of exercise-induced oxidative stress, accelerate the recovery of muscular function, and enhance performance. These processes can be efficiently modulated by antioxidant supplementation. The existing literature has failed to provide unequivocal evidence that dietary polyphenols should be promoted specifically among athletes. This narrative review summarizes the current knowledge regarding polyphenols' bioavailability, their role in exercise-induced oxidative stress, antioxidant status, and supplementation strategies in athletes. Overall, we draw attention to the paucity of available evidence suggesting that most antioxidant substances are beneficial to athletes. Additional research is necessary to reveal more fully their impact on exercise-induced oxidative stress and athletes' antioxidant status, as well as optimal dosing methods.

Impact of the DRD2 Polymorphisms on the Effectiveness of the Training Program.

Dopamine receptor D2 gene (DRD2) polymorphisms have been associated with cognitive abilities, obesity, addictions, and physical-activity-related behaviors, which may underlie differences in the effectiveness of training programs. What is not yet clear is the impact of DRD2 polymorphisms on the effectiveness of exercise programs. Thus, the aim of this study was to investigate the association between the DRD2 polymorphic sites (rs1076560, rs12364283, rs1799732, rs1800497, and rs1800498) and the body's response to regular physical activity. We studied genotypes and haplotypes distribution in a group of 165 females measured for body mass and body composition measurements, lipid profile, and glucose levels before and after realization of a 12-week training program. When tested individually, statistical analyses revealed one significant genotype by training interaction under the general model (for the basal metabolic rate, BMR, p = 0.033). Carriers of the rs1076560 CC genotype exhibited a decrease in BMR in response to training (p = 0.006). Haplotype analyses also showed that (i) the CACCC and CACTT haplotypes were associated with a post-training decrease in glucose level (ß = -4.11, p = 0.032; ß = -6.86, p = 0.020, respectively); (ii) the CGCCT with an increase in BMR (ß = 0.65, p = 0.003) and fat free mass (FFM, ß = 1.20, p = 0.009); (iii) the CA-CT with a decrease in low-density lipoprotein cholesterol (LDL, ß = -17.26, p = 0.046). These results provide some evidence that the DRD2 polymorphisms may play a role in post-training changes in lipid and carbohydrate metabolism, and, as a consequence, in the effectiveness of training programs.

Transmission Distortion of MCT1 rs1049434 among Polish Elite Athletes.

BACKGROUND: To date, nearly 300 genetic markers were linked to endurance and power/strength traits. The current study aimed to compare genotype distributions and allele frequencies of the common polymorphisms: MCT1 rs1049434, NRF2 rs12594956, MYBPC3 rs1052373 and HFE rs1799945 in Polish elite athletes versus nonathletes. METHODS: The study involved 101 male elite Polish athletes and 41 healthy individuals from the Polish population as a control group. SNP data were extracted from whole-genome sequencing (WGS) performed using the following parameters: paired reads of 150 bps, at least 90 Gb of data per sample with 300 M reads and 30× mean coverage. RESULTS: All the analyzed polymorphisms conformed to Hardy-Weinberg equilibrium (HWE) in athletes and the control group, except the MCT1 rs1049434, where allele T was over-represented in the elite trainers' group. No significant between-group differences were found for analyzed polymorphisms. CONCLUSIONS: The MCT1 rs1049434 transmission distortion might be characteristic of Polish athletes and the effect of strict inclusion criteria. This result and the lack of statistically significant changes in the frequency of other polymorphisms between the groups might result from the small group size.

Association of Interleukin Genes IL10 and IL10RB with Parameters of Overweight in Military Students.

BACKGROUND: To date, nearly 300 single-nucleotide polymorphisms (SNPs) associated with BMI, waist-to-hip ratio, and other adiposity traits have been identified by GWAS. With regards to IL10, at least 49 IL10-associated polymorphisms have been reported. However, little is known regarding the relationship between SNPs of the IL10 gene and the risk of obesity in young men. The aim of the present study was to investigate the relationship between SNPs of the IL10 and IL10RB genes and the risk of obesity in young men. METHODS: A cohort of 139 male students were enrolled and the following IL10 and IL10RB SNPs were analyzed: IL10 (rs1518110), IL10 (rs3024491), IL10RB (rs2834167). The subjects were divided into groups depending on obesity parameters: body mass index (BMI), fat mass index (FMI) and fat percentage (Fat%). Statistical analysis was conducted for a single locus and haplotypes, an association between SNPs and body composition parameters was tested with four genetic models: dominant, recessive, codominant and overdominant mode of inheritance (MOI). RESULTS: Significant association was found for interaction IL10 (rs1518110) × IL10RB (rs2834167) with Fat% value exceeding 20 in codominant (p-value = 0.03, OR = 0.34, 95% CI 0.08 1.44) and dominant model (p-value = 0.03, OR = 0.34, 95% CI 0.08 1.44) Conclusion: Our study shows for the first time that there is a correlation between the occurrence of specific polymorphisms of IL10 gene (rs1518110, rs3024491 and rs2834167) and the possibility of obesity.

Genome-Wide Association Study of Exercise-Induced Fat Loss Efficiency.

There is a wide range of individual variability in the change of body weight in response to exercise, and this variability partly depends on genetic factors. The study aimed to determine DNA polymorphisms associated with fat loss efficiency in untrained women with normal weight in response to a 12-week aerobic training program using the GWAS approach, followed by a cross-sectional study in athletes. The study involved 126 untrained young Polish women (age 21.4 ± 1.7 years; body mass index (BMI): 21.7 (2.4) kg/m2) and 550 Russian athletes (229 women, age 23.0 ± 4.1; 321 men, age 23.9 ± 4.7). We identified one genome-wide significant polymorphism (rs116143768) located in the ACSL1 gene (acyl-CoA synthetase long-chain family member 1, implicated in fatty acid oxidation), with a rare T allele associated with higher fat loss efficiency in Polish women (fat mass decrease: CC genotype (n = 122) -3.8%; CT genotype (n = 4) -31.4%; p = 1.18 × 10-9). Furthermore, male athletes with the T allele (n = 7) had significantly lower BMI (22.1 (3.1) vs. 25.3 (4.2) kg/m2, p = 0.046) than subjects with the CC genotype (n = 314). In conclusion, we have shown that the rs116143768 T allele of the ACSL1 gene is associated with higher fat loss efficiency in response to aerobic training in untrained women and lower BMI in physically active men.

Implications of Adipose Tissue Content for Changes in Serum Levels of Exercise-Induced Adipokines: A Quasi-Experimental Study.

Human adipocytes release multiple adipokines into the bloodstream during physical activity. This affects many organs and might contribute to the induction of inflammation. In this study, we aimed to assess changes in circulating adipokine levels induced by intense aerobic and anaerobic exercise in individuals with different adipose tissue content. In the quasi-experimental study, 48 male volunteers (aged 21.78 ± 1.98 years) were assigned to groups depending on their body fat content (BF): LBF, low body fat (<8% BF, n = 16); MBF, moderate body fat (8−14% BF, n = 19); and HBF, high body fat (>14% BF, n = 13). The volunteers performed maximal aerobic effort (MAE) and maximal anaerobic effort (MAnE) exercises. Blood samples were collected at five timepoints: before exercise, immediately after, 2 h, 6 h, and 24 h after each exercise. The selected cytokines were analyzed: adiponectin, follistatin-like 1, interleukin 6, leptin, oncostatin M, and resistin. While the participants' MAnE and MAE performance were similar regardless of BF, the cytokine response of the HBF group was different from that of the others. Six hours after exercise, leptin levels in the HBF group increased by 35%. Further, immediately after MAnE, resistin levels in the HBF group also increased, by approximately 55%. The effect of different BF was not apparent for other cytokines. We conclude that the adipokine exercise response is associated with the amount of adipose tissue and is related to exercise type.

Inhibition of Classical and Alternative Modes of Respiration in Candida albicans Leads to Cell Wall Remodeling and Increased Macrophage Recognition.

The human fungal pathogen Candida albicans requires respiratory function for normal growth, morphogenesis, and virulence. Mitochondria therefore represent an enticing target for the development of new antifungal strategies. This possibility is bolstered by the presence of characteristics specific to fungi. However, respiration in C. albicans, as in many fungal organisms, is facilitated by redundant electron transport mechanisms, making direct inhibition a challenge. In addition, many chemicals known to target the electron transport chain are highly toxic. Here we made use of chemicals with low toxicity to efficiently inhibit respiration in C. albicans We found that use of the nitric oxide donor sodium nitroprusside (SNP) and of the alternative oxidase inhibitor salicylhydroxamic acid (SHAM) prevents respiration and leads to a loss of viability and to cell wall rearrangements that increase the rate of uptake by macrophages in vitro and in vivo We propose that treatment with SNP plus SHAM (SNP+SHAM) leads to transcriptional changes that drive cell wall rearrangement but which also prime cells to activate the transition to hyphal growth. In line with this, we found that pretreatment of C. albicans with SNP+SHAM led to an increase in virulence. Our data reveal strong links between respiration, cell wall remodeling, and activation of virulence factors. Our findings demonstrate that respiration in C. albicans can be efficiently inhibited with chemicals that are not damaging to the mammalian host but that we need to develop a deeper understanding of the roles of mitochondria in cellular signaling if they are to be developed successfully as a target for new antifungals.IMPORTANCE Current approaches to tackling fungal infections are limited, and new targets must be identified to protect against the emergence of resistant strains. We investigated the potential of targeting mitochondria, which are organelles required for energy production, growth, and virulence, in the human fungal pathogen Candida albicans Our findings suggest that mitochondria can be targeted using drugs that can be tolerated by humans and that this treatment enhances their recognition by immune cells. However, release of C. albicans cells from respiratory inhibition appears to activate a stress response that increases the levels of traits associated with virulence. Our results make it clear that mitochondria represent a valid target for the development of antifungal strategies but that we must determine the mechanisms by which they regulate stress signaling and virulence ahead of successful therapeutic advance.

A transgenic zebrafish model for the in vivo study of the blood and choroid plexus brain barriers using claudin 5.

The central nervous system (CNS) has specific barriers that protect the brain from potential threats and tightly regulate molecular transport. Despite the critical functions of the CNS barriers, the mechanisms underlying their development and function are not well understood, and there are very limited experimental models for their study. Claudin 5 is a tight junction protein required for blood brain barrier (BBB) and, probably, choroid plexus (CP) structure and function in vertebrates. Here, we show that the gene claudin 5a is the zebrafish orthologue with high fidelity expression, in the BBB and CP barriers, that demonstrates the conservation of the BBB and CP between humans and zebrafish. Expression of claudin 5a correlates with developmental tightening of the BBB and is restricted to a subset of the brain vasculature clearly delineating the BBB. We show that claudin 5a-expressing cells of the CP are ciliated ependymal cells that drive fluid flow in the brain ventricles. Finally, we find that CP development precedes BBB development and that claudin 5a expression occurs simultaneously with angiogenesis. Thus, our novel transgenic zebrafish represents an ideal model to study CNS barrier development and function, critical in understanding the mechanisms underlying CNS barrier function in health and disease.

Vomocytosis of live pathogens from macrophages is regulated by the atypical MAP kinase ERK5.

Vomocytosis, or nonlytic extrusion, is a poorly understood process through which macrophages release live pathogens that they have failed to kill back into the extracellular environment. Vomocytosis is conserved across vertebrates and occurs with a diverse range of pathogens, but to date, the host signaling events that underpin expulsion remain entirely unknown. We use a targeted inhibitor screen to identify the MAP kinase ERK5 as a critical suppressor of vomocytosis. Pharmacological inhibition or genetic manipulation of ERK5 activity significantly raises vomocytosis rates in human macrophages, whereas stimulation of the ERK5 signaling pathway inhibits vomocytosis. Lastly, using a zebrafish model of cryptococcal disease, we show that reducing ERK5 activity in vivo stimulates vomocytosis and results in reduced dissemination of infection. ERK5 therefore represents the first host signaling regulator of vomocytosis to be identified and a potential target for the future development of vomocytosis-modulating therapies.

Cryptococcus neoformans Intracellular Proliferation and Capsule Size Determines Early Macrophage Control of Infection.

Cryptococcus neoformans is a significant fungal pathogen of immunocompromised patients. Many questions remain regarding the function of macrophages in normal clearance of cryptococcal infection and the defects present in uncontrolled cryptococcosis. Two current limitations are: 1) The difficulties in interpreting studies using isolated macrophages in the context of the progression of infection, and 2) The use of high resolution imaging in understanding immune cell behavior during animal infection. Here we describe a high-content imaging method in a zebrafish model of cryptococcosis that permits the detailed analysis of macrophage interactions with C. neoformans during infection. Using this approach we demonstrate that, while macrophages are critical for control of C. neoformans, a failure of macrophage response is not the limiting defect in fatal infections. We find phagocytosis is restrained very early in infection and that increases in cryptococcal number are driven by intracellular proliferation. We show that macrophages preferentially phagocytose cryptococci with smaller polysaccharide capsules and that capsule size is greatly increased over twenty-four hours of infection, a change that is sufficient to severely limit further phagocytosis. Thus, high-content imaging of cryptococcal infection in vivo demonstrates how very early interactions between macrophages and cryptococci are critical in the outcome of cryptococcosis.

A zebrafish compound screen reveals modulation of neutrophil reverse migration as an anti-inflammatory mechanism.

Diseases of failed inflammation resolution are common and largely incurable. Therapeutic induction of inflammation resolution is an attractive strategy to bring about healing without increasing susceptibility to infection. However, therapeutic targeting of inflammation resolution has been hampered by a lack of understanding of the underlying molecular controls. To address this drug development challenge, we developed an in vivo screen for proresolution therapeutics in a transgenic zebrafish model. Inflammation induced by sterile tissue injury was assessed for accelerated resolution in the presence of a library of known compounds. Of the molecules with proresolution activity, tanshinone IIA, derived from a Chinese medicinal herb, potently induced inflammation resolution in vivo both by induction of neutrophil apoptosis and by promoting reverse migration of neutrophils. Tanshinone IIA blocked proinflammatory signals in vivo, and its effects are conserved in human neutrophils, supporting a potential role in treating human inflammation and providing compelling evidence of the translational potential of this screening strategy.