While comprehensive molecular profiling of histone H3.3 mutant pediatric high-grade glioma has revealed extensive dysregulation of the chromatin landscape, the exact mechanisms driving tumor ...formation remain poorly understood. Since H3.3 mutant gliomas also exhibit high levels of copy number alterations, we set out to address if the H3.3K27M oncohistone leads to destabilization of the genome. Hereto, we established a cell culture model allowing inducible H3.3K27M expression and observed an increase in mitotic abnormalities. We also found enhanced interaction of DNA replication factors with H3.3K27M during mitosis, indicating replication defects. Further functional analyses revealed increased genomic instability upon replication stress, as represented by mitotic bulky and ultrafine DNA bridges. This co-occurred with suboptimal 53BP1 nuclear body formation after mitosis in vitro, and in human glioma. Finally, we observed a decrease in ultrafine DNA bridges following deletion of the K27M mutant H3F3A allele in primary high-grade glioma cells. Together, our data uncover a role for H3.3 in DNA replication under stress conditions that is altered by the K27M mutation, promoting genomic instability and potentially glioma development.
BACKGROUND The global obesity epidemic has paralleled a decrease in semen quality. Yet, the association between obesity and sperm parameters remains controversial. The purpose of this report was to ...update the evidence on the association between BMI and sperm count through a systematic review with meta-analysis. METHODS A systematic review of available literature (with no language restriction) was performed to investigate the impact of BMI on sperm count. Relevant studies published until June 2012 were identified from a Pubmed and EMBASE search. We also included unpublished data (n = 717 men) obtained from the Infertility Center of Bondy, France. Abstracts of relevant articles were examined and studies that could be included in this review were retrieved. Authors of relevant studies for the meta-analysis were contacted by email and asked to provide standardized data. RESULTS A total of 21 studies were included in the meta-analysis, resulting in a sample of 13 077 men from the general population and attending fertility clinics. Data were stratified according to the total sperm count as normozoospermia, oligozoospermia and azoospermia. Standardized weighted mean differences in sperm concentration did not differ significantly across BMI categories. There was a J-shaped relationship between BMI categories and risk of oligozoospermia or azoospermia. Compared with men of normal weight, the odds ratio (95% confidence interval) for oligozoospermia or azoospermia was 1.15 (0.93-1.43) for underweight, 1.11 (1.01-1.21) for overweight, 1.28 (1.06-1.55) for obese and 2.04 (1.59-2.62) for morbidly obese men. CONCLUSIONS Overweight and obesity were associated with an increased prevalence of azoospermia or oligozoospermia. The main limitation of this report is that studied populations varied, with men recruited from both the general population and infertile couples. Whether weight normalization could improve sperm parameters should be evaluated further.
▶ Protective alkyd paints containing polyaniline. ▶ Anodic protection of steel using coatings containing electroactive polymers. ▶ Protection of steel by a metallic free paint coating.
A study was ...carried out to investigate the performance of anti-corrosion coatings obtained from alkyd paints containing polyaniline and polyaniline derivatives applied on carbon steel. The polyaniline, the polyaniline derivates and the paints were characterized through FTIR and Raman spectroscopies and thermogravimetric analysis. Cyclic voltammetry studies showed that polyaniline and its derivates gave electroactive properties to the paints. Accelerated corrosion experiments (salt spray and humidity chamber) revealed a significant improvement in the performance of the coatings which contained the electroactive polymer compared to conventional coatings. These results were verified by evaluation of the electrical resistance and capacitance measurements of the films using electrochemical impedance spectroscopy. For some of the samples, the Raman spectra demonstrated the presence of an oxide layer at the coating/substrate interface composed basically of Fe2O3 and Fe3O4. The results of this study reinforce the possibility of protecting carbon steel against corrosion through the formation of a protective layer of oxides using coatings which contain electroactive polymers.
On 24 August 2016, a Mw 6.0 normal‐faulting earthquake struck central Italy, causing about 300 fatalities and heavy damage. A geological survey collected the coseismic effects observed at the surface ...in order to evaluate two competing hypotheses about their nature: surface faulting versus gravitational deformation. We find that the most significant geological effect is a 5.2 km long alignment of ground ruptures along the Mount Vettore Fault System. These ruptures are independent from lithology, topography, morphology, and change in slope and exhibit an average dip‐slip displacement of ~13 cm. Geometry, kinematics, and dimensional properties of this zone of deformation strongly lead us to favor the primary surface faulting hypothesis that fits well the predicted estimates from experimental scaling law relationships. Our study provides relevant hints for surface faulting in extensional domains, contributing to implement the worldwide database of the moderate earthquakes.
Key Points
Detailed documentation of subtle primary coseismic surface faulting induced by moderate magnitude earthquake masked by later seismic event
Contribute to the worldwide database of the moderate earthquakes surface faulting events in extensional domains
Neonatal hypoxia ischemia (HI) is the main cause of newborn mortality and morbidity. Preclinical studies have shown that the immature rat brain is more resilient to HI injury, suggesting innate ...mechanisms of neuroprotection. During neonatal period brain metabolism experience changes that might greatly affect the outcome of HI injury. Therefore, the aim of the present study was to investigate how changes in brain metabolism interfere with HI outcome in different stages of CNS development. For this purpose, animals were divided into 6 groups: HIP3, HIP7 and HIP11 (HI performed at postnatal days 3, 7 and 11, respectively), and their respective shams. In vivo 18FFDG micro positron emission tomography (microPET) imaging was performed 24 and 72 h after HI, as well as ex-vivo assessments of glucose and beta-hydroxybutyrate (BHB) oxidation. At adulthood behavioral tests and histology were performed. Behavioral and histological analysis showed greater impairments in HIP11 animals, while HIP3 rats were not affected. Changes in 18FFDG metabolism were found only in the lesion area of HIP11, where a substantial hypometabolism was detected. Furthermore, 18FFDG hypometabolism predicted impaired cognition and worst histological outcomes at adulthood. Finally, substrate oxidation assessments showed that glucose oxidation remained unaltered and higher level of BHB oxidation found in P3 animals, suggesting a more resilient metabolism. Overall, present results show 18FFDG microPET predicts long-term injury outcome and suggests that higher BHB utilization is one of the mechanisms that confer the intrinsic neuroprotection to the immature brain and should be explored as a therapeutic target for treatment of HI.
•HI injury has different prognosis depending on the age it is induced.•While P3 brain is more resilient, the P11 brain is greatly affected.•Higher usage of BHB, instead of glucose, is a possible mechanism of P3 resiliency.
Although the close link between body weight and fertility has been known for eons, only recently have the peripheral signals and neuroendocrine networks responsible for such a phenomenon begun to be ...identified. A key event in this field was the cloning of the adipocyte-derived hormone leptin, which has been demonstrated as a pivotal regulator for the integration of energy homeostasis and reproduction. In addition, other metabolic hormones, such as insulin, contribute to this physiological integration. Moreover, compelling experimental evidence implicates hormonal products of the gastrointestinal tract as adjuncts in the complex coordination and regulation of body weight and reproduction. Here, we review recent studies evaluating the reproductive effects and sites of action of ghrelin and PYY
3-36, two hormonal signals of gastrointestinal origin involved in the control food intake and energy balance. In addition, we summarize the potential contribution of kisspeptin, the recently characterized gatekeeper of the GnRH system encoded by
Kiss1 gene, to integrating reproductive function and energy status. Evidence suggests that besides having direct gonadal effects, ghrelin may participate in the regulation of gonadotropin secretion and it may influence the timing of puberty. Likewise, PYY
3-36 modulates GnRH and gonadotropin release. In addition, the hypothalamic KiSS-1 system is sensitive to nutritional status, and its diminished expression during states of negative energy balance might contribute to the suppression of reproductive function in such conditions. We propose that the peripheral hormones, ghrelin and PYY
3-36, and the central neuropeptide, kisspeptin, are ‘novel’ players in the neuroendocrine networks that integrate energy balance and reproduction.
Ghrelin, the endogenous ligand of GH secretagogue receptor type 1a, has emerged as pleiotropic modulator of diverse biological functions, including energy homeostasis and, recently, reproduction. ...Although inhibitory actions of ghrelin on LH secretion and puberty onset have been reported previously, the receptor mechanisms mediating these actions, and the potential gonadotropic effects of the unacylated isoform of ghrelin (UAG), remain unclear. In this work, the effects of single and repeated administration of ghrelin or UAG on LH secretion were compared in pubertal and adult male rats. In addition, the effects of ghrelin were assessed in models of transient or persistent hypergonadotropism. Daily injection of ghrelin or UAG throughout puberty similarly decreased LH levels and partially delayed balanopreputial separation. Likewise, chronic infusion of ghrelin or UAG to adult males resulted in significant decreases in circulating LH and FSH concentrations. Moreover, acute injection of ghrelin induced a transient reduction in LH levels in freely moving males, an effect that was fully mimicked by administration of UAG. Yet in contrast to ghrelin, UAG failed to modify GH secretion. Finally, injection of ghrelin moderately, but significantly, reduced the duration of LH secretory responses to the potent gonadotropin secretagogue kisspeptin-10, whereas ghrelin infusion in a model of chronic elevation of serum gonadotropin levels (the transgenic growth retarded male rat) evoked a significant reduction of LH concentrations. Altogether our present results further substantiate the inhibitory effect of ghrelin on basal and stimulated LH secretion in a wide array of experimental conditions. Moreover, our data are the first to demonstrate the ability of UAG, originally considered an inert form of the molecule, to mimic the actions of acylated ghrelin on LH release. These observations reinforce the contention that ghrelin, as putative signal for energy insufficiency, may operate as negative modifier of male puberty and LH secretion, an effect that might be, at least partially, conducted through a GH secretagogue receptor type 1a-independent mechanism.
•Astrocytes play a key role in the progression of neonatal hypoxic ischemic injury (HI).•Arundic acid (AA) alters astrocytic response to HI injury, reducing S100b release into CSF.•AA administration ...reduced HI-induced learning deficits, brain damage and increased survival of astrocytes.
Perinatal hypoxia-ischemia (HI) is one of the main causes of mortality and chronic neurological morbidity in infants and children. Astrocytes play a key role in HI progression, becoming reactive in response to the injury, releasing S100 calcium binding protein B (S100B). Since S100B inhibition seems to have neuroprotective effects on central nervous system injury models, here we evaluated the neuroprotective effects of an S100B inhibitor, arundic acid (AA) in a HI model.
On the 7th postnatal day, animals were submitted to the combination of common carotid artery occlusion and hypoxic atmosphere (8% O2) for 60 min. Three experiments were performed in order to: (1) define AA dose (0.1, 1 or 10 mg/kg, pre-hypoxia i.p. injection), (2) test if repeated AA administrations (10 mg/kg at 3 time points: Pre-hypoxia, 24 h and 48 h after HI) would improve the response and (3) investigate biochemical mechanisms involved in AA protection two days after HI.
AA at a dose of 10 mg/kg applied before and after hypoxia, was the only treatment protocol that was able to improve HI-induced memory deficits, to reduce tissue damage, to promote astrocytic survival in the hippocampus and to reduced extracellular release of S100B in the cerebrospinal fluid.
Overall, AA treatment showed beneficial effects on memory deficits, tissue damage, promoting astrocyte survival likely by reducing S100B release. Protection aided to astrocytes by AA treatment against HI lesion may lead to development of new therapeutic strategies that target these particular cells.
Abstract It has been demonstrated, in normal and aged rats and mice, that acute i.c.v. ghrelin (Ghr) administration increases memory retention. In order to evaluate if this treatment, restores memory ...retention in animals exhibiting impaired memory, in the present work we selected a chronic food restriction mouse model (since undernutrition prejudices higher nervous functions). We employed adult female mice with 28 days of 50% food restriction and evaluated: a) behavioral performance using novel object recognition test for memory, and plus maze for anxiety-like behavior, b) some morphometric parameters as body and hepatic weights and c) plasma Ghr levels. The animals with 50% food restriction showed an increase in plasma Ghr levels and a decrease in morphometric parameters and in the percentage of novel object recognition time. When the peptide was i.c.v. injected in food-restricted animals (0.03, 0.3 or 3.0 nmol/μl), memory increases in relation to food-restricted mice injected with vehicle, reaching a performance similar to controls.
Neonatal hypoxia-ischemia (HI) is a major cause of cognitive impairments in infants. Antenatal strategies improving the intrauterine environment can have high impact decreasing pregnancy-derived ...intercurrences. Physical exercise alters the mother-fetus unity and has been shown to prevent the energetic challenge imposed by HI. This study aimed to reveal neuroprotective mechanisms afforded by pregnancy swimming on early metabolic failure and late cognitive damage, considering animals' sex as a variable. Pregnant Wistar rats were submitted to daily swimming exercise (20′ in a tank filled with 32 °C water) during pregnancy. Neonatal HI was performed in male and female pups at postnatal day 7. Electron chain transport, mitochondrial mass and function and ROS formation were assessed in the right brain hemisphere 24 h after HI. From PND45, reference and working spatial memory were tested in the Morris water maze. MicroPET-FDG images were acquired 24 h after injury (PND8) and at PND60, following behavioral analysis. HI induced early energetic failure, decreased enzymatic activity in electron transport chain, increased production of ROS in cortex and hippocampus as well as caused brain glucose metabolism dysfunction and late cognitive impairments. Maternal swimming was able to prevent mitochondrial dysfunction and to improve spatial memory. The intergenerational effects of swimming were sex-specific, since male rats were benefited most. In conclusion, maternal swimming was able to affect the mitochondrial response to HI in the offspring's brains, preserving its function and preventing cognitive damage in a sex-dependent manner, adding relevant information on maternal exercise neuroprotection and highlighting the importance of mitochondria as a therapeutic target for HI neuropathology.
Pregnancy swimming has a great impact in the offspring's brain development. Maternal exercise induces a sex-dependent preconditioning response in the brain tissue following neonatal hypoxia-ischemia, mainly through early mitochondrial function preservation, preventing energetic failure and ROS production, improving brain glucose utilization and decreasing HI-induced cognitive impairments at adult age. Display omitted
•Brain energetic failure is a primary cause of damage following neonatal hypoxia ischemia (HI).•Pregnancy swimming has shown beneficial effects preventing HI brain damage.•Mitochondrial function is preserved following HI in the offspring of exercised dams.•Spatial memory impairments induced by HI were prevented by maternal swimming.•Beneficial effects of maternal exercise for treating HI are sexually dimorphic
PDF
