Background Excessive glutamate release followed by N-methyl-D-aspartate receptor (NMDAR) activation displays an important cascade in the pathophysiology of perinatal brain injury. We have previously ...shown that dextromethorphan, a low-affinity NMDAR antagonist, is neuroprotective in an animal model of neonatal excitotoxic brain injury. Of interest, dextromethorphan also shows agonistic properties at the sigma-1 receptor (σ1R). Sigma-1 agonists have given beneficial results in animal models of adult brain injury. Aim of the study To evaluate the effect of the selective σ1R agonist 2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate (PRE-084) in neonatal excitotoxic brain injury. Results A single intraperitoneal injection of 0.1 µg/g (low dose) or 10 µg/g (high dose) bodyweight (bw) PRE-084, given 1 h after the excitotoxic insult, significantly reduced lesion size in cortical gray matter 24 h and 120 h after the insult. Repetitive injections of 0.1 µg/g PRE-084 proved to be equally effective. PRE-084 treatment resulted in a decrease in cell death indicated by reduced TUNEL positivity and caspase-3 activation. PRE-084 reduced the number of isolectin B4-positive, activated microglial cells. Quantitative real-time PCR analysis showed no effect on σ1R gene expression at 1, 4, 8, 12, 24 and 48 h after intracranial ibotenate injection compared to healthy controls. In vitro PRE-084 protected against glutamate-induced morphological and functional changes in primary hippocampal neurons. Conclusion We demonstrate that systemic treatment with the highly selective σ1R agonist PRE-084 protects against NMDAR-mediated excitotoxic brain damage.
Background Supraphysiologic oxygen concentrations are toxic to the developing brain. Inflammatory processes increase the risk of brain injury. We have previously shown a protective effect of ...dextromethorphan, a NMDA receptor antagonist and sigma-1 receptor (σ1R) agonist, in an animal model of hyperoxia-induced neonatal brain injury. In adult brain injury, sigma agonists have a proven therapeutic potential. Aim To assess the highly selective σ1R agonist PRE-084 in a newborn animal model of inflammation-sensitized hyperoxia-induced brain injury. Methods Rat pups were randomly pre-sensitized with a single intraperitoneal (ip) injection of i) LPS or ii) vehicle on postnatal day 3. On postnatal day 5, pups were ip-injected with i) PRE-084 1µg/g bodyweight or ii) vehicle and were subsequently subjected to either i) hyperoxia (HX, FiO2>0.9) or ii) normoxia (NX, FiO2=0.21) for 24 hours. At the end of exposure, animals were sacrificed and brains were processed for caspase-3 analysis using immunohistochemistry and Western Blotting. Results A single LPS injection significantly increased the number of activated caspase-3-positive cells in cortical grey matter after hyperoxic exposure, which was reduced by PRE-084 administration (mean number of cells ±SEM; LPS_NX_vehicle 31.26±1.29 vs. LPS_HX_vehicle 38.11±1.13, p<0.01 vs. LPS_HX_PRE-084 33.66±1.54, p<0.05; n=6–7). Western Blot analyses showed a strong reduction in caspase-3 cleavage in PRE-084-treated pups compared to vehicle-injected controls in both pre-sensitized and non-pre-sensitized animals after hyperoxic exposure. Conclusion PRE-084 reduces inflammation-sensitized hyperoxia-induced injury in the developing rat brain by inhibition of apoptosis. Sigma agonists are a potential therapeutic approach in perinatal brain injury and merit further studies.
Excitotoxicity and inflammation play crucial roles in the etiopathogenesis of perinatal brain injury. We have shown that the sigma-1 receptor agonist 2-(4-morpholinethyl) ...1-phenylcyclohexanecarboxylate (PRE-084) protects against N-methyl-d-aspartate (NMDA) receptor-mediated excitotoxic brain injury. In models of adult central nervous system pathology, PRE-084 has demonstrated potent anti-inflammatory properties, which makes it a promising candidate for countering inflammation-enhanced perinatal brain injury. In the present study we evaluated the effect of PRE-084 in a neonatal mouse model of inflammation-sensitized excitotoxic brain injury. From postnatal days 1 to 4, pups were pre-sensitized by intraperitoneal injections of IL-1beta (10ng). Two hours after the last IL-1beta dose, pups received an intracranial ibotenate injection, 1 hour after the insult they were randomly treated with i) 0.1 µg/g bodyweight PRE-084 or ii) vehicle. Administration of PRE-084 resulted in a significant decrease in cortical grey (mean length of the lesion: vehicle 780.00µm ± 495.35 vs. PRE-084 433.33µm±116.51; n=8–9; p<0.05) and adjacent white matter damage (mean length of the lesion: vehicle 767.50µm ± 489.07 vs. PRE-084 391.11µm±126.14; n=8–9; p<0.05). No sex-specific differences in lesion size were detected (n=3–6, p>0.05). PRE-084 treatment significantly reduced the number of isolectin B4-positive activated microglial cells in perilesional white matter (mean number of isolectin B4-positive activated microglia vehicle 36.40±6.96 vs. PRE-084 19.93±11.99; n=5; p<0.05). We are the first to report that PRE-084 reduces inflammation-sensitized NMDAR-mediated excitotoxic perinatal brain damage. Since sigma-1 receptor agonists are investigated in clinical trials in adult neurological diseases, they might be considered a promising therapeutic option also in perinatal brain injury.
Magnonics addresses the physical properties of spin waves and utilizes them for data processing. Scalability down to atomic dimensions, operation in the GHz-to-THz frequency range, utilization of ...nonlinear and nonreciprocal phenomena, and compatibility with CMOS are just a few of many advantages offered by magnons. Although magnonics is still primarily positioned in the academic domain, the scientific and technological challenges of the field are being extensively investigated, and many proof-of-concept prototypes have already been realized in laboratories. This roadmap is a product of the collective work of many authors, which covers versatile spin-wave computing approaches, conceptual building blocks, and underlying physical phenomena. In particular, the roadmap discusses the computation operations with the Boolean digital data, unconventional approaches, such as neuromorphic computing, and the progress toward magnon-based quantum computing. This article is organized as a collection of sub-sections grouped into seven large thematic sections. Each sub-section is prepared by one or a group of authors and concludes with a brief description of current challenges and the outlook of further development for each research direction.
Ketosis-prone diabetes (KPD) is a phenotypically defined form of diabetes characterized by male predominance and severe insulin deficiency. Neurogenin3 (NGN3) is a proendocrine gene, which is ...essential for the fate of pancreatic β cells. Mice lacking ngn3 develop early insulin-deficient diabetes. Thus, we hypothesized that gender and variants in NGN3 could predispose to KPD. We have studied clinical and metabolic parameters according to gender in patients with KPD (n = 152) and common type 2 diabetes (T2DM) (n = 167). We have sequenced NGN3 in KPD patients and screened gene variants in T2DM and controls (n = 232). In KPD, male gender was associated with a more pronounced decrease in β-cell insulin secretory reserve, assessed by fasting C-peptide mean (ng/ml) ± s.d., M: 1.1 ± 0.6, F: 1.5 ± 0.9; p = 0.02 and glucagon-stimulated C-peptide mean (ng/ml) ± s.d., M: 2.2 ± 1.1, F: 3.1 ± 1.7; p = 0.03. The rare affected females were in an anovulatory state. We found two new variants in the promoter -3812T/C (af: 2%) and -3642T/C (af: 1%), two new coding variants S171T (af: 1%) and A185S (af: 1%) and the variant already described S199F (af: 69%). These variants were not associated with diabetes. Clinical investigation revealed an association between 199F and hyperglycaemia assessed by glycated haemoglobin HbA1c (%, ±s.d.) S199: 12.6 ± 1.6, S199F: 12.4 ± 1.4 and 199F: 14.1 ± 2.2; p = 0.01. In vitro, the P171T, A185S and S199F variants did not reveal major functional alteration in the activation of NGN3 target genes. In conclusion, male gender, anovulatory state in females and NGN3 variations may influence the pathogenesis of KPD in West Africans. This has therapeutic implications for potential tailored pharmacological intervention in this population.
In an earlier study of 37 candidate genes for polycystic ovary syndrome (PCOS), the strongest evidence for genetic linkage was found with the region of the follistatin gene. We have now carried out ...studies to detect variation in the follistatin gene and assess its relevance to PCOS. By sequencing the gene in 85 members of 19 families of PCOS patients, we found sequence variants at 17 sites. Of these, 16 sites have variants that are too rare to make a major contribution to susceptibility; the only common variant is a single base pair change in the last exon at a site that is not translated. In our sample of 249 families, the evidence for linkage between PCOS and this variant is weak. We also examined the expression of the follistatin gene; messenger RNA levels in cultured fibroblasts from PCOS and control women did not differ appreciably. We conclude that contributions to the etiology of PCOS from the follistatin gene, if any, are likely to be small.
The manufacture of press-formed parts often involves deep-drawing operations. Deep drawing, however, can be deemed an industrial branch in its own right. Today, many experimental as well as numerical ...methods are available for designing and optimizing deep drawing operations. The best option, however, is to combine both approaches. The present paper describes one such investigation. Here, measurements and numerical simulation were used for mapping the impact of anisotropy on thickness variation in a spherical-shaped drawn part of DC01 steel. Variation in sheet thickness was measured on spherical-shaped drawn parts of various geometries by means of two cameras, and evaluated with digital image correlation using the ARAMIS software from the company GOM. The forming experiment was carried out on an INOVA 200 kN servohydraulic testing machine in which the force vs. piston displacement curve was recorded. The same experiment was then numerically simulated and analyzed using the AUTOFORM software. Various parameters were monitored, such as thinning, strain magnitude, formability, and others. For the purpose of this simulation, a series of mechanical tests was conducted to obtain descriptions of the experimental material of 1.5 mm thickness. A material model was constructed from the tests data involving the work-hardening curve, the impact of anisotropy, and the forming limit diagram. Specifically, these tests included tensile tests, the Nakajima test, and the stacked test, which were carried out to determine materials data for the model. The actual sheet thickness was measured on a sectioned spherical-shaped drawn part using a NIKON optical microscope. The variations in thickness along defined lines on the sectioned drawn part were compared with the numerical simulations data using digital image correlation. The above-described experimental programme is suitable for calibrating a material model for any computational software and can correctly solve deep-drawing problems.
Abstract
The main goal of this paper was to define a new limit line, which expands Forming Limit Curve (FLC) more precisely Fracture Forming Limit Curve (FFLC). The new limit line was defined by ...damage models transformed from triaxiality-fracture strain space to the major/minor strain space and we focused on the shear area. Because FLC and FFLC have some limitations, for example, some Advanced High Strength Steels (AHSS) fractures before thinning. Another limitation can be seen on the left side of the diagrams in the shear region, where the part can break in the process without crossing the FLC or FFLC. The different shapes of samples were used for finding a new line of the FFLC and Deep Drawing Test (DDT) was used for verification. The fracture points from measurement were used for calibration of simple uncoupled damage models. The simple model means model, which is calibrated based on one or two measurements (tensile test or tensile test + shear test). This paper was used an Advanced High Strength Steel (AHSS) DP1000 sheet with a thickness of 0.8 mm for the experiments.
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