The use of magnesium alloys has enormous potential in terms of weight saving, resource availability and sustainability. This contrasts with the need to protect the surface from wear and corrosion, ...which is necessary to increase the depth of application of this promising material in industrial applications.
The general requirements for the surface protection and surface functionalization can be fulfilled in particular by PVD coatings. However, so far there are no industrial PVD coatings available that meet the requirements for corrosion protection of the magnesium substrate. Common PVD coatings cannot be applied to magnesium due to the risk of severe galvanic corrosion between substrate and coating.
In previous studies, TiMgN was identified as a prospective layer material for the corrosion protection of magnesium alloys as well as for the functionalization of the surface with regard to wear resistance and decoration.
In the present work, the TiMgN coating concept has been applied to an industrial 4-cathode magnetron sputter unit of the type Cemecon CC800/9-HiPIMS. As substrate material the magnesium alloy AZ31hp was used. In addition to pure TiMgN, the rare earth elements Y and Gd were alloyed to the TiMgN coating in order to improve the corrosion properties. The influences of coating composition, target design and sputtering mode (Direct Current — DC and High Power Impulse Magnetron Sputtering — HiPIMS) were examined with regard to the chemical, mechanical and structural properties as well as the corrosion properties.
It will be shown, that the corrosion properties of the TiMgN coated magnesium alloys depend significantly on the deposition conditions and on the coating microstructure, while the defect density seems to be of minor influence. Alloying of Gd to the coating leads to a further increase in corrosion resistance to more than 300h in the salt spray test, while alloying of Y shows no positive effect.
•A new PVD coating concept was developed by using an industrial PVD deposition unit.•Alloying of TiN with Mg reduces the susceptibility to galvanic corrosion.•Gd alloyed TiMgN coatings withstand the salt spray test for more than two weeks.•HiPIMS as well as alloying of Gd promotes hydrophobic behavior.
In life sciences, the material properties of suspended cells have attained significance close to that of fluorescent markers but with the advantage of label-free and unbiased sample characterization. ...Until recently, cell rheological measurements were either limited by acquisition throughput, excessive post processing, or low-throughput real-time analysis. Real-time deformability cytometry expanded the application of mechanical cell assays to fast on-the-fly phenotyping of large sample sizes, but has been restricted to single material parameters as the Young's modulus. Here, we introduce dynamic real-time deformability cytometry for comprehensive cell rheological measurements at up to 100 cells per second. Utilizing Fourier decomposition, our microfluidic method is able to disentangle cell response to complex hydrodynamic stress distributions and to determine viscoelastic parameters independent of cell shape. We demonstrate the application of our technology for peripheral blood cells in whole blood samples including the discrimination of B- and CD4+ T-lymphocytes by cell rheological properties.
Background
Septic cardiomyopathy worsens the prognosis of critically ill patients. Clinical data suggest that interleukin‐1β (IL‐1β), activated by the NLRP3 inflammasome, compromises cardiac ...function. Whether or not deleting Nlrp3 would prevent cardiac atrophy and improve diastolic cardiac function in sepsis was unclear. Here, we investigated the role of NLRP3/IL‐1β in sepsis‐induced cardiomyopathy and cardiac atrophy.
Methods
Male Nlrp3 knockout (KO) and wild‐type (WT) mice were exposed to polymicrobial sepsis by caecal ligation and puncture (CLP) surgery (KO, n = 27; WT, n = 33) to induce septic cardiomyopathy. Sham‐treated mice served as controls (KO, n = 11; WT, n = 16). Heart weights and morphology, echocardiography and analyses of gene and protein expression were used to evaluate septic cardiomyopathy and cardiac atrophy. IL‐1β effects on primary and immortalized cardiomyocytes were investigated by morphological and molecular analyses. IonOptix and real‐time deformability cytometry (RT‐DC) analysis were used to investigate functional and mechanical effects of IL‐1β on cardiomyocytes.
Results
Heart morphology and echocardiography revealed preserved systolic (stroke volume: WT sham vs. WT CLP: 33.1 ± 7.2 μL vs. 24.6 ± 8.7 μL, P < 0.05; KO sham vs. KO CLP: 28.3 ± 8.1 μL vs. 29.9 ± 9.9 μL, n.s.; P < 0.05 vs. WT CLP) and diastolic (peak E wave velocity: WT sham vs. WT CLP: 750 ± 132 vs. 522 ± 200 mm/s, P < 0.001; KO sham vs. KO CLP: 709 ± 152 vs. 639 ± 165 mm/s, n.s.; P < 0.05 vs. WT CLP) cardiac function and attenuated cardiac (heart weight–tibia length ratio: WT CLP vs. WT sham: −26.6%, P < 0.05; KO CLP vs. KO sham: −3.3%, n.s.; P < 0.05 vs. WT CLP) and cardiomyocyte atrophy in KO mice during sepsis. IonOptix measurements showed that IL‐1β decreased contractility (cell shortening: IL‐1β: −15.4 ± 2.3%, P < 0.001 vs. vehicle, IL‐1RA: −6.1 ± 3.3%, P < 0.05 vs. IL‐1β) and relaxation of adult rat ventricular cardiomyocytes (time‐to‐50% relengthening: IL‐1β: 2071 ± 225 ms, P < 0.001 vs. vehicle, IL‐1RA: 564 ± 247 ms, P < 0.001 vs. IL‐1β), which was attenuated by an IL‐1 receptor antagonist (IL‐1RA). RT‐DC analysis indicated that IL‐1β reduced cardiomyocyte size (P < 0.001) and deformation (P < 0.05). RNA sequencing showed that genes involved in NF‐κB signalling, autophagy and lysosomal protein degradation were enriched in hearts of septic WT but not in septic KO mice. Western blotting and qPCR disclosed that IL‐1β activated NF‐κB and its target genes, caused atrophy and decreased myosin protein in myocytes, which was accompanied by an increased autophagy gene expression. These effects were attenuated by IL‐1RA.
Conclusions
IL‐1β causes atrophy, impairs contractility and relaxation and decreases deformation of cardiomyocytes. Because NLRP3/IL‐1β pathway inhibition attenuates cardiac atrophy and cardiomyopathy in sepsis, it could be useful to prevent septic cardiomyopathy.
The purpose of this study was to investigate the relationship between physical workload and injury risk in elite youth football players.
The workload data and injury incidence of 32 players were ...monitored throughout 2 seasons. Multiple regression was used to compare cumulative (1, 2, 3 and 4-weekly) loads and acute:chronic (A:C) workload ratios (acute workload divided by chronic workload) between injured and non-injured players for specific GPS and accelerometer-derived variables:total distance (TD), high-speed distance (HSD), accelerations (ACC) and total load. Workloads were classified into discrete ranges by z-scores and the relative risk was determined.
A very high number of ACC (≥9254) over 3 weeks was associated with the highest significant overall (relative risk (RR)=3.84) and non-contact injury risk (RR=5.11). Non-contact injury risk was significantly increased when a high acute HSD was combined with low chronic HSD (RR=2.55), but not with high chronic HSD (RR=0.47). Contact injury risk was greatest when A:C TD and ACC ratios were very high (1.76 and 1.77, respectively) (RR=4.98).
In general, higher accumulated and acute workloads were associated with a greater injury risk. However, progressive increases in chronic workload may develop the players' physical tolerance to higher acute loads and resilience to injury risk.
The methylthioadenosine phosphorylase (MTAP) gene is located adjacent to the cyclin-dependent kinase inhibitor 2A (CDKN2A) tumor-suppressor gene and is co-deleted with CDKN2A in approximately 15% of ...all cancers. This co-deletion leads to aggressive tumors with poor prognosis that lack effective, molecularly targeted therapies. The metabolic enzyme methionine adenosyltransferase 2α (MAT2A) was identified as a synthetic lethal target in MTAP-deleted cancers. We report the characterization of potent MAT2A inhibitors that substantially reduce levels of S-adenosylmethionine (SAM) and demonstrate antiproliferative activity in MTAP-deleted cancer cells and tumors. Using RNA sequencing and proteomics, we demonstrate that MAT2A inhibition is mechanistically linked to reduced protein arginine methyltransferase 5 (PRMT5) activity and splicing perturbations. We further show that DNA damage and mitotic defects ensue upon MAT2A inhibition in HCT116 MTAP−/− cells, providing a rationale for combining the MAT2A clinical candidate AG-270 with antimitotic taxanes.
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•Development of MAT2A inhibitors (MAT2Ai) AGI-24512 and AG-270 with improved potency•AGI-24152 and AG-270 reduce proliferation of cancer cells and tumors that lack MTAP•MAT2Ai reduce PRMT5 activity affecting mRNA splicing and inducing DNA damage•Antiproliferative effects of AG-270 are synergistic with taxanes in vitro and in vivo
Kalev et al. characterize potent inhibitors of the metabolic enzyme MAT2A, including the clinical candidate AG-270, which reduces proliferation of MTAP-deficient cancer cells and tumors. This is mediated by deregulation of splicing, DNA damage, and reduced DNA damage repair, enabling synergistic combinations with antimitotic taxanes.
Somatic gain-of-function mutations in isocitrate dehydrogenases (
) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (
)-2-hydroxyglutarate ...(2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation.
studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human
mutation-positive acute myeloid leukemia (AML) cells
and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2
-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with
mutation-positive advanced hematologic malignancies.
Mutations in
are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development.
.
A number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These mutations alter residues in the enzyme active sites and confer ...a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite (R)-2-hydroxyglutarate (2HG). We developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymology analysis were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.
Patients with chronic daily headaches (CDH) are often a diagnostic challenge and frequently undergo neuroimaging. One common underlying cause of CDH is idiopathic intracranial hypertension (IIH). ...However, certain neuroimaging abnormalities that suggest IIH, such as optic nerve sheath diameters (ONSD), pituitary gland height, and venous sinus diameter, require interpretation due to the absence of established normative values. Notably, intracranial pressure is known to varies with age, sex and weight, further complicating the determination of objectively abnormal findings within a specific patient group. This study aims to assist clinical neuroradiologists in differentiating neuroimaging results in CDH by providing weight-adjusted normative values for imaging characteristics of IIH. In addition to age and BMI we here assessed 1924 population-based T1-weighted MRI datasets of healthy participants for relevant MRI aspects of IIH. Association to BMI was analyzed using linear/logistic regression controlled for age and stratified for sex. ONSD was 4.3 mm 2.8; 5.9/4.6 mm 3.6; 5.7 and diameter of transverse sinus was 4.67 mm 1.6; 6.5/4.45 mm 3.0; 7.9. Height of pituitary gland was 5.1 mm 2.2;8.1/4.6 mm 1.9;7.1 for female and male respectively. Values generally varied with BMI with regression slopes spanning 0.0001 to 0.05 and were therefor presented as normative values stratified by BMI. Protrusion of ocular papilla, empty sella and transverse sinus occlusion were rare in total. Our data show an association between BMI and commonly used MRI features for diagnosing IIH. We provide categorized normative BMI values for ONSD, pituitary gland height, and transverse sinus diameter. This distinction helps objectively identify potential IIH indicators compared to regular population norms, enhancing diagnostic accuracy for suspected IIH patients. Notably, optic nerve head protrusion, empty sella, and transverse sinus occlusion are rare in healthy individuals, solidifying their importance as imaging markers regardless of BMI.
The assessment of cardiorespiratory fitness (CRF) is an important tool for prognosis evaluation of cardiovascular events. The gold standard to measure CRF is cardiopulmonary exercise testing (CPET) ...to determine peak oxygen uptake (VO2peak). However, CPET is not only time consuming but also expensive and is therefore not widely applicable in daily practice. The aim of our study was to analyze, whether and which anthropometric markers derived from a 3D body scanner were related to VO2peak in a general population-based study. We analyzed data (SHIP-START-3) from 3D body scanner and CPET of 1035 subjects (529 women; 51.1%, age range 36-93). A total of 164 anthropometric markers were detected with the 3D body scanner VITUS Smart XXL using the software AnthroScan Professional. Anthropometric measurements were standardized and associated with CRF by sex-stratified linear regression models adjusted for age and height. Anthropometric markers were ranked according to the - log- p values derived from these regression models. In men a greater left and right thigh-knee-ratio, a longer forearm-fingertip length, a greater left thigh circumference and greater left upper arm circumference were most strongly associated with a higher VO2peak. In women a greater left and right thigh circumference, left calf circumference, thigh thickness and right calf circumference were most strongly associated with a higher VO2peak. The detected VO2peak-related anthropometric markers could be helpful in assessing CRF in clinical routine. Commonly used anthropometric markers, e.g. waist and hip circumference, were not among the markers associated with VO2peak.
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