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The WHO (2021) Classification classified a group of pediatric-type high-grade gliomas as IDHwildtype, H3wildtype but as of currently, they are characterized only by negative molecular features of IDHand H3. We recruited 35 cases of pediatric IDHwildtype and H3wildtype hemispheric glioblastomas. We evaluated them with genome-wide methylation profiling, targeted sequencing, RNAseq, TERTpromoter sequencing, and FISH. The median survival of the cohort was 27.6 months. With Capper et al.’s36methylation groups as a map, the cases were found to be epigenetically heterogeneous and were clustered in proximity or overlay of methylation groups PXA-like (n= 8), LGG-like (n= 10), GBM_MYCN (n= 9), GBM_midline (n= 5), and GBM_RTKIII (n= 3). Histology of the tumors in these groups was not different from regular glioblastomas. Methylation groups were not associated with OS. We were unable to identify groups specifically characterized by EGFRor PDGFRAamplification as proposed by other authors. EGFR, PDGFRA,and MYCNamplifications were not correlated with OS. 4/9 cases of the GBM_MYCN cluster did not show MYCNamplification; the group was also enriched for EGFRamplification (4/9 cases) and the two biomarkers overlapped in two cases. Overall, PDGFRAamplification was found in only four cases and they were not restricted to any groups. Cases in proximity to GBM_midline were all hemispheric and showed loss of H3K27me3 staining. Fusion genes ALK/NTRK/ROS1/METcharacteristic of infantile glioblastomas were not identified in 17 cases successfully sequenced. BRAF V600Ewas only found in the PXA group but CDKN2Adeletion could be found in other methylation groups. PXA-like cases did not show PXA histological features similar to findings by other authors. No case showed TERTpromoter mutation. Mutations of mismatch repair (MMR) genes were poor prognosticators in single (p≤ 0.001) but not in multivariate analyses (p= 0.229). MGMThad no survival significance in this cohort. Of the other common biomarkers, only TP53and ATRXmutations were significant poor prognosticators and only TP53mutation was significant after multivariate analyses (p= 0.024). We conclude that IDHwildtype, H3wildtype pediatric hemispheric glioblastomas are molecularly heterogeneous and in routine practice, TP53, ATRX,and MMR status could profitably be screened for risk stratification in laboratories without ready access to methylation profiling.

The WHO (2021) Classification classified a group of pediatric-type high-grade gliomas as IDHwildtype, H3wildtype but as of currently, they are characterized only by negative molecular features of IDHand H3. We recruited 35 cases of pediatric IDHwildtype and H3wildtype hemispheric glioblastomas. We evaluated them with genome-wide methylation profiling, targeted sequencing, RNAseq, TERTpromoter sequencing, and FISH. The median survival of the cohort was 27.6 months. With Capper et al.'s36methylation groups as a map, the cases were found to be epigenetically heterogeneous and were clustered in proximity or overlay of methylation groups PXA-like (n= 8), LGG-like (n= 10), GBM_MYCN (n= 9), GBM_midline (n= 5), and GBM_RTKIII (n= 3). Histology of the tumors in these groups was not different from regular glioblastomas. Methylation groups were not associated with OS. We were unable to identify groups specifically characterized by EGFRor PDGFRAamplification as proposed by other authors. EGFR, PDGFRA,and MYCNamplifications were not correlated with OS. 4/9 cases of the GBM_MYCN cluster did not show MYCNamplification; the group was also enriched for EGFRamplification (4/9 cases) and the two biomarkers overlapped in two cases. Overall, PDGFRAamplification was found in only four cases and they were not restricted to any groups. Cases in proximity to GBM_midline were all hemispheric and showed loss of H3K27me3 staining. Fusion genes ALK/NTRK/ROS1/METcharacteristic of infantile glioblastomas were not identified in 17 cases successfully sequenced. BRAF V600Ewas only found in the PXA group but CDKN2Adeletion could be found in other methylation groups. PXA-like cases did not show PXA histological features similar to findings by other authors. No case showed TERTpromoter mutation. Mutations of mismatch repair (MMR) genes were poor prognosticators in single (p≤ 0.001) but not in multivariate analyses (p= 0.229). MGMThad no survival significance in this cohort. Of the other common biomarkers, only TP53and ATRXmutations were significant poor prognosticators and only TP53mutation was significant after multivariate analyses (p= 0.024). We conclude that IDHwildtype, H3wildtype pediatric hemispheric glioblastomas are molecularly heterogeneous and in routine practice, TP53, ATRX,and MMR status could profitably be screened for risk stratification in laboratories without ready access to methylation profiling.

WHO 2016 classified glioblastomas into IDH-mutant and IDH-wildtype with the former having a better prognosis but there was no study on IDH-mutant primary glioblastomas only, as previous series included secondary glioblastomas. We recruited a series of 67 IDH-mutant primary glioblastomas/astrocytoma IV without a prior low-grade astrocytoma and examined them using DNA-methylation profiling, targeted sequencing, RNA sequencing and TERTpromoter sequencing, and correlated the molecular findings with clinical parameters. The median OS of 39.4 months of 64 cases and PFS of 25.9 months of 57 cases were better than the survival data of IDH-wildtype glioblastomas and IDH-mutant secondary glioblastomas retrieved from datasets. The molecular features often seen in glioblastomas, such as EGFRamplification, combined +7/−10, and TERTpromoter mutations were only observed in 6/53 (11.3%), 4/53 (7.5%), and 2/67 (3.0%) cases, respectively, and gene fusions were found only in two cases. The main mechanism for telomere maintenance appeared to be alternative lengthening of telomeres as ATRXmutation was found in 34/53 (64.2%) cases. In t-SNE analyses of DNA-methylation profiles, with an exceptional of one case, a majority of our cases clustered to IDH-mutant high-grade astrocytoma subclass (40/53; 75.5%) and the rest to IDH-mutant astrocytoma subclass (12/53; 22.6%). The latter was also enriched with G-CIMP high cases (12/12; 100%). G-CIMP-high status and MGMTpromoter methylation were independent good prognosticators for OS (p= 0.022 and p= 0.002, respectively) and TP53mutation was an independent poor prognosticator (p= 0.013) when correlated with other clinical parameters. Homozygous deletion of CDKN2A/Bwas not correlated with OS (p= 0.197) and PFS (p= 0.278). PDGFRAamplification or mutation was found in 16/59 (27.1%) of cases and was correlated with G-CIMP-low status (p= 0.010). Aside from the three well-known pathways of pathogenesis in glioblastomas, chromatin modifying and mismatch repair pathways were common aberrations (88.7% and 20.8%, respectively), the former due to high frequency of ATRXinvolvement. We conclude that IDH-mutant primary glioblastomas have better prognosis than secondary glioblastomas and have major molecular differences from other commoner glioblastomas. G-CIMP subgroups, MGMTpromoter methylation, and TP53mutation are useful prognostic adjuncts.

Chronic administration of methamphetamine (METH) leads to physical and psychological dependence. It is generally accepted that METH exerts rewarding effects via competitive inhibition of the dopamine transporter (DAT), but the molecular mechanism of METH addiction remains largely unknown. Accumulating evidence shows that mitochondrial function is important in regulation of drug addiction. In this study,  we investigated the role of Clk1, an essential mitochondrial hydroxylase for ubiquinone (UQ), in METH reward effects. We showed that Clk1+/−mutation significantly suppressed METH-induced conditioned place preference (CPP), accompanied by increased expression of DAT in plasma membrane of striatum and hippocampus due to Clk1 deficiency-induced inhibition of DAT degradation without influencing de novosynthesis of DAT. Notably, significantly decreased iron content in striatum and hippocampus was evident in both Clk1+/−mutant mice and PC12 cells with Clk1 knockdown. The decreased iron content was attributed to increased expression of iron exporter ferroportin 1 (FPN1) that was associated with elevated expression of hypoxia-inducible factor-1α (HIF-1α) in response to Clk1 deficiency both in vivo and in vitro. Furthermore, we showed that iron played a critical role in mediating Clk1 deficiency-induced alteration in DAT expression, presumably via upstream HIF-1α. Taken together, these data demonstrated that HIF-1α-mediated changes in iron homostasis are involved in the Clk1 deficiency-altered METH reward behaviors.

WHO 2016 classified glioblastomas into IDH-mutant and IDH-wildtype with the former having a better prognosis but there was no study on IDH-mutant primary glioblastomas only, as previous series included secondary glioblastomas. We recruited a series of 67 IDH-mutant primary glioblastomas/astrocytoma IV without a prior low-grade astrocytoma and examined them using DNA-methylation profiling, targeted sequencing, RNA sequencing and TERTpromoter sequencing, and correlated the molecular findings with clinical parameters. The median OS of 39.4 months of 64 cases and PFS of 25.9 months of 57 cases were better than the survival data of IDH-wildtype glioblastomas and IDH-mutant secondary glioblastomas retrieved from datasets. The molecular features often seen in glioblastomas, such as EGFRamplification, combined +7/−10, and TERTpromoter mutations were only observed in 6/53 (11.3%), 4/53 (7.5%), and 2/67 (3.0%) cases, respectively, and gene fusions were found only in two cases. The main mechanism for telomere maintenance appeared to be alternative lengthening of telomeres as ATRXmutation was found in 34/53 (64.2%) cases. In t-SNE analyses of DNA-methylation profiles, with an exceptional of one case, a majority of our cases clustered to IDH-mutant high-grade astrocytoma subclass (40/53; 75.5%) and the rest to IDH-mutant astrocytoma subclass (12/53; 22.6%). The latter was also enriched with G-CIMP high cases (12/12; 100%). G-CIMP-high status and MGMTpromoter methylation were independent good prognosticators for OS (p= 0.022 and p= 0.002, respectively) and TP53mutation was an independent poor prognosticator (p= 0.013) when correlated with other clinical parameters. Homozygous deletion of CDKN2A/Bwas not correlated with OS (p= 0.197) and PFS (p= 0.278). PDGFRAamplification or mutation was found in 16/59 (27.1%) of cases and was correlated with G-CIMP-low status (p= 0.010). Aside from the three well-known pathways of pathogenesis in glioblastomas, chromatin modifying and mismatch repair pathways were common aberrations (88.7% and 20.8%, respectively), the former due to high frequency of ATRXinvolvement. We conclude that IDH-mutant primary glioblastomas have better prognosis than secondary glioblastomas and have major molecular differences from other commoner glioblastomas. G-CIMP subgroups, MGMTpromoter methylation, and TP53mutation are useful prognostic adjuncts.

The metabolic genes encoding isocitrate dehydrogenase (IDH1, 2) are frequently mutated in gliomas. Mutation of IDHdefines a distinct subtype of glioma and predicts therapeutic response. IDHmutation has a remarkable neomorphic activity of converting α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which is now commonly referred to as an oncometabolite and biomarker for gliomas. PCR-sequencing (n= 220), immunohistochemistry staining (IHC, n= 220), and gas chromatography mass spectrometry (GC-MS, n= 87) were applied to identify IDHmutation in gliomas, and the sensitivity and specificity of these strategies were compared. PCR-sequencing and IHC staining are reliable for retrospective assessment of IDH1mutation in gliomas, but both methods usually take 1–2 days, which hinders their application for rapid diagnosis. GC-MS-based methods can detect 2-HG qualitatively and quantitatively, offering information on the IDH1mutation status in gliomas with the sensitivity and specificity being 100%. Further optimization of the GC-MS based methodology (so called as the mini-column method) enabled us to determine 2-HG within 40 min in glioma samples without complex or time-consuming preparation. Most importantly, the ratio of 2-HG/glutamic acid was shown to be a reliable parameter for determination of mutation status. The mini-column method enables rapid identification of 2-HG, providing a promising strategy for intraoperative diagnosis of IDH1-mutated gliomas in the future.

The metabolic genes encoding isocitrate dehydrogenase (IDH1, 2) are frequently mutated in gliomas. Mutation of IDHdefines a distinct subtype of glioma and predicts therapeutic response. IDHmutation has a remarkable neomorphic activity of converting α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG), which is now commonly referred to as an oncometabolite and biomarker for gliomas. PCR-sequencing (n= 220), immunohistochemistry staining (IHC, n= 220), and gas chromatography mass spectrometry (GC-MS, n= 87) were applied to identify IDHmutation in gliomas, and the sensitivity and specificity of these strategies were compared. PCR-sequencing and IHC staining are reliable for retrospective assessment of IDH1mutation in gliomas, but both methods usually take 1–2 days, which hinders their application for rapid diagnosis. GC-MS-based methods can detect 2-HG qualitatively and quantitatively, offering information on the IDH1mutation status in gliomas with the sensitivity and specificity being 100%. Further optimization of the GC-MS based methodology (so called as the mini-column method) enabled us to determine 2-HG within 40 min in glioma samples without complex or time-consuming preparation. Most importantly, the ratio of 2-HG/glutamic acid was shown to be a reliable parameter for determination of mutation status. The mini-column method enables rapid identification of 2-HG, providing a promising strategy for intraoperative diagnosis of IDH1-mutated gliomas in the future.

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The independent influence of microstructural features on fracture toughness of TC21 alloy with lamellar microstructure was investigated. Triple heat treatments were designed to obtain lamellar microstructures with different parameters, which were characterized by OM and SEM. The size and content of αplates were mainly determined by cooling rate from single βphase field and solution temperature in two-phase field; while the precipitation behavior of secondary αplatelets was dominantly controlled by aging temperature in two-phase field. The content and thickness of αplates and the thickness of secondary αplatelets were important microstructural features influencing the fracture toughness. Both increasing the content of αplates and thickening αplates (or secondary αplatelets) could enhance the fracture toughness of TC21 alloy. Based on energy consumption by the plastic zone of crack tip in αplates, a toughening mechanism for titanium alloys was proposed.

Extremely low expansion glass ceramics are widely used in integrated circuit (IC), liquid crystal display (LCD) lithography, high-precision measurement and astronomy, due to their excellent mechanical properties and chemical stability at higher temperatures. Nevertheless, the extremely low expansion glass ceramics are hard-to-machine materials due to their hard-brittle nature, resulting in cracking, chipping and scratching induced in conventional machining. This leads to higher surface roughness, and is not qualified for high-performance devices. In this study, surface roughness of 0.447 and 4.904 nm are achieved for Ra and peak-to valley (PV), respectively with a measurement area of 70×53 μm2 after chemical mechanical polishing (CMP). Firstly, the glass ceramic wafers are lapped using silicon carbide (SiC) abrasives on a cast-iron plate. After lapping, the wafers are polished by CeO2 slurry in a sequence of 3 μm and 500 nm in diameter, and polyurethane and floss pads are used correspondingly. Finally, CMP is employed on the glass ceramic wafers. Floss pad and silica slurry are used in CMP in an alkaline solution with a pH value of 8.5. After CMP, the wafers are cleaned and dried by deionized wafer and compressed air, respectively.

A nanotwinned surface is formed on a titanium alloy under nanoindentations. Prior to nanoindentation, blocks of a ternary titanium alloy are machined by chemical mechanical polishing. The surface roughness Ra and peak-to-valley values are 1.135 nm and 8.82 nm, respectively. The hardness in the indented surface is greatly increased, indicated from the load-displacement curves compared to the polished surfaces. Nanotwins are confirmed using transmission electron microscopy. The nanotwinned surface is uniformly generated by nanoindentations at room temperature, which is different from previous findings, in which high temperature, high pressure, or chemical reagents are usually used. The nanotwinned surface is produced by pure mechanical stress, neither material removal nor addition.

In this study, nanotwinned surface is fabricated on a Nickel alloy by means of a developed diamond panel with tips array. The diamond panel has an area of 10×10 mm2, and is grown using microwave chemical vapor deposition. The diamond tips are submicron in radius and formed on a silicon substrate with an array full of uniformed inverted pyramid pits. The nanotwinned surface is produced under the pressure of 1 MPa exerted by the diamond panel with tips array. Nanotwins are confirmed using transmission electron microscopy. The nanotwinned surface is generated by indention of diamond panel at room temperature using mechanical force, neither material removal nor chemical reagents. This is different from previous reports, in which high temperature, high pressure, chemical reagents or vacuum conditions are employed usually.

A diamond tip with included angle of 90° and fillet radius of 45 nm is developed combining precision grinding and focused ion beam. Relatively high speed scratching at 8.4 m/s induced by the developed diamond tip is conducted on silicon (Si) (111) plane using an ultraprecision grinder. Width at the onset of chip formation on a Si wafer is 193 nm. Width and depth at the onset of crack formation are 1125 and 94 nm, respectively. Calculated normal forces at the onset of chip and crack formations are 424 μN and 14 mN, respectively, corresponding to the depth of cut is 44 and 466 nm.

The high-temperature flow behavior of TC11/Ti–22Al–25Nb electron beam (EB) weldments was investigated by the isothermal compression tests at the temperature of 900–1060 °C and the strain rate of 0.001–10 s−1. Based on the experimental data, the constitutive equation that describes the flow stress as a function of strain rate and deformation temperature is obtained. The apparent activation energy of deformation is calculated, which decreases with increasing the strain and the value is 334 kJ/mol at strain of 0.90. The efficiency of power dissipation ηchanges obviously with the variation of deformation conditions. Under the strain rates of 0.01, 0.1 and 1 s−1, the value of ηincreases with increasing the true strain for different deformation temperatures. While the value of ηdecreases with increasing the strain under the strain rates of 0.001 and 10 s−1. The optimum processing condition is (topi=1060 °C, opi=0.1 s−1) with the peak efficiency of 0.51. Under this deformation, dynamic recrystallization (DRX) is observed obviously in the microstructure of welding zone. Under the condition of 1060 °C and 0.001 s−1, the deformation mechanism is dominated by dynamic recovery (DRV) and the value of ηdecreases sharply (η=0.02). The flow instability is predicted to occur since the instability parameter ξ() becomes negative. The hot working process can be carried out safely in the domain with the strain rate of 0.001–0.6 s−1and the temperature of 900–1060 °C.

Microstructure and tensile properties of TC21 titanium alloy after near-isothermal forging with different parameters plus solution treatment and aging were investigated. It is found that the residual βmatrix, which was strengthened by fine secondary αplatelets forming during aging, exists in all the samples; while primary equiaxed αphase, bent lamellar αphase and αplates are simultaneously or individually present in one sample. The strength of alloy increases proportionally with increasing the content of residual βmatrix, which is the result of increasing α/βinterphase boundary. The plasticity of alloy has a downward trend as the content of residual βmatrix increases. This attributes to the increase of fine secondary αplatelets, which are cut by dislocations during the deformation. Additionally, coarse αplates with long axis parallel to the maximum resolved shear stress (MRSS) also reduce the plasticity of TC21 alloy.

Influence of thermomechanical treatments (mill annealing, duplex annealing, solution treatment plus aging and triple annealing) on microstructures and mechanical properties of TC4-DT titanium alloy was investigated. Results showed that thermomechanical treatments had a significant influence on the microstructure parameters and higher annealing and aging temperature and lower cooling rate led to the decrease of the volume fraction of primary α and the size of prior-β and the increase of the width of grain boundary α and secondary α. The highest strength was obtained by solution treatment and aging due to a large amount of transformed β and finer grain boundary α and secondary α at the expense of slight decrease of elongation and the ultimate strength, yield strength, elongation, reduction of area were 1100 MPa, 1030 MPa, 13% and 53% separately. A good combination of strength and ductility has been obtained by duplex annealing with the above values 940 MPa, 887.5 MPa, 15% and 51% respectively. Analysis between microstructure parameters and tensile properties showed that with the volume fraction of transformed β phase and the prior-β grain size increasing, the ultimate strength, yield strength and reduction of area increased, but the elongation decreased. While the width of grain boundary α and secondary α showed a contrary effect on the tensile properties. Elimination of grain boundary α as well as small prior-β grain size can also improve ductility.

NiZnO films were grown on sapphire substrates by metal-organic chemical vapor deposition (MOCVD). Then the films were annealed in vacuum at different temperatures for 1h. The UV emission peak was blue shifted in the photoluminescence (PL) spectra and a dramatic shift of (002) diffraction peak to higher angle was observed in X-ray diffraction (XRD) pattern with the increasing anneal temperature. It showed the band gap and the lattice parameter of NiZnO had been affected by anneal in vacuum. From the X-ray photoelectron spectroscopy (XPS) of the NiZnO film, we can find that the anneal temperature had an important effect on the content of each element in NiZnO quantificationally. In addition, the value of x in NiZnO varied slightly with the anneal temperature increasing. The above phenomena indicated that anneal in vacuum could slightly adjust the percentage of Ni indirectly in NiZnO film and offer a good idea in NiZnO devices facture.

NiZnO thin films had been fabricated on c-plane sapphire substrates using photo-assisted metal organic chemical vapour deposition system. The crystal quality of the films had been improved greatly comparing to the results in earlier reports. The crystal structure analysis indicated the NiZnO kept the basic wurtzite structure until the content of Ni attained 0.18. The crystal and electrical properties of the films showed the content of Ni had an important effect on the properties of NiZnO films.

The primary purpose of the present work is to investigate the effects of annealing after equal channel angular pressing (ECAP) on microstructure and microhardness of TA15 titanium alloy. A study was performed by annealing treatment on the microstructure evolution and microhardness variation of ECAPed TA15 alloy. The results state that, static recrystallization occurred distinctly during annealing after ECAP. Since a sample was annealed at a proper temperature and for proper time after ECAP, a larger amount of well globularized and more homogeneous equiaxed α phase has been attained, grains have not grown observably, and the relief of residual stress and work hardening for subsequent processing and using has also been achieved. Accordingly, the optimum annealing parameters of ECAPed TA15 alloy were optimized to be 973 K and 1 hour. The microhardness level of the sample annealed after ECAP was lower than that unannealed, and the microhardness level decreased with the increasing annealing temperature and time.

A study was conducted by optical microscope (OM) and transmission electron microscope (TEM) on the microstructure evolution of TA15 alloy by severe plastic deformation (SPD) and annealing after SPD. In this study, equal channel angular pressing (ECAP) was taken as the method of SPD. The chief aim of the present work is to investigate the temperature effects of ECAP and annealing after ECAP on microstructure of TA15 alloy. The results indicate that equiaxed microstructure has been obtained by ECAP at the temperatures of α+β phase region, and that with the increase in pressing temperature, equiaxed grains have become coarser and the content of α phase has reduced. β grains have been coarsened severely since the pressing temperature was above the α-β transformation temperature (Tβ). Annealed at proper temperature after ECAP, the α phase of TA15 alloy has been more homogeneous, prior α phase has been well globularized, and grains have not grown obviously. According to the testing of TA15 alloy, the optimized temperature parameters of ECAP and annealing after ECAP are 900℃ and 700℃. Observation and Analysis of the TEM morphological images illustrate that a quantity of twinning deformations have been produced by ECAP at the temperatures below Tβ, which leads to the continued plastic deformation through the restarting of many slip bands.

A Correction to this paper has been published: https://doi.org/10.1038/s41379-021-00802-0

A Correction to this paper has been published: https://doi.org/10.1038/s41379-021-00802-0