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The attainment and maintenance of a low temperature environment is essential for aerospace cryogenic detectors to achieve their required performance. Developing cryocoolers with features of high efficiency, compact structure, and long lifetime is the main challenge for cryogenic detector cooling. In this paper, a high efficiency thermally-coupled two-stage Stirling type pulse tube cryocooler working at 35 K for HgCdTe long wave infrared detector cooling is designed and tested. The thermally-coupled type avoids gas distribution at cold side which minimizes the inter-stage influence. The whole cryocooler is driven by one linear compressor which enables compact structure. The influence of operation frequency and mean pressure is studied by numerical calculation and experiments to determine the optimum operation condition. Acoustic impedance characteristics of both stages and the whole cold finger are also analyzed by comparing performance of cryocooler with different frequency, mean pressure and structure dimensions. The distributions of acoustic power and phase angle are presented to study the relation between impedance characteristic and the cooling performance. Impedance match between compressor and cold finger is also discussed by analyzing the efficiency of the linear compressor and the performance of cryocooler with different pulse tubes. Under optimum impedance match and operation condition of a working frequency of 39.2 Hz and a mean pressure of 2.45 MPa, the cryocooler provides a cooling power of 1 W at 35.1 K with an input electrical power of 150 W, which indicates a relative Carnot efficiency of 5%. This is a rather high efficiency for developed Stirling type multi-stage pulse tube cryocooler working at 35 K with only inertance tubes as phase shifter. The development of this cryocooler lays a solid base for the further optimization to realize a competitive candidate for aerospace cooling requirements.

This supplementary file contains methods for menin immunohistochemistry, reagents, cell culture, proliferation assays, western blotting, plasmids and transfections, RT-PCR, cell visualization assays including clonogenicity, H&E staining, and live cell imaging, ChIP assays, and calcium resin competition assays.

Supplemental Figure S1: Menin inhibition has minimal effects on cell growth in colon cancer cells. Supplemental Figure S2: Inhibition of menin selectively sensitizes colon cancer cells to iEGFRs. Supplemental Figure S3: BAPTA rescues cells from the combination of gefitinib plus MI-2-2. Supplemental Figure S4: SERCA2 over-expression rescues cells from thapsigargin but not gefitinib. Supplemental Figure S5: Gefitinib induced CRC suppression is mediated by activation of IP3R3. Supplemental Figure S6: Menin inhibition, gefitinib, and TG all decrease SKP2 levels. Supplemental Figure S7: Regulation of SKP2 transcription by menin and intracellular calcium levels.

Menin is a nuclear epigenetic regulator that can both promote and suppress tumor growth in a highly tissue-specific manner. The role of menin in colorectal cancer, however, remains unclear. Here, we demonstrate that menin was overexpressed in colorectal cancer and that inhibition of menin synergized with small-molecule inhibitors of EGFR (iEGFR) to suppress colorectal cancer cells and tumor xenografts in vivo in an EGFR-independent manner. Mechanistically, menin bound the promoter of SKP2, a pro-oncogenic gene crucial for colorectal cancer growth, and promoted its expression. Moreover, the iEGFR gefitinib activated endoplasmic reticulum calcium channel inositol trisphosphate receptor 3 (IP3R3)–mediated release of calcium, which directly bound menin. Combined inhibition of menin and iEGFR-induced calcium release synergistically suppressed menin-mediated expression of SKP2 and growth of colorectal cancer. Together, these findings uncover a molecular convergence of menin and the iEGFR-induced, IP3R3-mediated calcium release on SKP2 transcription and reveal opportunities to enhance iEGFR efficacy to improve treatments for colorectal cancer.Significance:Menin acts as a calcium-responsive regulator of SKP2 expression, and small molecule EGFR inhibitors, which induce calcium release, synergize with Menin inhibition to reduce SKP2 expression and suppress colorectal cancer.

The highly tunable properties of multi-principal element alloys, commonly known as high-entropy alloys (HEAs), provide a remarkable potential for the development of superior materials for critical structural applications that involve extreme conditions. However, the optimization of the properties of HEAs has been primarily limited to behavior at either low or high temperatures. Here, we report on a non-equiatomic, heterostructured, high-entropy alloy FeNiCoAlTaB which possesses remarkable combinations of mechanical properties across a wide range of temperatures from 77 K to 1073 K. The current metastable alloy presents good ductility and superior engineering tensile strengths of 2.2 GPa, 1.4 GPa, 800 MPa, and 500 MPa at 77 K, 298 K, 873 K, and 1073 K, respectively. This behavior is achieved by a synergic sequence of individual mechanisms that are activated at different temperatures. The alloy even displays pseudoelasticity at 77 K with an applied load up to 2 GPa. This work provides a methodology for tailoring structural heterogeneity and metastability in the design and fabrication of multifunctional HEAs that will outperform known metals and alloys over a wide range of temperatures.

Refractory high-entropy alloys (RHEAs) are considered promising candidate materials for high-temperature structural applications that currently use superalloys. However, for most of the reported RHEAs, their poor ductility and negligible cold-workability at room temperature have hindered their use. Here, we report a new class of non-equiatomic NbTaTi-based RHEAs that can be cold-rolled to a reduction of over 90% from the as-cast state without surface treatment and/or intermediate annealing. This excellent cold-workability is facilitated by activation of a high-density of dislocations and deformation twins as well as by high diffusivity paths, such that these RHEAs can be rendered homogeneous at lower annealing temperatures for much shorter time durations. In addition, we report that the RHEAs retain their high strength at elevated temperatures and exhibit considerable ductility at cryogenic conditions, evading the traditional strength–ductility trade-off. This class of super-formable RHEAs provides a novel design pathway to fabricate high-temperature structural materials via an energy- and time-saving method.

Objective: To verify if AngII/NOX/ROS/MAPK signaling pathway is involved in Doxorubicin (DOX)-induced myocardial injury and if mesenchymal stem cells (MSCs) could enhance the protective effects of valsartan (Val) on attenuating DOX-induced injury in vitro. Methods: Reactive oxygen species (ROS) formation and the protein expression of AT1R, NOX2, NOX4, caspase-3, caspase-9 and MAPK signaling were assessed in H9c2 cardiomyocytes exposed to DOX for 24 h in the absence or presence of Val, NADPH oxidase inhibitor DPI or knockdown and overexpression of NADPH oxidase subunit: NOX2 and NOX4, co-culture with MSCs, respectively. Finally, MTT assay was used to determine the cell viability of H9c2 cells, MDA-MB-231 breast cancer cells and A549 pulmonary cancer cells under Val, DOX and Val+ DOX treatments. Results: DOX increased ROS formation and upregulated proteins expression of AT1R, NOX2, NOX4, caspase-3, caspase-9 and MAPK signaling including p-p38, p-JNK, p-ERK in H9c2 cells. These effects could be attenuated by Val, DPI, NOX2 siRNA and NOX4 siRNA. Meanwhile, overexpression of NOX2 and NOX4 could significantly increase DOX-induced ROS formation and further upregulate apoptotic protein expressions and protein expressions of MAPK signaling. MSCs on top of Val further enhanced the protective effects of Val on reducing the DOX-induced ROS formation and downregulating the expression of apoptotic proteins and MAPK signaling as compared with Val alone in DOX-treated H9c2 cells. Simultaneous Val and DOX treatment did not affect cell viability of DOX-treated MDA-MB-231 breast cancer cells or A549 pulmonary cancer cells but significantly improved cell viability of DOX-treated H9c2 cardiomyocytes. Conclusions: AT1R/NOX/ROS/MAPK signaling pathway is involved in DOX-induced cardiotoxicity. Val treatment significantly attenuated DOX-induced cardiotoxicity, without affecting the anti-tumor effect of DOX. MSCs enhance the protective effects of Val on reducing the DOX-induced toxicity in H9c2 cells.

For the first time, a group of CaB6-typed cubic rare earth high-entropy hexaborides have been successfully fabricated into dense bulk pellets (>98.5 % in relative densities). The specimens are prepared from elemental precursors via in-situ metal-boron reactive spark plasma sintering. The sintered bulk pellets are determined to be single-phase without any detectable oxides or other secondary phases. The homogenous elemental distributions have been confirmed at both microscale and nanoscale. The Vickers microhardness are measured to be 16−18 GPa at a standard indentation load of 9.8 N. The nanoindentation hardness and Young’s moduli have been measured to be 19−22 GPa and 190−250 GPa, respectively, by nanoindentation test using a maximum load of 500 mN. The material work functions are determined to be 3.7–4.0 eV by ultraviolet photoelectron spectroscopy characterizations, which are significantly higher than that of LaB6.

Background Gliomas, as the most common aggressive type of primary brain tumors, are highly prevalent and incurable among adults. The dysregulation of transcription factors, including sex determining region Y (SRY)-related high-mobility group (HMG) box (SOX) genes, are considered to be important in cancer development and progression. The aim of our study was to evaluate the effect of SOX9 in the prognosis of glioma. Results We revealed aberrant regulation of most SOX family genes by using 1289 glioma samples from the Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) cohorts. We identified 4 critical genes, SOX3, SOX6, SOX8 and SOX9, -based risk signature model through LASSO regression and a specific SOX9 + cell state with more pronounced malignancy through high-quality single-cell RNA sequencing data analysis. The up regulation of SOX9 and the downregulation of SOX3, SOX6, and SOX8 indicate a decrease in overall survival. The SOX9 + cell state represents a greater proliferative capacity and invasive metastatic properties and is a primary source of attraction for infiltration of bone marrow-derived myeloid (BMM) cells, which are also demonstrated by multicolor immunofluorescence analysis. Conclusions Our study suggests that SOX9 is an independent prognostic and predictive factor for glioma, and the potential interaction between SOX9 + malignant cells and BMM deserves further investigation.

Single-phase high-entropy monoborides (HEMBs) of the CrB prototype structure have been synthesized for the first time. Reactive spark plasma sintering of ball milled mixtures of elemental precursor powders produced bulk (V0.2Cr0.2Nb0.2Mo0.2Ta0.2)B, (V0.2Cr0.2Nb0.2Mo0.2W0.2)B, and (V0.2Cr0.2Nb0.2Ta0.2W0.2)B HEMB specimens of ~98.3–99.5% relative densities. Vickers hardness was measured to be ~22–26 GPa at an indentation load of 9.8 N and ~32–37 GPa at 0.98 N. In particular, the load-dependent hardness of (V0.2Cr0.2Nb0.2Ta0.2W0.2)B is higher than those of ternary (Ta0.5W0.5)B (already considered as superhard) and hardest reported high-entropy metal diborides, and on a par with the classical superhard boride WB4.

A piston pump is one of the key components in a hydraulic system. Therefore, a failure may severely hurt the reliability of the hydraulic system and cause great loss. Currently, how to effectively evaluate the health condition of the piston pump remains an open problem. In this paper, a novel health assessment method based on an integration of Laplacian eigenmaps and random forests is proposed, which takes full advantage of both the fusion ability of correlated features enabled by the Laplacian eigenmaps and the optimized feature-selection ability provided by the random forest. The proposed method (LE-RF) is applied to piston pumps for validation. The results indicate that the Laplacian eigenmaps-random forest (LE-RF) technique can provide an effective tool for piston pump health condition assessment. Compare with other manifold methods, e.g., LLE and ISOMAP and classification method of KNN, the LE-RF method can achieve better and more accurate assessment results.

A novel non-equiatomic NbTaTi-based refractory complex concentrated alloy (RCCA) capable of being cold-rolled up to a reduction in thickness of over 90% directly from the as-cast state is studied. Instead of conventional heat-treatment at temperatures greater than 0.8Tm for long durations, the excellent cold-workability in this RCCA allows for tunable microstructural features, including fine-grained, coarse-grained, and heterogeneous lamella (HL) structures, through proper heat-treatment at relatively lower temperatures for shorter duration. By tailoring microstructures, balanced tensile properties are achieved in this RCCA, through back-stress strengthening of HL structures. This study demonstrates an energy-saving and efficient way to fabricate high-performance RCCAs.

FeAl-based Metallic-Intermetallic Laminate (MIL) composites exhibit enhanced strength and ductility compared to previously studied MIL composites. The deformation and fracture evolution of the FeAl-based MIL composites are investigated here via incremental compression testing. Microstructure assessment via electron backscatter diffraction suggests that deformation proceeds in a fairly homogeneous manner across gradients in the microstructure. Eventual failure is mainly induced by normal stresses, whereas other MIL composites typically fail by shear induced localizations. Geometrically necessary dislocation analysis indicates the FeAl regions deform in similar manners for the three MIL composites (Fe-FeAl-MIL, 430SS-FeAl-MIL, and 304SS-FeAl-MIL), and each fails in a similar mode. While the FeAl phase is the majority constituent of the composites, the mechanical properties are significantly influenced by the softer metal layers. The transition layer formed between the Fe-based metal layers and FeAl regions is the most critical constituent of the composites. Although the volume fraction of the transition layer is only ∼15%, a stronger transition layer can improve the work hardening behavior of the FeAl phase, increasing MIL composite strength by as much as 1 GPa. The findings can guide the design of the MIL composites to achieve even better mechanical properties.

The emergence of commercial electron backscatter diffraction (EBSD) equipment ushered in an era of information rich maps produced by determining the orientation of user-selected crystal structures. Since then, a technological revolution has occurred in the quality, rate detection, and analysis of these diffractions patterns. The next revolution in EBSD is the ability to directly utilize the information rich diffraction patterns in a high-throughput manner. Aided by machine learning techniques, this new methodology is, as demonstrated herein, capable of accurately separating phases in a material by crystal symmetry, chemistry, and even lattice parameters with fewer human decisions. This work is the first demonstration of such capabilities and addresses many of the major challenges faced in modern EBSD. Diffraction patterns are collected from a variety of samples, and a convolutional neural network, a type of machine learning algorithm, is trained to autonomously recognize the subtle differences in the diffraction patterns and output phase maps of the material. This study offers a path to machine learning coupled phase mapping as databases of EBSD patterns encompass an increasing number of the possible space groups, chemistry changes, and lattice parameter variations.

The electromigration effect in spark plasma sintering (SPS) (a.k.a. field assisted sintering) is quantitively analyzed in the Fe-Al diffusion couple system. In SPS, the samples are heated by a high applied voltage and electric current, which can lead to an electromigration effect. Finite element analysis is utilized to determine the voltage applied to the Fe-Al diffusion couple, which is found to be order of magnitudes smaller than the overall system voltage, indicating the electron wind force would be the dominant mechanism for electromigration in SPS. Additionally, the simulation suggests the temperature and current density distribution is uniform across the metallic diffusion couple, which makes quantitative measurement feasible. A mathematic algorithm that allows diffusivity and electromigration coefficients to be solved, is developed for the Fe-Al, where multiple intermetallic phases coexist. At temperatures below aluminum melting, Fe2Al5 is the single intermetallic phases formed in Fe-Al system, for which electromigration is negligible. At temperatures above aluminum melting, FeAl2, FeAl and α-Fe solid solution phases coexist. Among them, the electromigration effect is noticeable in FeAl phase and is significant in the FeAl2 phase. The corresponding electromigration enhancement constants are calculated.