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Fatigue failure is invariably the most crucial failure mode for metallic structural components. Most microstructural strategies for enhancing fatigue resistance are effective in suppressing either crack initiation or propagation, but often do not work for both synergistically. Here, we demonstrate that this challenge can be overcome by architecting a gradient structure featuring a surface layer of nacre-like nanolaminates followed by multi-variant twinned structure in pure titanium. The polarized accommodation of highly regulated grain boundaries in the nanolaminated layer to cyclic loading enhances the structural stability against lamellar thickening and microstructure softening, thereby delaying surface roughening and thus crack nucleation. The decohesion of the nanolaminated grains along horizonal high-angle grain boundaries gives rise to an extraordinarily high frequency (≈1.7 × 103 times per mm) of fatigue crack deflection, effectively reducing fatigue crack propagation rate (by 2 orders of magnitude lower than the homogeneous coarse-grained counterpart). These intriguing features of the surface nanolaminates, along with the various toughening mechanisms activated in the subsurface twinned structure, result in a fatigue resistance that significantly exceeds those of the homogeneous and gradient structures with equiaxed grains. Our work on architecting the surface nanolaminates in gradient structure provides a scalable and sustainable strategy for designing more fatigue-resistant alloys.

Sphingolipids (SL) are a class of chemically diverse lipids that have important structural and physiological functions in eukaryotic cells. SL entail a long chain base (LCB) as the common structural element, which is typically formed by the condensation of L-serine and long chain acyl-CoA. This condensation is the first and the rate-limiting step in the de novo SL synthesis and catalyzed by the enzyme serine palmitoyltransferase (SPT). Although palmitoyl-CoA is the preferred substrate, SPT can also metabolize other acyl-CoAs, thereby forming a variety of LCBs, which differ in structures and functions. The mammalian SPT enzyme is composed of three core subunits: SPTLC1, SPTLC2, and SPTLC3. Whereas SPTLC1 and SPTLC2 are ubiquitously expressed, SPTLC3 expression is restricted to a few specific tissues. The SPTLC1 subunit is essential and can associate with either SPTLC2 or SPTLC3 to form an active enzyme. Depending on the stoichiometry of the SPTLC2 and SPTLC3 subunits, the spectrum of SPT products varies. While SPTLC1 and SPTLC2 primarily form C18 and C20 LCBs, the combination of SPTLC1 and SPTLC3 produces a broader spectrum of LCBs. Genetic and population based studies have shown that SPTLC3 expression and function are associated with an altered plasma SL profile and an increased risk for cardio-metabolic diseases. Animal and in vitro studies showed that SPTLC3 might be involved in hepatic and cardiac pathology and could be a therapeutic target for these conditions.Here we present an overview of the current data on the role of SPTLC3 in normal and pathological conditions.

Wen Hu,1,2,* Panpan Yang,3,* Zhenzhen Fu,1 Yongqing Wang,4 Ying Zhou,1 Zhengqin Ye,1 Yingyun Gong,1 Aijie Huang,1 Luning Sun,4 Yang Zhao,5 Tao Yang,1 Zhong Li,6,7 Xian-Cheng Jiang,8 Weinan Yu,2 Hongwen Zhou1,6 1Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Department of Endocrinology and Metabolism, The Affiliated Huai’an Hospital of Xuzhou Medical College, Huai’an, Jiangsu, People’s Republic of China; 3Department of Respiratory Diseases, The Affiliated Huai’an Hospital of Xuzhou Medical College, Huai’an, Jiangsu, People’s Republic of China; 4Research Division of Clinical Pharmacology, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 5School of Public Health Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 6Key Laboratory of Rare Metabolic Diseases, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 7Jiangsu Province Key Laboratory of Human Functional Genomics, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 8Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY, USA*These authors contributed equally to this workCorrespondence: Hongwen Zhou, Department of endocrinology, The First Affiliated Hospital, Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People’s Republic of China, Tel +862583718836-6893, Fax +862583781781, Email drhongwenzhou@njmu.edu.cn Weinan Yu, Department of Endocrinology and Metabolism, Huai’an Hospital Affiliated to Xuzhou Medical University and Huai’an Second People’s Hospital, Huai’an, 223001, People’s Republic of China, Email hayuweinan@163.comObjective: Branched-chain amino acids (BCAAs) are essential AAs which are widely used as antioxidants in pa

While the region of western Guangxi-southeastern Yunan is known and considered prospective for manganese deposits, carrying out prospectivity mapping in this region is challenging due to the diversity of geological factors, the complexity of the geological process and the asymmetry of geo-information. In this work, the manganese potential mapping for further exploration targeting is implemented via spatial analysis and modal-adaptive prospectivity modelling. On the basis of targeting criteria developed by the mineral systems approach, the spatial analysis is leveraged to extract the predictor variables to identify features of the geological process. Specifically, a metallogenic field analysis approach is proposed to extract metallogenic information that quantifies the regional impacts of the synsedimentary faults and sedimentary basins. In the integration of the extracted predictor variables, a modal-adaptive prospectivity model is built, which allows to adapt different data availability and geological process. The resulting prospective areas of high potential not only correspond to the areas of known manganese deposits but also provide a number of favourable targets in the region for future mineral exploration. (Authors.), While the region of western Guangxi-southeastern Yunan is known and considered prospective for manganese deposits, carrying out prospectivity mapping in this region is challenging due to the diversity of geological factors, the complexity of the geological process and the asymmetry of geo-information. In this work, the manganese potential mapping for further exploration targeting is implemented via spatial analysis and modal-adaptive prospectivity modelling. On the basis of targeting criteria developed by the mineral systems approach, the spatial analysis is leveraged to extract the predictor variables to identify features of the geological process. Specifically, a metallogenic field analysis approach is proposed to extract metallogenic information that quantifies the regional impacts of the synsedimentary faults and sedimentary basins. In the integration of the extracted predictor variables, a modal-adaptive prospectivity model is built, which allows to adapt different data availability and geological process. The resulting prospective areas of high potential not only correspond to the areas of known manganese deposits but also provide a number of favourable targets in the region for future mineral exploration. (Authors.)

Yan-Qiong Wu,1,* Shi-Yan Cheng,2,* Xian-Cheng Xu,1 Wen-Cui Li3 1Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China; 2Department of Respiratory Medicine, Suizhou Central Hospital, Hubei University of Medicine, Suizhou 441300, China; 3Department of Laboratory Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, China *These authors contributed equally to this work Introduction: Previous epidemiological studies have suggested that CD14 rs2569190 C>T polymorphism plays an important role in ischemic stroke (IS) risk, but the results were inconsistent. Therefore, we conducted a meta-analysis to determine the association between CD14 rs2569190 C>T polymorphism and IS susceptibility.Methods: Online databases were searched from inception up to July 1, 2018, for studies concerning CD14 rs2569190 C>T polymorphism and its association with IS susceptibility. ORs and corresponding 95% CIs were calculated in the genetic models of each polymorphism locus with Stata Version 14.0. Furthermore, heterogeneity, meta-regression, accumulative analyses, sensitivity analyses, and publication bias were examined.Results: Overall, 10 observed studies involving 5,277 subjects were included in this meta-analysis on CD14 rs2569190 C>T polymorphism. Generally, no significant associations were found between CD14 rs2569190 C>T polymorphism and IS risk (allele contrast of T vs C: OR =1.03, 95% CI =0.96–1.12, P=0.41, I2=27.8%; co-dominant models of CT vs CC: OR =1.01, 95% CI =0.81–1.25, P=0.95, I2=51.9%; co-dominant models of TT vs CC: OR =1.04, 95% CI =0.89–1.22, P=0.62, I2=25.1%; dominant model of CT + TT vs CC: OR =1.02, 95% CI =0.84–1.25, P=0.82, I2=51.4%; recessive model of TT vs CC + CT: OR =1.07, 95% CI =0.95–1.22, P=0.28, I2=0%), similar to the results in the subgroup analysis.Conclusion: The current evidence indicated that CD14 rs2569190 C&gt

Yan-na Zhang, Xiao-gang Duan, Wen-hui Zhang, Ai-ling Wu, Huan-Huan Yang, Dong-ming Wu, Yu-Quan Wei, Xian-cheng Chen State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China Abstract: Cancer stem cells (CSCs) are critical for tumor initiation/maintenance and recurrence or metastasis, so they may serve as a potential therapeutic target. However, CSC-established multitherapy resistance and immune tolerance render tumors resistant to current tumor-targeted strategies. To address this, renewable multiepitope-integrated spheroids based on placenta-derived mesenchymal stem cells (pMSCs) were X-ray-modified, at four different irradiation levels, including 80, 160, 240, and 320 Gy, as pluripotent biologics, to inoculate hosts bearing Lewis lung carcinoma (LL2) and compared with X-ray-modified common LL2 cells as control. We show that the vaccines at the 160/240 Gy irradiation levels could rapidly trigger tumor cells into the apoptosis loop and evidently prolong the tumor-bearing host’s survival cycle, in contrast to vaccines irradiated at other levels (P<0.05), with tumor-sustaining stromal cell-derived factor-1/CXCR4 pathway being selectively blockaded. Meanwhile, almost no or minimal toxicity was detected in the vaccinated hosts. Importantly, 160/240 Gy-irradiated vaccines could provoke significantly higher killing of CSCs and non-CSCs, which may provide an access to developing a novel biotherapy against lung carcinoma. Keywords: lung carcinoma, placenta-derived mesenchymal stem cells (pMSCs), attenuated vaccine, irradiation level

Besides bulk amounts of SM, mammalian cells produce small quantities of the SM analog ceramide phosphoethanolamine (CPE). Little is known about the biological role of CPE or enzymes responsible for CPE production. Heterologous expression studies revealed that SM synthase (SMS) 2 is a bifunctional enzyme producing both SM and CPE, whereas SMS-related protein (SMSr) serves as monofunctional CPE synthase. Acute disruption of SMSr catalytic activity in cultured cells causes a rise in endoplasmic reticulum (ER) ceramides, fragmentation of ER exit sites, and induction of mitochondrial apoptosis. To address the relevance of CPE biosynthesis in vivo, we analyzed the tissue-specific distribution of CPE in mice and generated mouse lines lacking SMSr and SMS2 catalytic activity. We found that CPE levels were >300-fold lower than SM in all tissues examined. Unexpectedly, combined inactivation of SMSr and SMS2 significantly reduced, but did not eliminate, tissue-specific CPE pools and had no obvious impact on mouse development or fertility. While SMSr is widely expressed and serves as the principal CPE synthase in the brain, blocking its catalytic activity did not affect ceramide levels or secretory pathway integrity in the brain or any other tissue. Our data provide a first inventory of CPE species and CPE-biosynthetic enzymes in mammals.

Hua-shan Shi1,* Xiang Gao,1,3,* Dan Li,1,* Qiong-wen Zhang,1 Yong-sheng Wang,2 Yu Zheng,1 Lu-Lu Cai,1 Ren-ming Zhong,2 Ao Rui,1 Zhi-yong Li,1 Hao Zheng,1 Xian-cheng Chen,1 Li-juan Chen,11State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medicine School, Sichuan University, Chengdu, Sichuan, People's Republic of China; 2State Key Laboratory of Biotherapy and Department of Thoracic Oncology, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, People's Republic of China; 3Deparment of Pathophysiology, College of Preclinical and Forensic Medical Sciences, Sichuan University, Chengdu, People's Republic of China*These authors contributed equally to this workAbstract: Radiation pneumonitis (RP) is an important dose-limiting toxicity during thoracic radiotherapy. Previous investigations have shown that curcumin is used for the treatment of inflammatory conditions and cancer, suggesting that curcumin may prevent RP and sensitize cancer cells to irradiation. However, the clinical advancement of curcumin is limited by its poor water solubility and low bioavailability after oral administration. Here, a water-soluble liposomal curcumin system was developed to investigate its prevention and sensitizing effects by an intravenous administration manner in mice models. The results showed that liposomal curcumin inhibited nuclear factor-κB pathway and downregulated inflammatory factors including tumor necrosis factor-α, interleukin (IL)-6, IL-8, and transforming growth factor-β induced by thoracic irradiation. Furthermore, the combined treatment with liposomal curcumin and radiotherapy increased intratumoral apoptosis and microvessel responses to irradiation in vivo. The significantly enhanced inhibition of tumor growth also was observed in a murine lung carcinoma (LL/2) model. There were no obvious toxicities observed in mice. The current results indicate that li

Hua-shan Shi1,* Xiang Gao,1,3,* Dan Li,1,* Qiong-wen Zhang,1 Yong-sheng Wang,2 Yu Zheng,1 Lu-Lu Cai,1 Ren-ming Zhong,2 Ao Rui,1 Zhi-yong Li,1 Hao Zheng,1 Xian-cheng Chen,1 Li-juan Chen,11State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medicine School, Sichuan University, Chengdu, Sichuan, People's Republic of China; 2State Key Laboratory of Biotherapy and Department of Thoracic Oncology, West China Hospital, West China Medical School, Sichuan University, Chengdu, Sichuan, People's Republic of China; 3Deparment of Pathophysiology, College of Preclinical and Forensic Medical Sciences, Sichuan University, Chengdu, People's Republic of China*These authors contributed equally to this workAbstract: Radiation pneumonitis (RP) is an important dose-limiting toxicity during thoracic radiotherapy. Previous investigations have shown that curcumin is used for the treatment of inflammatory conditions and cancer, suggesting that curcumin may prevent RP and sensitize cancer cells to irradiation. However, the clinical advancement of curcumin is limited by its poor water solubility and low bioavailability after oral administration. Here, a water-soluble liposomal curcumin system was developed to investigate its prevention and sensitizing effects by an intravenous administration manner in mice models. The results showed that liposomal curcumin inhibited nuclear factor-κB pathway and downregulated inflammatory factors including tumor necrosis factor-α, interleukin (IL)-6, IL-8, and transforming growth factor-β induced by thoracic irradiation. Furthermore, the combined treatment with liposomal curcumin and radiotherapy increased intratumoral apoptosis and microvessel responses to irradiation in vivo. The significantly enhanced inhibition of tumor growth also was observed in a murine lung carcinoma (LL/2) model. There were no obvious toxicities observed in mice. The current results indicate that li

To investigate the metabolism and energy utiliztion during the early development of Odontobutis potamophila, the oxygen consumption rate and NH3-N excretion rate were measured between 20.8 ℃ and 24.6 ℃ in this paper. The results showed that the oxygen consumption rate was very low during the early embryonic development, and the metabolism was kept at a low level. But it increased significantly at the prehatching stage from 0.315 1 *. Thereafter, oxygen consumption rate increased linearly with the development of O. potamophila; In addition, the NH3-N excretion rate increased with the development of O.potamophila too, while it had no significant difference during the early embryonic development. When the embryo earched the eye pigmentation stage, the NH3-N excretion rate increased rapidly(P<0.05) and achieved maximum value of embryonic stage, yet a slightly decreased after hatching. It increased from 8 d to 16 d after hating (P<0.05), and then NH3-N excretion rate keeps still. The results indicated that the metabolism improved gradually during the early development of O. potamophila. As a substrate oxidation, protein provided major energy during the embryonic development.(* Indicates a formula, please see the full text)

A 3D morphological analysis method, based on 3D raster models, for obtaining the quantitative relationship between intrusive body morphology and skarn mineralisation, as exemplified by Xinwuli intrusive body in Fenghuangshan copper deposit, Tongling, Anhui province, China, is presented. The method comprises extraction of morphological characteristic parameters using mathematical morphology and Euclidean distance transformation, quantitative analysis of the relationship between the parameters and ore bodies, and correlational analyses (correlation coefficients and regression effectiveness) between the parameters and mineralisation indices. The results indicate the ability of morphological parameters to locate concealed ore bodies in the skarn deposit and the most advantageous skarn mineralisation positions., A 3D morphological analysis method, based on 3D raster models, for obtaining the quantitative relationship between intrusive body morphology and skarn mineralisation, as exemplified by Xinwuli intrusive body in Fenghuangshan copper deposit, Tongling, Anhui province, China, is presented. The method comprises extraction of morphological characteristic parameters using mathematical morphology and Euclidean distance transformation, quantitative analysis of the relationship between the parameters and ore bodies, and correlational analyses (correlation coefficients and regression effectiveness) between the parameters and mineralisation indices. The results indicate the ability of morphological parameters to locate concealed ore bodies in the skarn deposit and the most advantageous skarn mineralisation positions.

The discovered Jinchuan Cu-Ni(PGE) sulphide deposit occurs in two ultrabasic dykes and the two main orebodies II-1 and II-2 are located in one ultrabasic dyke on the southeastern side. In order to prove the particularity and connection of parental magma of II-1 and II-2 orebodies during magma evolution, the contents of major elements, REE and trace elements in both orebodies were measured and compared with each other. Both orebodies belong to iron-ultrabasic rocks and have the following features: rich in MgO (10.4-33.5 wt%), poor in Al2O3 (0.67-15.35 wt%) and K2O (0.01-1.42 wt%). They have similar REE- and trace element distribution, strongly fractionated REE pattern (Total(LREE)/Total(HREE) = 3.27-9.63), and enriched LILE relative to HFSE, reflecting that the parental magmas are closely related. It is suggested that the parental magma is generated by 30-40% fractional melting of the garnet lherzolite, contaminated with 5-20% crustal material and produced olivine crystallisation. There is, however, an obvious difference in MgO value of II-2 which shows a more complicated relationship with other major elements than that of II-1, which suggests that both parental magmas have experienced an independent evolution during their cooling stage. Two coordinated conduit magma systems have emerged during the crystallisation process, and as a consequence, the evolution and metallogenic process of magma from each conduit are independent., The discovered Jinchuan Cu-Ni(PGE) sulphide deposit occurs in two ultrabasic dykes and the two main orebodies II-1 and II-2 are located in one ultrabasic dyke on the southeastern side. In order to prove the particularity and connection of parental magma of II-1 and II-2 orebodies during magma evolution, the contents of major elements, REE and trace elements in both orebodies were measured and compared with each other. Both orebodies belong to iron-ultrabasic rocks and have the following features: rich in MgO (10.4-33.5 wt%), poor in Al2O3 (0.67-15.35 wt%) and K2O (0.01-1.42 wt%). They have similar REE- and trace element distribution, strongly fractionated REE pattern (Total(LREE)/Total(HREE) = 3.27-9.63), and enriched LILE relative to HFSE, reflecting that the parental magmas are closely related. It is suggested that the parental magma is generated by 30-40% fractional melting of the garnet lherzolite, contaminated with 5-20% crustal material and produced olivine crystallisation. There is, however, an obvious difference in MgO value of II-2 which shows a more complicated relationship with other major elements than that of II-1, which suggests that both parental magmas have experienced an independent evolution during their cooling stage. Two coordinated conduit magma systems have emerged during the crystallisation process, and as a consequence, the evolution and metallogenic process of magma from each conduit are independent.

Wang Q., Ma N., Shi J., et al. Unraveling microforging principle during in situ shot-peening-assisted cold spray additive manufacturing aluminum alloy through a multi-physics framework. Materials and Design 236, 112451 (2023); https://doi.org/10.1016/j.matdes.2023.112451., Cold spray (CS) is a highly potential solid-state additive manufacturing (AM) technique. In situ shot-peening-assisted CSAM was proposed to additively manufacture fully dense deposits using cost-effective and renewable nitrogen gas. The role of in situ shot-peening particles is critical but remains unclear. Here, the process was quantitatively modeled to visualize the dynamic deformation, energy conversion, as well as cell/sub-grain size and microhardness evolutions, compared to those during the conventional CSAM process, identifying the key role of in situ shot-peening particles in the AA6061 extreme deformation and microstructure characteristics during in situ shot-peening-assisted CSAM. High-fidelity modeling was verified fully by comparing the experimental and model-reproduced deformation profiles, cell/sub-grain size distributions, and increases in microhardness. The results show that the kinetic energy of in situ shot-peening particles was 470 times higher and dissipated mainly through AA6061 plastic deformation (86.36% of total energy), leading to significant enhancement of microhardness and tensile strength. Moreover, the mixing ratio of large-size SS410 particles required to create a fully dense deposit was evaluated from an energy perspective, in good agreement with the experiment. This study elucidates the microforging principle during in situ shot-peening-assisted CSAM, providing scientific guidelines for high-quality and low-cost CSAM of high-strength aluminum alloys.

Wang Q., Ma N., Shi J., et al. Unraveling microforging principle during in situ shot-peening-assisted cold spray additive manufacturing aluminum alloy through a multi-physics framework. Materials and Design 236, 112451 (2023); https://doi.org/10.1016/j.matdes.2023.112451., Cold spray (CS) is a highly potential solid-state additive manufacturing (AM) technique. In situ shot-peening-assisted CSAM was proposed to additively manufacture fully dense deposits using cost-effective and renewable nitrogen gas. The role of in situ shot-peening particles is critical but remains unclear. Here, the process was quantitatively modeled to visualize the dynamic deformation, energy conversion, as well as cell/sub-grain size and microhardness evolutions, compared to those during the conventional CSAM process, identifying the key role of in situ shot-peening particles in the AA6061 extreme deformation and microstructure characteristics during in situ shot-peening-assisted CSAM. High-fidelity modeling was verified fully by comparing the experimental and model-reproduced deformation profiles, cell/sub-grain size distributions, and increases in microhardness. The results show that the kinetic energy of in situ shot-peening particles was 470 times higher and dissipated mainly through AA6061 plastic deformation (86.36% of total energy), leading to significant enhancement of microhardness and tensile strength. Moreover, the mixing ratio of large-size SS410 particles required to create a fully dense deposit was evaluated from an energy perspective, in good agreement with the experiment. This study elucidates the microforging principle during in situ shot-peening-assisted CSAM, providing scientific guidelines for high-quality and low-cost CSAM of high-strength aluminum alloys.