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Ti6Al4V lattice structures (LSs) have great potentials in medical implants due to their excellent biocompatibility and high strength-to-weight ratio. This paper investigates the manufacturability and performance of unique Ti6Al4V heterogeneous glass sponge (GS) LSs fabricated via laser powder bed fusion (LPBF). Compared with the commonly used LSs, including Cross, body-centered cubic (BCC), Diamond and octet-truss (OCT), Ti6Al4V GS LSs exhibit the strongest compressive strength and energy absorption ability of 58 MPa and 23.84 J/cm3, respectively. Finite element (FE) models are established to evaluate the macroscopic deformation, microscopic stress and strain evolution in the solid struts of five different LSs. Local plastic stresses are found to generate near the nodes of Cross, BCC, Diamond and OCT LSs, thus forming plastic hinges, while the GS LSs can evenly transfer local plastic stresses to the grid-like rods of each layer, eventually showing a uniform stress distribution. Moreover, all the LSs are featured with satisfactory biocompatibility concerning cytotoxicity, cell proliferation, and cell attachment. The results indicate that the Ti6Al4V GS LSs can address the conflict between lightness and strength simultaneously, thus achieving excellent energy absorption performance, compressive properties and great biocompatibility, endowing it with tremendous application potential in the field of medical implants.

The plasma rotating electrode process (PREP) is an ideal method for the preparation of metal powders such as nickel-based, titanium-based, and iron-based alloys due to its low material loss and good degree of sphericity. However, the preparation of silver alloy powder by PREP remains challenging. The low hardness of the mould casting silver alloy leads to the bending of the electrode rod when subjected to high-speed rotation during PREP. The mould casting silver electrode rod can only be used in low-speed rotation, which has a negative effect on particle refinement. This study employed continuous casting (CC) to improve the surface hardness of S800 Ag (30.30% higher than mould casting), which enables a high rotation speed of up to 37,000 revolutions per minute, and silver alloy powder with an average sphericity of 0.98 (5.56% higher than gas atomisation) and a sphericity ratio of 97.67% (36.28% higher than gas atomisation) has been successfully prepared. The dense S800 Ag was successfully fabricated by laser powder bed fusion (LPBF), which proved the feasibility of preparing high-quality powder by the “CC + PREP” method. The samples fabricated by LPBF have a Vickers hardness of up to 271.20 HV (3.66 times that of mould casting), leading to a notable enhancement in the strength of S800 Ag. In comparison to GA, the S800 Ag powder prepared by “CC + PREP” exhibits greater sphericity, a higher sphericity ratio and less satellite powder, which lays the foundation for dense LPBF S800 Ag fabrication.

A challenge remains in achieving adequate surface roughness of SLM fabricated interior channels, which is crucial for fuel delivery in the space industry. This study investigated the surface roughness of interior fine flow channels (1 mm diameter) embedded in SLM fabricated TC4 alloy space components. A machine learning approach identified layer thickness as a significant factor affecting interior channel surface roughness, with an importance score of 1.184, followed by scan speed and laser power with scores of 0.758 and 0.512, respectively. The roughness resulted from thin layer thickness of 20 µm, predominantly formed through powder adherence, while from thicker layer of 50 µm, the roughness was mainly due to the stair step effect. Slow scan speeds increased melt pools solidification time at roof overhangs, causing molten metal to sag under gravity. Higher laser power increased melt pools temperature and led to dross formation at roof overhangs. Smaller hatch spaces increased roughness due to overlapping of melt tracks, while larger hatch spaces reduced surface roughness but led to decreased part density. The surface roughness was recorded at 34 µm for roof areas and 26.15 µm for floor areas. These findings contribute to potential adoption of TC4 alloy components in the space industry.

Background and Aims: Embryo vitrification is widely applied as a routine procedure of assisted reproductive technology. Cohort studies showed frozen embryo transfer (FET) was associated with an elevated risk of adverse maternal and neonatal outcomes compared with fresh embryo transfer. This study aimed to explore the effects of blastocyst vitrification on embryo development and long-term metabolic health in mice. Method: Mitochondrial function, apoptotic levels and cell numbers were examined in blastocysts with/without vitrification. Implantation rates, fetal growth and placentation were analysed after fresh and frozen blastocyst transfer. Energy consumptions were measured by indirect calorimetry. Metabolic tests were performed in adult mice offspring, including glucose tolerance, insulin tolerance and pyruvate tolerance. Serum lipid profiles were examined, and fetal and adult hepatic transcriptome status were detected by RNA-sequencing and qRT-PCR. Results: Mitochondrial dysfunction increased apoptotic levels and decreased cell numbers were observed in vitrified blastocysts. The implantation and live pup rates on embryonic day18.5 were not significantly different between the fresh and frozen groups. However, fetal weights and placental efficiencies such as the ratio of labyrinth layer/ junctional zone and microvascular density were significantly reduced after FET. Offspring aged 36 weeks in the FET group had decreased whole energy consumption, impaired glucose and pyruvate tolerance, insulin resistance, higher serum triglyceride, low-density lipoprotein and total cholesterol levels compared with the fresh group. However, these metabolic effects were not observed in mice offspring aged 14 weeks. The FET group also had altered hepatic gene expression and signaling pathways related to metabolic regulation, apoptotic cell clearance, and regulation of response to reactive oxygen species etc. Conclusion: The data indicated that blastocyst vitrification has short-term and long-term adverse effects in the mouse model. Further studies are needed to optimize vitrification procedure.

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common and malignant tumors in the digestive tract. Tumor Suppressor Candidate 3 (TUSC3) is one subunit of the endoplasmic reticulum Oligosaccharyl transferase (OST) complex, which plays an important role in N-glycosylation during the protein folding process. However, the role of TUSC3 in the initiation and progression of HCC has not been mentioned yet. In the present study, we aim to investigate the effects of TUSC3 on the initiation and progression of HCC. Methods Immunohistochemical assay and qRT-PCR were used to detect the expression of TUSC3 and lipase C hepatic type (LIPC) in HCC tissue and cells. Loss-of-function and gain-of-function were applied to detect the function of TUSC3 and LIPC in vivo and in vitro. Immunofluorescence assay and co-immunoprecipitation were used to detect the relationship between TUSC3 and LPC. Western blot was applied to detect the expression of epithelial–mesenchymal transition (EMT) markers and the Akt signaling pathway. Results TUSC3 was aberrantly decreased in hepatocellular carcinoma tissues compared to the matched adjacent normal tissues, which resulted in bigger size of tumor (P = 0.001, Table 2), worse differentiation (P = 0.006, Table 2) and an advanced BCLC stage. Down-regulation of TUSC3 led to the enhanced proliferation and migration of hepatocellular carcinoma cells in vivo and vitro, whereas the opposite effect could be observed in the TUSC3-overexpression group. The analysis of TUSC3 microarray showed that LIPC, a glycoprotein primarily synthesized and secreted by hepatocytes, was a downstream target of TUSC3, and it negatively modulated the development of HCC. The morphological changes in HCC cells indicated that TUSC3 regulated the epithelial-mesenchymal transition (EMT). Mechanistically, TUSC3 inhibited EMT progression through the LIPC/AKT axis. Conclusion Down-regulation of TUSC3 promotes EMT progression by activating AKT signaling via targeting LIPC in HCC, which is probably the possible mechanism driving TUSC3-deficient hepatocellular carcinoma cells toward a malignant phenotype.

Phosphorus treatment can reduce Cd accumulation and Cd toxicity in rice, but alterations in the internal regulatory network of rice during this process have rarely been reported. We have removed the effect of cadmium phosphate precipitation from the hydroponic system, treated a pair of different Cd-response rice varieties with different levels of phosphorus and cadmium and examined the changes in physiological indicators and regulatory networks. The results demonstrated that phosphorus treatment significantly reduced Cd accumulation in both types of rice, although the antioxidant systems within the two types of rice produced opposite responses. Overall, 3 mM phosphorus treatment to Cd-N decreased the expression of OsIAA17 and OsACO1 by 32% and 37%, respectively, while increasing the expression of OsNR2 by 83%; these three genes regulate the synthesis of auxin, ethylene, and nitric oxide in rice. IAA and NO levels in rice shoots increased by 24% and 96%, respectively, and these changes contribute to Cd detoxification. The cadmium transporter genes OsHMA2, OsIRT1, and OsABCC1 were significantly down-regulated in Cd-N roots after triple phosphorus treatment. These data suggest that phosphorus treatment can reduce Cd accumulation and enhance Cd resistance in rice by affecting the expression of signaling molecules.

Abstract Background Serine/arginine-rich splicing factor 9 (SRSF9) is a classical RNA-binding protein that is essential for regulating gene expression programs through its interaction with target RNA. Whether SRSF9 plays an essential role in colorectal cancer (CRC) progression and can serve as a therapeutic target is largely unknown. Here, we highlight new findings on the role of SRSF9 in CRC progression and elucidate the underlying mechanism. Methods CRC cell lines and clinical tissue samples were used. qRT-PCR, Western blotting, immunohistochemistry (IHC), gain- and loss-of-function assays, animal xenograft model studies, bioinformatic analysis, methylated single-stranded RNA affinity assays, gene-specific m6A quantitative qRT-PCR, dual-luciferase reporter assays and RNA stability assays were performed in this study. Results The expression level of SRSF9 was higher in CRC cell lines than that in an immortal human intestinal epithelial cell line. Overexpression of SRSF9 was positively associated with lymph node metastasis and Dukes stage. Functionally, SRSF9 promoted cell proliferation, migration and invasion in vitro and xenograft growth. The results of bioinformatic analysis indicated that DSN1 was the downstream target of SRSF9. In CRC cells and clinical tissue samples, the expression of SRSF9 was positively associated with the expression of DSN1. Knockdown of DSN1 partially inhibited the SRSF9-induced phenotype in CRC cells. Mechanistically, we further found that SRSF9 is an m6A-binding protein and that m6A modifications were enriched in DSN1 mRNA in CRC cells. Two m6A modification sites (chr20:36773619–36773620 and chr20:36773645–chr20:36773646) in the SRSF9-binding region (chr20:36773597–36773736) of DSN1 mRNA were identified. SRSF9 binds to DSN1 in an m6A motif- and dose-dependent manner. SRSF9 modulates the expression of DSN1 in CRC cells. Such expression regulation was largely impaired upon methyltransferase METTL3 knockdown. Moreover, knockdown of SRSF9 accelerated DSN1 mRNA turnover, while overexpression of SRSF9 stabilized DSN1 mRNA in CRC cells. Such stabilizing was also weakened upon METTL3 knockdown. Conclusion Overexpression of SRSF9 was associated with lymph node metastasis and Dukes stage in CRC. Knockdown of DSN1 eliminated the effects by SRSF9 overexpression in CRC. Our results indicated that SRSF9 functions as an m6A-binding protein (termed “reader”) by enhancing the stability of DSN1 mRNA in m6A-related manner. Our study is the first to report that SRSF9-mediated m6A recognition has a crucial role in CRC progression, and highlights SRSF9 as a potential therapeutic target for CRC management.

Abstract Background l-Tryptophan (l-Trp) derivatives such as 5-hydroxytryptophan (5-HTP) and 5-hydroxytryptamine (5-HT), N-Acetyl-5-hydroxytryptamine and melatonin are important molecules with pharmaceutical interest. Among, 5-HT is an inhibitory neurotransmitter with proven benefits for treating the symptoms of depression. At present, 5-HT depends on plant extraction and chemical synthesis, which limits its mass production and causes environmental problems. Therefore, it is necessary to develop an efficient, green and sustainable biosynthesis method to produce 5-HT. Results Here we propose a one-pot production of 5-HT from l-Trp via two enzyme cascades for the first time. First, a chassis cell that can convert l-Trp into 5-HTP was constructed by heterologous expression of tryptophan hydroxylase from Schistosoma mansoni (SmTPH) and an artificial endogenous tetrahydrobiopterin (BH4) module. Then, dopa decarboxylase from Harminia axyridis (HaDDC), which can specifically catalyse 5-HTP to 5-HT, was used for 5-HT production. The cell factory, E. coli BL21(DE3)△tnaA/BH4/HaDDC-SmTPH, which contains SmTPH and HaDDC, was constructed for 5-HT synthesis. The highest concentration of 5-HT reached 414.5 ± 1.6 mg/L (with conversion rate of 25.9 mol%) at the optimal conditions (substrate concentration,2 g/L; induced temperature, 25℃; IPTG concentration, 0.5 mM; catalysis temperature, 30℃; catalysis time, 72 h). Conclusions This protocol provided an efficient one-pot method for converting. l-Trp into 5-HT production, which opens up possibilities for the practical biosynthesis of natural 5-HT at an industrial scale.

Background: Nicotinamide mononucleotide (NMN) is the physiological circulating NAD precursor thought to elevate the cellular level of NAD+ and to ameliorate various age-related diseases. An inseparable link exists between aging and tumorigenesis, especially involving aberrant energetic metabolism and cell fate regulation in cancer cells. However, few studies have directly investigated the effects of NMN on another major ageing-related disease: tumors. Methods: We conducted a series of cell and mouse models to evaluate the anti-tumor effect of high-dose NMN. Transmission electron microscopy and a Mito-FerroGreen-labeled immunofluorescence assay (Fe2+) were utilized to demonstrate ferroptosis. The metabolites of NAM were detected via ELISA. The expression of the proteins involved in the SIRT1–AMPK–ACC signaling were detected using a Western blot assay. Results: The results showed that high-dose NMN inhibits lung adenocarcinoma growth in vitro and in vivo. Excess NAM is produced through the metabolism of high-dose NMN, whereas the overexpression of NAMPT significantly decreases intracellular NAM content, which, in turn, boosts cell proliferation. Mechanistically, high-dose NMN promotes ferroptosis through NAM-mediated SIRT1–AMPK–ACC signaling. Conclusions: This study highlights the tumor influence of NMN at high doses in the manipulation of cancer cell metabolism, providing a new perspective on clinical therapy in patients with lung adenocarcinoma.

A first palladium-catalyzed asymmetric intramolecular Heck reaction for the construction 3,4-dihydro-1-(2H)-isoquinolinone containing the quaternary carbon chiral center has been developed. The salient features of this reaction include high efficiency, high enantioselectivity, the novel chiral ligand and diverse transformations.

Abstract Background Autophagy is a double-edged sword during the initiation and progression of multiple tumors. The Hippo pathway effector YAP has been proved to be involved in autophagy processes. The present study aimed to investigate how YAP regulates cell proliferation via autophagy in lung adenocarcinomas (LUAD). Methods Data of LUAD chip GSE43458 was obtained from Gene Expression Omnibus (GEO). RT-qPCR and Western blot were performed to assess YAP expression in LUAD cell lines. CCK-8 assay, xenograft tumor model, immunochemistry and GFP-mRFP-LC3 fusion proteins were utilized to evaluate the effect of YAP on autophagy of LUAD cells in vitro and in vivo. Autophagy inhibitor treatment and rescue experiments were carried out to elucidate the mechanism by which YAP manipulates autophagy in LUAD cells. Results YAP was significantly overexpressed in samples of LUAD patients and its expression level is related to 5-year survival. YAP manipulated the proliferation and autophagy in A549 and H1299 LUAD cells. YAP could induce activation of Akt/mTOR signaling pathway via suppressing PTEN in a Hippo-pathway-dependent manner. 3-Methyladenine impeded autophagy flux and promoted the proliferation in vitro and in vivo. Conclusions Hippo pathway critical transcriptional coactivators YAP manipulates the proliferation of lung adenocarcinoma, which is regulated by PTEN/AKT/mTOR autophagic signaling.

Ag and Cu have different advantages and are widely used in key fields due to their typical highly electrical and thermal conductive (HETC) properties. Laser powder bed fusion (LPBF), an innovative technology for manufacturing metallic multi-material components with high accuracy, has expanded the application of Ag–Cu in emerging high-tech fields. In this study, the multi-material sandwich structures of Ag7.5Cu/Cu10Sn/Ag7.5Cu were printed using LPBF, and the formation mechanism, interface characteristics, and molten pool behavior of the Ag7.5Cu/Cu10Sn (A/C) and Cu10Sn/Ag7.5Cu (C/A) interfaces were studied to reveal the influence of different building strategies. At the A/C interface, pre-printed Ag7.5Cu promoted Marangoni turbulence at a relatively low energy density (EA/C = 125 J/mm3). Due to the recoil pressure, the molten pool at the A/C interface transformed from a stable keyhole mode to an unstable keyhole mode. These phenomena promoted the extensive migration of elements, forming a wider diffusion zone and reduced thermal cracking. At the C/A interface, the molten pool was rationed from the conduction mode with more pores to the transition mode with fewer defects due to the high energy density (EC/A = 187.5 J/mm3). This work offers a theoretical reference for the fabrication of HETC multi-material structures via LPBF under similar conditions.

D-1,2,4-Butanetriol (BT) has attracted much attention for its various applications in energetic materials and the pharmaceutical industry. Here, a synthetic pathway for the biosynthesis of BT from d-arabinose was constructed and optimized in Escherichia coli. First, E. coli Trans1-T1 was selected for the synthesis of BT. Considering the different performance of the enzymes from different organisms when expressed in E. coli, the synthetic pathway was optimized. After screening two d-arabinose dehydrogenases (ARAs), two d-arabinonate dehydratases (ADs), four 2-keto acid decarboxylases (ADXs), and three aldehyde reductases (ALRs), ADG from Burkholderia sp., AraD from Sulfolobus solfataricus, KivD from Lactococcus lactis IFPL730, and AdhP from E. coli were selected for the bio-production of BT. After 48 h of catalysis, 0.88 g/L BT was produced by the recombinant strain BT5. Once the enzymes were selected for the pathway, metabolic engineering strategy was conducted for further improvement. The final strain BT5ΔyiaEΔycdWΔyagE produced 1.13 g/L BT after catalyzing for 48 h. Finally, the fermentation conditions and characteristics of BT5ΔyiaEΔycdWΔyagE were also evaluated, and then 2.24 g/L BT was obtained after 48 h of catalysis under the optimized conditions. Our work was the first report on the biosynthesis of BT from d-arabinose which provided a potential for the large-scale production of d-glucose-based BT.

The poor wettability and weak interfacial bonding of diamond/copper composites are due to the incompatibility between diamond and copper which are inorganic nonmetallic and metallic material, respectively, which limit their further application in next-generation heat management materials. Coating copper and titanium on the diamond particle surface could effectively modify and improve the wettability of the diamond/copper interface via electroless plating and evaporation methods, respectively. Here, these dense and complex composites were successfully three-dimensionally printed via selective laser melting. A high thermal conductivity (TC, 336 W/mK) was produced by 3D printing 1 vol.% copper-coated diamond/copper mixed powders at an energy density of 300 J/mm3 (laser power = 180 W and scanning rate = 200 mm/s). 1 and 3 vol.% copper-coated diamond/copper composites had lower coefficients of thermal expansions and higher TCs. They also had stronger bending strengths than the corresponding titanium-coated diamond/copper composites. The interface between copper matrix and diamond reinforcement was well bonded, and there was no cracking in the 1 vol.% copper-coated diamond/copper composite sample. The optimization of the printing parameters and strategy herein is beneficial to develop new approaches for the further construction of a wider range of micro-sized diamond particles reinforced metal matrix composites.

Background: The effects of ambient air pollutants on adverse pregnancy outcomes have been reported. However, studies about air pollutants exposure and pregnancy outcomes in patients undergoing IVF were limited and inconclusive. To date Shanghai has been the only city in China to implement a compulsory single embryo transfer policy for all patients undergoing their first embryo transfer procedure effective from January 2019. We aimed to investigate the associations between exposure to ambient air pollutants and biochemical pregnancy and live births, and to identify potential vulnerability characteristics of patients undergoing IVF in Shanghai, China. Methods: A retrospective cohort study was conducted on 2766 infertile patients aged ≤ 45 years who underwent first fresh or frozen-thawed cleavage stage embryo transfer in the Shanghai First Maternity and Infant Hospital during April 2016 and December 2019. Daily average ambient levels of six air pollutants (PM2.5, PM10, NO2, SO2, CO and O3 max-8h) were obtained from fixed air monitors located in closest proximity to patients’ residences. The cumulative average level was calculated during three different exposure periods (period1: three months before oocyte retrieval to serum hCG test; period 2: from serum hCG test to live birth outcome; period 3: from three months before oocyte retrieval to live birth). Multiple logistic regression model was performed to investigate associations between exposure to ambient air pollutants and pregnancy outcomes. Stratified analyses were conducted to explore the potential effects modifier. Results: The biochemical pregnancy rate and live birth rate were 54.2% and 36.4%, respectively. The ambient NO2 exposure was significantly associated with a 14% lower pregnancy rate during period 1 (aOR = 0.86, 95%CI: 0.75–0.99). The ambient PM10 was related to significantly increased risk of lowering live birth rate among the patients during period 3 [aOR = 0.88(0.79–0.99)]. Stratified analysis showed that ambient PM10 was also significantly associated with a reduced pregnancy rate (aOR = 0.82, 95% CI: 0.69–0.97) in patients who underwent single embryo transfer during period 1. Subjects who underwent single embryo transfer also had a decreased likelihood of a live birth when exposed to ambient SO2 and O3 during period 3 [aOR = 0.74(0.57–0.95), and 0.92 (0.83–0.98), respectively]. Moreover, O3 exposure was associated with decreased live birth rates in patients living in non-urban areas. Sensitivity analyses indicated robust negative association between PM10 exposure and live birth outcomes. Conclusions: Our study suggested that exposure to ambient air pollutants, in particular NO2 and PM10, was associated with an increased risk of lower rates of pregnancy and live birth respectively in patients undergoing IVF. Stratified analyses indicated that ambient SO2 and O3 levels were related to adverse pregnancy outcomes in some subgroups of IVF patients in this study. Notably, patients who underwent single embryo transfer were more susceptible to ambient air pollution exposure. Thus, prospective cohort studies are needed to investigate the underlying mechanisms and the susceptibility windows for women undergoing IVF treatment.