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Sepsis is characterized by a dysregulation of immune response to infection, leading to life-threatening organ dysfunction. Sepsis-associated liver injury (SALI) is considered an independent risk factor for predicting death in the intensive care unit (ICU). With the increasing number of studies on the gut-liver axis in recent years, the close linkage of gut microbiota and liver diseases has been gradually revealed. Dysbiosis of gut microbiota has been shown to induce SALI through the mitogen-activated protein kinase/nuclear transcription factorκB (MAPK/NF-κB) signaling pathway and damage to the intestinal barrier. Meanwhile, fecal microbiota transplantation (FMT) and the application of probiotics have great potential in the treatment of SALI. This paper reviews the relevant research progress in recent years both at home and abroad, in order to provide new insights into the pathogenesis and treatment of SALI.

In this work, a degenerate diffusion state is identified for common L12 intermetallics in well-defined five-frequency model (FFM) and anti-site bridge model (ASB). The relative energy barrier [Formula: see text] ([Formula: see text] in FFM and [Formula: see text] in ASB) of the degenerate state serves as a decomposer which not only bifurcates the degenerate pathways, but also determines the most probable diffusion model. The diffusion coefficients obtained from the most probable diffusion model coincides the experimental value. We find the proposed decomposer complies with the Onsager phenomenological theory and atomistic correlation understanding, and is also supported by the relative work [Formula: see text] done by electronic wind force.

The resistance to intergranular corrosion (IGC) is crucial for 7xxx series high-strength aluminum alloy. The grain boundary characteristics and nanoscale intergranular precipitates are the most significant factors affecting the IGC performance of alloys. Exploring the influences of the two factors on the mechanism and kinetics of corrosion is a fundamental issue for IGC processes. In this paper, the multi-phase field model for electrochemical corrosion is employed to study the IGC processes. The effects of grain size, GB overpotential, and the status of nano-precipitates on the mechanism and kinetics of IGC are systematically and quantitatively investigated. Polycrystalline alloys with the averaged grain sizes in micrometer and nanoscale show typical IGC (GB network propagation) regime and massive corrosion regime respectively. The IGC tendency of micrometer-sized grains increases with the average grain size, while that of nanoscale grains exhibits the opposite trend due to different corrosion mechanisms. For the IGC in the presence of nano-precipitates, our simulations quantify that the orientation, size, and distribution of precipitates could substantially affect the corrosion rate. Nanoscale precipitates exhibit completely different corrosion regimes in the process of IGC, with trenching and penetrating corrosion patterns depending on the overpotential. The multi-phase field model lays a foundation for revealing the corrosion mechanism as well as designing new corrosion resistant materials.

In this work, the influence of the mechanical equilibrium among interfacial tensions at three-phase triple junctions on the morphological evolution of growing eutectic lamella was quantitatively investigated through the phase-field simulations. We found that, when eutectic lamella grows at the steady-state, the orientations of the three interfacial tensions under mechanical equilibrium state are highly coincident with the tangent lines of the contour of the corresponding interfacial morphologies at the three phases’ triple junction. It is argued that the eutectic lamellar growth is unable to reach the steady state when the interfacial tensions fail to achieve mechanical equilibrium at the triple junctions. Moreover, a strong dependence of interfacial morphology on the state of the mechanical equilibrium between interfacial tensions is determined, and quantified through the change of lamella spacing and local curvature radius of lamella with the interfacial tensions. Furthermore, the underlying mechanism about the effects of mechanical equilibrium state on eutectic morphological evolution is also explained. We conclude that the final steady-state of eutectic growth is determined by the complex interplay among solute diffusion, eutectic morphology and the mechanical equilibrium of interfacial tensions.

The evolution of L12 Al3X (X = Ti, Zr, Hf) nano-precipitates in Al-X alloys was studied by multi-scale diffusion simulation using a combination of first principles calculation and finite element method. The results show that the diffusion coefficient in Al-X solid-solution phase follows DAl>DZr>DHf>DTi, which are in excellent agreement with available experimental values. On the other hand, the mobility of X atoms in L12 Al3X phases is reversed, following DAlAl3X>DTiAl3Ti>DHfAl3Hf>DZrAl3Zr. The calculated Al and X diffusion coefficients in both Al-X solid-solution and L12 Al3X ordered phases were used to simulate the evolution of L12 nano-precipitate embedded in Al-X solid-solution matrix. It is found that only Zr could promote the formation of nano-precipitates at 650 K, the common heat-treatment temperature for advanced Al alloys. At lower temperature, the sluggish atomic movement hinder the nucleation of L12 phase, while at higher temperature the precipitates redissolve into the Al matrix. The multi-scale diffusion simulation underlines the indispensable role of diffusion in L12 Al3X phases on the nano-precipitate evolution, and also provides a feasible way to the rationally design of precipitate strengthening alloys.

Effects of pre-treatment (either pre-deformation or composed of pre-aging and pre-deformation prior to aging) on the dislocation morphologies and subsequent precipitation, corrosion behaviors, and mechanical properties of a novel Al-8.26Zn-1.95Mg-1.89Cu-0.08Sc-0.17Zr (wt.%) alloy were investigated. Pre-existing Al3(Sc, Zr) dispersoids can pin dislocations induced by pre-deformation before aging to form dislocation cells and cell walls. As a result, bimodal microstructures are formed during the subsequent aging process, with coarse precipitates dispersed along dislocation walls and fine precipitates inside dislocation cells. Meanwhile, dislocations pinned by Al3(Sc, Zr) dispersoids nearby grain boundaries inhibit the diffusion of solutes towards grain boundaries, which can modify grain boundary features by decreasing the potential difference between grain boundaries and grain interiors, and reducing precipitation-free zone width and grain boundary precipitate size. In particular, pre-aging prior to pre-deformation makes the dislocation distribution more uniform, which increases the volume fraction of nanoprecipitates without significant coarsening and further improves the grain boundary characteristics. Compared with the traditional T74 treated sample, these multiple microstructures significantly enhance the corrosion resistance of the alloy with less strength degradation. This study offers novel insights into the strengthening and corrosion mechanisms of pre-treated Al–Zn–Mg–Cu alloys with Zr and Sc microalloying.

Co-based diamond tools are widely appreciated for their exceptional mechanical properties and good holding ability for diamonds. However, the reliance on cobalt (Co) poses challenges due to its high cost and scarcity as a strategic resource. A potential alternative is the Fe–Co–Cu alloy, emerging as a promising substitute for Co matrix alloys. In this work, hot-press sintering was utilized to create pure matrix and diamond tools utilizing Fe–Co–Cu pre-alloyed powders of varying compositions as raw materials without the use of any sintering additives. The investigation explores the influence of different Fe: Cu ratios on the mechanical properties of diamond tools produced from Fe–Co–Cu alloys, focusing on the diamond holding force, microstructure, and phase structure evolution. Results indicate that at a Co content of 15 wt% and Fe: Cu ratios ranging from 7.5:1 to 1:7.5, the Fe–Co–Cu alloy's phase structure primarily comprises α-Fe and a Cu-rich phase. Co predominantly exists in α-Fe as a solid solution. As the Fe: Cu ratio decreases, the alloy's phase structure gradually transitions from α-Fe to a Cu-rich phase, accompanied by a progressive decline in both bending strength and hardness, while the densities gradually increase. The matrix's holding force on the diamond exhibits an increasing and then diminishing trend, peaking at the Fe: Cu ratio of 6:1. The Fe–Co–Cu alloy sintered by hot-pressing has a nearly equiaxed grain structure with no obvious texture.

Cyclosporine is an immunosuppressant used to prevent organ rejection in kidney, liver, and heart allogeneic transplants. This study aimed to assess the safety of cyclosporine through the analysis of adverse events (AEs) related to cyclosporine in the US Food and Drug Administration Adverse Event Reporting System (FAERS). To detect AEs associated with cyclosporine, a pharmacovigilance analysis was conducted using four algorithms on the FAERS database: reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayes geometric mean (EBGM). A statistical analysis was performed on data extracted from the FAERS database, covering 19,582 case reports spanning from 2013 to 2022. Among these cases, 3,911 AEs were identified, with 476 linked to cyclosporine as the primary suspected drug. Cyclosporin-induced AEs targeted 27 System Organ Classes (SOCs). Notably, the highest case at the SOC level included eye disorders, injury, poisoning, and procedural complications, as well as immune system disorders, all of which are listed on the cyclosporine label. Furthermore, we discovered novel potential AEs associated with hepatobiliary disorders, among others. Moreover, unexpected adverse drug reactions (ADRs), such as biliary anastomosis complication and spermatozoa progressive motility decrease, were identified. Importantly, these newly identified ADRs were not mentioned on the cyclosporine label, which were involved in injury, poisoning, and procedural complications, and investigations at the SOC level. The study used pharmacovigilance analysis of FAERS database to identify new and unexpected potential ADRs relating to cyclosporine, which can provide safety tips for the safe use of cyclosporine.

Abstract Background There is no evidence supporting the feasibility of laparoscopic pancreaticoduodenectomy (LPD) compared to open pancreatoduodenectomy (OPD) following neoadjuvant chemotherapy (NACT) for pancreatic ductal adenocarcinoma (PDAC). Methods The clinical data of consecutive patients with borderline resectable PDAC who received NACT and underwent either LPD or OPD between January 2020 and December 2022 at Fudan University Shanghai Cancer Center was prospectively collected and retrospectively analyzed. Results The analysis included 57 patients in the OPD group and 20 in the LPD group. Following NACT, the LPD group exhibited a higher median CA19-9 decrease rate compared to the OPD group (85.3% vs. 66.9%, P = 0.042). Furthermore, 3 anatomically borderline PDACs in the LPD group and 5 in the OPD group were downstaged into resectable status (30.0% vs. 12.3%, P = 0.069). According to RECIST criteria, 51 (66.2%) patients in the entire cohort were evaluated as having stable disease. The median operation time for the LPD group was longer than the OPD group (419 vs. 325 min, P 3 cm before NACT (HR 2.185) and poor tumor differentiation (HR 1.805) were independent risk factors for recurrence-free survival, and a decrease rate of CA19-9 > 70% (OR 0.309) was a protective factor for early tumor recurrence and overall survival. Conclusions LPD for PDAC following NACT is feasible and oncologically equivalent to OPD. Effective control of CA19-9 levels is beneficial in reducing early tumor recurrence and improving overall survival.

In order to understand the underlying material evolution during liquid phase sintering (LPS) process in hot isostatic pressing process (HIP), microstructure and mechanical properties of 90 W–Ni–Fe–Cu alloys fabricated at 1400 °C/150 MPa are examined systematically. For 90W-4.2Ni-1.8Fe–4Cu alloy, the typical LPS microstructure, which are spherical W grains uniformly surrounded by continuously distributed γ- (Ni, Fe, Cu) matrix phase with the lowest W–W contiguity of 0.31, is achieved successfully after HIP at 1400 °C/150 MPa. The excellent tensile strength reaches as high as 873 MPa with elongation of 17.3% due to the soft γ- (Ni, Fe, Cu) matrix phase. Moreover, the relationship between the microstructure parameters VM(1−CW−W) and elongation ε are established and analyze the association with dislocation motion in depth through electron backscattered diffraction (EBSD) characterization. To our best knowledge, the LPS behavior of tungsten alloy is in-situ revealed by high-temperature confocal scanning laser microscopy (HT-CSLM) for the first time. The current research provides a novel strategy for designing and fabricating powder metallurgy materials by LPS with pressure.

Purpose: Ferredoxin reductase (FDXR) is a flavoprotein that functions in both iron sulfur cluster biogenesis and steroid biosynthesis pathways in the mitochondria. Not surprisingly, loss of FDXR function causes severe mitochondrial diseases in humans. Although several FDXR-related mitochondriopathy (FRM) cohorts have been reported in the literature, further characterization of the natural history of FRM is warranted. Methods: To better understand the spectrum of FRM, a natural history study of FRM was performed. New cases were added to previously reported FRM cases for analysis (n = 62 cases). Results: Optic atrophy, movement disorder, and developmental delay were frequent findings. Mortality is high, with 18% of patients, often infants, passing from complications. Notably, 25% of cases were homozygous or compound heterozygous for the previously reported p.Arg386Trp “hotspot” variant. Of the obtained ancestry, all but 1 individual heterozygous for the p.Arg386Trp variant was Hispanic, with many reporting Mexican heritage. Utilizing recent large-scale genome sequencing surveys, the carrier frequency of the p.Arg386Trp variant was estimated as 1 of 185 in the Mexican population. Conclusion: Given the high mortality of FRM and carrier frequency of the common variant, consideration of a new approach for population carrier screening and development of therapeutics for affected individuals is needed.

Pacific white shrimp (Penaeus vannamei) is one of the main shrimp species cultivated around the world. Despite its high yields and easy handling, water pollution from intensive shrimp cultivation remains a serious problem in China. In this study, a compound aquaculture model of P. vannamei and water spinach (Ipomoea aquatica) was used to investigate the effect of a water spinach floating raft on water quality, antioxidants, non-specific immune response, growth performance, and microbial diversity. The experimental design of this study consisted of two groups with three replicates for each, i.e., control group: aquatic monoculture (AM) system with only P. vannamei; treatment group: P. vannamei-I. aquatica raft aquaponics (AP) system with a 50% cover ratio with a water spinach floating raft. The experiment lasted for seven weeks. The results show that the concentrations of total phosphorus (TP), total nitrogen (TN), nitrate nitrogen (NO3−-N), ammonia nitrogen (NH4+-N), nitrite nitrogen (NO2−-N), and active phosphorus (AP) in the AM group were higher than those in the AP group at different sampling times. The water quality index of the AP group was better than that of the AM group, indicating that water spinach can remove the nutrients from aquaculture water bodies. The average daily gain and survival rate of shrimp in the AP group were higher than those in the AM group. The total antioxidant capacity (T-AOC), catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA), and acid phosphatase (ACP) in the AP group were better than those in the AM group. The Shannon–Wiener and Simpson indices of the gut, water, and sediment of the AP system were significantly higher than those in the AM system, which implied a higher abundance of microorganisms in the AP system. These results demonstrate that the application of a water spinach floating raft in aquaponics can not only improve the water quality, but also improve the growth performance, antioxidant system, and non-specific immune responses of Pacific white shrimp, while increasing the abundance of microorganisms in the aquaculture system and improving the ecological benefits in terms of the expenditure.

The large-scale ingot of the 7xxx-series aluminum alloys fabricated by direct chill (DC) casting often suffers from foundry defects such as cracks and cold shut due to the formidable challenges in the precise controlling of casting parameters. In this manuscript, by using the integrated computational method combining numerical simulations with machine learning, we systematically estimated the evolution of multi-physical fields and grain structures during the solidification processes. The numerical simulation results quantified the influences of key casting parameters including pouring temperature, casting speed, primary cooling intensity, and secondary cooling water flow rate on the shape of the mushy zone, heat transport, residual stress, and grain structure of DC casting ingots. Then, based on the data of numerical simulations, we established a novel model for the relationship between casting parameters and solidification characteristics through machine learning. By comparing it with experimental measurements, the model showed reasonable accuracy in predicting the sump profile, microstructure evolution, and solidification kinetics under the complicated influences of casting parameters. The integrated computational method and predicting model could be used to efficiently and accurately determine the DC casting parameters to decrease the casting defects.

Abstract Background China’s 35 largest cities, including Wuhan, are inhabited by approximately 18% of the Chinese population, and account for 40% energy consumption and greenhouse gas emissions. Wuhan is the only sub-provincial city in Central China and, as the eighth largest economy nationwide, has experienced a notable increase in energy consumption. However, major knowledge gaps exist in understanding the nexus of economic development and carbon footprint and their drivers in Wuhan. Methods We studied Wuhan for the evolutionary characteristics of its carbon footprint (CF), the decoupling relationship between economic development and CF, and the essential drivers of CF. Based on the CF model, we quantified the dynamic trends of CF, carbon carrying capacity, carbon deficit, and carbon deficit pressure index from 2001 to 2020. We also adopted a decoupling model to clarify the coupled dynamics among total CF, its accounts, and economic development. We used the partial least squares method to analyze the influencing factors of Wuhan’s CF and determine the main drivers. Results The CF of Wuhan increased from 36.01 million t CO2eq in 2001 to 70.07 million t CO2eq in 2020, a growth rate of 94.61%, which was much faster than that of the carbon carrying capacity. The energy consumption account (84.15%) far exceeded other accounts, and was mostly contributed by raw coal, coke, and crude oil. The carbon deficit pressure index fluctuated in the range of 8.44–6.74%, indicating that Wuhan was in the relief zone and the mild enhancement zone during 2001–2020. Around the same time, Wuhan was in a transition stage between weak and strong CF decoupling and economic growth. The main driving factor of CF growth was the urban per capita residential building area, while energy consumption per unit of GDP was responsible for the CF decline. Conclusions Our research highlights the interaction of urban ecological and economic systems, and that Wuhan’s CF changes were mainly affected by four factors: city size, economic development, social consumption, and technological progress. The findings are of realistic significance in promoting low-carbon urban development and improving the city’s sustainability, and the related policies can offer an excellent benchmark for other cities with similar challenges.

Background: Tumors involving the main pancreatic duct (MPD) used to be a contraindication for enucleation. Methods: Clinical data of consecutive patients with pancreatic tumors who received laparoscopic or robotic enucleation (LEN or REN) between January 2019 and December 2021 at Fudan University Shanghai Cancer Center were analyzed. Results: Ninety-six patients were included in the analysis, with 55 in the LEN group and 41 in the REN group, and no conversion to laparotomy. Most tumors were located in the head of pancreas (71.9 %). The tumor diameter (3.1 vs. 1.9 cm) was larger, and more cystic tumors (92.7 % vs. 56.4 %) and more tumors involving the MPD (34.1 % vs. 3.6 %) were observed in the REN group. MPD support tube insertion was performed in 15 cases, with 11 in the REN group and 4 in the LEN group. The incidence of biochemical and grade B postoperative pancreatic fistula (POPF) was both 46.9 %, and no grade C POPF occurred. Among the 45 patients with grade B POPF, 28 cases (62.2 %) were due to carrying drainage tube >3 weeks without additional treatment, and only 4 cases required invasive treatment. For patients with MPD support tube implantation (n = 15), support tube fall-offs were observed in 12 cases, 2 patients had MPD dilatation, and no MPD stricture, stone formation or pancreatic atrophy was observed during follow-up. Conclusions: The incidence of POPF was high but still controllable without serious complications after minimally invasive enucleation. The MPD is no longer a restricted area, and the robotic system has advantages in handling complex enucleations.

Background and objective: Sacituzumab govitecan (SG), the first antibody-drug conjugate targeting human trophoblast cell-surface antigen 2 (Trop-2), has been approved by the Food and Drug Administration (FDA) for the treatment of advanced or metastatic breast cancer and urothelial cancer. However, there is currently a dearth of information regarding the safety profiles of SG in a large sample cohort. The objective of the present study is to investigate SG-related adverse events (AEs) in real-world settings leveraging the FDA Adverse Event Reporting System (FAERS) database to guide the safety management of clinical medication.Methods: The FAERS database was retrospectively queried to extract reports associated with SG from April 2020 to March 2023. To identify and evaluate potential AEs in patients receiving SG, various disproportionality analyses such as reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) were employed.Results: Overall, 2069 reports of SG as the “primary suspect” were identified. Noteworthy, SG was significantly associated with an increased risk of blood lymphatic system disorders (ROR, 7.18; 95% CI, 6.58–7.84) and hepatobiliary disorders (ROR, 2.68; 95% CI, 2.17–3.30) at the System Organ Class (SOC) level. Meanwhile, 61 significant disproportionality preferred terms (PTs) simultaneously complied with all four algorithms were adopted. Therein, anemia, thrombocytopenia, neutropenia, leukopenia, diarrhea, asthenia, alopecia, and electrolyte imbalance were consistent with the common AEs described in the clinical trials and specification of SG. Furthermore, unexpected significant AEs include colitis (ROR, 12.09; 95% CI, 9.1–16.08), heart rate increased (ROR, 5.11; 95% CI, 3.84–6.79), sepsis (ROR, 4.77; 95% CI, 3.59–6.34), cholestasis (ROR, 6.28; 95% CI, 3.48–11.36), blood bilirubin increased (ROR, 4.65; 95% CI, 2.42–8.94) and meningitis (ROR, 7.23; 95% CI, 2.71–19.29) were also be detected. The median time to onset of SG-related AEs was 14 [interquartile range (IQR), 7–52] days, with the majority occurring within the initial month of SG treatment.Conclusion: Our study validates the commonly known AEs and also found some potentially emerging safety issues related to SG in real-world clinical practice, which could provide valuable vigilance evidence for clinicians and pharmacists to manage the safety issues of SG.

Summary: Background: Asthenozoospermia is the primary cause of male infertility; however, its genetic aetiology remains poorly understood. Adenylate kinase 9 (AK9) is highly expressed in the testes of humans and mice and encodes a type of adenosine kinase that is functionally involved in cellular nucleotide homeostasis and energy metabolism. We aimed to assess whether AK9 is involved in asthenozoospermia. Methods: One-hundred-and-sixty-five Chinese men with idiopathic asthenozoospermia were recruited. Whole-exome sequencing (WES) and Sanger sequencing were performed for genetic analyses. Papanicolaou staining, Haematoxylin and eosin staining, scanning electron microscopy, and transmission electron microscopy were used to observe the sperm morphology and structure. Ak9-knockout mice were generated using CRISPR-Cas9. Sperm adenosine was detected by liquid chromatography–mass spectrometry. Targeted sperm metabolomics was performed. Intracytoplasmic sperm injection (ICSI) was used to treat patients. Findings: We identified five patients harbouring bi-allelic AK9 mutations. Spermatozoa from men harbouring bi-allelic AK9 mutations have a decreased ability to sustain nucleotide homeostasis. Moreover, bi-allelic AK9 mutations inhibit glycolysis in sperm. Ak9-knockout male mice also presented similar phenotypes of asthenozoospermia. Interestingly, ICSI was effective in bi-allelic AK9 mutant patients in achieving good pregnancy outcomes. Interpretation: Defects in AK9 induce asthenozoospermia with defects in nucleotide homeostasis and energy metabolism. This sterile phenotype could be rescued by ICSI. Funding: The National Natural Science Foundation of China (82071697), Medical Innovation Project of Fujian Province (2020-CXB-051), open project of the NHC Key Laboratory of Male Reproduction and Genetics in Guangzhou (KF202004), Medical Research Foundation of Guangdong Province (A2021269), Guangdong Provincial Reproductive Science Institute Innovation Team grants (C-03), and Outstanding Young Talents Program of Capital Medical University (B2205).

This study demonstrated Da Vinci robot assisted pancreaticoduodenectomy with superior mesenteric vein (SMV) resection and reconstruction. The patient was diagnosed with pancreatic head cancer preoperatively. After anesthesia, trocars were placed by “six-hole method”, and then constant pressure pneumoperitoneum was established. The first step was to remove the gallbladder, open the gastrocolonic ligament, and expose the pancreas and surrounding tissues. After making a Kocher incision, we dissected duodenum, inferior vena cava and uncinate process of pancreas, and then cleaned lymph nodes in groups 13 and 16A. After the stomach was severed using linear stapler, the right gastric artery was dissected and ligated. In this case, the adhesion around the pancreas and common hepatic artery was serious, so the pancreas was transected firstly. The gastroduodenal artery was dissected from the upper edge of the pancreas, and the lymph nodes in groups 7, 8, 9 and 12 were cleaned to expose the common bile duct and portal vein. The common bile duct was transected above the confluence plane of the cystic duct. After opening the colonic mesentery on the left side of the superior mesenteric artery (SMA), the jejunum was severed with a linear cutting obturator. The uncinate process was treated through the middle artery approach; the inferior pancreaticoduodenal artery was severed and lymph nodes were cleaned to the root of SMA and celiac trunk. The tumor and part of the invaded SMV were removed and end-to-end SMV anastomosis was performed. The proper hepatic artery was wrapped with the round hepatic ligament. To protect the stump of gastroduodenal artery, we padded the round hepatic ligament below the pancreaticoduodenal anastomosis. The modified Blumgart method was used for pancreaticointestinal duct to mucosal anastomosis. 4-0 ​V-Lock suture was used for continuous suture of posterior wall and anterior wall respectively, and finally gastrointestinal side-to-side anastomosis was performed. The operation time was 360 ​min and the intraoperative bleeding was 200 ​mL. The patient was discharged 7 days after operation.

Background: To retrospectively analyze the outcomes of patients treated with isthmusectomy for a solitary papillary thyroid carcinoma (PTC) confined to the isthmus, and re-assess the role of isthmusectomy in these patients. Methods: The medical records of 65 patients who underwent isthmusectomy for a solitary PTC confined to the isthmus at the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College between 1985 and 2015 were retrospectively reviewed. Demographic data, surgical procedures, pathological characteristics, stages, and outcomes were analyzed. Results: Patients’ median age was 39 years (range, 19–63), and the majority were female (86.2% female, 13.8% male). All patients had a solitary PTC confined to the isthmus and were treated with isthmusectomy. Pretracheal lymph node dissection was performed in 34 patients, in which unilateral central neck dissection was performed in 4 patients and bilateral central neck dissection in 2 patients. Microscopic extrathyroidal extension (ETE) was observed in 23 (35.4%) patients, and macroscopic ETE was observed in 3 (4.6%) patients. Thirty-eight (58.5%) patients were stage pT1a, 19 (29.2%) patients were stage pT1b, 5 (7.7%) patients were stage pT2, and 3 (4.6%) patients were stage p3b. Fifteen (23.1%) patients were stage pN1a. Median follow-up time was 78 months (range, 12–274). Two patients experienced a recurrence and both achieved remission after re-operation. The 10-year recurrence-free survival was 92.1%. The 10-year overall survival and disease specific survival were 98.3% and 100%, respectively. Conclusions: Isthmusectomy is effective and sufficient for select patients with a solitary PTC confined to the isthmus.

One-pot synthesis of continuously compositionally intermetallic graded material is desirable for the industries, but has proven to be difficult, as each constituent layer presents distinct crystal structure and microstructure. In this work, we demonstrate that a continuously compositionally Ti/Al intermetallic graded material can be successfully fabricated by a well-controlled laser parameter and powder feeding speed. Scanning electron microscopy (SEM), energy dispersive spectrometer (EDS), micro-area X-ray diffraction analysis (XRD), electron probe microanalysis (EPMA) and transmission electron microscopy (TEM) are utilized in characterizing the resulting graded material and its structural signatures. Results show that Ti5Si3, Ti3Al, TiAl, TiAl3 and Ti7Al5Si12 form from the Ti6Al4V side to AlSi10Mg side. Clear phase interface can be seen from SEM and TEM, but no macroscopic cracks appear on the graded or phase boundaries. The elemental distribution indicates the microstructure of gradually changes from initial network structure to columnar and dendritic structure from Ti6Al4V to AlSi10Mg. The hardness of the prepared Ti/Al graded material displays a parabolic shape with a maximum in the middle layers. Our findings suggest that continuously compositionally Ti6Al4V/AlSi10Mg intermetallic graded material could be synthesized in one time through laser powder deposition, and the continuously microstructure and hardness implies its application potential in aerospace, especially in the field of space debris protection.

In recent years, electrochemical exfoliation of layered materials has attracted increasing attention owing to its wide feasibility in the fast and high-yield preparation of various two-dimensional (2D) nanomaterials. This process typically involves the use of an electric field to drive the intercalation of counter ions into the layered structure. The regulation of the interlayer chemistry plays a crucial rule in electrochemical exfoliation, yet it is often overlooked in existing review articles. To fill this gap, we present a summary of the most recent progress made in understanding the role of interlayer chemistry regulation in electrochemical, with a particular emphasis on the impact of redox reactions that lead to the electrochemical degradation of electrolytes and solvents, as well as the covalent modification necessary for creating 2D functional derivatives. The opportunities and challenges in this field are provided in the end, with a focus on the critical roles played by the electrochemical kinetics and interface observation in the development of large-scale industrial methods. These factors are pivotal for the continued progress and advancement of prospective techniques in this area.

In this study, the T85-treated Al-3.78Cu-1.17Li-0.7 Mg-0.32Ag-0.25Mn-0.33Zn-0.12Zr alloy thermally exposed at a series of temperatures (100–300 °C) for 100 h, 500 h, and 1000 h was systematically investigated. The results show that the thermal stability of the alloy is more closely correlated with thermal exposure temperature than with exposure duration. Excellent thermal stability in strength is obtained below 150 °C, which can be linked to the diameter and number density of T1 (Al2CuLi) precipitates continually increasing with a thickness less than 2 nm. However, the widened precipitation-free zones (PFZs) associated with continuous grain boundary precipitates (GBPs) benefit intergranular fracture, contributing to a decrease in toughness and elongation. In the window of 175–200 °C, T1 precipitates tend to thicken and are gradually substituted by coarse θ′-Al2Cu and S-Al2CuMg with elevating temperature. Simultaneously, the continuous GBPs transverse to discrete circle-like shapes, and thus intergranular ductile fracture becomes dominant. Therefore, the related hardness and strength decrease, while the electrical conductivity and toughness are the opposite. At temperatures over 250 °C, thermal exposure can reduce the dislocation density and dissolve T1 phases to form T2-Al6Cu(Li, Mg)3 and cubic C phases, leading to a dramatic decrease in strength and toughness.

In this study, the effects of the combined addition of CeLa and GdY on the microstructure and mechanical properties of as-cast Al-4Cu-1Mn alloys were investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and tensile testing. The results show that the minor addition of CeLa and GdY leads to a refinement of grain size. The addition of CeLa results in the formation of supersaturated vacancies in the Al matrix, whereas the addition of GdY leads to a decrease in the precipitation temperature of the Al2Cu phase. The combined CeLa and GdY additions can significantly increase ultimate tensile strength (UTS) while losing only a small amount of elongation (EL). Compared with the unmodified alloy, the grain size and SDAS of the alloy (0.2 wt.% CeLa + 0.1 wt.% GdY) were diminished by 67.2% and 58.7%, respectively, while maximum hardness and UTS rose by 31.2% and 36.9%, respectively.

The Al-Mg-Li alloy is ideal for ultra-lightweight aircraft components, and its further performance improvement is of great interest in the aerospace industry. In this study, the effects of various beryllium (Be) additions (Be-free, 0.1, 0.25, 0.50 wt.%) on the microstructure, mechanical, and corrosion performance of the Al-Mg-Li alloys were systematically investigated. The optimal tensile property was obtained in the alloy which added 0.1 wt.% Be with an ultimate tensile strength (UTS), yield strength (YS), and elongation (El) of 530 MPa, 370 MPa, and 9.2%, respectively. Trace Be addition promotes the grain refinement of the as-cast alloy ingot and contributes positive effects to the recrystallization, bringing improvement of the tensile property. Meanwhile, the best anti-corrosion behavior is also presented at 0.1 wt.% Be is added, due to its potential to reduce the width of precipitates free zone (PFZ). As the Be content increases to an excessive level, the comprehensive performance decreases. Therefore, it is strongly recommended that adding trace Be elements into Al-Mg-Li alloys has a positive effect on the comprehensive service performance.

Objectives To analyze the causes of misdiagnosis and missed diagnosis in spinal osteoid osteoma, and to put forward solutions to improve diagnosis accuracy and treatment efficacy in patients. Methods We performed a retrospective cohort study on patients with spinal osteoid osteoma in Beijing Jishuitan Hospital from January 1983 to September 2019. All patients underwent surgery. The outcome measures were the extent of local pain, nocturnal pain, radicular symptoms of extremities after surgery, and reduction or disappearance of lesions on CT after surgery. Results Thirty‐seven patients with spinal osteoid osteoma were recruited in the study. A total of 27% were female, and the mean (SD) age at diagnosis was 21.3 (8.7) years. A total of 87.0% of patients presented with nocturnal pain, and 94.7% of patients were responsive to NSAIDS treatment. The mean (SD) time from the initial onset of symptoms to the final diagnosis was 14.7 (12.5) months. Only four of 37 (10.8%) patients were correctly diagnosed with spinal osteoid osteoma on the first visit to the local hospital. CT is associated with a higher diagnosis rate than X‐ray or MRI on the first visit. Surgical navigation was used in 88.9% of patients who underwent curettage resection, and in 10% of patients who underwent en bloc resection. A total of 37 of 37 patients (100%) reported relief of local pain and radicular symptoms of extremities after surgery, and no recurrence of tumors was found during follow‐ups. Conclusions Spinal CTs are recommended to be performed if osteoid osteoma is suspected based on clinical manifestation, including nocturnal pain and responsiveness to NSAIDS treatment, to avoid misdiagnosis and missed diagnosis of spinal osteoid osteoma.

Abstract Background Although some factors that predict the prognosis in pancreatic neuroendocrine tumor (pNET) have been confirmed, the predictive value of lymph node metastasis (LNM) in the prognosis of pNETs remains conflicting and it is not clear whether regional lymphadenectomy should be performed in all grades of tumors. Methods We included pNET patients undergoing surgery in Shanghai pancreatic cancer institute (SHPCI). The risk factors for survival were investigated by the Kaplan–Meier method and Cox regression model. We evaluated the predictors of LNM using Logistic regression. Results For 206 patients in the SHPCI series, LNM was an independent prognostic factor for entire cohort suggested by multivariate Cox regression analysis. LNM (P = 0.002) predicted poorer overall survival (OS) in grade 2/3 cohort, but there is no significant association between LNM and OS in grade 1 cohort. Grade (P 4 cm tumors. On the other way, LNM was seems to be not associated with prognosis in patients with grade 1 tumors less than 4 cm. Moreover, tumor grade and tumor size seem to act as independent predictors of LNM. Thus, regional lymphadenectomy should be performed in grade 2/3 patients but was not mandatory in grade 1 tumors

Laser shock loading is a more promising technology for investigating spallation damage in materials under shock-wave loading. In this paper, shock-induced spallation in a 90W–Ni–Fe alloy at an ultrahigh tensile strain rate of 106 s−1 is investigated using a superintense ultrafast laser facility. The spallation of the 90W–Ni–Fe alloy was dominated by a transgranular fracture of tungsten(W) particles with a high spall strength of 6.46 GPa. Here, we found an interesting phenomenon that the formation of nanograins inside W particles leads to a new mode of transcrystalline fracture of W particles during the laser shock loading. Futhermore, most voids were nucleated inside the W particles rather than at the W/γ-(Ni, Fe) matrix-phase interface. This result contradicts the fracture theory under quasi-static loading, which posits that the W/γ-(Ni, Fe) matrix-phase interface is not the preferred site for the initial failure under shock loading.

In this paper, the factors causing the change in carbon emissions from direct energy consumption in the construction industry in Beijing–Tianjin–Hebei are decomposed using the logarithmic mean divisia index (LMDI) method to analyze the effect values and contribution rates of each macrofactor. Based on the decomposition results and given relevant national policies, five scenarios are set up for each influencing factor, and a regression stochastic impact on population, affluence, and technology (STIRPAT) with ridge regression analysis is applied to each scenario combination for scenario prediction, forming a scientific and reasonable theoretical system to predict the future time of carbon peaking and carbon neutrality in the construction industry of Beijing–Tianjin–Hebei. The results show that (1) energy intensity and energy structure have a suppressive effect on direct energy consumption carbon emissions in the construction industry in Beijing–Tianjin–Hebei, and the industrial structure, economy, and population will promote an increase in carbon emissions. Energy intensity and the economy have a more significant effect on carbon emissions in the construction industry. (2) The peak year of carbon emissions varies with different scenarios, and the energy efficiency scenario achieves peak carbon in 2028, the earliest peak time, and the lowest peak, as it is the optimal emission reduction projection scenario.

Asthenozoospermia is the most common cause of male infertility. Dynein protein arms play a crucial role in the motility of sperm flagella and defects in these proteins generally impair the axoneme structure and affect sperm flagella function. In this study, we performed whole exome sequencing for a cohort of 126 infertile patients with asthenozoospermia and identified homozygous DNALI1 mutation in one patient from a consanguineous family. This identified homozygous mutation was verified by Sanger sequencing. In silico analysis showed that this homozygous mutation is very rare, highly pathogenic, and very conserved. Sperm routine analysis confirmed that the motility of the spermatozoa from the patient significantly decreased. Further sperm morphology analysis showed that the spermatozoa from the patient exhibited multiple flagella morphological defects and a specific loss in the inner dynein arms. Fortunately, the patient was able to have his child via intracytoplasmic sperm injection treatment. Our study is the first to demonstrate that homozygous DNALI1 mutation may impair the integration of axoneme structure, affect sperm motility and cause asthenoteratozoospermia in human beings.

Solid state phase reactions are complicated and sometimes a black box because of the copious reactants and versatile pathways. In this work, the phase relationship in W-Fe-C ternary system is systematically studied by means of the symmetry principles in crystal chemistry and first-principles thermodynamics. According to group-subgroup relation, ternary carbides FexWxC (x = 6, 3, and 2) are likely to form via the intermediate W2C and FeW3C phases at C-rich condition. At C-poor condition, those ternary carbides are prone to be transformed from Fe7W6 with residual C element in the matrix or C from Fe3C in steel. Based on percolation theory, we find the direct phase transition from Fe6W6C to Fe3W3C undergoes with transient Fe2W2C. The calculated Gibbs reaction free energy is in good agreement with various experimental observation and clarifies the discrepancies and controversaries among different experiments in the literature. The success in predicting the phase relationship of W-Fe-C ternary system suggests that the symmetry principles in crystal chemistry combined with first-principles calculations not only unravel the intrinsic mechanism behind the phase reaction, but also should be incorporated into future designs of covalent materials, such as carbides, nitrides, and oxides.

To improve the low compactness and limited size of powder metallurgy (P/M) aluminum alloy materials, cold rolling deformation on P/M aluminum alloy was carried out in this work. And the microstructure and mechanical properties of P/M aluminum alloy during cold rolling were investigated from multi-dimensional and multi-scale perspectives. The results indicate that the microstructure gradually evolved from the original equiaxial structure to the fiber structure after cold rolling. Also, the grain size decreased with an increase in cumulative reductions. When the cumulative reduction was increased from 0 to 80%, the relative density and tensile strength of the samples increased from 98.31% to 221.94 MPa to 99.04% and 302.88 MPa, respectively. On this basis, the synergetic effect of microstructure densification and deformation strengthening of the P/M 2024 Al alloy during cold rolling was investigated. The improved mechanical properties mainly resulted from the combined effects of the increased microstructural compactness and deformation strengthening.

The deformation behavior and microstructure evolution of Al–5.06Mg–1.67Li–0.51Zn alloy was investigated under hot compression at a range of temperature from 623 K to 753 K and different strain rates of 0.01–10 s−1. The constitutive equation on hyperbolic sine function and the hot processing maps were established. The hot deformation characteristics of the alloy were studied by optical microscopy and electron backscatter diffraction analysis. It was indicated that the flow stress decreased with the increase of the deformation temperature and the decrease of the strain rate. After the flow stress reached the peak stress at the strain rate of 0.01 s−1, the effects of dynamic recrystallization and work hardening alternated with each other. Meanwhile, the dynamic balance was reached between them, where the flow stress curves appeared periodic fluctuations. With decreasing the lnZ value, the proportion of low-angle grain boundaries in the deformed specimens decreased, and the average misorientation of each grain showed the opposite trend. The low-angle grain boundaries transformed to the high-angle grain boundaries. The migration of high-angle grain boundaries, as well as the merging of sub-grains, was more pronounced. The main dynamic softening mechanism changed from particle-stimulated dynamic recrystallization to geometric dynamic recrystallization and continuous dynamic recrystallization due to the reduced lnZ.

Improving the reliability of the solder joint has been the recent research focus in the electronic packaging field due to the increasing degree of integration in the electronic devices. During the reflow soldering process, when the local component is heterogeneous, the coarse structure of the solder joint is easy to grow, which deteriorates the performance of the solder joint. In this study, Au-20Sn/Au/Ni(P)/Kovar joints were prepared using ultrasonic-assisted reflow soldering process. Ultrasonication during reflow improved the wettability and shear strength between the Au-20Sn solder and Kovar substrate. The applied ultrasound can break the primary Au5Sn grain and refine the eutectic microstructure through acoustic cavitation. Meanwhile, ultrasound induced the formation of a new intermetallic compound (IMC) layer that was identified as Ni3P (ca 120 nm), which inhibited the diffusion of Ni from substrate into the solder matrix. The mechanical properties of Au-20Sn/Au/Ni(P)/Kovar joint treated with 80 W ultrasonic vibration (USV) increased by 46.94% as compared to the control sample. The current study provides a new strategy for high-performance packaging in electronic devices in extreme environments.

This paper proposed a novel low-pressure sintering process contraposing to characteristics of pre-alloyed aluminum powders and analyzed its feasibility. The low pressure was set to 0.1 MPa in this study. Meanwhile, 0 MPa and 10 MPa were set as control group. With gas-atomized 2024 aluminum powders as raw material, the microstructure and tensile properties of specimens sintered under three orders of magnitude of pressure (0 MPa, 0.1 MPa and 10 MPa) at two representative temperatures (525 °C and 575 °C) were compared. The results showed that it was difficult for pressureless sintering (0 MPa) to densify pre-alloyed aluminum powders, but low-pressure sintering could. As the liquid phase formed at supersolidus temperature was squeezed out, the loss of alloying elements such as Cu and Mg, which would play an important role in subsequent heat treatment, during low-pressure sintering was apparently less than that of 10 MPa. The density of aluminum sintered under 0.1 MPa at 575 °C was 2.732 g/cm3 and the ultimate tensile strength was 228.16 MPa with ductility of 12 %, which achieved a good balance of plasticity and strength. These findings will bring new insights to the industrialization of aluminum powder metallurgy (APM).

Abstract Background ALDOA is a glycolytic enzyme found mainly in developing embryos, adult muscle and various malignant tumours, including pancreatic tumours. Our previous study revealed that ALDOA, an oncogene, can promote the proliferation and metastasis of pancreatic tumours. Furthermore, ALDOA could predict poor prognosis in patients with pancreatic tumours. Methods IHC analysis of PDAC tissues was conducted. Western blotting, PCR, cellular IF experiments and cell cycle assessment were conducted utilizing cell lines. GSEA and KEGG pathway analysis were used to identify potential downstream pathways. Results To explore the effects of ALDOA on the occurrence and development of pancreatic tumours, we analysed the RNA sequencing results and found that ALDOA could inhibit the DDR. Under normal circumstances, when DNA is damaged, initiation of the DDR causes cell cycle arrest, DNA repair or cell apoptosis. Further experiments showed that ALDOA could inhibit DNA repair and reverse cell cycle arrest induced by DNA damage so that DNA damage persisted to promote the occurrence and progression of cancer. Conclusions Regarding the molecular mechanism, we found that ALDOA inhibited the DDR and improved activation of the cell cycle checkpoint PLK1 by suppressing ATM, which promotes tumour cell progression. Consequently, ALDOA has a profound effect on pancreatic cancer development.

Daucus carota is a biennial herb of the Umbelliferae family, which is a candidate plant for the phytoremediation of Mn pollution. To reveal the mechanism of this plant to adapt to Mn stress, plant growth, anatomical structure, Mn accumulation characteristic, Mn subcellular distribution, and chemical forms of D. carota under six Mn2+ concentrations by pot culture experiments were studied. The results showed that with the rising Mn concentrations, the total dry weight and leaf area of D. carota increased firstly and then decreased, while the specific leaf area increased. The thickness of the main vein, upper epidermis, and lower epidermis; the thickness of the palisade tissue; and the thickness of the spongy tissue of the leaves increased firstly and then decreased. The Mn content in the aboveground and underground parts of D. carota increased, and the values of the bioconcentration factor (BCF) and translocation factor (TF) were higher than 1. The Mn existing in the cell wall and soluble components accounted for the largest proportion, and the proportion of Mn in the cell wall increased with increasing concentrations of Mn. In addition, Mn mainly existed in ethanol extraction state, deionized water extraction state, and sodium chloride extraction state. The results showed that D. carota could alleviate the damage caused by high manganese concentration by storing most of manganese in the cell wall and vacuole and existing in the form of low-activity state.

The paper explores the possibility of reducing the sintering temperature of the 90W–7Ni–3Fe alloy by introducing Cu without sacrificing the comprehensive mechanical properties. The effect of Cu content on the sintering behavior, microstructure and mechanical properties of the 90W–7Ni–3Fe alloy was systematically investigated in the range from 1250 to 1350 °C. The results indicate that Cu significantly decreased the liquidus temperature of the 90W–7Ni–3Fe alloy, which directly influence the sintering behavior. With increasing of Cu content, the sintering behavior of the 90W–7Ni–3Fe alloy changed from solid to liquid phase sintering. The relative density of sintered alloys obtained at 1350 °C increased consistently from 81.61% without Cu to 98.85% with Cu concentration up to 5 wt.%. The X–ray diffraction (XRD) and transmission electron microscopy (TEM) results reveal that, Cu diffused with γ–(Ni, Fe) phase during sintering process and this results in the formation of the γ–(Ni, Fe, Cu) phase, which is well bonded with W grains. The formation process of γ–(Ni, Fe, Cu) phase is also discussed. The tensile strength and hardness of the 90W–7Ni–3Fe alloys were improved obviously by adding Cu. At 1350 °C, the tensile strength of alloys with 5 wt.% Cu is as high as 864 MPa, which was four times than that of the alloy without Cu.

Application aspects in aerospace have led to extensive explores and researches on the Al-Li alloys. Advance of alloy properties and balance of comprehensive performances depend largely on regulation of nano precipitates. However, introduction of further solute elements in Al-Li alloys leads to a greater complexity of precipitation behavior of nano second phase. A pivotal step in understanding the strengthening mechanism is to determine the crystal structure and the evolution pattern of nano precipitate. In this critical review, several major nano precipitates and precursors, as well as composite nano precipitates in Al-Li alloys, are surveyed from composition, atomic structure and orientation relationship with matrix. Nucleation mechanism and evolution process are then discussed. Based on a proper understanding of crystallography, great details are provided on precipitate-dislocation interactions by analyzing the interfacial structure between precipitate and matrix. Finally, the review offers a summary of advances in this field and some inspirations for future research directions.

Powder metallurgy hot isostatic pressing (HIP) is a promising technology for producing complex ultrahigh strength steel (UHSS) components. In the present study, a kind of China UHSS, 30CrMnSiNi2A steel, was prepared by HIP with different processing temperatures. The microstructure and tensile properties of HIPed compacts were analyzed in depth via scanning electron microscopy, X–ray diffraction, electron back–scattered diffraction, transmission electron microscopy, tensile testing and nanoindentation experiment. Results show that all HIPed compacts are granular bainitic structure composed of bainitic ferrite matrix and M–A islands. With the HIP temperature increasing, the volume fraction of M–A islands decreases, and the average grain size increases. Besides, a harmful structure (that is prior particle boundaries, PPBs), which is composed of a great number of Mn–rich and Si–rich oxide inclusions, is formed in the HIPed compacts. Notably, increasing HIP temperature is beneficial to eliminate PPBs. The volume fraction of M–A islands, grain size and the state of PPBs together determine the tensile properties of HIPed compacts, in which the state of PPBs has a most significant impact. With the HIP temperature rising, the tensile fracture mode changes from inter–particle debonding to transgranular quasi–cleavage, which benefits from the elimination of PPBs.

Abstract Background The loss of ovarian function in women, referred to as premature ovarian insufficiency (POI), is associated with a series of concomitant diseases. POI is genetically heterogeneous, and in most cases, the etiology is unknown. Methods Whole-exome sequencing (WES) was performed on DNA samples obtained from patients with POI, and Sanger sequencing was used to validate the detected potentially pathogenic variants. An in silico analysis was carried out to predict the pathogenicity of the variants. Results We recruited 24 patients with POI and identified variants in POI-related genes in 14 patients, including bi-allelic mutations in DNAH6, HFM1, EIF2B2, BNC, and LRPPRC and heterozygous variants in BNC1, EIF2B4, FOXL2, MCM9, FANCA, ATM, EIF2B3, and GHR. No variants in the above genes were detected in the WES data obtained from 29 women in a control group without POI. Determining a clear genetic etiology could significantly increase patient compliance with appropriate intervention strategies. Conclusions Our study confirmed that POI is a genetically heterogeneous condition and that whole-exome sequencing is a powerful tool for determining its genetic etiology. The results of this study will aid researchers and clinicians in genetic counseling and suggests the potential of WES for the detection of POI and thus early interventions for patients with POI.

Abstract Background Pancreatic cancer continues to be one of the most aggressive malignant tumors. Work in recent years in cancer molecular biology has revealed that metabolic reprogramming is an additional hallmark of cancer that is involved in the pathogenesis of cancers, and is intricately linked to gene mutations. Main text However, though oncogenes such as KRAS and c-Myc play important roles in the process, and have been extensively studied, no substantial improvements in the prognosis of pancreatic cancer have seen. Therefore, some scientists have tried to explain the mechanisms of abnormal cancer metabolism from the perspective of tumor suppressor genes. In this paper, we reviewed researches about how metabolic reprogramming was regulated by tumor suppressor genes in pancreatic cancer and their clinical implications. Conclusion Abnormal metabolism and genetic mutations are mutually causal and complementary in tumor initiation and development. A clear understanding of how metabolic reprogramming is regulated by the mutated genes would provide important insights into the pathogenesis and ultimately treatment of pancreatic cancer.

Chemotherapy-induced peripheral neurotoxicity is a common dose-limiting side effect of several cancer chemotherapeutic agents, and no effective therapies exist. Here we constructed a systems pharmacology model of intracellular signaling in peripheral neurons to identify novel drug targets for preventing peripheral neuropathy associated with proteasome inhibitors. Model predictions suggested the combinatorial inhibition of TNFα, NMDA receptors, and reactive oxygen species should prevent proteasome inhibitor-induced neuronal apoptosis. Dexanabinol, an inhibitor of all three targets, partially restored bortezomib-induced reduction of proximal action potential amplitude and distal nerve conduction velocity in vitro and prevented bortezomib-induced mechanical allodynia and thermal hyperalgesia in rats, including a partial recovery of intraepidermal nerve fiber density. Dexanabinol failed to restore bortezomib-induced decreases in electrophysiological endpoints in rats, and it did not compromise bortezomib anti-cancer effects in U266 multiple myeloma cells and a murine xenograft model. Owing to its favorable safety profile in humans and preclinical efficacy, dexanabinol might represent a treatment option for bortezomib-induced neuropathic pain.

BackgroundThe neddylation pathway is aberrantly overactivated in multiple human cancers and has been indicated as an effective target for anticancer therapy in clinical trials. We aimed to study whether the neddylation pathway is upregulated in pancreatic cancer and whether pevonedistat, a first-in-class anticancer agent specifically targeting this pathway, will suppress cancer tumorigenesis and progression.MethodsWe evaluated the expression pattern of neddylation pathway components in 179 pancreatic adenocarcinoma (PAAD) compared with 171 normal tissues from The Cancer Genome Atlas (TCGA) dataset and further assessed PAAD patient prognosis with high neddylation pathway expression via Gene Expression Profiling Interactive Analysis (GEPIA). We then analyzed malignant cancer phenotypes both in vitro and in vivo, as well as intrinsic molecular mechanisms upon pevonedistat treatment.ResultsWe found that the neddylation pathway was hyperactivated in pancreatic cancer. Patients with high neddylation pathway expression exhibited worse prognoses. Pevonedistat significantly inhibited the cancer cell cycle, cell growth, and proliferation; increased cell apoptosis; and decreased cancer cell xenografts in a mouse model. Mechanistically, pevonedistat treatment and the siRNA knockdown neddylation pathway were able to remarkably induce the accumulation of Wee1, p27, and p21. Further mechanistic studies revealed that pevonedistat mainly impaired the ubiquitination level and delayed the protein degradation of Wee1, p27, and p21.ConclusionsOur results showed that pevonedistat targeted the overexpression of the neddylation pathway in pancreatic cancer to induce cell growth suppression by inducing the accumulation of the cell cycle regulators Wee1, p27, and p21, which provides sound evidence for the clinical trial of pevonedistat for pancreatic cancer therapy.

In this study, tungsten alloy/steel composite structure has been successfully fabricated by co-sintering method using hot isotactic pressing (HIP). The microstructure and mechanical properties of co-sintered samples were investigated systematically. Experimental results show that dense co-sintered base materials were obtained with good tensile properties (870 MPa for 90 W-4.2Ni-1.8Fe-4Cu alloy and 1350 MPa for 30CrMnSiNi2A steel). The co-sintered joint contains five regions: the W alloy matrix, the diffusion-affected zone of the W alloy (η-carbides contain Fe3W3C and Fe6W6C), the reaction interlayer, the diffusion-affected zone of the steel ((Ni, Fe, Cu) solid solution), and the steel matrix. The interlayer shows solidification structure, which is composed of Fe0.64Ni0.36, Cu0.81Ni0.19, Fe3W3C and Fe2W Laves phases. The η-carbides transitional belt with thickness of 4–6 μm formed along the W grain boundaries at the interfacial region between W alloy and interlayer, which is the weakest area of the interface according to the TEM and nanoindentation test results. Furthermore, the formation mechanism of the interfacial structure is deeply discussed. The interfacial shear and tensile strengths of the co-sintered specimen is 310 MPa and 148 MPa, respectively. This technique provides a reliable method of efficient preparation of tungsten alloy/steel composite structure.

Abstract Leaf anatomical traits play key roles in plant functions and display evolutionary adaptive changes to suit the surrounding environment. To reveal the adaptive mode and mechanisms of plants in response to global warming, we analyzed leaf morphology and anatomical structures in three different species, Epilobium amurense Hausskn., Pedicularis densispica Franch., and Potentilla fulgens Wall. ex Hook., growing along an elevational gradient (3,000–4,600 m) in the Yulong Mountains. The results showed leaf length and width decreased, whereas leaf thickness increased with increasing altitude in all three species. Thickness of leaf upper epidermis, lower epidermis, palisade and spongy mesophyll, and main vein increased with rising altitude. Stomatal density in each species increased with rising elevation. These results illustrate that plants can adapt to the environmental changes that accompany high altitudes by decreasing leaf area and increasing leaf thickness, mesophyll tissue thickness, and stomatal density. Such morphological and anatomical plasticity would lead to lower transpiration rates, enhanced internal temperature and water status, and improved photosynthetic capability.

Spermatocyte meiosis is the cornerstone of mammalian production. Thousands of long noncoding RNAs (lncRNAs) have been reported to be functional in various cellular processes, but the function of lncRNAs in meiosis remains largely unknown. Here, we profiled lncRNAs in spermatocytes at stage I of meiosis and identified a testis-specific lncRNA, Rbakdn, as a vital regulator of meiosis. Rbakdn is dynamically expressed during meiosis I, and Rbakdn knockdown inhibits meiosis in vitro. Furthermore, Rbakdn knockdown in testes in mice by intratesticular injection disturbs meiosis, reduces testicular volume, and increases apoptosis of spermatocytes, resulting in vacuolation of the seminiferous tubules. Rbakdn can bind to Ptbp2, an RNA-binding protein that is important in the regulation of the alternative splicing of many genes in spermatogenesis. Rbakdn knockdown leads to a decrease in Ptbp2 through the ubiquitination degradation pathway, indicating that Rbakdn maintains the stability of Ptbp2. In conclusion, our study identified an lncRNA, Rbakdn, with a crucial role in meiosis.