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Abstract Cancer remains a leading cause of mortality globally and a major health burden, with chemotherapy often serving as the primary therapeutic option for patients with advanced-stage disease, partially compensating for the limitations of non-curative treatments. However, the emergence of chemotherapy resistance significantly limits its efficacy, posing a major clinical challenge. Moreover, heterogeneity of resistance mechanisms across cancer types complicates the development of universally effective diagnostic and therapeutic approaches. Understanding the molecular mechanisms of chemoresistance and identifying strategies to overcome it are current research focal points. This review provides a comprehensive analysis of the key molecular mechanisms underlying chemotherapy resistance, including drug efflux, enhanced DNA damage repair (DDR), apoptosis evasion, epigenetic modifications, altered intracellular drug metabolism, and the role of cancer stem cells (CSCs). We also examine specific causes of resistance in major cancer types and highlight various molecular targets involved in resistance. Finally, we discuss current strategies aiming at overcoming chemotherapy resistance, such as combination therapies, targeted treatments, and novel drug delivery systems, while proposing future directions for research in this evolving field. By addressing these molecular barriers, this review lays a foundation for the development of more effective cancer therapies aimed at mitigating chemotherapy resistance.

Background In this study, effective antigens of mRNA vaccine were excavated from the perspective of ICD, and ICD subtypes of PRAD were further distinguished to establish an ICD landscape, thereby determining suitable vaccine recipients.Research design and methods TCGA and MSKCC databases were applied to acquire RNA-seq data and corresponding clinical data of 554 and 131 patients, respectively. GEPIA was employed to measure prognostic indices. Then, a comparison of genetic alterations was performed utilizing cBioPortal, and correlation of identified ICD antigens with immune infiltrating cells was analyzed employing TIMER. Moreover, ICD subtypes were identified by means of consensus cluster, and ICD landscape of PRAD was depicted utilizing graph learning-based dimensional reduction.Results In total, 4 PRAD antigens were identified in PRAD, including FUS, LMNB2, RNPC3, and ZNF700, which had association with adverse prognosis and infiltration of APCs. PRAD patients were classified as two ICD subtypes based on their differences in molecular, cellular, and clinical features. Furthermore, ICD modulators and immune checkpoints were also differentially expressed between two ICD subtype tumors. Finally, the ICD landscape of PRAD showed substantial heterogeneity among individual patients.Conclusions In summary, the research may provide a theoretical foundation for developing mRNA vaccine against PRAD as well as determining appropriate vaccine recipients.

Benign prostatic hyperplasia (BPH), characterized by the non-malignant enlargement of the prostate, exhibits a pronounced association with inflammation resulting from androgen receptor (AR) deficiency. Ferroptosis, a cell death mechanism triggered by iron-dependent lipid peroxidation and closely linked to inflammation, has yet to be fully understood in the context of BPH. Using RNA sequencing, we observed a significant elevation of taurine-upregulated gene 1 (TUG1) long noncoding RNA (lncRNA) in BPH tissues compared to normal prostate tissue. High levels of TUG1 exhibited a discernible correlation with both prostate volume and the extent of inflammatory infiltration in BPH patients. The suppression of TUG1 not only led to a reduction in prostate size but also ameliorated AR-deficiency-induced prostatic hyperplasia. Mechanistically, a decrease in AR in prostate luminal cells prompted macrophage aggregation and the release of IL-1β, subsequently fostering the transcription of TUG1 via MYC. Induced TUG1, through competitive binding with miR-188-3p, facilitated the expression of GPX4, thereby diminishing intracellular ROS levels and impeding ferroptosis in prostate luminal cells. Notably, the ferroptosis inducer JKE-1674 alleviated inflammation-induced prostatic hyperplasia in vivo. Together, these findings suggest that AR deficiency crucially inhibits ferroptosis, promoting BPH via the TUG1/miR-188-3p/GPX4 signaling axis, and making ferroptosis induction a promising therapeutic strategy for BPH patients with AR deficiency.

Abstract The pathogenesis of thyroid dysgenesis (TD) is not well understood. Here, using a combination of single-cell RNA and spatial transcriptome sequencing, we identify a subgroup of NF-κB-activated thyrocytes located at the center of thyroid tissues in postnatal mice, which maintained a partially mesenchymal phenotype. These cells actively protruded out of the thyroid primordium and generated new follicles in zebrafish embryos through continuous tracing. Suppressing NF-κB signaling affected thyrocyte migration and follicle formation, leading to a TD-like phenotype in both mice and zebrafish. Interestingly, during thyroid folliculogenesis, myeloid cells played a crucial role in promoting thyrocyte migration by maintaining close contact and secreting TNF-α. We found that cebpa mutant zebrafish, in which all myeloid cells were depleted, exhibited thyrocyte migration defects. Taken together, our results suggest that myeloid-derived TNF-α-induced NF-κB activation plays a critical role in promoting the migration of vertebrate thyrocytes for follicle generation.

Procambarus clarkii is commonly known as crayfish and has become one of the main species of freshwater aquaculture in China because of its delicious meat and strong adaptability to the environment. The incredible demand promotes the rapid development of the crayfish breeding industry. Viral diseases caused by white spot syndrome virus (WSSV) are widely spread in crustaceans, including P. clarkii. WSSV has become a serious threat to the crayfish breeding industry because of its extremely fast transmission and associated high mortality. Virus infection can directly induce autophagy mechanisms. Autophagosomes can wrap virus particles and transport them to lysosomes for degradation. As a highly conserved cellular defense mechanism, autophagy plays an important role in the regulation of virus infections. However, many viruses have evolved special mechanisms to resist autophagy regulation or use the membrane structure produced by autophagy body formation to complete their own replication. In this study, WSSV in susceptible P. clarkii were explored to determine how autophagy related genes of P. clarkii participate in the regulation of virus infection. To study the role of the autophagy related gene (Atg2) in the innate immunity of P. clarkii, the full-length sequence of the Atg2 gene in P. clarkii (named PcAtg2) was cloned using the total RNA of P. clarkii hepatopancreas as a template with the rapid-amplification of cDNA ends technique (RACE). The bioinformatic analysis showed that the total length of the PcAtg2 gene sequence in P. clarkii was 9 966 bp, including a 582 bp 5' non coding region, 2 817 bp 3' non coding region, and 6 567 bp open reading frame. We speculate it encodes 2 189 amino acids. Multiple sequence alignments showed the PcAtg2 gene had the characteristic sequence of the Atg family, with 65 serine phosphorylation sites, and 48 glycosylation sites. The amino acid sequence of PcAtg2 in P. clarkii had the highest homology with the Homarus americanus Atg2 gene. The distribution of the PcAtg2 gene in the gill, heart, midgut, hepatopancreas, stomach, muscle, hemocyte, epidermis, testis, ovary, abdominal ganglion, and eyestalk of P. clarkii were detected by real-time fluorescence quantitative PCR (RT-qPCR). The results showed that there was no significant difference in the expression of the PcAtg2 gene between male and female individuals. However, there were variations in expression in the different tissues. PcAtg2 was expressed in all tissues of P. clarkii, with the highest expression in the hepatopancreas and the lowest expression in the eyestalk. Under WSSV infection, PcAtg2 was initially up-regulated and then down-regulated in the different tissues, after induced expression. These findings suggest that PcAtg2 is involved in the regulation of autophagy in P. clarkii infected with the WSSV virus, and also plays an important regulatory role in the immune response. RNA interference (RNAi) technology was used to further explore the autophagy related genes PcAtg2 of P. clarkii and their role in WSSV infection. In the WSSV infection experiment with P. clarkii, the copy number of the WSSV virus in the dsPcAtg2 injection group was significantly lower than that in the control group and the dsGFP injection group, indicating that the replication of the WSSV virus was inhibited to some extent during the gene silencing of PcAtg2. The mortality results also showed that silencing PcAtg2 could reduce the mortality of P. clarkii infected with WSSV. In this experiment, after PcAtg2 was silenced, the transmission electron microscope images showed that after 24 and 48 hours of WSSV stress, autophagy vacuoles began to appear in the lysosomes in the hepatopancreas of P. clarkii in the control group, the injected dsPcAtg2 group, and the dsGFP injected group. More autophagosomes appeared and accumulated near the nucleus, indicating that P. clarkii can activate the regulation of cell autophagy under WSSV stress. Among them, more autophagosomes appeared in the hepatopancreas of P. clarkii in the dsPcAtg2 injection group, indicating the PcAtg2 gene promoted the formation of autophagosomes. WSSV virus proliferation can take advantage of autophagy. To avoid using the virus, cells will relatively down regulate the expression of autophagy related genes, and reduce the level of autophagy. In this experiment, by silencing the expression of the PcAtg2 gene, P. clarkii can promote autophagy regulation by up-regulating the expression of other autophagy related genes. In conclusion, the full-length sequences of the autophagy related gene PcAtg2 in P. clarkii were obtained for the first time, allowing us to reveal the effect and mechanism of WSSV infection on autophagy in P. clarkii. The effect of regulating autophagy on WSSV replication was analyzed, and the mechanism of the PcAtg2 gene acting on virus replication by regulating the formation of autophagosome was clarified. The PcAtg2 gene plays an important role in anti-virus immune defense in P. clarkii. We provide a theoretical basis for investigating anti-virus strategies from the perspective of autophagy. Further research on the host defense mechanism regulated by autophagy will provide new antiviral strategies.

Purpose: To investigate the regulatory effect and mechanism of Vitamin D receptor (VDR) on mitochondrial function in renal tubular epithelial cell under diabetic status. Methods: The diabetic rats induced by streptozotocin (STZ) and HK-2 cells under high glocose(HG)/transforming growth factor beta (TGF-β) stimulation were used in this study. Calcitriol was administered for 24 weeks. Renal tubulointerstitial injury and some parameters of mitochondrial function including mitophagy, mitochondrial fission, mitochondrial ROS, mitochondrial membrane potential (MMP), mitochondrial ATP, Complex V activity and mitochondria-associated ER membranes (MAMs) integrity were examined. Additionally, paricalcitol, 3-MA (an autophagy inhibitor), VDR over-expression plasmid, VDR siRNA and Mfn2 siRNA were applied in vitro. Results: The expression of VDR, Pink1, Parkin, Fundc1, LC3II, Atg5, Mfn2, Mfn1 in renal tubular cell of diabetic rats were decreased significantly. Calcitriol treatment reduced the levels of urinary albumin, serum creatinine and attenuated renal tubulointerstitial fibrosis in STZ induced diabetic rats. In addition, VDR agonist relieved mitophagy dysfunction, MAMs integrity, and inhibited mitochondrial fission, mitochondrial ROS. Co-immunoprecipitation analysis demonstrated that VDR interacted directly with Mfn2. Mitochondrial function including mitophagy, mitochondrial membrane potential (MMP), mitochondrial Ca2+, mitochondrial ATP and Complex V activity were decreased dramatically in HK-2 cells under HG/TGF-β ambience. In vitro pretreatment of HK-2 cells with autophagy inhibitor 3-MA, VDR siRNA or Mfn2 siRNA negated the activating effects of paricalcitol on mitochondrial function. Pricalcitol and VDR over-expression plasmid activated Mfn2 and then partially restored the MAMs integrity. Additionally, VDR restored mitophagy was partially associated with MAMs integrity through Fundc1. Conclusion: Activated VDR could contribute to restore mitophagy through Mfn2-MAMs-Fundc1 pathway in renal tubular cell. VDR could recover mitochondrial ATP, complex V activity and MAMs integrity, inhibit mitochondrial fission and mitochondrial ROS. It indicating that VDR agonists ameliorate renal tubulointerstitial fibrosis in diabetic rats partially via regulation of mitochondrial function.

This study applied free bulging to fabricate a teardrop-shaped pressure hull and analyzed the nonlinear buckling behavior of this hull. A preform made from stainless steel plates was fabricated, involving blanking, bending, and welding. Then, a teardrop-shaped pressure hull was formed through free bulging. Seven conical segments were installed inside the pressure hull. The segments near the poles had a nominal thickness of 0.851 mm, and the two middle segments of the preform had a nominal thickness of 1.084 mm. Theoretical and experimental analyses were conducted to determine the equivalent stress and yield load of the teardrop-shaped hull and preform. Subsequently, the buckling behavior of the fabricated hull was investigated. Finally, a nonlinear finite element method was used to analyze the bulging and buckling of the teardrop-shaped pressure hull. The findings indicate that free bulging contributes to promisingly manufacturing teardrop-shaped pressure hulls for underwater observatories and other related equipment.

Apoptosis is programmed cell death and is regulated by a series of related genes. It is of great significance in resistance to pathogen invasion and maintaining homeostasis in the environment. The release of cytochrome c (Cytc) from the mitochondria into the cytoplasm is a key step in the initiation of apoptosis. Increasing evidence from investigation of Cytc in cell apoptosis and immunity shows that it can participate in cell apoptosis induced by virus infection. For example, white spot syndrome virus (WSSV) stimulation can induce Cytc gene expression in Litopenaeus vannamei hepatopancreas and hemocytes, and the apoptosis of Epinephelus akaara hepatocytes induced by red-spotted grouper nervous necrosis virus (RGNNV) is related to the release of Cytc. However, the role of Cytc-mediated apoptosis in Procambarus clarkii WSSV infection has not yet been reported. Therefore, in this study, the full length of the the cytochrome c gene of P. clarkii (PcCytc) was cloned, and the role of PcCytc in P. clarkii was analyzed. Its expression in various tissues of P. clarkii proved that WSSV infection can induce the expression of PcCytc. The mechanism of PcCytc involvement in cell apoptosis during WSSV infection was also explored using RNA interference technology, to gain a deeper understanding of the potential role of apoptosis-related factors in the immune response of P. clarkii.In this study, PcCytc was cloned using RACE technology, with a total length of 897 bp, including the 163 bp 5′-UTR, 419 bp 3′-UTR, and 315 bp open reading frame; it encoded 104 amino acids. The structure prediction showed that PcCytc contained a conserved Cytochrom_C domain, proving that it is related to energy production and tends to be conserved in evolution.The results of the quantitative PCR showed that the PcCytc gene was expressed in all tissues of P. clarkii. The expression was lowest in the stomach and higher in the gills, intestines, and muscles, which showed, respectively, 9.46, 8.65 and 7.88 times greater PcCytc expression than that in the stomach. PcCytc showed relatively high expression in tissues with high energy consumption, such as the intestines and muscles, which is consistent with previous studies in Penaeus vannamei. The highest expression level was observed in the gills of the main immune and respiratory tissues of P. clarkii, indicating that PcCytc may be involved in the related biological processes. Based on the above results, we speculate that PcCytc may play different functions in different tissues.WSSV infection experiments showed that the expression level of PcCytc in the tested hepatopancreas, intestines, and muscle tissues increased after virus infection, and reached the highest value at 24 h (P < 0.01), after which it began to decrease until it returned to a normal level at 96 h; the overall performance was an induced expression pattern. This showed that PcCytc is involved in the process of WSSV infection. In addition, considering that PcCytc can participate in ATP production as a key element in the mitochondrial respiratory chain, the low expression of PcCytc leads to energy deficiency. We speculate that once the virus disrupts the energy metabolism of the host cell, the host may compensate for the loss by upregulating the expression of PcCytc.RNAi technology revealed the role of PcCytc in the process of WSSV infection. At 24 and 48 h after WSSV infection, the WSSV copies of the PcCytc RNAi group were significantly increased compared to the uninterrupted group (P < 0.01), and at 72 h were still significantly increased (P < 0.05). These results indicate that PcCytc plays an important role in inhibiting the replication of WSSV in P. clarkii and delays the infection process. To further confirm whether PcCytc mainly inhibits WSSV infection through the apoptotic pathway, we tested the expression changes of some important apoptosis-related genes (bcl-2, bax, and caspase-3). Among them, caspase-3 is an effector protein that regulates cell apoptosis, and its expression directly reflects the result of cell apoptosis. The ratio of bcl-2/bax is considered to be an indicator of the process of cell apoptosis; an increase in the ratio indicates that apoptosis has been affected. Inhibition (a decrease in the ratio) indicates that apoptosis was promoted. The test results were as follows: compared with the PBS group, the expression of bcl-2, bax, and caspase-3 genes of P. clarkii in the WSSV group was up-regulated to varying degrees, with a very significant difference in values (P < 0.01). This shows that WSSV can cause hemolymph apoptosis in P. clarkii, which is consistent with observations in mud crab and shrimp. In addition, the expression of caspase-3 in the dsCytc injection group was significantly downregulated (P < 0.01), indicating that apoptosis was inhibited after interfering with PcCytc. The value of bcl-2/bax in the dsCytc injection group was significantly increased (P < 0.01), which supported this conclusion.In summary, our results indicate that PcCytc can inhibit WSSV infection by regulating the apoptotic pathway. The results of this study provide new insights into the immune response of P. clarkii to WSSV infection.

Although the issue of sparse expert samples at the early stage of training in inverse reinforcement learning (IRL) is successfully resolved by the introduction of generative adversarial network (GAN), the inherent drawbacks of GAN result in ineffective generated samples. Therefore, we propose an algorithm for generative adversarial inverse reinforcement learning that is based on deep deterministic policy gradient (DDPG). We use the deterministic strategy to replace the random noise input of the initial GAN model and reconstruct the generator of the GAN based on the Actor-Critic mechanism in order to improve the quality of GAN-generated samples during adversarial training. Meanwhile, we mix the GAN-generated virtual samples with the original expert samples of IRL as the expert sample set of IRL. Our approach not only solves the problem of sparse expert samples at the early stage of training, but most importantly, it makes the decision-making process of IRL occurring under GAN more efficient. In the subsequent IRL decision-making process, we also analyze the differences between the mixed expert samples and the non-expert trajectory samples generated by the initial strategy to determine the best reward function. The learned reward function is used to drive the RL process positively for policy updating and optimization, on which further non-expert trajectory samples are generated. By comparing the differences between the new non-expert samples and the mixed expert sample set, we hope to iteratively arrive at the reward function and optimal policy. Performance tests in the MuJoCo physical simulation environment and trajectory prediction experiments in Grid World show that our model improves the quality of GAN-generated samples and reduces the computational cost of the network training by approximately 20% for each given environment, applying to decision planning for autonomous driving.

Background: Parabens are common preservatives in personal care products, cosmetics, and medical goods. In the past few years, animal studies showed the male reproductive toxicity associated with some parabens. Yet, epidemiological studies have generated inconsistent findings and research rarely has focused on the mixture effects of the parabens. We aimed to explore the associations between individual paraben exposure as well as the mixture and semen quality parameters. Methods: A total of 795 male partners from preconception couples were included in the study. Their urine samples were analyzed for the concentrations of six parabens, namely methyl paraben (MeP), ethyl paraben (EtP), propyl paraben (PrP), butyl paraben (BuP), benzyl paraben (BzP) and heptyl paraben (HeP). Multiple linear regression models and weighted quantile sum regression (WQS) models were utilized to assess the relationships between individual paraben exposure and paraben mixture with semen quality parameters, respectively. Results: After adjusting for covariates, exposure to a paraben mixture was significantly associated with declining sperm concentration, total sperm count, and progressive motility, among which BuP was identified as the main contributor to sperm concentration and total sperm count while MeP to progressive motility. Results from multiple linear regression models were generally in line with the WQS analysis. Conclusions: Our results suggest negative associations between paraben mixture and sperm concentration, total sperm count, and sperm motility among reproductive-aged men.

Abstract Although vaccines have been evaluated and approved for SARS-CoV-2 infection prevention, there remains a lack of effective treatments to reduce the mortality of COVID-19 patients already infected with SARS-CoV-2. The global data on COVID-19 showed that men have a higher mortality rate than women. We further observed that the proportion of mortality of females increases starting from around the age of 55 significantly. Thus, sex is an essential factor associated with COVID-19 mortality, and sex related genetic factors could be interesting mechanisms and targets for COVID-19 treatment. However, the associated sex factors and signaling pathways remain unclear. Here, we propose to uncover the potential sex associated factors using systematic and integrative network analysis. The unique results indicated that estrogens, e.g., estrone and estriol, (1) interacting with ESR1/2 receptors, (2) can inhibit SARS-CoV-2 caused inflammation and immune response signaling in host cells; and (3) estrogens are associated with the distinct fatality rates between male and female COVID-19 patients. Specifically, a high level of estradiol protects young female COVID-19 patients, and estrogens drop to an extremely low level in females after about 55 years of age causing the increased fatality rate of women. In conclusion, estrogen, interacting with ESR1/2 receptors, is an essential sex factor that protects COVID-19 patients from death by inhibiting inflammation and immune response caused by SARS-CoV-2 infection. Moreover, medications boosting the down-stream signaling of ESR1/ESR2, or inhibiting the inflammation and immune-associated targets on the signaling network can be potentially effective or synergistic combined with other existing drugs for COVID-19 treatment.

In this study, we investigated toroidal shell wrinkling in free hydroforming. We specifically focused on toroidal shells with a regular hexagonal cross-section. Membrane theory was used to examine the distribution of stress and yield load in both preform and toroidal shells. The wrinkling moment was then predicted using an empirical formula of shell buckling. In addition, the wrinkling state was investigated using a general statics method, and the free hydroforming of toroidal shells was simulated using the Riks method. Subsequently, nonlinear buckling and equilibrium paths were analyzed. A toroidal preform was manufactured, and free hydroforming experiments were conducted. Overall, the experimental results confirmed the accuracy of the theoretical predictions and numerical simulations. This indicates that the prediction method used in the study was effective. We also found that wrinkling occurs during hydroforming in the inner region of toroidal shells due to compressive stress. Consequently, we improved the structure of the toroidal shells and performed analytical calculations and numerical simulations for the analysis. Our results indicate that wrinkling can be eliminated by increasing the number of segments on the inner side of toroidal preforms, thereby improving the quality of toroidal shells.

Abstract Background Gallbladder cancer is associated with late diagnosis and poor prognosis. Current study aims to develop a prognostic nomogram for predicting survival of gallbladder cancer patients after surgery. Methods Two large cohorts were included in this analysis. One consisted of 1753 gallbladder cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database, and the other consisted of 239 patients from Shanghai Renji hospital. Significant prognostic factors were identified and integrated to develop the nomogram. Then the model was subjected to bootstrap internal validation and external validation. Results Univariate and multivariate analysis indicated that age, tumor histology, T-stage, N-stage and M-stage were significant prognostic factors, which were all included to build the nomogram. The model showed good discrimination, with a concordance index (C-index) of 0.724 (95% CI, 0.708–0.740), and good calibration. Application of the nomogram in the validation cohort still presented good discrimination (C-index, 0.715 [95% CI 0.672–0.758]) and good calibration. In the primary cohort, the C-index of the nomogram was 0.724, which was significantly higher than the Nevin staging system (C-index = 0.671; P

In order to achieve the requirement of high throughput and low-power in wireless communication, a parallel Turbo decoder has attracted extensive attention.By analyzing the calculating of the state metrics, a low-resource parallel Turbo decoder architecture scheme based on merging the forward and backward state metrics calculation modules was proposed, and effectiveness of the new architecture was demonstrated through field-programmable gate array (FPGA) hardware realization.The results show that, compared with the existing parallel Turbo decoder architectures, the proposed design architecture reduces the logic resource of state metrics calculation module about 50%, while the dynamic power dissipation of the decoder architecture is decreased by 5.26% at the frequency of 125 MHz.Meanwhile the decoding algorithm is close to the decoding performance of the parallel algorithm.

Abstract Long noncoding RNAs (lncRNAs) participate in biological processes in multiple types of tumors. However, the regulatory patterns of lncRNAs in prostate cancer remain largely unclear. Here, we evaluated the expression and roles of the lncRNA DLEU2 in prostate cancer. Our results showed that DLEU2 was upregulated in advanced prostate cancer tissues. Patients with prostate cancer displaying high expression of DLEU2 had a poor prognosis. Moreover, we demonstrated that overexpression of DLEU2 facilitated the proliferation, migration, and invasion of prostate cancer in vitro. Mechanistically, DLEU2 promoted serum and glucocorticoid-induced protein kinase 1 (SGK1) expression by acting as an miR-582-5p sponge, and the transcription of DLEU2 was activated by the dysregulation of E2F transcription factor 2 (E2F2) expression in prostate cancer. Furthermore, knockdown of DLEU2 attenuated prostate cancer tumorigenesis in vivo. Notably, these findings suggested that E2F2-activated DLEU2 may function as a competing endogenous RNA to facilitate prostate cancer progression by targeting the miR-582-5p/SGK1 axis.

In this study, the dieless bulging and nonlinear buckling behaviours of a stainless longan-shaped pressure hull were investigated. According to the Cassini oval equation, the longan shape has a shape index of 0.1. The lengths of the major and minor axes of the designed longan-shaped pressure hull were approximately 400 and 396 mm, respectively. The wall thickness of this pressure hull was 1 mm. The Huber–von Mises stress and first yielding load of the designed longan-shaped shell and its inscribed polyhedral preform were investigated analytically and experimentally. Moreover, the dieless bulging of the designed longan-shaped pressure hull was investigated numerically and experimentally by using the nonlinear finite element method and a hydrostatic test, respectively. The analytical, experimental, and numerical results exhibited good agreement with each other.

To better improve the ride comfort and handling stability of vehicles, a new two-stage ISD semi-active suspension structure is designed, which consists of the three elements, including an adjustable damper, spring, and inerter. Meanwhile, a new semi-active ISD suspension control strategy is proposed based on this structure. Firstly, the fuzzy neural network’s initial parameters are optimized using the grey wolf optimization algorithm. Then, the fuzzy neural network with the optimal parameters is adjusted to the PID parameters. Finally, a 1/4 2-degree-of-freedom ISD semi-active suspension model is constructed in Matlab/Simulink, and the dynamics simulation is carried out for the three schemes using PID control, fuzzy neural network PID control, and improved fuzzy neural network PID control, respectively. The results show that compared with adopting PID control and fuzzy neural network PID control strategy, the vehicle body acceleration and tire dynamic loads are significantly reduced after using the grey wolf optimized fuzzy neural network PID control strategy, which shows that the control strategy proposed in this paper can significantly improve the vehicle smoothness and the stability of the handling.

Abstract Renal tubulointerstitial fibrosis was a crucial pathological feature of diabetic nephropathy (DN), and renal tubular injury might associate with abnormal mitophagy. In this study, we investigated the effects and molecular mechanisms of AMPK agonist metformin on mitophagy and cellular injury in renal tubular cell under diabetic condition. The high fat diet (HFD) and streptozotocin (STZ)-induced type 2 diabetic mice model and HK-2 cells were used in this study. Metformin was administered in the drinking water (200 mg/kg/d) for 24 weeks. Renal tubulointerstitial lesions, oxidative stress and some indicators of mitophagy (e.g., LC3II, Pink1, and Parkin) were examined both in renal tissue and HK-2 cells. Additionally, compound C (an AMPK inhibitor) and Pink1 siRNA were applied to explore the molecular regulation mechanism of metformin on mitophagy. We found that the expression of p-AMPK, Pink1, Parkin, LC3II, and Atg5 in renal tissue of diabetic mice was decreased obviously. Metformin reduced the levels of serum creatinine, urine protein, and attenuated renal oxidative injury and fibrosis in HFD/STZ induced diabetic mice. In addition, Metformin reversed mitophagy dysfunction and the over-expression of NLRP3. In vitro pretreatment of HK-2 cells with AMPK inhibitor compound C or Pink1 siRNA negated the beneficial effects of metformin. Furthermore, we noted that metformin activated p-AMPK and promoted the translocation of Pink1 from the cytoplasm to mitochondria, then promoted the occurrence of mitophagy in HK-2 cells under HG/HFA ambience. Our results suggested for the first time that AMPK agonist metformin ameliorated renal oxidative stress and tubulointerstitial fibrosis in HFD/STZ-induced diabetic mice via activating mitophagy through a p-AMPK-Pink1-Parkin pathway.

Quantifying carbon in root exudates and exploring their influencing factors are essential to understand soil organic carbon dynamics in cropland. A pot experiment was carried out to explore quantitative relations between root exuded carbon and root traits in wheat and rapeseed. The result showed that rapeseed had a similar pattern in root carbon exudation intensity (EI) as the wheat, but its EI per plant was obviously higher than that in wheat. Rapeseed plants had higher EI per root biomass than wheat plants in the early growth period but lower in the late growth period. EI per root biomass in both crops had significant exponential relationships with the specific root length (RL), surface area (RSA), volume (RV), root C/N ratio and root soluble sugar content. However, EI per plant of both crops had a markedly quadratic relationship with RL, RSA, RV and root biomass. During the whole growth period, the rapeseed had cumulative root carbon exudation of 14.09 g/plant, which was almost twice of that in the wheat plant. Root traits had close relations to root carbon exudation in both crops. Quantitative regression models between them could be referred to estimate root C exudation in rapeseed and wheat farmland.

The internal hydroforming of large stainless-steel eggshells from a stepped preform is investigated in this paper. The nominal major and minor axes of the eggshell were 1537 and 1070 mm, respectively. The stepped preform was fabricated from thin-walled (1.9 mm thick) stainless-steel sheets and comprised twelve conical segments inscribed inside the target eggshell. The preform was then hydroformed, and its wall thickness and shape were measured. The yield load distribution and material hardening of the hydroforming process were investigated analytically. Nonlinear finite-element analyses were employed to further investigate hydroforming behaviors and the effect of weld lines on hydroforming. The experimental, numerical, and analytical results were consistent. The results confirm that, during the hydroforming process, considerable springback occurs for large eggshells, which greatly affects forming precision. However, this effect can be reduced by accounting for the strengthening effect of weld lines.

Gallbladder cancer (GBC) is the most common malignancy of the biliary tract, with extremely dismal prognosis. Limited therapeutic options are available for GBC patients. We used whole-exome sequencing of human GBC to identify the ErbB and epigenetic pathways as two vulnerabilities in GBC. We screened two focused small-molecule libraries that target these two pathways using GBC cell lines and identified the mTOR inhibitor INK-128 and the histone deacetylase (HDAC) inhibitor JNJ-26481585 as compounds that inhibited proliferation at low concentrations. Both significantly suppressed tumor growth and metastases in mouse models. Both synergized with the standard of care chemotherapeutic agent gemcitabine in cell lines and in mouse models. Furthermore, the activation of the mTOR pathway, measured by immunostaining for phosphorylated mTOR and downstream effector S6K1, is correlated with poor prognosis in GBC. Phosphorylated mTOR or p-S6K1 in clinical samples is an independent indicator for overall survival in GBC patients. Taken together, our findings suggest that mTOR inhibitors and HDAC inhibitors can serve as potential therapeutics for GBC, and the phosphorylation of mTOR and S6K1 may serve as biomarkers for GBC.

Long Noncoding RNAs (LncRNAs) have recently been identified as key regulator in tumor progression. The LncRNA MAFG-AS1 has been reported to facilitate the progression of multiple cancers, however, its role in prostate cancer is still unknown. Here, we reported that MAFG-AS1 was upregulated in prostate cancer. Importantly, high expression of MAFG-AS1 indicated advanced stage prostate cancer. Univariate and Multivariate Cox regression analyses showed that high MAFG-AS1 expression was independently correlated with poor progression-free interval (PFI). According to the result of The Cancer Genome Atlas (TCGA) database and tissue microarray, high MAFG-AS1 expression indicated a poor prognosis in prostate cancer patients. In addition, gene functional enrichment analysis revealed that MAFG-AS1 may be involved in ribosome biogenesis, ribonucleoprotein complex subunit organization, ribonucleoprotein complex assembly, rRNA metabolic process, structural constituent of ribosome, and ribonucleoprotein complex binding. Furthermore, MAFG-AS1 knockdown by siRNA markedly impaired prostate cancer cell proliferation, migration, and invasion.

Background5-Methylcytidine (m5C) methylation is an emerging epigenetic modification in recent years, which is associated with the development and progression of various cancers. However, the prognostic value of m5C regulatory genes and the correlation between m5C methylation and the tumor microenvironment (TME) in prostate cancer remain unknown.MethodsIn the current study, the genetic and transcriptional alterations and prognostic value of m5C regulatory genes were investigated in The Cancer Genome Atlas and Gene Expression Omnibus datasets. Then, an m5C prognostic model was established by LASSO Cox regression analysis. Gene set variation analyses (GSVA), gene set enrichment analysis (GSEA), clinical relevance, and TME analyses were conducted to explain the biological functions and quantify the TME scores between high-risk and low-risk subgroups. m5C regulatory gene clusters and m5C immune subtypes were identified using consensus unsupervised clustering analysis. The Cell-type Identification By Estimating Relative Subsets of RNA Transcripts algorithm was used to calculate the contents of immune cells.ResultsTET3 was upregulated at transcriptional levels in PCa compared with normal tissues, and a high TET3 expression was associated with poor prognosis. An m5C prognostic model consisting of 3 genes (NSUN2, TET3, and YBX1) was developed and a nomogram was constructed for improving the clinical applicability of the model. Functional analysis revealed the enrichment of pathways and the biological processes associated with RNA regulation and immune function. Significant differences were also found in the expression levels of m5C regulatory genes, TME scores, and immune cell infiltration levels between different risk subgroups. We identified two distinct m5C gene clusters and found their correlation with patient prognosis and immune cell infiltration characteristics. Naive B cells, CD8+ T cells, M1 macrophages and M2 macrophages were obtained and 2 m5C immune subtypes were identified. CTLA4, NSUN6, TET1, and TET3 were differentially expressed between immune subtypes. The expression of CTLA4 was found to be correlated with the degree of immune cell infiltration.ConclusionsOur comprehensive analysis of m5C regulatory genes in PCa demonstrated their potential roles in the prognosis, clinical features, and TME. These findings may improve our understanding of m5C regulatory genes in the tumor biology of PCa.

Prostate cancer is still the main male health problem in the world. The role of metabolism in the occurrence and development of prostate cancer is becoming more and more obvious, but it is not clear. Here we firstly identified a metabolism-related gene-based subgroup in prostate cancer. We used metabolism-related genes to divide prostate cancer patients from The Cancer Genome Atlas into different clinical benefit populations, which was verified in the International Cancer Genome Consortium. After that, we analyzed the metabolic and immunological mechanisms of clinical beneficiaries from the aspects of functional analysis of differentially expressed genes, gene set variation analysis, tumor purity, tumor microenvironment, copy number variations, single-nucleotide polymorphism, and tumor-specific neoantigens. We identified 56 significant genes for non-negative matrix factorization after survival-related univariate regression analysis and identified three subgroups. Patients in subgroup 2 had better overall survival, disease-free interval, progression-free interval, and disease-specific survival. Functional analysis indicated that differentially expressed genes in subgroup 2 were enriched in the xenobiotic metabolic process and regulation of cell development. Moreover, the metabolism and tumor purity of subgroup 2 were higher than those of subgroup 1 and subgroup 3, whereas the composition of immune cells of subgroup 2 was lower than that of subgroup 1 and subgroup 3. The expression of major immune genes, such as CCL2, CD274, CD276, CD4, CTLA4, CXCR4, IL1A, IL6, LAG3, TGFB1, TNFRSF4, TNFRSF9, and PDCD1LG2, in subgroup 2 was almost significantly lower than that in subgroup 1 and subgroup 3, which is consistent with the results of tumor purity analysis. Finally, we identified that subgroup 2 had lower copy number variations, single-nucleotide polymorphism, and neoantigen mutation. Our systematic study established a metabolism-related gene-based subgroup to predict outcomes of prostate cancer patients, which may contribute to individual prevention and treatment.

Straw return is an effective way to improve crop grain yield and potassium (K) use efficiency by increasing soil K content. However, the effects of straw return on soil K supplying capacity, replacement of K fertilizer, and K-use efficiency under maize (Zea mays L.)–rice (Oryza sativa L.) cropping systems are little studied. A two-year field experiment was conducted to determine the physiological determinants of K-use efficiency under straw return with four K fertilization rates. Sr33 (straw returned plus 33% of K fertilizer applied) and Sr67 (straw returned plus 67% of K fertilizer applied) increased annual crop yields by 1.5% and 3.2% and increased agronomic K-use efficiency by respectively 2.9 and 1.3-fold on average in the two years, compared with the conventional practice S0K100 (no straw returned plus normal amounts of K fertilizer applied). The Sr33 and Sr67 treatments resulted in significantly greater equilibrium K concentration ratios (CR0K) and specifically exchangeable K (KX) values according to quantity/intensity (Q/I) relationship analyses, indicating improvement of the potential soil K supply capacity. However, the Sr67 better maintained the soil exchangeable K level and K balance. The results suggested that K released from maize and rice straw can replace about half of chemical K fertilizer, depending on the available K content in maize–rice cropping system production.

Abstract Background The Coronavirus Disease 2019 (COVID-19) pandemic has infected over 10 million people globally with a relatively high mortality rate. There are many therapeutics undergoing clinical trials, but there is no effective vaccine or therapy for treatment thus far. After affected by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), molecular signaling pathways of host cells play critical roles during the life cycle of SARS-CoV-2. Thus, it is significant to identify the involved molecular signaling pathways within the host cells. Drugs targeting these molecular signaling pathways could be potentially effective for COVID-19 treatment. Methods In this study, we developed a novel integrative analysis approach to identify the related molecular signaling pathways within host cells, and repurposed drugs as potentially effective treatments for COVID-19, based on the transcriptional response of host cells. Results We identified activated signaling pathways associated with the infection caused SARS-CoV-2 in human lung epithelial cells through integrative analysis. Then, the activated gene ontologies (GOs) and super GOs were identified. Signaling pathways and GOs such as MAPK, JNK, STAT, ERK, JAK-STAT, IRF7-NFkB signaling, and MYD88/CXCR6 immune signaling were particularly activated. Based on the identified signaling pathways and GOs, a set of potentially effective drugs were repurposed by integrating the drug-target and reverse gene expression data resources. In addition to many drugs being evaluated in clinical trials, the dexamethasone was top-ranked in the prediction, which was the first reported drug to be able to significantly reduce the death rate of COVID-19 patients receiving respiratory support. Conclusions The integrative genomics data analysis and results can be helpful to understand the associated molecular signaling pathways within host cells, and facilitate the discovery of effective drugs for COVID-19 treatment.

Double-maize cropping system is an effective option for coping with climate change in the North China Plain. However, the effects of changes in climate on the growth and yield of maize in the two seasons are poorly understood. Forty-six cultivars of maize with different requirements for growing degree days (GDD), categorized as high (H), medium (M) or low (L), and three cultivar combinations for two seasons as LH (using JD27 and DMY1 from category L in the first season; and YD629 and XD22 from category H in the second season), MM (using JX1 and LC3 from category M in the first season; and ZD958 and JX1 from category M in the second season) and HL (using CD30 and QY9 from category H in the first season; and XK10 and DMY3 from category L in the second season) were tested to examine the eco-physiological determinants of maize yield from 2015 to 2017. The correlations between the combinations of cultivars and grain yield were examined. The combination LH produced the highest annual grain yield and total biomass, regardless of the year. It was followed, in decreasing order, by MM and HL. Higher grain yield and biomass in LH were mainly due to the greater grain yield and biomass in the second season, which were influenced mainly by the lengths of the pre- and post-silking periods and the rate of plant growth (PGR). Temperature was the primary factor that influenced dry matter accumulation. In the first season, low temperatures during pre-silking decreased both the duration and PGR in LH, whereas high temperatures during post-silking decreased the PGR in MM and HL, resulting in no significant differences in biomass being observed among the three combinations. In the second season, high temperatures decreased both the PGR and pre- and post-silking duration in MM and HL, and consequently, the biomass of those two combinations were lower than that in LH. Moreover, because of lower GDD and radiation in the first season and higher grain yield in the second season, production efficiency of temperature and radiation (Ra) was the highest in LH. More importantly, differences in temperature and radiation in the two seasons significantly affected the rate and duration of growth in maize, and thereby affecting both dry matter and grain yield. Our study indicated that the combination of LH is the best for optimizing the double-maize system under changing climatic conditions in the North China Plain.

Cell lineage reprogramming is the main approach for cancer cells to acquire drug resistance and escape targeted therapy. The use of potent targeted therapies in cancers has led to the development of highly aggressive carcinoma, including neuroendocrine prostate cancer (NEPC). Although metabolic reprogramming has been reported to be essential for tumor growth and energy production, the relationship between metabolic reprogramming and lineage differentiation which can cause hormone therapy resistance has never been reported in prostate cancer (PCa). Moreover, as there is still no efficient therapy for NEPC, it is urgent to reverse this lineage differentiation during the hormone therapy. Here for the first time, we used in vitro and in vivo human PCa models to study the effect of metabolic reprogramming on the lineage differentiation from the androgen receptor (AR)–dependent adenocarcinoma to AR-independent NEPC. This lineage differentiation leads to antiandrogen drug resistance and tumor development. This phenotype is enabled by the loss of mitochondrial pyruvate carrier (MPC), the gate for mitochondrial pyruvate influx, and can be reversed by MPC overexpression. Morphologic and cellular studies also demonstrate that the pyruvate kinase M2 (PKM2) involved epithelium–mesenchymal transition process mediated this lineage alteration. Its inhibition is a potential treatment for MPC-lo tumors. All of these results suggest that metabolic rewiring can act as a starter for increased cellular plasticity which leads to antiandrogen therapy resistance through lineage differentiation. This study provides us with a potent treatment target for therapy-induced, enzalutamide-resistant NE-like prostate cancer.

To evaluate the stochastic characteristics of ultimate strength for spherical shells subjected to external pressure, uncertainty analysis is conducted in this study. Experimental measurements and result analysis of dimensions, as well as ultimate strength, are performed. The basic theories of the surrogate model and probability-box method for ultimate strength are introduced briefly. Uncertainty analysis of ultimate strength is completed utilizing double-nested random sampling based on the established Gaussian process model with high precision, and the results are compared with the experimental findings. The results show that the experimental empirical cumulative distribution function is contained in the probability-box obtained while considering the influence of welding, and the absolute errors of the mean value, as well as those of the standard deviation, are much smaller. The study verified that the influence of welding cannot be ignored, and the prediction of ultimate strength, considering uncertainties, can eliminate the occasionalities of simulations and experimental tests.

ObjectivesExisting prognostic risk assessment strategies for prostate cancer (PCa) remain unsatisfactory. Similar treatments for patients at the same disease stage can lead to different survival outcomes. Thus, we aimed to explore a novel immune landscape-based prognostic predictor and therapeutic target for PCa patients.MethodsA total of 490 PCa patients from The Cancer Genome Atlas Project (TCGA) cohort were analyzed to obtain immune landscape-based prognostic features. Then, analyses at different levels were performed to explore the relevant survival mechanisms, prognostic predictors, and therapeutic targets. Finally, experimental verification was performed using a tissue microarray (TMA) from 310 PCa patients. Furthermore, a nomogram was constructed to provide a quantitative approach for predicting the prognosis of patients with PCa.ResultsThe immune landscape-based risk score (ILBRS) was obtained. Then, VAV1, which presented a significant positive correlation with Treg infiltration and ILBRS, was screened and identified to be significantly related to the prognosis of PCa. Finally, experimental verification confirmed the prognostic value of VAV1 for PCa prognosis at the protein level.ConclusionsVAV1 has the potential to be developed as an immune landscape-based PCa prognostic predictor and therapeutic target and will help improve prognosis by enabling the selection of individualized, targeted therapy.

Gemcitabine is used to treat gallbaldder cancer but patient responses are variable. Here, the authors use a genome-wide CRISPR screen and identify the translational elongator protein ELP5 as a protein that is important for mediating gemcitabine-induced apoptosis.

Abstract Background CircRNAs are found to affect initiation and progression of several cancer types. However, whether circRNAs are implicated in gallbladder cancer (GBC) progression remains obscure. Methods We perform RNA sequencing in 10 pairs of GBC and para-cancer tissues. CCK8 and clone formation assays are used to evaluate proliferation ability of GBC cells. qPCR and Western blot are used to determine expression of RNAs and proteins, respectively. CircRNA-protein interaction is confirmed by RNA pulldown, RNA immunoprecipitation, and fluorescence in situ hybridization. Results We find that circRNA expression pattern is tremendously changed during GBC development. Among dozens of significantly changed circRNAs, a circRNA generated from the oncogene ERBB2, named as circERBB2, is one of the most significant changes. CircERBB2 promotes GBC proliferation, in vitro and in vivo. Other than being a miRNA sponge, circERBB2 accumulates in the nucleoli and regulates ribosomal DNA transcription, which is one of the rate-limiting steps of ribosome synthesis and cellular proliferation. CircERBB2 regulates nucleolar localization of PA2G4, thereby forming a circERBB2-PA2G4-TIFIA regulatory axis to modulate ribosomal DNA transcription and GBC proliferation. Increased expression of circERBB2 is associated with worse prognosis of GBC patients. Conclusions Our findings demonstrate that circERBB2 serves as an important regulator of cancer cell proliferation and shows the potential to be a new therapeutic target of GBC.

Background: Oxidative stress and their effectors play critical roles in carcinogenesis and chemoresistance. However, the role of oxidative stress-related genes variants in biliary tract cancer (BTC) chemoresistance remains unknown. In this work, we aim to investigate oxidative stress-dependent molecular mechanisms underlying chemoresistance, and find potential biomarkers to predict chemotherapy response for BTC. Methods: Sixty-six SNPs in 21 oxidative stress-related genes were genotyped and analyzed in 367 BTC patients. Immunoblot, immunohistochemical, immunofluorescent, quantitative PCR, chromatin immunoprecipitation analysis and study of animal xenograft models were performed to discover oxidative stress-related susceptibility genes underlying chemoresistance mechanism of BTC. Findings: We found that 3 functional polymorphisms (CAT_rs769217, GPX4_rs4807542, and GSR_rs3779647), which were shown to affect their respective gene expression levels, modified the effect of chemotherapy on overall survival (OS). We then demonstrated that knockdown of GPX4, CAT, or GSR induced chemoresistance through elevation of ROS level and activation of Nrf2-ABCG2 pathway in BTC cell lines. Moreover, the association between Nrf2 expression and BTC prognosis is only found in patients who received chemotherapy. Knockdown of Nrf2 enhanced chemosensitivity or even eliminated postoperative recurrence in BTC xenograft mouse models. Importantly, upon chemotherapy treatment patients harboring high oxidative stress-related score received higher survival benefit from adjuvant chemotherapy compared with patients with low oxidative stress-related score. Interpretation: The result of our study suggests, for the first time, that the oxidative stress-related score calculated by combining variations in CAT, GPX4, and GSR or Nrf2 expression could be used for predicting the chemosensitivity of BTC patients. Fund: This work was supported by the National Science Foundation of China, Foundation of Shanghai Shen Kang Hospital Development Center, and Shanghai Outstanding Academic Leaders Plan. Keywords: Biliary tract cancer, Single nucleotide polymorphism, Oxidative stress, Nrf2, Chemosensitivity

Abstract Background Gallbladder cancer (GBC) is an extremely malignant tumor with a high mortality rate. Little is known about its invasion and metastasis mechanism so far. Methods To identify the driver genes in GBC metastasis, we performed a mRNA microarray of metastatic GBC and paired non-tumor samples, and found PLEK2 was markedly upregulated in GBC tissues. Next, the expression of PLEK2 in GBC were examined in a larger cohort of patients by qRT-PCR, western blot and IHC staining. The clinicopathologic correlation of PLEK2 was determined by statistical analyses. The biological involvement of PLEK2 in GBC metastasis and the underlying mechanisms were investigated. Results In this study, we found that PLEK2 had higher expression in GBC tumor tissues compared to non-cancerous adjacent tissues and cholecystolithiasis tissues. The clinicopathologic analyses showed PLEK2 expression was positively correlated with tumor TNM stage, distant metastasis and PLEK2 was an independent predictor of overall survival (OS) in GBC patients. The cellular function assays showed PLEK2 promoted GBC cells migration, invasion and liver metastasis in mouse model via the regulation of epithelial-mesenchymal transition (EMT) process. Our mass spectrum and co-immunoprecipitation (co-IP) assays demonstrated that PLEK2 could interact with the kinase domain of EGFR and suppress EGFR ubiquitination mediated by c-CBL, leading to constitutive activation of EGFR signaling. Furthermore, RNA-sequencing and qRT-PCR results demonstrated chemokine (C-C motif) ligand 2 (CCL2), a target gene downstream of PLEK2/EGFR signaling, mediated the motility-promoting function of PLEK2. Conclusions On the basis of these collective data, we propose that PLEK2 promotes the invasion and metastasis of GBC by EGFR/CCL2 pathway and PLEK2 can serve as a potential therapeutic target for GBC treatment.

The extracellular matrix (ECM) is made up of noncellular components that have special properties for influencing cell behavior and tissue structure. Small leucine-rich proteoglycans (SLRPs) are nonfibrillar ECM components that serve as structural scaffolds and signaling molecules. osteoglycin (OGN), a class III SLRP, is a ubiquitous ECM component that not only helps to organize the extracellular matrix but also regulates a number of important biological processes. As a glycosylated protein in the ECM, OGN was originally considered to be involved in fiber assembly and was reported to have a connection with fibrosis. In addition to these functions, OGN is found in a variety of cancer tissues and is implicated in cellular processes linked to tumorigenesis, including cell proliferation, invasion, metastasis, and epithelial-mesenchymal transition (EMT). In this review, we summarize the structure and functions of OGN as well as its biological and clinical importance in the context of fibrotic illness and tumorigenesis. This review aims to improve our understanding of OGN and provide some new strategies for the treatment of fibrosis and cancer.

This paper is devoted to the hydroforming performances of toroidal pressure hulls with octagonal cross-sections, together with the buckling performances of hydroformed hulls. The octagonal cross-sections of toroidal preforms are inscribed from the circular cross-sections of perfect toroidal shells with a 150 mm major radius, a 75 mm section radius, and a 1.058 mm wall thickness. The nonlinear finite-element method was employed to study the hydroforming and buckling performances under various hydroforming pressures. To verify the numerical findings, three nominally identical toroidal pressure hulls with discrete octagonal cross-sections were tentatively manufactured, internally hydroformed, and externally collapsed. The numerical and experimental data exhibited satisfactory agreement. It is indicated that the hydroforming technique could greatly enhance the loading capacity of toroidal pressure hulls.

To evaluate the collapse pressure of the steel–composite hybrid cylinders under external pressure without excessive computational cost, an analytical formula was derived in this study. The rationality of the derived formula was verified by the comparison with experimental and numerical results. The experimental results indicate that samples are manufactured and tested with good quality. The derived formula considered material failure and could reasonably predict the collapse pressure of the steel–composite hybrid cylinders with a maximum difference of 3.1%. Moreover, the effects of the wrap angle, thickness, and length on the collapse pressure of the hybrid cylinders were theoretically analyzed. The loading capacity of the hybrid cylinders was maximized under a wrap angle of ±55° for the composite layer. These findings are mainly because the hoop stress is twice the value of axial stress for a cylinder under uniform pressure.

Background: The mesh infection is mostly related to the gram-negative bacteria, such as Escherichia coli (E. coli) for emergency surgery of incarcerated hernia. However, few study investigated the effects of E. coli concentration, mesh materials and antibiotic prophylaxis on mesh infection after hernioplasty. The aim of this study was to evaluate the bacterial resistance to E. coli for three different materials of mesh, and to measure the minimum E. coli concentration for mesh infection with and without antibiotic prophylaxis in a rat model.Methods: Three types of mesh (polytetrafluoroethylene, polypropylene, and biologic meshes) were used in the repair of an acute ventral hernia rat model in the setting of different concentrations of E. coli loads and antibiotics. At the 8th day after surgery, mesh samples were sent for microbiologic and histologic analyses.Results: The positive rates of bacterial culture increased with E. coli concentration. The biologic mesh showed better bacterial resistance compared to polytetrafluoroethylene mesh and polypropylene mesh when the concentration of E. coli ranges from 106 CFU/ml to 108 CFU/ml (P = 0.002 and P = 0.029, respectively). Prophylactical ceftriaxone treatment could not decrease the colonization rate of E. coli at 106 CFU/ml or 108 CFU/ml in each group (P > 0.05). The scores of neovascularization in polypropylene mesh and biologic mesh were similar, which was higher than that of polytetrafluoroethylene mesh (P < 0.05). Compared with other meshes, biologic mesh showed better tolerance to 106 CFU/ml E. coli with respect to inflammation, depth of inflammation, neovascularization, cellular repopulation and foreign body giant cells.Conclusion: The biologic mesh had better E. coli resistance compared to polytetrafluoroethylene mesh and polypropylene mesh when the E. coli concentration is higher than 106 CFU/ml in rats. Antibiotic prophylaxis was useful when the contamination was not particularly severe.

The role of high-fat diet (HFD) induced gut microbiota alteration and Ghrelin as well as their correlation in benign prostatic hyperplasia (BPH) were explored in our study. The gut microbiota was analyzed by 16s rRNA sequencing. Ghrelin levels in serum, along with Ghrelin and Ghrelin receptor in prostate tissue of mice and patients with BPH were measured. The effect of Ghrelin on cell proliferation, apoptosis, and induction of BPH in mice was explored. Our results indicated that BPH mice have the highest ratio of Firmicutes and Bacteroidetes induced by HFD, as well as Ghrelin level in serum and prostate tissue was significantly increased compared with control. Elevated Ghrelin content in the serum and prostate tissue of BPH patients was also observed. Ghrelin promotes cell proliferation while inhibiting cell apoptosis of prostate cells. The effect of Ghrelin on enlargement of the prostate was found almost equivalent to that of testosterone propionate (TP) which may be attenuated by Ghrelin receptor antagonist YIL-781. Ghrelin could up-regulate Jak2/pJak2/Stat3/pStat3 expression in vitro and in vivo. Our results suggested that Gut microbiota may associate with Ghrelin which plays an important role in activation of Jak2/Stat3 in BPH development. Gut microbiota and Ghrelin might be pathogenic factors for BPH and could be used as a target for mediation.

Hepatopancreatic necrosis disease (HPND) is a highly lethal disease that first emerged in 2015 in Jiangsu Province, China. So far, most researchers believe that this disease is caused by abiotic factors. However, its true pathogenic mechanism remains unknown. In this study, the effects of HPND on the metabolism and other biological indicators of the Chinese mitten crab (Eriocheir sinensis) were evaluated by integrating transcriptomics and metabolomics. Our findings demonstrate that the innate immunity, antioxidant activity, detoxification ability, and nervous system of the diseased crabs were affected. Additionally, metabolic pathways such as lipid metabolism, nucleotide metabolism, and protein metabolism were dysregulated, and energy production was slightly increased. Moreover, the IL-17 signaling pathway was activated and high levels of autophagy and apoptosis occurred in diseased crabs, which may be related to hepatopancreas damage. The abnormal mitochondrial function and possible anaerobic metabolism observed in our study suggested that functional hypoxia may be involved in HPND progression. Furthermore, the activities of carboxylesterase and acetylcholinesterase were significantly inhibited, indicating that the diseased crabs were likely stressed by pesticides such as pyrethroids. Collectively, our findings provide new insights into the molecular mechanisms altered in diseased crabs, as well as the etiology and pathogenic mechanisms of HPND.

In order to evaluate the effects of climatic conditions on maize grain yield (GY), kernel weight (KW), and kernel filling and identify the optimal climatic factors for GY and KW, 2-year field experiments in three seasons, i.e., spring (SPM), summer (SUM), and autumn (AUM), on maize were conducted in Central China. The results showed that SUM had more growing degree days (GDDs) than SPM and AUM due to the higher mean temperature (MT), and also resulted in higher temperature stress (killing degree days (KDDs)) in maize growth duration. Meanwhile, after silking, SPM and SUM had more GDDs and KDDs than AUM because of the higher MT, and the accumulated solar radiation (Ra) for SUM was significantly higher than for SPM and AUM. The GY of SPM was significantly higher than that of SUM and AUM, while SUM’s GY was always the lowest, because the GDDGD, MTGD, and KDDGD played significantly negative roles on GY. The final KW for SUM was always the lowest, with GDD, MT, KDD, and Ra causing significantly negative effects, and M△T and precipitation having significant positive effects, resulting in a lower kernel filling rate during the linear kernel filling period (KFRlkf) and a lower GDD at the maximum kernel filling rate (GDDKFRmax). Maize KFRlkf has significant negative linear dependences on GDD, MT, and Ra. In summary, because of the higher MT, KDD, and GDD during maize growth and kernel filling duration negatively affecting the maize kernel filling rate, the GY and KW for SPM were the highest, and for SUM, they were the lowest; therefore, farmers should plant SPM first and then AUM in Central China.

In this paper, strength prediction of spherical electronic cabins with pitting corrosion under external pressure was investigated. The finite element model of a spherical electronic cabin with random pitting was established using self-written code. The effects of the pitting distribution shape, pitting morphology and size on the ultimate buckling load were numerically studied. In addition, the analytical formula for predicting the ultimate load of spherical cabin with random pitting corrosion was proposed and verified by experiments. This study can be used by engineering designers for relevant design and evaluation basis and provides a reference for the development of a new design code for the buckling stability of spherical cabins with pitting corrosion.

Background: Pancreatic cancer (PC) is one of the most lethal solid malignancies in the world due to its excessive cell proliferation and aggressive metastatic features. Emerging evidences revealed the importance of posttranscriptional modifications of RNAs in PC progression. However, knowledge about the 5-methylcytosine (m5C) RNA modification in PC is still extremely limited. In this study, we attempted to explore the expression changes and clinical significances of 12 known m5C-related genes among PC patients. Methods: A total of 362 normal and 382 tumor specimens from PC patients were examined for candidate m5C-related gene and protein expression by using quantitative PCR (qPCR) and immunohistochemistry (IHC). The proliferation rate of PC cells was detected by MTS assay. Xenograft mouse models were used to assess the role of NSUN6 in PC tumor formation. Findings: Through analyzing the four Gene Expression Omnibus (GEO) databases, six m5C-related genes shown significant and consistent alterations were selected for further examination in our 3 independent PC cohorts. Finally, we identified the reduction of NSUN6 as a common feature of all PC sample sets examined. NSUN6 expression correlated with clinicopathologic parameters including T stage, and Ki67+ cell rate. Further assessing the transcriptional profiles of 50 PC tissues, we found biological processes associated with cell proliferation like cell cycle and G2M checkpoint were enriched in NSUN6 lower expression group. Helped by in vitro PC cell lines and in vivo xenograft mouse models, we confirmed the role of NSUN6 in regulating cell proliferation and PC tumor growth. Last but also importantly, we also show the good performance of NSUN6 in evaluating tumor recurrence and survival among PC patients. Interpretation: Our data suggested that NSUN6 is an important factor involved in regulating cell proliferation of PC, and highlights the potential of novel m5C-based clinical modalities as a therapeutic approach in PC patients. Funding: This study was supported by the National Natural Science Foundation of China (Grant Nos. 81803014, 81802424, and 81802911).

Due to relatively low yield as well as low resources use efficiency with double rice (Oryza sativa L.) cropping systems (RR), exploring new cropping systems to increase yield and resources use efficiency simultaneously has become a large challenge of the middle reaches of the Yangtze River (MRYR). Our previous study demonstrated that the maize (Zea mays L.)–rice cropping system (MR) exhibited higher superiority of yield and resource use efficiency compared with the conventional double-rice cropping system. However, the reason for the yield increases in both maize and rice and the physiological processes involved in those two crops under MR are poorly understood. A 3-year field experiment was conducted at two sites (Wuxue and Jingmen) from 2016 to 2018 to examine the differences in dry matter (DM) accumulation, soil properties, and resources use efficiency between the MR and RR cropping systems. Compared with RR, the annual yield of MR was 18.2–26.3% and 15.4–31.5% higher across three years at Wuxue and Jingmen, respectively. The average yield of maize in MR was 36.5% and 21.9% higher than that of early rice in RR at Wuxue and Jingmen, respectively. The yield increase for maize was mainly attributed to the 29.7% (Wuxue) and 28.5% (Jingmen) increases in post-silking DM accumulation due to the higher plant growth rate promoted by the higher net assimilation rate and radiation use efficiency. For the late rice in MR, the average yield was 10.9% and 14.5% higher than that of late rice in RR at Wuxue and Jingmen, respectively, which was promoted by the 7.8–23.3% increase in pre-anthesis DM accumulation due to improved soil properties. Compared with RR, the MR cropping system exhibited increased soil pH, total organic carbon, and mineral nitrogen, and decreased the bulk density in the late rice season. As a result of greater yield in both seasons under MR, the annual accumulated temperature and radiation use efficiency, partial factor productivity from applied nitrogen, and water use efficiency of MR were 17.7–26.4%, 22.2–25.5%, 5.5–7.8%, and 33.6–48.7% higher than those of RR, respectively. We conclude that the higher yield in the MR than in the RR cropping system was mainly attributed to the accumulation of post-silking biomass due to maximized use of radiation in the maize season, and the accumulation of pre-anthesis biomass due to improved soil nutrients in the late rice season.

Abstract Background Gallbladder carcinoma is highly aggressive and resistant to chemotherapy, with no consistent strategy to guide first line chemotherapy. However, patient-derived xenograft (PDX) model has been increasingly used as an effective model for in preclinical study of chemosensitivity. Methods Mini-PDX model was established using freshly resected primary lesions from 12 patients with gallbladder to examine the sensitivity with five of the most commonly used chemotherapeutic agents, namely gemcitabine, oxaliplatin, 5-fluorouracil, nanoparticle albumin-bound (nab)-paclitaxel, and irinotecan. The results were used to guide the selection of chemotherapeutic agents for adjunctive treatment after the surgery. Kaplan–Meier method was used to compare overall survival (OS) and disease free survival (DFS) with 45 patients who received conventional chemotherapy with gemcitabine and oxaliplatin. Results Cell viability assays based on mini-PDX model revealed significant heterogeneities in drug responsiveness. Kaplan–Meier analysis showed that patients in the PDX-guided chemotherapy group had significantly longer median OS (18.6 months; 95% CI 15.9–21.3 months) than patients in the conventional chemotherapy group (13.9 months; 95% CI 11.7–16.2 months) (P = 0.030; HR 3.18; 95% CI 1.47–6.91). Patients in the PDX-guided chemotherapy group also had significantly longer median DFS (17.6 months; 95% CI 14.5–20.6 months) than patients in the conventional chemotherapy group (12.0 months; 95% CI 9.7–14.4 months) (P = 0.014; HR 3.37; 95% CI 1.67–6.79). Conclusion The use of mini-PDX model to guide selection of chemotherapeutic regimens could improve the outcome in patients with gallbladder carcinoma.

Abstract In the energy resource-constrained wireless applications, turbo codes are frequently employed to guarantee reliable data communication. To both reduce the power dissipation of the turbo decoder and the probability of data frame retransmission in the physical layer, memory capacity reduced near optimal turbo decoder is of special importance from the perspective of practical implementation. In this regard, a state metrics compressed decoding technique is proposed. By inserting two modules in the conventional turbo decoding architecture, a smaller quantization scheme can be applied to the compressed state metrics. Furthermore, structure of the inserted modules is described in detail. We demonstrate that one or two rounds of compression/decompression are performed in most cases during the iterative decoding process. At the cost of limited dummy decoding complexity, the state metrics cache (SMC) capacity is reduced by 53.75%. Although the proposed technique is a lossy compression strategy, the introduced errors only have tiny negative influence on the decoding performance as compared with the optimal Log-MAP algorithm.

Demanded by high-performance wireless (WirelessHP) networks for industrial control applications, channel coding should be used and optimized. However, the adopted coding schemes in modern wireless communication standards are not sufficient for WirelessHP applications, in terms of both low latency and high reliability. Starting from the essential characteristics of WirelessHP regarding channel coding, this paper gives a detailed analysis of currently used short packet coding schemes in industrial wireless sensor networks, including seven coding schemes and their possible variants. The metrics employed for evaluation are bit-error rate, packet error rate, and throughput. To find suitable coding schemes from a large number of options, we propose four principles to filter the most promising coding schemes. Based on overall comparison from the perspective of practical implementation, challenges of the available coding schemes are analyzed, and directions are recommended for future research. Some reflections on how to construct specially designed coding schemes for short packets to meet the high reliability and low-latency constraints of WirelessHP are also provided.