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Abstract Iron, an essential mineral in the body, is involved in numerous physiological processes, making the maintenance of iron homeostasis crucial for overall health. Both iron overload and deficiency can cause various disorders and human diseases. Ferroptosis, a form of cell death dependent on iron, is characterized by the extensive peroxidation of lipids. Unlike other kinds of classical unprogrammed cell death, ferroptosis is primarily linked to disruptions in iron metabolism, lipid peroxidation, and antioxidant system imbalance. Ferroptosis is regulated through transcription, translation, and post-translational modifications, which affect cellular sensitivity to ferroptosis. Over the past decade or so, numerous diseases have been linked to ferroptosis as part of their etiology, including cancers, metabolic disorders, autoimmune diseases, central nervous system diseases, cardiovascular diseases, and musculoskeletal diseases. Ferroptosis-related proteins have become attractive targets for many major human diseases that are currently incurable, and some ferroptosis regulators have shown therapeutic effects in clinical trials although further validation of their clinical potential is needed. Therefore, in-depth analysis of ferroptosis and its potential molecular mechanisms in human diseases may offer additional strategies for clinical prevention and treatment. In this review, we discuss the physiological significance of iron homeostasis in the body, the potential contribution of ferroptosis to the etiology and development of human diseases, along with the evidence supporting targeting ferroptosis as a therapeutic approach. Importantly, we evaluate recent potential therapeutic targets and promising interventions, providing guidance for future targeted treatment therapies against human diseases.

Abstract Ferroptosis, a unique type of cell death, is characterized by iron-dependent accumulation and lipid peroxidation. It is closely related to multiple biological processes, including iron metabolism, polyunsaturated fatty acid metabolism, and the biosynthesis of compounds with antioxidant activities, including glutathione. In the past 10 years, increasing evidence has indicated a potentially strong relationship between ferroptosis and the onset and progression of age-related orthopedic diseases, such as osteoporosis and osteoarthritis. Therefore, in-depth knowledge of the regulatory mechanisms of ferroptosis in age-related orthopedic diseases may help improve disease treatment and prevention. This review provides an overview of recent research on ferroptosis and its influences on bone and cartilage homeostasis. It begins with a brief overview of systemic iron metabolism and ferroptosis, particularly the potential mechanisms of ferroptosis. It presents a discussion on the role of ferroptosis in age-related orthopedic diseases, including promotion of bone loss and cartilage degradation and the inhibition of osteogenesis. Finally, it focuses on the future of targeting ferroptosis to treat age-related orthopedic diseases with the intention of inspiring further clinical research and the development of therapeutic strategies.

Abstract Fibrotic hypersensitivity pneumonitis (FHP) remains one of fatal interstitial pulmonary disease. Comprehensively dissecting the cellular heterogeneity of FHP paves the way for developing general gene therapeutic solutions for FHP. Here, utilizing an integrated strategy based on scRNA-seq, scTCR-seq, and bulk RNA-seq analysis of FHP profiles, we identified ten major cell types and 19 unique subtypes. FHP exhibited higher features of EMT and inflammation-promoting than normal control. In distinct subsets of lung macrophages in FHP, FN1high, PLA2G7high, and MS4A6Ahigh macrophages with predominant M2 phenotype exhibited higher activity of inflammatory responses and para-inflammation than other macrophages. KRT17high basal-like epithelial cells were significantly increased in FHP, and showed higher ability to induce EMT. We identified roles for ACTA2high, COL1A1high, and PLA2G2Ahigh fibroblasts in FHP, which were significantly related to interstitial fibrosis. NK cells and KLRG1+ effector CD8+ T cells had greater activity in inflammation-promoting. Our results provide a comprehensive portrait of cellular heterogeneity in FHP, and highlight the indispensable role of cell subpopulations in shaping the complexity and heterogeneity of FHP. These subpopulations are potentially key players for FHP pathogenesis.

Pancreatic ductal adenocarcinoma (PDAC) has an atypical, highly stromal tumour microenvironment (TME) that profoundly contributes to its poor prognosis 1 . Here, to better understand the intercellular signalling between cancer and stromal cells directly in PDAC tumours, we developed a multidimensional proteomic strategy called TMEPro. We applied TMEPro to profile the glycosylated secreted and plasma membrane proteome of 100 human pancreatic tissue samples to a great depth, define cell type origins and identify potential paracrine cross-talk, especially that mediated through tyrosine phosphorylation. Temporal dynamics during pancreatic tumour progression were investigated in a genetically engineered PDAC mouse model. Functionally, we revealed reciprocal signalling between stromal cells and cancer cells mediated by the stromal PDGFR-PTPN11-FOS signalling axis. Furthermore, we examined the generic shedding mechanism of plasma membrane proteins in PDAC tumours and revealed that matrix-metalloprotease-mediated shedding of the AXL receptor tyrosine kinase ectodomain provides an additional dimension of intercellular signalling regulation in the PDAC TME. Importantly, the level of shed AXL has a potential correlation with lymph node metastasis, and inhibition of AXL shedding and its kinase activity showed a substantial synergistic effect in inhibiting cancer cell growth. In summary, we provide TMEPro, a generically applicable clinical functional proteomic strategy, and a comprehensive resource for better understanding the PDAC TME and facilitating the discovery of new diagnostic and therapeutic targets., Competing Interests: Competing interests R.T. is a founder of BayOmics., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

This study aimed to elucidate the effects of long day and night shifts on immune cells in a population of nurses. This cross-sectional study in December 2019 was based on a group of nurses. 1568 physically healthy caregivers were included, including 1540 women and 28 men. 1093 nurses had long-term shift work (working in a rotating system for > 1 year). The receiver operating characteristic curve, Ensemble Learning, and Logistic regression analyses were used to evaluate factors related to long-term shift work. The night shift group nurses had significantly higher MPV, PLCR, and WBC and significantly lower BASO%, ELR, MCHC, PLR, RDW-CV, and RDW-SD (P < 0.01). ROC curves showed that WBC, PLR, ELR, RDW&#95;CV, and BASO% were more related to the night shift. Ensemble Learning, combined with the LASSO model, finally filtered out three indicators of night shifts related to ELR, WBC, and RDW&#95;SD. Finally, logistic regression analysis showed that the nurses' night shift situation greatly influenced two peripheral blood ELR and WBC indicators (ELR: log (OR) =  - 3.9, 95% CI: - 5.8- - 2.0; WBC: log (OR) = 0.25, 95% CI: 0.18-0.32). Finally, we showed that, unlike WBC, the relative riskiness of ELR showed opposite results among junior nurses and middle-senior nurses (log (OR) 6.5 (95% CI: 1.2, 13) and - 7.1 (95% CI: - 10, - 3.8), respectively). Our study found that prolonged night shifts were associated with abnormal WBC and ELR, but after strict age matching, WBC remained significantly different. These findings help to confirm that COVID-19 and tumorigenesis (e.g., breast cancer) are significantly associated with circadian rhythm disruption. However, more detailed studies are needed to confirm this., (© 2024. The Author(s).)

Atherosclerosis (AS), a leading cause of cardio-cerebrovascular disease worldwide, is driven by the accumulation of lipid contents and chronic inflammation. Traditional strategies primarily focus on lipid reduction to control AS progression, leaving residual inflammatory risks for major adverse cardiovascular events (MACEs). While anti-inflammatory therapies targeting innate immunity have reduced MACEs, many patients continue to face significant risks. Another key component in AS progression is adaptive immunity, but its potential role in preventing AS remains unclear. To investigate this, we conducted a retrospective cohort study on tumor patients with AS plaques. We found that anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb) significantly reduces AS plaque size. With multi-omics single-cell analyses, we comprehensively characterized AS plaque-specific PD-1 + T cells, which are activated and pro-inflammatory. We demonstrated that anti-PD-1 mAb, when captured by myeloid-expressed Fc gamma receptors (FcγRs), interacts with PD-1 expressed on T cells. This interaction turns the anti-PD-1 mAb into a substitute PD-1 ligand, suppressing T-cell functions in the PD-1 ligands-deficient context of AS plaques. Further, we conducted a prospective cohort study on tumor patients treated with anti-PD-1 mAb with or without Fc-binding capability. Our analysis shows that anti-PD-1 mAb with Fc-binding capability effectively reduces AS plaque size, while anti-PD-1 mAb without Fc-binding capability does not. Our work suggests that T cell-targeting immunotherapy can be an effective strategy to resolve AS in humans., (© 2024. The Author(s).)

Cereal/legume intercropping is becoming a popular production strategy for higher crop yields and net profits with reduced inputs and environmental impact. However, the effects of different spatial arrangements on the growth, grain yield, nitrogen uptake, and land-use advantage of wheat/soybean relay intercropping are still unclear, particularly under arid irrigated conditions. Therefore, in a three-year field study from 2018 to 2021, soybean was relay intercropped with wheat in different crop configurations (0.9 m, narrow strips; 1.8 m, medium strips; and 2.7 m, wide strips), and the results of intercropping systems were compared with their sole systems. Results revealed that intercrops with wide strips outperformed the narrow and medium strips, when the objective was to obtain higher total leaf area, dry matter, nitrogen uptake, and grain yield on a given land area due to reduced interspecific competition between intercrops. Specifically, at maturity, wide strips increased the dry matter accumulation (37% and 58%) and its distribution in roots (37% and 55%), straw (40% and 61%), and grains (30% and 46%) of wheat and soybean, respectively, compared to narrow strips. This enhanced dry matter in wide strips improved the soybean's competitive ability (by 17%) but reduced the wheat's competitive ability (by 12%) compared with narrow strips. Noticeably, all intercropping systems accumulated a significantly higher amount of nitrogen than sole systems, revealing that wheat/soybean relay intercropping requires fewer anthropogenic inputs (nitrogen) and exerts less pressure on the ecosystem than sole systems. Overall, in wide strips, intercropped wheat and soybean achieved 62% and 71% of sole wheat and soybean yield, respectively, which increased the greater total system yield (by 19%), total land equivalent ratio (by 24%), and net profit (by 34%) of wide strips compared to narrow strips. Our study, therefore, implies that the growth parameters, grain yields, nutrient accumulation, and land-use advantage of intercrop species could be improved with the proper spatial arrangement in cereal/legume intercropping systems., (© 2023. Springer Nature Limited.)

Hybrid larch is the main timber and afforestation tree species in Northeast China. To solve the problem of rooting difficulties in larch cutting propagation, enzyme activity determination and transcriptome sequencing were carried out on the rooting tissues at five timepoints after cutting. peroxidase (POD), indole acetic acid oxidase (IAAO) and polyphenol oxidase (PPO) play important roles in the larch rooting process after cutting. A total of 101.20 Gb of clean data was obtained by transcriptome sequencing, and 43,246 unigenes were obtained after further screening and assembly. According to GO analysis and KEGG enrichment analysis, we think that plant hormones play an important role in the rooting process of larch stem cuttings. in the plant hormone signal transduction pathway, a larch gene c141104.graph&#95;c0 that is homologous to the Arabidopsis AUX1 was found to be significantly up-regulated. We suggest that AUX1 may promote IAA transport in larch, thus affecting adventitious root development. According to the results of POD, PPO IAAO indexes and GO analysis, we think s1 and s2 periods may be important periods in the rooting process of larch stem cuttings, so we built a gene regulatory network, a total of 14genes, including LBD, NAC, AP2/ERF, bHLH and etc., may be important in different stages of cutting propagation. As the rooting rate after cutting inhibits the development of larch clone propagation, identifying the genes that regulate rooting could help us to preliminarily understand the molecular mechanism of adventitious root formation and select a better treatment method for cutting propagation., (© 2023. The Author(s).)

With a 5-year survival rate of approximately 10%, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies in humans. A poor understanding of the underlying biology has resulted in a lack of effective targeted therapeutic strategies. Tissue microarray and bioinformatics analyses have revealed that the downstream transcriptional coactivator of the Hippo pathway, transcriptional coactivator with PDZ-binding motif (TAZ), might be a therapeutic target in PDAC. Since pharmacological inhibition of TAZ is challenging, we performed unbiased deubiquitinase (DUB) library screening to explore the pivotal regulators of TAZ ubiquitination as potential targets in PDAC models. We found that USP14 contributed to Yes-associated protein (YAP)/TAZ transcriptional activity and stabilized TAZ but not YAP. Mechanistically, USP14 catalyzed the K48-linked deubiquitination of TAZ to promote TAZ stabilization. Moreover, TAZ facilitated the transcription of USP14 by binding to the TEA domain transcription factor (TEAD) 1/4 response element in the promoter of USP14. USP14 was found to modulate the expression of TAZ downstream target genes through a feedback mechanism and ultimately promoted cancer progression and liver metastasis in PDAC models in vitro and in vivo. In addition, depletion of USP14 led to proteasome-dependent degradation of TAZ and ultimately arrested PDAC tumour growth and liver metastasis. A strong positive correlation between USP14 and TAZ expression was also detected in PDAC patients. The small molecule inhibitor of USP14 catalytic activity, IU1, inhibited the development of PDAC in subcutaneous xenograft and liver metastasis models. Overall, our data strongly suggested that the self-amplifying USP14-TAZ loop was a previously unrecognized mechanism causing upregulated TAZ expression, and identified USP14 as a viable therapeutic target in PDAC., (© 2022. The Author(s).)

Regulated cell death (RCD), also well-known as programmed cell death (PCD), refers to the form of cell death that can be regulated by a variety of biomacromolecules, which is distinctive from accidental cell death (ACD). Accumulating evidence has revealed that RCD subroutines are the key features of tumorigenesis, which may ultimately lead to the establishment of different potential therapeutic strategies. Hitherto, targeting the subroutines of RCD with pharmacological small-molecule compounds has been emerging as a promising therapeutic avenue, which has rapidly progressed in many types of human cancers. Thus, in this review, we focus on summarizing not only the key apoptotic and autophagy-dependent cell death signaling pathways, but the crucial pathways of other RCD subroutines, including necroptosis, pyroptosis, ferroptosis, parthanatos, entosis, NETosis and lysosome-dependent cell death (LCD) in cancer. Moreover, we further discuss the current situation of several small-molecule compounds targeting the different RCD subroutines to improve cancer treatment, such as single-target, dual or multiple-target small-molecule compounds, drug combinations, and some new emerging therapeutic strategies that would together shed new light on future directions to attack cancer cell vulnerabilities with small-molecule drugs targeting RCD for therapeutic purposes., (© 2022. The Author(s).)

To study the function of LoHDZ2 in larch, we first constructed a VB191103-LoHDZ2::GUS overexpression vector. Through Agrobacterium-mediated infection, the expression vector was transferred into a larch embryogenic cell line. A stable resistant cell line was subsequently screened, and mature embryos were induced to grow until they developed into seedlings. Antagonistic cell lines were identified at both the DNA and RNA levels. The transgenic cell lines were then subjected to GUS staining, and transgenic cell lines were ultimately identified and obtained. These transgenic cell lines were sequenced to identify differentially expressed genes, and a cluster analysis was performed. The resistant cell lines were cultured under stress conditions involving 20% PEG 6000 and 200 mM NaCl proliferation media (1/10-BM). After the stress treatment, the contents of peroxidase (POD), malondialdehyde (MDA) and superoxide dismutase (SOD) in both wild-type and transgenic cell lines were measured. The results are summarized below: (1) When the specific fragment of the target gene in the genome of the resistant cell line was amplified. At the RNA level, the expression of the fragment in four resistant lines increased. In addition, GUS staining showed a blue reaction, indicating that LoHDZ2 was successfully integrated into the larch embryonic cell lines. (2) To verify the accuracy and reliability of the transcriptome data, 10 differentially expressed genes (5 upregulated and 5 down regulated genes) were subjected to qRT-PCR verification. The results showed that the expression trend of the 10 differentially expressed genes was the same as that revealed by RNA-Seq, indicating that the transcriptome data were reliable. (3) The transcriptome sequencing showed that 176 genes were upregulated and that 140 genes were down regulated. Through GO enrichment analysis and KEGG metabolic pathway analysis, the screened differentially expressed genes were related to biological processes such as larch metabolism and response to stimuli, indicating that these genes may be closely involved in the regulation of the larch response to external stimuli, including heat stress, drought stress, metal ion stress and bacterial infection, and may participate in the growth process. (4) After 20% PEG 6000 treatment, the POD enzyme activity of the transgenic cell line was greater than that of the wild-type; this activity could effectively remove the amount of peroxide produced. The MDA content of the transgenic cell lines was lower than that of the wild-type cell lines, and the accumulation degree of harmful substances was low, indicating that the degree of oxidative damage of the transgenic cell lines was lower than that of the wild-type cell lines. The SOD content of the transgenic cell lines was lower than that of the wild-type cell lines, indicating that the drought resistance of the transgenic cell lines was enhanced. After 200 mM NaCl treatment, although the increase in SOD content was not obvious, the same trend was detected, indicating that the resistance of the transgenic cell lines was indeed stronger than that of the wild-type cell lines. According to the results of previous experiments, after this gene was overexpressed in tobacco, the transformed plants showed obvious dwarfing, which may indicate that the stress resistance of the plant was enhanced. In conclusion, a transgenic larch cell line was successfully obtained, and transgenic larch seedlings were successfully induced. LoHDZ2 may participate in the response of plants to the external environment, and may participate in the growth and development of Larix olgensis by affecting plant metabolic pathways., (© 2022. The Author(s).)

Emergency fire service (EFS) systems provide rescue operations for emergencies and accidents. If properly designed, they can decrease property loss and mortality. This paper proposes a distributionally robust model (DRM) for optimizing the location of fire stations, the number of fire trucks, and demand assignment for long term planning in an EFS system. This is achieved by minimizing the worst-case expected total cost, including fire station construction cost, purchase cost for fire trucks, transportation cost, and penalty cost for not providing adequate service. The ambiguity in demands and travel durations distributions are captured through moment information and mean absolute deviation. A cutting plane method is used to solve the problem. Due to fact that it is computationally intensive for larger problems, two approximate methods are introduced; one that uses linear decision rules (LDRs), and another that adopts three-point approximations of the distributions. The results show that the heuristic method is especially useful for solving large instances of DRM. Extensive numerical experiments are conducted to analyze the model's performance with respect to different parameters. Finally, data obtained from Hefei (China) demonstrates the practical applicability and value of the model in designing an EFS system in a large metropolitan setting., (© 2022. The Author(s).)

Long non-coding RNAs (LncRNAs) play vital roles in the tumorigenesis of many cancers. Single nucleotide polymorphisms (SNPs) of the lncRNA also play vital roles in tumorigenesis. We explored lncRNA rs944289 and rs7990916 polymorphisms and analyzed the relationship between these lncRNA polymorphisms with the colorectal cancer (CRC) risk in a Chinese population. We recruited 1003 CRC patients from the Affiliated People's Hospital of Jiangsu University and the Fujian Medical University Union Hospital from October 2014 to August 2017. Genomic DNA was extracted using a DNA Kit from lymphocytes of peripheral blood and the genotyping was performed with a SNPscan method. We found that the rs944289 TT homozygote was associated with the decreased CRC risk in the overall population. LncRNA rs944289 TT decreased the CRC risk in the subgroup of female, male, age ≥ 61, without alcohol intake, smoking and BMI ≥ 24 by logistic regression. The subgroup analysis revealed that lncRNA rs7990916 was not associated with CRC risk except for age < 61. Logistic regression analysis revealed that lncRNA rs944289 TT homozygote was associated with the increased risk of rectum cancer (TT vs. CC + CT: adjusted OR = 1.29, 95% CI 1.10-1.66, P = 0.041) or colon cancer. In summary, we proved that lncRNA rs944289 might be significantly related to the decreased CRC risk in the Chinese Han populations and lncRNA rs7990916 was not associated with the CRC risk except for patients of age < 61. In the future, studies with larger samples should be conducted to validate our results., (© 2022. The Author(s).)

The development of flexible capacitive pressure sensors has wide application prospects in the fields of electronic skin and intelligent wearable electronic devices, but it is still a great challenge to fabricate capacitive sensors with high sensitivity. Few reports have considered the use of interdigital electrode structures to improve the sensitivity of capacitive pressure sensors. In this work, a new strategy for the fabrication of a high-performance capacitive flexible pressure sensor based on MXene/polyvinylpyrrolidone (PVP) by an interdigital electrode is reported. By increasing the number of interdigital electrodes and selecting the appropriate dielectric layer, the sensitivity of the capacitive sensor can be improved. The capacitive sensor based on MXene/PVP here has a high sensitivity (~1.25 kPa -1 ), low detection limit (~0.6 Pa), wide sensing range (up to 294 kPa), fast response and recovery times (~30/15 ms) and mechanical stability of 10000 cycles. The presented sensor here can be used for various pressure detection applications, such as finger pressing, wrist pulse measuring, breathing, swallowing and speech recognition. This work provides a new method of using interdigital electrodes to fabricate a highly sensitive capacitive sensor with very promising application prospects in flexible sensors and wearable electronics., Competing Interests: Conflict of interestThe authors declare no competing interests., (© The Author(s) 2021.)

Homeodomain-leucine zippers (HD-Zip) are plant-specific transcription factors that participate in different plant development processes and differentially regulate metabolic processes. LoHDZ2 is an HD-ZipII subfamily transcription factor gene that we identified from a transcriptomic analysis of Larix olgensis. To understand its function, we built a LoHDZ2 expression vector and then inserted it into tobacco by genetic transformation. Transgenic plants were identified at the DNA and RNA levels. Phenotypic index analysis of transgenic tobacco showed dwarfed growth with larger leaves and earlier flowering than the wild type. LoHDZ2 was expressed differently after hormone treatment with IAA, MeJA and 2,4-D. The results suggested that LoHDZ2 may respond to hormones and be involved in regulating growth and metabolism. These results helped us better understand the function of LoHDZ2 and provided a candidate gene for Larix olgensis molecular breeding., (© 2021. The Author(s).)

Treatment options for gallbladder carcinoma (GBC) are limited and GBC prognosis remains poor. There is no well-accepted targeted therapy to date, so effective biomarkers of GBC are urgently needed. Here we investigated the expression and correlations of fibroblast growth factor receptors (FGFR1-4) and 18 fibroblast growth factors (FGFs) in two independent patient cohorts and evaluated their prognostic significance. Consequently, we demonstrated that both FGF19 and FGFR4 were unfavorable prognostic biomarkers, and their co-expression was a more sensitive predictor. By analyzing the correlations between all 18 FGFs and FGFR4, we showed that FGF19 expression was significantly associated with FGFR4 and promoted GBC progression via stimulating FGFR4. With experiments using GBC cells, GPBAR1 -/- mice models, and human subjects, we demonstrated that elevated bile acids (BAs) could increase the transcription and expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. FGF19 secreted from GBC cells promoted GBC progression by stimulating FGFR4 and downstream ERK in an autocrine manner with bile as a potential carrier. Patients with GBC had significantly higher FGF19 in serum and bile, compared to patients with cholelithiasis. BLU9931 inhibited FGFR4 and attenuated its oncogenic effects in GBC cell line. In conclusion, upregulation of BAs elevated co-expression of FGF19 and FGFR4 by activating GPBAR1-cAMP-EGR1 pathway. Co-expression of FGF19 and FGFR4 was a sensitive and unfavorable prognostic marker. GBC cells secreted FGF19 and facilitated progression by activating FGFR4 with bile as a potential carrier in an autocrine pathway., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Maize/soybean relay intercropping system (MSR) is a popular cultivation method to obtain high yields of both crops with reduced inputs. However, in MSR, the effects of different strip widths on competitive strengths and grain yields of intercrop species are still unclear. Therefore, in a two-year field experiment, soybean was relay-intercropped with maize in three different strip-width arrangements (narrow-strips, 180 cm; medium-strips, 200 cm; and wide-strips, 220 cm), and all intercropping results were compared with sole maize (SM) and sole soybean (SS). Results showed that the optimum strip-width for obtaining high grain yields of maize and soybean was 200 cm (medium-strips), which improved the competitive-ability of soybean by maintaining the competitive-ability of maize in MSR. On average, maize and soybean produced 98% and 77% of SM and SS yield, respectively, in medium-strips. The improved grain yields of intercrop species in medium-strips increased the total grain yield of MSR by 15% and land equivalent ratio by 22%, which enhanced the net-income of medium-strips (by 99%, from 620 US $ ha -1 in wide-strips to 1233 US $ ha -1 in medium-strips). Overall, these findings imply that following the optimum strip-width in MSR, i. e., strip-width of 200 cm, grain yields, and competitive interactions of intercrop species can be improved.

This was a retrospective study. We aimed to compare the clinical efficacy and safety between minimally invasive and traditional open transforaminal lumbar interbody fusion in the treatment of low-grade lumbar degenerative spondylolisthesis (LDS). 81 patients with LDS grades 1 and 2 treated in our spinal department from January 2014 to July 2016 were retrospectively analyzed. The MIS-TLIF group included 23 males and 11 females, while the TO-TLIF group included 29 males and 18 females. Follow-up points were set at 7 days, 3 months, 6 months, 12 months postoperatively and the last follow-up. Various clinical and radiological indicators were used to evaluate and compare the efficacy and safety between the two procedures. 8 cases (3 in the MIS-TLIF group and 5 in the TO-TLIF group) were loss of follow-up after discharge. And the remaining 73 patients were followed up for at least 2 years. No statistically significant difference was observed in the terms of age, sex, BMI, slippage grade, and surgical segments. The MIS-TLIF group had a longer operation and fluoroscopy time compared with the TO-TLIF group. But the MIS-TLIF group was associated with less blood loss, ambulation time, hospital stay, and time of return to work. In each group, significant improvement were observed in BP-VAS, ODI and vertebral slip ratio at any time-point of follow-up when compared with the preoperative condition. When the time-point of follow-up was less than 1 year, the MIS-TLIF group had significant advantages in the BP-VAS and ODI compared with TO-TLIF group. But no significant difference was observed in the BP-VAS and ODI at either 12 month follow-up or the last follow-up. Besides, no statistical difference was detected in vertebral slip ratio at any time-point of follow-up between the two groups. Successful intervertebral bone fusion was found in all patients and no significant difference was found in the incidence of total complications. Thus, we considered that MIS-TLIF and TO-TLIF both achieve satisfactory clinical efficacy in the treatment of low-grade single-segment LDS. But MIS-TLIF appears to be a more efficacious and safe technique with reduced tissue damage, less blood loss and quicker recovery.

Anterior reduction and interbody fusion fixation has not been compared directly with posterior reduction and short-segmental pedicle screw fixation for lower cervical dislocation, and so consensus is lacking as to which is the optimal method. The purpose of this paper is to compare long-term outcomes of the anterior versus posterior approach for traumatic cervical dislocation with spinal cord injury. One hundred and fifty-nine patients could be followed for more than 10 years (follow-up rate 84.1%). Ninety-two patients underwent anterior reduction and interbody fusion and fixation, and 67 patients underwent posterior reduction and short-segmental pedicle screw fixation. Japanese Orthopaedic Association (JOA) scores, the Neck Disability Index (NDI), the American Spinal Injury Association grading (ASIA), Odom's criteria, cervical kyphosis, operative parameters, and surgical or post-operative complications were evaluated. Patients were followed for 10 to 17 years. There was no significant difference in main JOA scores, NDI scores or ASIA scores between the two groups at follow-up. The posterior approach was associated with greater loss of alignment by two years (P = 0.012) and at final follow-up (P < 0.001). The posterior approach group had more blood loss (P < 0.001), longer operation times (P < 0.001), longer hospital stays (P < 0.001) and fewer complications than the anterior approach group. The anterior approach is better than the posterior approach for preserving cervical lordosis, which is associated with a better long-term effect.

Autoimmune hemolytic anemia (AIHA) is an acquired autoimmune disease mediated by antibodies against the patient's red blood cells. However, the underlying mechanisms for antibody production are not fully understood. Previous studies of etiology and pathogenesis of AIHA mainly focus on autoreactive B cells that have escaped tolerance mechanisms. Few studies have reported the function of T FH and T FR cells in the process of AIHA. The present study aimed to explore the potential mechanism of T FH and T FR cells in the pathogenesis of AIHA. With the model of murine AIHA, increased ratios of T FH :T FR , elevated serum IL-21 and IL-6 levels, and upregulated Bcl-6 and c-Maf expression were reported. Also, adoptive transfer of purified CD4 + CXCR5 + CD25 - T cells from immunized mice promoted the induction of autoantibody in the AIHA mouse model. Altogether, our data demonstrate the important role of T FH cells for control and induction of AIHA. In the light of the key contributions of T FH cells to the immune response in AIHA, strategies aimed at inhibiting the T FH development or function should be emphasized.

The production of American ginseng (Panax quinquefolius L.) is severely limited by the replant disorders in China. Crop rotation with maize might reduce the replant problems, but little information is available on the effect of maize rotation on soil cultivated with ginseng. In this study, we analyzed nutrients, phenolic acids, and microbial communities in soils from the fields with continuous maize, mono-culture ginseng, and 1-, 3-, and 5-year maize rotation after ginseng. Pot experiments were also conducted to evaluate the performance of replanting ginseng in these soils. The results showed that Mn, Cu, and 5 phenolic acids in ginseng-cultivated soil were significantly decreased by maize rotation. A 5-year maize rotation significantly increased the relative abundance of beneficial soil bacteria, such as Arthrobacter, rather than decreasing the abundances of potential pathogenic genera. Clustering analysis revealed that the physicochemical properties and microbial communities of 3- and 5-year maize rotation soil were more similar to CM than to G soil. The biomass of replanted ginseng root was improved, and root disease was reduced over 3 years of maize rotation. Overall, the results showed that at least a 3-year maize rotation is needed to overcome the replant failure of American ginseng.

A mesoscopic simulation method based on the integration of dissipative particle dynamics (DPD), smoothed particle hydrodynamics (SPH) and computational thermodynamics (CT) has been developed. The kinetic behaviours of miscible and immiscible fluids were investigated. The interaction force between multicomponent mesoscopic particles is derived from the system free energy. The diffusivity of the components in non-ideal solution is determined by the chemical potential. The proposed method provides convincing predictions to the effects of convection, diffusion and microscopic interaction on the non-equilibrium evolution of engineering fluids, and demonstrates a potential to simulate more complicated phenomena in materials processing.

Hypertension has a close affinity to brain degeneration and cognitive decline during the aging process. The default mode network (DMN) is usually affected in various diseases related to cognitive impairment (CI). The present research aimed to explore the alterations in the DMN and its subcomponents in hypertensive patients with and without CI and to investigate the associations between cognitive performance and network abnormalities. Resting-state functional magnetic resonance imaging and neuropsychological tests were performed in 74 subjects, namely, 30 hypertensive patients with normal cognition (HTN-NC), 25 hypertensive patients with CI (HTN-CI), and 19 healthy controls. Seed-based functional connectivity (FC) analysis was performed to identify the DMN patterns. The group differences in the DMN were mainly shown in brain regions related to the core subsystem and the dorsal medial subsystem of the DMN. Post hoc analysis revealed a trend of dissociation among the DMN subsystems in the HTN-NC group. In contrast, the HTN-CI group displayed extensively increased FC in both subsystems. Importantly, increased FC of the dorsal medial subsystem in the HTN-CI patients was associated with poor cognitive performance, such as scores on Mini-Mental State Examination (ρ = -0.438, P = 0.029) and Montreal Cognitive Assessment (ρ = -0.449, P = 0.025). The findings suggest that extensively increased connectivities in the core subsystem and the dorsal media subsystem of the DMN may distinguish hypertension with CI from hypertension with normal cognition. The characteristic change in the dorsal medial subsystem may become an early imaging biomarker for the diagnosis and treatment of cognitive impairment associated with hypertension.

The programmed cell death pathway, necroptosis, relies on the pseudokinase, Mixed Lineage Kinase domain-Like (MLKL), for cellular execution downstream of death receptor or Toll-like receptor ligation. Receptor-interacting protein kinase-3 (RIPK3)-mediated phosphorylation of MLKL's pseudokinase domain leads to MLKL switching from an inert to activated state, where exposure of the N-terminal four-helix bundle (4HB) 'executioner' domain leads to cell death. The precise molecular details of MLKL activation, including the stoichiometry of oligomer assemblies, mechanisms of membrane translocation and permeabilisation, remain a matter of debate. Here, we dissect the function of the two 'brace' helices that connect the 4HB to the pseudokinase domain of MLKL. In addition to establishing that the integrity of the second brace helix is crucial for the assembly of mouse MLKL homotrimers and cell death, we implicate the brace helices as a device to communicate pseudokinase domain phosphorylation event(s) to the N-terminal executioner 4HB domain. Using mouse:human MLKL chimeras, we defined the first brace helix and adjacent loop as key elements of the molecular switch mechanism that relay pseudokinase domain phosphorylation to the activation of the 4HB domain killing activity. In addition, our chimera data revealed the importance of the pseudokinase domain in conferring host specificity on MLKL killing function, where fusion of the mouse pseudokinase domain converted the human 4HB + brace from inactive to a constitutive killer of mouse fibroblasts. These findings illustrate that the brace helices play an active role in MLKL regulation, rather than simply acting as a tether between the 4HB and pseudokinase domains.

Cardiovascular disease is the leading cause of death among patients receiving peritoneal dialysis. We aimed to develop and validate a risk prediction model for cardiovascular death within 2 years after the initiation of peritoneal dialysis (PD). A cohort including all patients registered with the Henan Peritoneal Dialysis Registry (HPDR) between 2007 and 2014. Multivariate logistic regression analysis was used to develop the risk prediction model. The HPDR data was randomly divided into two cohorts with 60% (1,835 patients) for model derivation, and 40% (1,219 patients) for model validation. The absolute rate of cardiovascular mortality was 14.2% and 14.4 in the derivation and validation cohort, respectively. Age, body mass index, blood pressure, serum lipids, fasting glucose, sodium, albumin, total protein, and phosphorus were the strongest predictors of cardiovascular mortality in the final model. Discrimination of the model was similar in both cohorts, with a C statistic above 0.70, with good calibration of observed and predicted risks. The new prediction model that has been developed and validated with clinical measurements that are available at the point of initiation of PD and could serve as a tool to screen for patients at high risk of cardiovascular death and tailor more intensive cardio-protective care.

This work reveals a torque from electric field to electrically neutral flakes that are suspended in a higher electrical conductive matrix. The torque tends to rotate the particles toward an orientation with its long axis parallel to the electric current flow. The alignment enables the anisotropic properties of tiny particles to integrate together and generate desirable macroscale anisotropic properties. The torque was obtained from thermodynamic calculation of electric current free energy at various microstructure configurations. It is significant even when the electrical potential gradient becomes as low as 100 v/m. The changes of electrical, electroplastic and thermal properties during particles alignment were discussed.

The split G-quadruplex DNAzyme has emerged as a valuable tool for visual DNA detection. Here, we successfully integrated colorimetric split G-quadruplex DNAzyme assay with nucleic acid sequence-based amplification to generate a novel detection approach, allowing visual and rapid detection for the RNA of Shimen and HCLV strains of Classic Swine Fever Virus (CSFV). CSFV is a RNA virus that causes a highly contagious disease in domestic pigs and wild boar. With this method, we were able to detect as little as 10 copies/ml of CSF viral RNA within 3 h in serum samples taken from the field. No interference was encountered in the amplification and detection of Classic Swine Fever Virus in the presence of non-target RNA or DNA. Moreover, Shimen and HCLV strains of Classic Swine Fever Virus could be easily differentiated using the NASBA-DNAzyme system. These findings indicate the NASBA-DNAzyme system is a rapid and practical technique for detecting and discriminating CSFV strains and may be applied to the detection of other RNA viruses.

The work reports an experimental observation on crystal rotation in a duplex (austenite + ferrite) steel induced by the electropulsing treatment at ambient temperature, while the temperature rising due to ohmic heating in the treatment was negligible. The results demonstrate that electric current pulses are able to dissolve the initial material's texture that has been formed in prior thermomechanical processing and to produce an alternative texture. The results were explained in terms of the instability of an interface under perturbation during pulsed electromigation., Competing Interests: The authors declare no competing financial interests.

The elongated droplets and grains can break up into smaller ones. This process is driven by the interfacial free energy minimization, which gives rise to a breakup limit. We demonstrated in this work that the breakup limit can be overpassed drastically by using electric current to interfere. Electric current free energy is dependent on the microstructure configuration. The breakup causes the electric current free energy to reduce in some cases. This compensates the increment of interfacial free energy during breaking up and enables the processing to achieve finer microstructure. With engineering practical electric current parameters, our calculation revealed a significant increment of the obtainable number of particles, showing electric current a powerful microstructure refinement technology. The calculation is validated by our experiments on the breakup of Fe 3 C-plates in Fe matrix. Furthermore, there is a parameter range that electric current can drive spherical particles to split into smaller ones.

The E. coli phosphomannose isomerase (EcPMI) gene is widely used as a selectable marker gene (SMG) in mannose (Man) selection-based plant transformation. Although some plant species exhibit significant PMI activity and active PMIs were even identified in Man-sensitive plants, whether plant PMIs can be used as SMGs remains unclear. In this study, we isolated four novel PMI genes from Chlorella variabilis and Oryza sativa. Their isoenzymatic activities were examined in vitro and compared with that of EcPMI. The active plant PMIs were separately constructed into binary vectors as SMGs and then transformed into rice via Agrobacterium. In both Indica and Japonica subspecies, our results indicated that the plant PMIs could select and produce transgenic plants in a pattern similar to that of EcPMI. The transgenic plants exhibited an accumulation of plant PMI transcripts and enhancement of the in vivo PMI activity. Furthermore, a gene of interest was successfully transformed into rice using the plant PMIs as SMGs. Thus, novel SMGs for Man selection were isolated from plants, and our analysis suggested that PMIs encoding active enzymes might be common in plants and could potentially be used as appropriate genetic elements in cisgenesis engineering.

A controlled motion of electrically neutral microparticles in a conductive liquid at high temperatures has not yet been realized under the uniform direct electric current field. We propose a simple method, which employs pulsed direct current to a conductive liquid metal containing low-conductivity objects at high temperature. The electric current enables the low-conductivity particles to pass from the centre towards the various surfaces of the high-conductivity liquid metal. Most interestingly, the directionality of microparticles can be controlled and their speed can be easily regulated by adjusting pulsed current density. We find that the movement may arise from the configuration of electrical domains which generates a driving force which exceeds the force of gravity and viscous friction. All of these features are of potential benefit in separating the particles of nearly equal density but distinctly different electrical conductivities, and also offer considerable promise for the precise and selective positioning of micro-objects or the controlled motion of minute quantities of surrounding fluids.

The sodium-iodide symporter (NIS) directs the uptake and concentration of iodide in thyroid cells. We have extended the use of NIS-mediated radioiodine therapy to prostate cancer. We have developed a prostate tumor specific conditionally replicating adenovirus that expresses hNIS (Ad5PB&#95;RSV-NIS). For radiovirotherapy to be effective in humans, the radioiodine dose administered in the pre-clinical animal model should scale to the range of acceptable doses in humans. We performed (131)I dose-response experiments aiming to determine the dose required in mice to achieve efficient radiovirotherapy. Efficacy was determined by measuring tumor growth and survival times. We observed that individual tumors display disparate growth rates that preclude averaging within a treatment modality indicating heterogeneity of growth rate. We further show that a statistic and stochastic approach must be used when comparing the effect of an anti-cancer therapy on a cohort of tumors. Radiovirotherapy improves therapeutic value over virotherapy alone by slowing the rate of tumor growth in a more substantial manner leading to an increase in survival time. We also show that the radioiodine doses needed to achieve this increase scaled well within the current doses used for treatment of thyroid cancer in humans.

The sodium iodide symporter (NIS) directs the uptake and concentration of iodide in thyroid cells. We have extended the use of NIS-mediated radioiodine therapy to other types of cancer, we transferred and expressed the NIS gene into prostate, colon and breast cancer cells using adenoviral vectors. To improve vector efficiency we have developed a conditionally replicating adenovirus (CRAd) in which the E1a gene is driven by the prostate-specific promoter, Probasin and the cassette RSV promoter human NIScDNA-bGH polyA replaces the E3 region (CRAd Ad5PB&#95;RSV-NIS). In vitro infection of the prostate cancer cell line LnCaP resulted in virus replication, cytolysis and release of infective viral particles. Conversely, the prostate cancer cell line PC-3 (androgen receptor negative) and the pancreatic cancer cell line Panc-1 were refractory to the viral cytopathic effect and did not support viral replication. Radioiodine uptake was readily measurable in LnCaP cells infected with Ad5PB&#95;RSV-NIS 24 h post-infection, confirming NIS expression. In vivo, LnCaP tumor xenografts in nude-mice injected intratumorally with Ad5PB&#95;RSV&#95;NIS CRAd expressed NIS actively as evidenced by ⁹⁹Tc uptake and imaging. Administration of therapeutic ¹³¹I after virus injection significantly increased survival probability in mice carrying xenografted LnCaP tumors compared with virotherapy alone. These data indicate that Ad5PB&#95;RSV&#95;NIS replication is stringently restricted to androgen-positive prostate cancer cells and results in effective NIS expression and uptake of radioiodine. This construct may allow multimodal therapy, combining cytolytic virotherapy with radioiodine treatment, to be developed as a novel treatment for prostate cancer.

Aim: To investigate the antihepatocellular carcinoma effects of chi-shen extract (CSE) from the water-soluble compounds of Salvia miltiorrhiza and Paeoniae radix., Methods: The effect of CSE on the growth of HepG2 cells (hepatocellular carcinoma cell line) was studied by 3-(4,5)-2,5-diphenyltetrazolium bromide assay. Apoptosis were detected through acridine orange (AO) and ethylene dibromide (EB) staining and DNA fragmentation assay. The effect of CSE on the cell cycle of HepG2 cells was studied by the propidium iodide staining method. The activation of caspases-3, -8 and -9 was examined by immunoassay kits. The transcription of the Bcl-2 family and p53 was detected by RT-PCR., Results: Our data revealed that CSE strongly induced HepG2 cell death in a dose- and time-dependent manner. CSE-induced cell death was considered to be apoptotic by observing the typical apoptotic morphological change by AO/EB staining and DNA fragmentation assay. The induction of HepG2 cell death was caused by an induction of apoptosis for the sub-G1 proportion increase, the downregulation of Bcl-2, the upregulation of Bax and p53, and the activation of the caspases-3 and -9 pathways., Conclusion: These results clearly demonstrated that CSE was able to inhibit the proliferation of HepG2 cells and cause apoptosis. Moreover, the anticancer effects of CSE were related to the Bcl-2 family pathway and the activation of caspases-3 and -9 in HepG2 cells.