Search

Abstract Background Neoadjuvant chemoradiotherapy (NCRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer (LARC). Mucinous adenocarcinoma (MAC) is a potential poor prognosis subgroup of rectal cancer. However, the predictive value of MAC in NCRT treatment of LARC is controversial. Methods A comprehensive literature search of PubMed, Embase, and the Cochrane Library was performed. All studies examining the effect of MAC on CRT response in LARC were included. Outcomes of MAC were compared with non-specific adenocarcinoma (AC) by using random-effects methods. Data were presented as odds ratios (ORs) with 95% confidence intervals (CIs). The main outcomes were the rates of pathological complete response (pCR), tumor and nodal down-staging, positive resection margin rate, local recurrence, and overall mortality. Results Fifteen studies containing comparative data on outcomes in a total of 9,238 patients receiving NCRT for LARC were eligible for inclusion. MAC had a reduced rate of pCR (OR, 0.38; 95% CI, 0.18–0.78) and tumor down-staging (OR, 0.31; 95% CI, 0.22–0.44) following NCRT compared with AC. MAC did not significantly affect nodal down-staging (OR, 0.42; 95% CI, 0.16–1.12) after NCRT. Conclusion MAC of LARC was found to be a negative predictor of response to NCRT with lower rates of pCR and tumor down-staging for LARC. The nodal down-staging of MAC was relatively lower than that of AC, although the differences were not statistically significant.

Abstract Tumor neovascularization is essential for the growth, invasion, and metastasis of tumors. Recent studies have highlighted the significant role of N6-methyladenosine (m6A) modification in regulating these processes. This review explores the mechanisms by which m6A influences tumor neovascularization, focusing on its impact on angiogenesis and vasculogenic mimicry (VM). We discuss the roles of m6A writers, erasers, and readers in modulating the stability and translation of angiogenic factors like vascular endothelial growth factor (VEGF), and their involvement in key signaling pathways such as PI3K/AKT, MAPK, and Hippo. Additionally, we outline the role of m6A in vascular-immune crosstalk. Finally, we discuss the current development of m6A inhibitors and their potential applications, along with the contribution of m6A to anti-angiogenic therapy resistance. Highlighting the therapeutic potential of targeting m6A regulators, this review provides novel insights into anti-angiogenic strategies and underscores the need for further research to fully exploit m6A modulation in cancer treatment. By understanding the intricate role of m6A in tumor neovascularization, we can develop more effective therapeutic approaches to inhibit tumor growth and overcome treatment resistance. Targeting m6A offers a novel approach to interfere with the tumor’s ability to manipulate its microenvironment, enhancing the efficacy of existing treatments and providing new avenues for combating cancer progression.

More steel scrap consumption in the iron and steel industry can not only mitigate the shortage of iron ore resources but also greatly lower production costs and carbon emissions to the atmosphere, which is a crucial link in low-carbon metallurgy. Because of the drawbacks of different factors, the amount of steel scrap consumed in the current converter steelmaking process is restricted, and the technology of multipoint adding scrap comes into play. Thus, steel scrap addition into ladles has gradually garnered attention from metallurgical experts, but there are few reports on the three-dimensional melting behavior of steel scrap in a real ladle environment with argon blowing. To examine the melting law of steel scrap in a ladle, in this study, the flow field, temperature distribution, and melting behavior of steel scrap in a 70 t refining ladle at various argon blowing rates with steel scrap addition of different specific surface areas and preheating temperatures were numerically investigated and compared using a mutiphysical mathematical model. The results revealed that the melting rate of steel scrap increases with increasing specific surface area, and bottom argon blowing can accelerate the melting of steel scrap, while the promoting effect gradually decreases with increasing specific area. With bottom argon blowing, the core temperature of steel scrap with specific surface areas of 120, 130.22, and 160.81 m2·m–3 increased by 7.06, 6.51, and 3.73 K·s–1, the melting rate was increased by 0.92, 0.88, and 0.28 cm3·s–1, and the melting time was shortened by 17, 15, and 3 s, respectively, compared with those without bottom blowing. When the initial temperature of steel scrap increases from 300 to 1000 K, the melting rate increases from 2.97 to 3.26 cm2·s–1 and the melting time is shortened by 3 s accordingly. The argon blowing rate significantly influenced the melting rate of steel scrap. When the argon blowing rate increases from 100 to 200 L·min–1, the melting time of steel scrap with specific surface areas of 120, 130.22, and 160.81 m2·m–3 is reduced from 44 to 35 s, 42 to 34 s, and 34 s to 31 s, respectively. Thus, on the premise of smooth production, the melting speed of the steel scrap in the ladle can be significantly increased by increasing the argon blowing rate and adding the slab scrap at higher initial temperatures and specific surface areas. This work offers a reference for developing steel scrap rapid-melting technology for ladles in steel plants.

ObjectiveTo investigate associations of ideal cardiovascular health behaviors with arterial stiffness and its progression in adults for providing a reference to the prevention and treatment of cardiovascular diseases. MethodsA questionnaire survey, physical examination, laboratory tests, and brachial-ankle pulse wave velocity (baPWV) measurement were conducted among 5 536 adult physical examinees recruited through convenient sampling in a general hospital located in Wuhan city, Hubei province from August 2018 to May 2019. The evaluation of cardiovascular health behavior was performed using an integrated overall score that encompassed smoking, dietary pattern, exercise routine, body mass index (BMI), blood pressure, fasting plasma glucose, and total cholesterol level. Among the surveyed participants who had complete information and no history of cardiovascular disease at baseline (n = 2 683), a follow-up baPWV measurement was conducted approximately two years later from June 2019 to February 2022. From this follow-up group of individuals with valid data for both baPWV measurements and baseline values below or equal to 1400 cm/s (n = 372), an analysis was conducted to investigate factors influencing the progression of arterial stiffness. An unconditional multivariate logistic regression model was employed to explore the correlations between ideal cardiovascular health behaviors and arterial hardening as well as its progression. ResultsAmong the 2 683 individuals without a history of cardiovascular disease at baseline survey, 34.03%, 48.16%, and 17.81% were assessed as having ideal, general, and poor cardiovascular health behaviors or factors respectively, while 31.83% were detected with arterial stiffness indicated by baPWV ≥ 1 400 cm/s. In contrast, among the 372 individuals with the two baPWV measurements and without baseline arterial stiffness (baPWV < 1 400 cm/s), the proportions of having ideal, general, and poor cardiovascular health behaviors were 43.55%, 42.74%, and 13.71% respectively; meanwhile, progressive arterial stiffness was observed in approximately one-fifth of them according to elevated baPWV values (≥ 1 400 cm/s). After adjusting for confounding factors such as gender, age, education level and family history of cardiovascular disease using multivariate logistic regression analysis method, the results showed that compared to those with poor cardiovascular health behavior or factors, individuals who had ideal or general cardiovascular health behavior had significantly decreased risk of developing arterial stiffness with odds ratios (OR) being equal to 0.28 (95% confidence interval [95%CI]: 0.21 – 0.37) and 0.64(95%CI: 0.51 – 0.81), respectively. Further adjustment for baseline baPWV values revealed that the risk of progressive arterial stiffness significantly decreased (OR = 0.29, 95%CI: 0.11 – 0.73) in individuals who had ideal rather than poor cardiovascular health behaviors. ConclusionThe ideal cardiovascular health behavior and factor scores exhibit a significant negative correlation with the occurrence and progression of arterial stiffness among Chinese adults. Moreover, early intervention aimed at promoting ideal cardiovascular health behavior and factors has the potential to effectively delay the onset and development of arterial stiffness.

Abstract Background The expression of biological traits is modulated by genetics as well as the environment, and the level of influence exerted by the latter may vary across characteristics. Photosynthetic traits in plants are complex quantitative traits that are regulated by both endogenous genetic factors and external environmental factors such as light intensity and CO2 concentration. The specific processes impacted occur dynamically and continuously as the growth of plants changes. Although studies have been conducted to explore the genetic regulatory mechanisms of individual photosynthetic traits or to evaluate the effects of certain environmental variables on photosynthetic traits, the systematic impact of environmental variables on the dynamic process of integrated plant growth and development has not been fully elucidated. Results In this paper, we proposed a research framework to investigate the genetic mechanism of high-dimensional complex photosynthetic traits in response to the light environment at the genome level. We established a set of high-dimensional equations incorporating environmental regulators to integrate functional mapping and dynamic screening of gene‒environment complex systems to elucidate the process and pattern of intrinsic genetic regulatory mechanisms of three types of photosynthetic phenotypes of Populus simonii that varied with light intensity. Furthermore, a network structure was established to elucidate the crosstalk among significant QTLs that regulate photosynthetic phenotypic systems. Additionally, the detection of key QTLs governing the response of multiple phenotypes to the light environment, coupled with the intrinsic differences in genotype expression, provides valuable insights into the regulatory mechanisms that drive the transition of photosynthetic activity and photoprotection in the face of varying light intensity gradients. Conclusions This paper offers a comprehensive approach to unraveling the genetic architecture of multidimensional variations in photosynthetic phenotypes, considering the combined impact of integrated environmental factors from multiple perspectives.

Objective Cage subsidence is a common morbidity after oblique lumbar interbody fusion (OLIF), with risk of compromising clinical and radiographic outcomes. The study aims to describe an innovative reverse lumbar pedicle screw (RLPS) technique in OLIF and compare its effect on restricting cage subsidence with classical lateral fixation (LF) in radiological and clinical evaluation. Method Consecutive patients having undergone single‐level OLIF‐LF/RLPS from 2018 to 2020 were retrospectively reviewed. In OLIF‐RLPS, the upper entry point was determined at the intersection between one horizontal line (1 cm above inferior endplate) and one vertical line (dissecting anterior and middle thirds of the vertebra) while the inferior entry point between one horizontal line (5 mm below superior endplate) and the same vertical line. Trajectories were from vertebrae reverse into contralateral pedicle. Radiological evaluation included disc height (DH) and segmental lordosis (SL); cage subsidence was evaluated by DH loss. Clinical assessment included visual analogue scale (VAS) and Oswestry disability index (ODI). Student t or Mann–Whitney U test was used for continuous variation according to normality analysis while Chi‐square test for category variation. Results A total of 29 patients had been enrolled in the study including 14 cases in the RLPS group and 15 cases in the LF group. The DH in the OLIF‐RLPS group had increased from the preoperative 9.07 ± 1.73 mm to 13.73 ± 1.83 mm postoperatively, without significant difference compared with the OLIF‐LF group during the perioperative, but decreased to 12.53 ± 1.74 mm in 3 months and maintained at 12.00 ± 1.45 mm in 12 months, significantly higher than the OLIF‐LF group (p

Abstract Mounting attention has been focused on defects of the autophagy-lysosomal pathway in sepsis, however, the precise mechanisms governing the autophagy-lysosomal process in sepsis are poorly known. We have previously reported that Erbin deficiency aggravated the inflammatory response and organ injuries caused by sepsis. In the present study, we found that Erbin knockout impaired the autophagy process in both muramyl dipeptide (MDP)-induced bone marrow-derived macrophages (BMDMs) and sepsis mouse liver and lung, as detected by the accumulation of LC3-II and SQSTM1/p62, and autophagosomes. Pretreatment with autophagy inhibitor chloroquine (CQ) further aggravated inflammatory response and organ injuries in vivo and in vitro sepsis model. We also observed that the impaired lysosomal function mediated autophagic blockade, as detected by the decreased expression of ATP6V, cathepsin B (CTSB) and LAMP2 protein. Immunoprecipitation revealed that the C-terminal of Erbin (aa 391–964) interacts with the N-terminal of transcription factor EB (TFEB) (aa 1–247), and affects the stability of TFEB-14-3-3 and TFEB-PPP3CB complexes and the phosphorylation status of TFEB, thereby promote the nucleus translocation of TFEB and the TFEB target genes transcription. Thus, our study suggested that Erbin alleviated sepsis-induced inflammatory responses and organ injuries by rescuing dysfunction of the autophagy-lysosomal pathway through TFEB-14-3-3 and TFEB-PPP3CB pathway.

N‐coordinated Ni sites (NiNx) are effective catalysts for the electrochemical reduction of CO2 to CO. In most researches, modulating the coordination environment of Ni atoms is focused on to improve electrochemical CO2 reduction (ECR) performance. However, the influence of the carbon substrate's structure on the intrinsic activity of NiNx is seldom investigated. The highly curved surface of carbon nanotubes (CNT) may provide a unique curvature effect on NiNx. It is found that the Ni residues in CNT can be atomized to form NiNx sites on the surface of CNT (Ni‐N/CNT@covalent triazine framework [CTF]) through high‐temperature pyrolysis, using a soluble CTF nanosheet as N precursor. The π‐conjugated and ultrathin 2D structure of CTF enables closer interfacial contact between CTF and CNT, which avoids the formation of a thick carbon layer to maximize the curvature effect. Theoretical data reveal that the NiN3 configuration may act as a highly active ECR site, and the curvature effect from CNT can further tune the electronic structure of NiN3, thus improving the ECR kinetics. The Ni‐N/CNT@CTF‐based flow‐cell electrolyzer exhibits a jCO of 201 mA cm−2 at −0.9 V with a high FECO of 98%.

Non-alcoholic fatty liver disease (NAFLD) represents a complex complication of type 2 diabetes mellitus (T2DM). Oxymatrine (OMT) is an alkaloid extracted from Sophora flavescens with broad pharmacological effects. However, there is currently a lack of research on OMT in the field of NAFLD. The present study aimed to explore the effects and underlying mechanisms of oxymatrine in treating T2DM with NAFLD. The T2DM mice model was induced by high-fat diet (HFD) combined with streptozotocin (STZ) injection in male C57BL/6 J mice. Animals were randomly divided into four groups (n = 8): Control group, DC group, OMT-L group (45 mg/kg i.g.), and OMT-H group (90 mg/kg, i.g.). The drug was administered once a day for 8 weeks. In addition, HepG2 hepatocytes were incubated with palmitic acid (PA) to establish a fatty liver cell model. Treated with OMT, the body weight and fasting blood glucose (FBG) of DC mice were reduced and the liver organ coefficient was significantly optimized. Meanwhile, OMT markedly enhanced the activities of key antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), and also reduced malondialdehyde (MDA) levels. These biochemical alterations were accompanied by noticeable improvements in liver histopathology. Furthermore, OMT down-regulated the expression of NOD-like receptor protein 3 (NLRP3), interleukin-1β (IL-1β), transforming growth factor-β1 (TGF-β1) and collagen I significantly, highlighting its potential in modulating inflammatory and fibrotic pathways. In conclusion, OMT improved liver impairment effectively in diabetic mice by suppressing oxidative stress, inflammation and fibrosis. These results suggest that OMT may represent a novel therapy for NAFLD with diabetes.

BackgroundObstructive sleep apnea (OSA) is an important but frequently overlooked risk factor for hypertension (HTN). The prevalence of hypertension is high in patients with OSA, but the differences in clinical symptoms and comorbidities between patients with OSA with hypertension and those with normal blood pressure have not been fully defined.MethodsThis study retrospectively analyzed OSA patients diagnosed for the first time in Lihuili Hospital Affiliated to Ningbo University from 2016 to 2020. Patients were divided into an OSA group with hypertension and an OSA group without hypertension. The sociodemographic information, clinical symptoms, comorbidities, and polysomnography results of the two groups were compared. The independent risk factors associated with hypertension in patients with OSA were explored.ResultsA total of 1108 patients with OSA initially diagnosed were included in the study, including 387 with hypertension and 721 without. Compared with OSA patients without hypertension, OSA patients with hypertension were older; had a higher body mass index (BMI) and Epworth sleepiness score (ESS); a higher incidence of nocturia; and a higher proportion of diabetes mellitus, coronary heart disease, and cerebrovascular disease. Multivariate analysis showed age (odds ratio [OR]:1.06, 95% confidence interval [CI]:1.04-1.08), BMI (OR:1.17, 95% CI:1.11-1.23), ESS score (OR:0.97, 95%CI: 0.94-1.00) and nocturia symptoms (OR:1.64, 95% CI:1.19-2.27) was independently associated with hypertension in OSA patients, and comorbid diabetes (OR: 3.86, 95% CI: 2.31-6.45), coronary heart disease (OR: 1.90, 95% CI:1.15-3.16), and ischemic stroke (OR: 3.69,95% CI:1.31-10.40) was independently associated with hypertension in OSA patients.ConclusionCompared to OSA patients with normal blood pressure, OSA patients with hypertension had more significant daytime sleepiness, more frequent nocturnal urination, and a higher risk of diabetes, coronary heart disease, and cerebrovascular disease.

According to the context of “carbon peak and carbon neutralization”, it is highly significant to investigate the melting mechanism and behavior of steel scrap in the converter to reduce the tap-to-tap time and enhance the usage of resource. In this paper, the melting behaviors of steel scrap in a full-scale converter under the conditions of without blowing, only top blowing, only bottom blowing and top-bottom combined blowing were numerically calculated by a three-dimensional turbulent-multiphase-melting-solute transport coupling model. Along with hot-state experiments, the mathematical model was verified. The results showed that the scrap melting in the converter is the result of the combined actions of heat transfer and mass transfer. When applying the top-bottom combined blowing, the melting time required for the scrap is about 485 s. Compared with bottom blowing, top blowing and without blowing, the melting time is shortened by about 45 s, 220 s and 290 s, respectively. The modes of top-bottom combined blowing and only bottom blowing can preferably promote the exchange of temperature and solute element carbon between the scrap and melt, leading to a stable temperature of 1700 K around the scrap, which is 10 K and 20 K higher than that of only top blowing and without blowing, respectively. Meanwhile, the end time of carburizing stage with top-bottom combined blowing is 200 s, which is about 100 s shorter than that of only top blowing and without blowing. The present study can provide theoretical guidance for deep understanding of scrap melting in converter, which is significant for improving the production efficiency.

Understanding the slag-metal reactions in Fe-based amorphous alloys is of paramount importance to evade the refining-induced trade-off between performance enhancement and alloy composition deviation. In this study, the B2O3 and B2O3–CaO slags refining-induced alloy composition deviation was theoretically and experimentally verified in Fe83Si2B12P3 (at.%) amorphous alloy, and a quaternary SiO2–B2O3–CaO–Al2O3 slag suitable for FeSiBP amorphous alloy was designed after the careful calculation of slag-metal equilibrium, slag viscosity and melting point. After refining with simple B2O3 and B2O3–CaO slags, the enrichment of B element and depletion of Si element in the FeSiBP amorphous alloy was confirmed due to the oxidation of constituent Si element and the reduction of B2O3 in the slag. The refining-induced alloy composition deviation can be effectively alleviated by using our designed slags, and the 20%SiO2–55%B2O3–10%CaO–15%Al2O3 (wt.%) slag is effective in removing the impurities and enhancing the glass-forming ability (GFA). In terms of the removal of impurities, the high activity of B2O3 in slag is crucial for the oxidation and removal of Mn, Al, Ti impurities. These results are quite vital for the design of refining slags suitable for Fe-based amorphous alloys and pave the way for the large-scale production of high-performance soft magnetic materials.

Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality worldwide. The unlimited proliferation of tumor cells is one of the key features resulting in the malignant development and progression of CRC. Consequently, understanding the potential proliferation and growth molecular mechanisms and developing effective therapeutic strategies have become key in CRC treatment. Pyroptosis is an emerging type of regulated cell death (RCD) that has a significant role in cells proliferation and growth. For the last few years, numerous studies have indicated a close correlation between pyroptosis and the occurrence, progression, and treatment of many malignancies, including CRC. The development of effective therapeutic strategies to inhibit tumor growth and proliferation has become a key area in CRC treatment. Thus, this review mainly summarized the different pyroptosis pathways and mechanisms, the anti-tumor (tumor suppressor) and protective roles of pyroptosis in CRC, and the clinical and prognostic value of pyroptosis in CRC, which may contribute to exploring new therapeutic strategies for CRC.

Context: Congenital hypopituitarism is a genetically heterogeneous cond ition. Whole exome sequencing (WES) is a promising approach for molecular di agnosis of patients with this condition. Objectives: The aim of this study is to conduct WES in a patient with cong enital hypopituitarism born to consanguineous parents, CDH2 screening in a cohort of patients with congenital hypopituitarism, and functional testing of a no vel CDH2 variant. Design: Genomic DNA from a proband and her consanguineous parents was analyzed by WES. Copy number variants were evaluated. The genetic varian ts were filtered for population frequency (ExAC, 1000 genomes, gnomAD, and ABraOM), in silico prediction of pathogenicity, and gene expression in the pituitary and/or h ypothalamus. Genomic DNA from 145 patients was screened for CDH2 by Sanger sequencing. Results: One female patient with deficiencies in growth hormone, thyroid -stimulating hormone, adrenocorticotropic hormone, luteinizing hormone, and follicle-stimulating hormone and ectopic posterior pituitary gland contained a rare homozygous c.865G>A (p.Val289Ile) variant in CDH2. To determine whether the p.Val289Ile variant in CDH2 affects cell adhesion properties, we stably transfected L1 fibrob last lines, labeled the cells with lipophilic dyes, and quantified aggregation. Large ag gregates formed in cells expressing wildtype CDH2, but aggregation was impaired in cells transfected with varian t CDH2 or non-transfected. Conclusion: A homozygous CDH2 allelic variant was found in one hypopituitarism patient, and the variant impaired cell aggregation function in vitro. No disease-causing variants were found in 145 other patients screened for CDH2 variants. Thus, CDH2 is a candidate gene for hypopituitarism that needs to be tested in different po pulations. Significance statement: A female patient with hypopituitarism was born from consanguineous parents and had a homozygous, likely pathogenic, CDH2 variant that impairs cell aggregation in vitro. No other likely pathogenic variants in CDH2 were identified in 145 hypopituitarism patients.

Abstract Purpose To advance a modified oblique lumbar interbody fusion (M-OLIF) achieving anterior debridement and posterior freehand instrumentation simultaneously in circumferential approach via dynamic position and compare with traditional combined anterior–posterior surgery (CAPS) in clinical and radiological evaluation. Patients and methods Innovative freehand instrumentation in floating position was described. Consecutive patients having undergone surgeries for lumbar tuberculosis from 2017 January to 2019 December had been retrospectively reviewed. Patients with follow-ups for at least 36 months were included and divided into M-OLIF or CAPS group according to surgical methods applied. Outcomes included operation time, estimated blood loss, complication profile for safety evaluation; Vascular Analogue Scale (VAS) and Oswestry Disability Index (ODI) for efficacy evaluation; C-reactive protein and Erythrocyte Sedimentation Rate for tuberculosis activity and recurrence evaluation; X-ray and CT scan for radiological evaluation. Results Totally 56 patients had been enrolled in the study (26 for M-OLIF and 30 for CAPS). Compared with CAPS group, M-OLIF group illustrated significantly decreased estimated blood loss, operation time, hospital stay, and less postoperative morbidities. Meanwhile, M-OLIF group showed earlier improvement in VAS in 3 days and ODI in the first month postoperatively, without obvious discrepancy in further follow-ups. The overall screw accuracy in M-OLIF and CAPS group was 93.8% and 92.3% respectively, without significant difference in perforation distribution. Conclusion M-OLIF was efficient for lumbar tuberculosis requiring multilevel fixation, with reduced operation time and iatrogenic trauma, earlier clinical improvement compared with traditional combined surgery.

Tree growth is the consequence of developmental interactions between above- and below-ground compartments. However, a comprehensive view of the genetic architecture of growth as a cohesive whole is poorly understood. We propose a systems biology approach for mapping growth trajectories in genome-wide association studies viewing growth as a complex (phenotypic) system in which above- and below-ground components (or traits) interact with each other to mediate systems behavior. We further assume that trait–trait interactions are controlled by a genetic system composed of many different interactive genes and integrate the Lotka-Volterra predator–prey model to dissect phenotypic and genetic systems into pleiotropic and epistatic interaction components by which the detailed genetic mechanism of above- and below-ground co-growth can be charted. We apply the approach to analyze linkage mapping data of Populus euphratica, which is the only tree species that can grow in the desert, and characterize several loci that govern how above- and below-ground growth is cooperated or competed over development. We reconstruct multilayer and multiplex genetic interactome networks for the developmental trajectories of each trait and their developmental covariation. Many significant loci and epistatic effects detected can be annotated to candidate genes for growth and developmental processes. The results from our model may potentially be useful for marker-assisted selection and genetic editing in applied tree breeding programs. The model provides a general tool to characterize a complete picture of pleiotropic and epistatic genetic architecture in growth traits in forest trees and any other organisms.

Abstract Background Resistance to immune checkpoint inhibitor (ICI) therapy narrows the efficacy of cancer immunotherapy. Although 4-1BB is a promising drug target as a costimulatory molecule of immune cells, no 4-1BB agonist has been given clinical approval because of severe liver toxicity or limited efficacy. Therefore, a safe and efficient immunostimulatory molecule is urgently needed for cancer immunotherapy. Methods HK010 was generated by antibody engineering, and the Fab/antigen complex structure was analyzed using crystallography. The affinity and activity of HK010 were detected by multiple in vitro bioassays, including enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), flow cytometry, and luciferase-reporter assays. Humanized mice bearing human PD-L1-expressing MC38 (MC38/hPDL1) or CT26 (CT26/hPDL1) tumor transplants were established to assess the in vivo antitumor activity of HK010. The pharmacokinetics (PK) and toxicity of HK010 were evaluated in cynomolgus monkeys. Results HK010 was generated as an Fc-muted immunoglobulin (Ig)G4 PD-L1x4-1BB bispecific antibody (BsAb) with a distinguished Fab/antigen complex structure, and maintained a high affinity for human PD-L1 (KD: 2.27 nM) and low affinity for human 4-1BB (KD: 493 nM) to achieve potent PD-1/PD-L1 blockade and appropriate 4-1BB agonism. HK010 exhibited synergistic antitumor activity by blocking the PD-1/PD-L1 signaling pathway and stimulating the 4-1BB signaling pathway simultaneously, and being strictly dependent on the PD-L1 receptor in vitro and in vivo. In particular, when the dose was decreased to 0.3 mg/kg, HK010 still showed a strong antitumor effect in a humanized mouse model bearing MC38/hPDL1 tumors. Strikingly, HK010 treatment enhanced antitumor immunity and induced durable antigen-specific immune memory to prevent rechallenged tumor growth by recruiting CD8+ T cells and other lymphocytes into tumor tissue and activating tumor-infiltrating lymphocytes. Moreover, HK010 not only did not induce nonspecific production of proinflammatory cytokines but was also observed to be well tolerated in cynomolgus monkeys in 5 week repeated-dose (5, 15, or 50 mg/kg) and single-dose (75 or 150 mg/kg) toxicity studies. Conclusion We generated an Fc-muted anti-PD-L1x4-1BB BsAb, HK010, with a distinguished structural interaction with PD-L1 and 4-1BB that exhibits a synergistic antitumor effect by blocking the PD-1/PD-L1 signaling pathway and stimulating the 4-1BB signaling pathway simultaneously. It is strictly dependent on the PD-L1 receptor with no systemic toxicity, which may offer a new option for cancer immunotherapy.

ABSTRACT Clostridioides difficile infection (CDI) is a major health concern and one of the leading causes of hospital-acquired diarrhea in many countries. C. difficile infection is challenging to treat as C. difficile is resistant to multiple antibiotics. Alternative solutions are needed as conventional treatment with broad-spectrum antibiotics often leads to recurrent CDI. Recent studies have shown that specific microbiota-based therapeutics such as bile acids (BAs) are promising approaches to treat CDI. Clostridium scindens encodes the bile acid-induced (bai) operon that carries out 7-alpha-dehydroxylation of liver-derived primary BAs to secondary BAs. This biotransformation is thought to increase the antibacterial effects of BAs on C. difficile. Here, we used an automated multistage fermentor to study the antibacterial actions of C. scindens and BAs on C. difficile in the presence/absence of a gut microbial community derived from healthy human donor fecal microbiota. We observed that C. scindens inhibited C. difficile growth when the medium was supplemented with primary BAs. Transcriptomic analysis indicated upregulation of C. scindens bai operon and suppressed expression of C. difficile exotoxins that mediate CDI. We also observed BA-independent antibacterial activity of the secretome from C. scindens cultured overnight in a medium without supplementary primary BAs, which suppressed growth and exotoxin expression in C. difficile mono-culture. Further investigation of the molecular basis of our observation could lead to a more specific treatment for CDI than current approaches. IMPORTANCE There is an urgent need for new approaches to replace the available treatment options against Clostridioides difficile infection (CDI). Our novel work reports a bile acid-independent reduction of C. difficile growth and virulence gene expression by the secretome of Clostridium scindens. This potential treatment combined with other antimicrobial strategies could facilitate the development of alternative therapies in anticipation of CDI and in turn reduce the risk of antimicrobial resistance.

Soil seed bank is the growth and reproduction source of vegetation community, playing an important role in vegetation establishment, succession and renewal, biodiversity maintenance. This study has selected the nascent wetland in the Yellow River Delta (YRD) formed in 1996 as study area and investigated the diversity and key influencing factors of soil seed bank diversity. The study results show that: (1) The soil seed bank in the study area has a simple structure, containing relatively few species. A total of five plant species, which belong to four families and five genera, were found in this bank, with Phragmites australis and Suaeda salsa being the dominant plants. (2) All species are herbs without woody species. One herb is annual herb and the others are perennial herbs. (3) From the sea to the river, the changes rules of the overall density and diversity of the seed bank are not obvious. (4) The dispersal distance from salt and freshwater has a significant influence on the density of the soil seed bank but has no significant influence on the diversity. Meanwhile, the soil salt content has a significant negative influence on the diversity of seed banks. (5) Aboveground vegetation did not closely relationship with diversity of soil seed bank. All above results can provide basic data and scientific evidence for the conservation of vegetation communities in the nascent wetlands and vegetation restoration in the degraded wetlands in the YRD.

A transcriptomic analysis of lncRNAs within copy-number variations identifies HSALNG0104472 as a potential lncRNA effector of cardiac defects in non-syndromic congenital heart disease.

Plant seed germination is easily influenced by endogenous gene expression, hormones and environmental conditions. Here, we investigated a Populus R2R3-MYB transcription factor (referred to as MYB94) that plays a role in seed germination in close relation to the hormone abscisic acid (ABA). Two independent Arabidopsis transgenic lines overexpressing MYB94 (Oe-lines) and wild-type (Wt) were no clear differences in the seed germination rates under normal conditions, but the germination rates of the two Oe-lines were both significantly delayed under ABA treatment. This delay in germination is most likely associated with the endogenous hormone abscisic acid (ABA). We find that the transcript levels of several representative genes in relation to ABA synthesis or signaling in the MYB94 Oe-lines showed significantly increased compared with those of the Wt plants. Taken together, our results here reveal the role of the Populus R2R3-MYB transcription factor MYB94 in regulating the ABA-responsive genes in plant seed germination.

Abstract Background Microglia pyroptosis-mediated neuroinflammation is thought to be the crucial pathogenesis of sepsis-associated encephalopathy (SAE). Erbin has been reported to be associated with various inflammatory diseases. However, the role of Erbin in SAE and the relationship between Erbin and microglia pyroptosis are unknown. In this study, we investigated the promising role and underlying molecular mechanism of Erbin in the regulation of microglia pyroptosis. Methods WT and Erbin knockout mice underwent cecum ligation perforation (CLP) to induce SAE. Primary mouse microglia and BV2 cells were treated with LPS/nigericin in vitro. Behavioral tests were performed to evaluate cognitive function. Nissl staining and transmission electron microscopy were used to assess histological and structural lesions. ELISA and qPCR were carried out to detect neuroinflammation. Western blot and immunofluorescence were used to analyze protein expression. Flow cytometry and confocal microscopy were utilized to observe the Ca2+ changes in the cytoplasm and endoplasmic reticulum (ER). To further explore the underlying mechanism, STF083010 was administered to block the IRE1α/Xbp1s pathway. Results Erbin deletion resulted in more pronounced neuronal damage and cognitive impairment in mice that underwent CLP. Erbin knockout promoted microglial pyroptosis and inflammatory cytokines secretion in vivo and in vitro, which was mediated by activation of the IRE1α/Xbp1s. Treatment with the selective inhibitor STF083010 significantly inhibited IRE1α/Xbp1s pathway activity, decreased intracytoplasmic Ca2+, attenuated microglial pyroptosis, reduced pro-inflammatory cytokine secretion, lessened neuronal damage, and improved cognitive function. Conclusions In SAE, Erbin inhibits IRE1/Xbp1s pathway activity and reduces the ER Ca2+ influx to the cytoplasm, reducing microglial pyroptosis.

ABSTRACT In vitro studies of synthetic gut microbial communities (SGMCs) can provide valuable insights into the ecological structure and function of gut microbiota. However, the importance of the quantitative composition of an SGMC inoculum and its effect on the eventual stable in vitro microbial community has not been studied. To address this, we constructed two 114-member SGMCs differing only in their quantitative composition—one reflecting the average human fecal microbiome and another mixed in equal proportions based on cell counts. We inoculated each in an automated anaerobic multi-stage in vitro gut fermentor simulating two different colonic conditions, mimicking proximal and distal colons. We replicated this setup with two different nutrient media, periodically sampled the cultures for 27 days, and profiled their microbiome compositions using 16S rRNA gene amplicon sequencing. While nutrient medium explained 36% of the variance in microbiome composition, initial inoculum composition failed to show a statistically significant effect. Under all four conditions, paired fecal and equal SGMC inoculums converged to reach stable community compositions resembling each other. Our results have broad implications for simplifying in vitro SGMC investigations. IMPORTANCE In vitro cultivation of synthetic gut microbial communities (SGMCs) can provide valuable insights into the ecological structure and function of gut microbiota. However, it is currently not known whether the quantitative composition of the initial inoculum can influence the eventual stable in vitro community structure. Hence, using two SGMC inoculums consisting of 114 unique species mixed in either equal proportions (Eq inoculum) or resembling proportions in an average human fecal microbiome (Fec inoculum), we show that initial inoculum compositions did not influence the final stable community structure in a multi-stage in vitro gut fermentor. Under two different nutrient media and two different colon conditions (proximal and distal), both Fec and Eq communities converged to resemble each other’s community structure. Our results suggest that the time-consuming preparation of SGMC inoculums may not be needed and has broad implications for in vitro SGMC studies.

Background: Arterial stiffness is an important indicator of cardiovascular aging. However, studies assessing the association between metal exposure and arterial stiffness are limited. Objective: The aim of this study was to investigate the independent and joint associations of metal exposure with arterial stiffness. Methods: This cross-sectional study recruited 2982 Chinese adults from August 2018 to March 2019 in Wuhan, China. The concentrations of 20 urinary metals were determined using inductively coupled plasma mass spectrometer. Arterial stiffness was assessed by brachial-ankle pulse wave velocity (baPWV). We used generalized linear model (GLM) to estimate the association of single metal exposure with baPWV. We used weighted quantile sum (WQS) regression to estimate the association of metal mixture with baPWV. Results: In GLM regression analysis, each doubling of urinary copper (Cu) and chromium (Cr) concentrations were associated with 6.48 (95 % CI: 2.51–10.45) cm/s and 3.78 (95 % CI: 0.42–7.14) cm/s increase in baPWV, respectively. In WQS regression analysis, each unit increase in WQS index of the metal mixture was associated with a 9.10 (95 % CI: 2.39–15.82) cm/s increase in baPWV. Cu, Zn, and Cr were the dominant urinary metals associated with baPWV. Conclusion: Metal exposure, both individually and in mixture, was associated with an increased risk of arterial stiffness. Our findings may provide a target for preventative strategies against cardiovascular aging.

This study aims to investigate the attitudes and actions of scientific journal editors in China towards open access. Semi-structured interviews were conducted with 17 Chinese editors from various scientific journals during September and October of 2022. The results indicate that the editors generally possess knowledge of open access and have implemented an appropriate open access model for their respective journals. However, the Chinese-language journal editors expressed a lack of motivation to adopt open access, unless there is a reform in the mechanism of academic publishing or a policy is imposed. On the other hand, the English-language journal editors acknowledged that they have no other choice but to adopt open access. This study helps us learn about Chinese editors’ understanding and attitudes towards open access, the current status of open access in China’s scientific journals, and the mechanisms of academic publishing in China.

The chemical diversity of peptides from ribosomal origin is a growing field of research. Here, the authors report the discovery, genomic and biosynthetic investigations of kintamdin, a ribosomally synthesized and post-translationally modified peptides featuring a beta-enamino acid and a bis-thioether macrocyclic motif.

ObjectiveAlthough the clinical application value of Aidi injection when treating non-small cell lung cancer (NSCLC) patients is explained only by the effectiveness of a certain literature or the improvement of a certain evaluation index, and the result is not convincing. To evaluate the effect of Aidi injection on life quality and incidence of adverse reactions in patients with NSCLCcompared with traditional chemotherapy.MethodsPubMed, EMBASE, ScienceDirect, Cochrane Library, China Journal full-text Database (CNKI), VIP full-text Database, Wanfang Database and Chinese Biomedical Literature data (CBM), search relevant Chinese and foreign periodicals, conference papers, degree papers, etc. were searched Database and China Biomedical Literature Database (CBM) to search case-control trials of Aidi injection when treating NSCLC patients. The retrieval period begins with the establishment of the database and ends when the database is closed. Cochrane Handbook 5.3 was adopted to assess the bias risk of each contained literature based on independently extracted data by two researchers. A meta-analysis of the collected data was carried out using RevMan5.3 statistical software.Results2306 articles were retrieved by computer database, 1422 articles were harvested by excluding repeated studies, 865 articles were harvested by preliminary reading of article titles and abstracts, and 533 articles were initially contained by excluding unrelated studies, reviews, case reports and uncontrolled articles, and then the full text of the literature was carefully read. Eight clinical controlled studies were finally included, with a total of 784 samples, after excluding 525 literatures with incomplete data and no primary outcome indicators. Data from the contained studies were not noticeably heterogeneous in the meta-analysis of treatment effectiveness. The fixed effect model analysis indicated that the treatment effective rate of the study group was noticeably better, and the difference was statistically significant(P0.05). A meta-analysis was conducted on the incidence of adverse reactions after treatment. The results of the heterogeneity test indicated that data from the contained research were evidently heterogeneous. The incidence was noticeably lower, and the difference was statistically significant (P

IntroductionThe cooperative strategy of phenotypic traits during the growth of plants reflects how plants allocate photosynthesis products, which is the most favorable decision for them to optimize growth, survival, and reproduction response to changing environment. Up to now, we still know little about why plants make such decision from the perspective of biological genetic mechanisms.MethodsIn this study, we construct an analytical mapping framework to explore the genetic mechanism regulating the interaction of two complex traits. The framework describes the dynamic growth of two traits and their interaction as Differential Interaction Regulatory Equations (DIRE), then DIRE is embedded into QTL mapping model to identify the key quantitative trait loci (QTLs) that regulate this interaction and clarify the genetic effect, genetic contribution and genetic network structure of these key QTLs. Computer simulation experiment proves the reliability and practicability of our framework.ResultsIn order to verify that our framework is universal and flexible, we applied it to two sets of data from Populus euphratica, namely, aboveground stem length - underground taproot length, underground root number - underground root length, which represent relationships of phenotypic traits in two spatial dimensions of plant architecture. The analytical result shows that our model is well applicable to datasets of two dimensions.DiscussionOur model helps to better illustrate the cooperation-competition patterns between phenotypic traits, and understand the decisions that plants make in a specific environment that are most conducive to their growth from the genetic perspective.

Isoniazid (INH) is a highly effective single and/or combined first-line anti-tuberculosis (anti-TB) therapy drug, and the hepatotoxicity greatly limits its clinical application. INH-induced liver injury (INH-DILI) is a typical immune-mediated idiosyncratic drug-induced liver injury. Existing mechanisms including genetic variations in drug metabolism and immune responses cannot fully explain the differences in susceptibility and sensitivity to INH-DILI, suggesting that other factors may be involved. Accumulating evidence indicates that the development and severity of immune-mediated liver injury is related to gut microbiota. In this study, INH exposure caused liver damage, immune disregulation and microbiota profile alteration. Depletion of gut microbiota ameliorated INH-DILI, and improved INH-DILI-associated immune disorder and inflammatory response. Moreover, hepatotoxicity of INH was ameliorated by fecal microbiota transplantation (FMT) from INH-treated mice. Notably, Bifidobacterium abundance was significantly associated with transaminase levels. In conclusion, our results suggested that the effect of gut microbiota on INH-DILI was related to immunity, and the difference in INH-DILI sensitivity was related to the structure of gut microbiota. Changes in the structure of gut microbiota by continuous exposure of INH resulted in the tolerance to liver injury, and probiotics such as Bifidobacterium might play an important role in INH-DILI and its ''adaptation'' phenomenon. This work provides novel evidence for elucidating the underlying mechanism of difference in individual’s response to INH-DILI and potential approach for intervening anti-TB drug liver injury by modulating gut microbiota.

Summary: Background: Opioid use disorder (OUD) is a chronic relapsing psychiatric disorder. An unconditioned stimulus (US)-triggers a memory reconsolidation updating procedure (MRUP) that has been developed and demonstrated its effectiveness in decreasing relapse to cocaine and heroin in preclinical models. However, utilizations of abused drugs as the US to initiate MRUP can be problematic. We therefore designed a translational rat study and human study to evaluate the efficacy of a novel methadone-initiated MRUP. Methods: In the rodent study, male rats underwent heroin self-administration training for 10 consecutive days, and were randomly assigned to receive saline or methadone at 10 min, 1 h or 6 h before extinction training after 28-day withdrawal. The primary outcome was operant heroin seeking after reinstatement. In the human experimental study, male OUD patients were randomly assigned to get MRUP at 10 min or 6 h after methadone or methadone alone. The primary outcomes included experimental cue-induced heroin craving change, sustained abstinence and retention in the study at post intervention and the 5 monthly follow-up assessments. The secondary outcomes were changes in physiological responses including experimental cue-induced blood pressure and heart rate. Findings: Methadone exposure but not saline exposure at 10 min or 1 h before extinction decreased heroin-induced reinstatement of heroin seeking after 28-day of withdrawal in rats (F (8,80) = 8.26, p < 0.001). In the human study, when the MRUP was performed 10 min, but not 6 h after methadone dosing, the MRUP promoted sustained abstinence from heroin throughout 5 monthly follow-up assessments compared to giving methadone alone without MRUP (Hazard Ratio [95%CI] of 0.43 [0.22, 0.83], p = 0.01). The MRUP at 10 min, but not at 6 h after dosing also decreased experimental cue-induced heroin craving and blood pressure increases during the 6-month study duration (group × months × cue types, F (12, 63·3) = 2.41, p = 0.01). Interpretation: The approach of MRUP within about 1 to 6 h after a methadone dose potently improved several key outcomes of OUD patients during methadone maintenance treatment, and could be a potentially novel treatment to prevent opioid relapse. Funding: National Natural Science Foundation of China (NO. U1802283, 81761128036, 82001400, 82001404 and 31671143) and Chinese National Programs for Brain Science and Brain-like Intelligence Technology (NO. 2021ZD0200800)

A low-crosstalk compact arrayed waveguide grating integrated with a tunable micro-ring resonator is demonstrated on silicon-on-insulator platform, The side-lobe of the silicon nanowire AWG, introduced by fabrication errors, can be effectively suppressed by the Ring Filter, The crosstalk level of the side-lobe can be reduced from -16.3 dB to -26.8dB, in addition, the crosstalk of integrate AWG have improved over the entire 3 dB bandwidth, with a maximum crosstalk improvement of 8.9 dB at the left and right wavelengths of the 3 dB bandwidth, and the excess loss from the ring resonator can be ignorable in principle.

In this paper, we propose a large wavelength bandwidth Mach-Zehnder modulator based on light intensity equalization structure. The modulator is designed into a symmetric structure to increase the optical operating bandwidth. Besides, two auxiliary MZIs are connected to the respective phase shifters of the main modulator to balance the optical intensity in them. Compared with a conventional Mach-Zehnder modulator, this design has a larger optical operating bandwidth over 56.1 nm. Besides, the maximum extinction ratio of this modulator is 26.2dB, which is 12 dB higher than that of a conventional one. The dynamic extinction ratios at speed of 40Gbps are 4.10 dB in the wavelength of 1530nm and 4.02 dB in the wavelength of 1560 nm respectively. The 3 dB electro-optical bandwidth of this modulator under different voltages are almost consistent with the performance of the conventional one. All of these prove that this structural design can effectively increases the performance of Mach-Zehnder modulators.

The edge-coupler of fiber-to-chip with ultra-low coupling loss is demonstrated on SOI platform. The edge-coupler is consisted of the cantilevered SiO2 waveguide, the amorphous silicon (α-Si) nano taper and the crystal silicon (c-Si) nano tapers. The thin α-Si layer is deposited on the c-Si layer to improve the pattern matching with fiber. The optical input signal from the optical fiber is launched into the suspended SiO2 waveguide, then coupled into the α-Si nano taper at the center of the SiO2 waveguide, and finally coupled into the c-Si nano taper. We characterized the cantilevered edge-coupler using cleaved single-mode optical fiber with a mode field diameter of 10.5 μm. The measured coupling loss is as low as -1.7 dB per facet for TE mode without index matching liquid at 1550 nm. The 1 dB bandwidth is more than 100 nm with 1 dB alignment tolerances of ±2.0 μm in both horizontal and vertical directions. Besides, potential hybrid optical integration could also be allowed with this results in the future.

Diabetic nephropathy (DN) is one of the most serious microvascular complications following diabetes mellitus (DM). Ferulic acid (FA), a phenolic acid widely found in plants, has multiple pharmacological effects such as anti-oxidation, anti-inflammation and anti-tumor. However, the current research on FA in the field of DN is insufficient. The present study aimed to explore the nephroprotective effect of FA on DN in mice and reveal its underlying mechanism. DN was induced by high-fat diet (HFD) combined with streptozotocin (STZ) injection in male C57BL/6J mice. Animals were randomly divided into four groups (n = 8): Control group, DN group, FA group (200 mg/kg FA, i.g.) and valsartan (VAL) group (12 mg/kg VAL, i.g.). The drug was administered once a day for 8 weeks. Treated with FA, the body weight and fasting blood glucose (FBG) of DN mice were reduced and the renal organ coefficient was significantly optimized. Meanwhile, FA decreased levels of 24-h urine protein excretion (24-h UP) in urine and blood urea nitrogen (BUN), creatinine (Cr) in serum, reduced levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) in serum. In addition, FA promoted light chain 3 (LC3) expression markedly, and inhibited the expressions of p62, NOD-like receptor family pyrin domain containing 3 (NLRP3) and interleukin-1β (IL-1β) in renal tissues. In conclusion, FA played a positive role in alleviating renal injury in HFD/STZ-induced DN mice by enhancing autophagy and suppressing excessive inflammation.

Abstract A geometric mapping establishes a correspondence between two domains. Since no real object has zero or negative volume, such a mapping is required to be inversion-free. Computing inversion-free mappings is a fundamental task in numerous computer graphics and geometric processing applications, such as deformation, texture mapping, mesh generation, and others. This task is usually formulated as a non-convex, nonlinear, constrained optimization problem. Various methods have been developed to solve this optimization problem. As well as being inversion-free, different applications have various further requirements. We expand the discussion in two directions to (i) problems imposing specific constraints and (ii) combinatorial problems. This report provides a systematic overview of inversion-free mapping construction, a detailed discussion of the construction methods, including their strengths and weaknesses, and a description of open problems in this research field.

Abstract High-grade serous ovarian cancers (HGSOC) represent the most common subtype of ovarian malignancies. Due to the frequency of late-stage diagnosis and high rates of recurrence following standard of care treatments, novel therapies are needed to promote durable responses. We investigated the anti-tumor activity of CD3 T cell engaging bispecific antibodies (TCBs) directed against the PAX8 lineage-driven HGSOC tumor antigen LYPD1 and demonstrated that anti-LYPD1 TCBs induce T cell activation and promote in vivo tumor growth inhibition in LYPD1-expressing HGSOC. To selectively target LYPD1-expressing tumor cells with high expression while sparing cells with low expression, we coupled bivalent low-affinity anti-LYPD1 antigen-binding fragments (Fabs) with the anti-CD3 scFv. In contrast to the monovalent anti-LYPD1 high-affinity TCB (VHP354), the bivalent low-affinity anti-LYPD1 TCB (QZC131) demonstrated antigen density-dependent selectivity and showed tolerability in cynomolgus monkeys at the maximum dose tested of 3 mg/kg. Collectively, these data demonstrate that bivalent TCBs directed against LYPD1 have compelling efficacy and safety profiles to support its use as a treatment for high-grade serous ovarian cancers.

Non-communicable diseases (NCDs), represented by cardiovascular diseases and cancer, have been the leading cause of death globally. Improvements in mortality from cardiovascular (CV) diseases (decrease of 14%/100,000, United States) or cancers (increase 7.5%/100,000, United States) seem unsatisfactory during the past two decades, and so the search for innovative and accurate biomarkers of early diagnosis and prevention, and novel treatment strategies is a valuable clinical and economic endeavor. Both tumors and cardiovascular system are rich in angiological systems that maintain material exchange, signal transduction and distant regulation. This pattern determines that they are strongly influenced by circulating substances, such as glycolipid metabolism, inflammatory homeostasis and cyclic non-coding RNA and so forth. Platelets, a group of small anucleated cells, inherit many mature proteins, mRNAs, and non-coding RNAs from their parent megakaryocytes during gradual formation and manifest important roles in inflammation, angiogenesis, atherosclerosis, stroke, myocardial infarction, diabetes, cancer, and many other diseases apart from its classical function in hemostasis. MicroRNAs (miRNAs) are a class of non-coding RNAs containing ∼22 nucleotides that participate in many key cellular processes by pairing with mRNAs at partially complementary binding sites for post-transcriptional regulation of gene expression. Platelets contain fully functional miRNA processors in their microvesicles and are able to transport their miRNAs to neighboring cells and regulate their gene expression. Therefore, the importance of platelet-derived miRNAs for the human health is of increasing interest. Here, we will elaborate systematically the roles of platelet-derived miRNAs in cardiovascular disease and cancer in the hope of providing clinicians with new ideas for early diagnosis and therapeutic strategies.

Sepsis is a series of clinical syndromes caused by immunological response to severe infection. As the most important and common complication of sepsis, acute respiratory distress syndrome (ARDS) is associated with poor outcomes and high medical expenses. However, well-described studies of analysis-based researches, especially related bioinformatics analysis on revealing specific targets and underlying molecular mechanisms of sepsis and sepsis-induced ARDS (sepsis/se-ARDS), still remain limited and delayed despite the era of data-driven medicine. In this report, weight gene co-expression network based on data from a public database was constructed to identify the key modules and screen the hub genes. Functional annotation by enrichment analysis of the modular genes also demonstrated the key biological processes and signaling pathway; among which, extensive immune-involved enrichment was remarkably associated with sepsis/se-ARDS. Based on the differential expression analysis, least absolute shrink and selection operator, and multivariable logistic regression analysis of the screened hub genes, SIGLEC9, TSPO, CKS1B and PTTG3P were identified as the candidate biomarkers for the further analysis. Accordingly, a four-gene-based model for diagnostic prediction assessment was established and then developed by sepsis/se-ARDS risk nomogram, whose efficiency was verified by calibration curves and decision curve analyses. In addition, various machine learning algorithms were also applied to develop extra models based on the four genes. Receiver operating characteristic curve analysis proved the great diagnostic and predictive performance of these models, and the multivariable logistic regression of the model was still found to be the best as further verified again by the internal test, training, and external validation cohorts. During the development of sepsis/se-ARDS, the expressions of the identified biomarkers including SIGLEC9, TSPO, CKS1B and PTTG3P were all regulated remarkably and generally exhibited notable correlations with the stages of sepsis/se-ARDS. Moreover, the expression levels of these four genes were substantially correlated during sepsis/se-ARDS. Analysis of immune infiltration showed that multiple immune cells, neutrophils and monocytes in particular, might be closely involved in the process of sepsis/se-ARDS. Besides, SIGLEC9, TSPO, CKS1B and PTTG3P were considerably correlated with the infiltration of various immune cells including neutrophils and monocytes during sepsis/se-ARDS. The discovery of relevant gene co-expression network and immune signatures might provide novel insights into the pathophysiology of sepsis/se-ARDS.

Non-ribosomal peptides are a group of structurally diverse natural products with various important therapeutic and agrochemical applications. Bacterial pyrrolizidine alkaloids (PAs), containing a scaffold of two fused five-membered ring system with a nitrogen atom at the bridgehead, have been found to originate from a multidomain non-ribosomal peptide synthetase to generate indolizidine intermediates, followed by multistep oxidation, catalysed by single Bayer-Villiger (BV) enzymes, to yield PA scaffolds. Although bacterial PAs are rare in natural product inventory, bioinformatics analysis suggested that the biosynthetic gene clusters (BGCs) that are likely to be responsible for the production of PA-like metabolites are widely distributed in bacterial genomes. However, most of the strains containing PA-like BGCs are not deposited in the public domain, therefore preventing further assessment of the chemical spaces of this group of bioactive metabolites. Here, we report a genomic scanning strategy to assess the potential of PA metabolites production in our culture collection without prior knowledge of genome information. Among the strains tested, we found fifteen contain the key BV enzymes that are likely to be involved in the last step of PA ring formation. Subsequently one-strain-many-compound (OSMAC) method, supported by a combination of HR-MS, NMR, SMART 2.0 technology, and GNPS analysis, allowed identification and characterization of a new [5 + 7] heterobicyclic carbamate, legoncarbamate, together with five known PAs, bohemamine derivatives, from Streptomyces sp. CT37, a Ghanaian soil isolate. The absolute stereochemistry of legoncarbamate was determined by comparison of measured and calculated ECD spectra. Legoncarbamate displays antibacterial activity against E. coli ATCC 25922 with an MIC value of 3.1 μg/mL. Finally, a biosynthetic model of legoncarbamate and other bohemamines was proposed based on the knowledge we have gained so far.

The potentiality on alkali activation of volcanic tuff with calcium-based materials, fly ash, and their mixtures as additives were comprehensively investigated in this study. Several characterization strategies have been employed for mechanism exploration. CaO and fly ash (FA) brought about more dramatic responses than CaSO4 and alkaline activator on activating the volcanic tuff-based geopolymer, which was relatively stable under the wet-dry alternated conditions. The symmetrical stretching vibration of Si–O–T (T = Al or Si) was right-shifted to the band at approximately 1036 cm−1, implying the incorporation of Ca into Si–O–T. FA accompanying with CaO enhanced the polycondensation, gelation, and hardening of geopolymer. However, too many quartz balls brought into geopolymer paste by an excessive amount of fly ash deteriorated the cementing quality and reduced the mechanical strengths. This work contributes to the module usage of volcanic tuff in the construction industries and supplies an innovative method in activating geopolymerization.

CRISPR-Cas12a is a promising system for targeting AT-rich regions of the genome. Here the authors identify Cas12a orthologs with expanded targeting scope and develop a highly multiplexable editing system in rice.

The steel flow, heat transfer, and inclusion removal behaviors in a five-strand bloom tundish for five baffles and two types of turbulence inhibitors (TIs) were investigated by a multiphysical model to enhance the consistency among the strands and the purity of molten steel. Water model experiments were conducted to verify the simulated results of flow and residence time distribution (RTD). The results showed that the simulated steel flow and RTD curves were basically consistent with those of the experiments. Compared to original conditions, the total residence time reaches 595.0 s, and the volume of the plug region increases by 4.8%, while the volume of dead zone decreases by 0.2% when applying the optimized baffle and TI. In addition, the response and residence times at the 3rd strand increase by 42.5 s and 264.6 s, the total average standard deviation decreases to 0.0057. Meanwhile, the maximum temperature drop decreases from 28.6 K to 22.8 K, and the temperature difference among strands decreases from 3.7 K to 1.4 K. The inclusions removal rate increases by 0.9% to 8.3% with diameters ranging from 10 μm to 100 μm and reaches 94.4% at 100 μm. Furthermore, the qualification rates of flaw detection and nonmetallic inclusions in high rails after optimization increase from 97.94% to 98.73% and from 97.3% to 99.1%, respectively, and the consistency among the strands is apparently enhanced. Keywords: Tundish, Baffle, Turbulence inhibitor, Residence time distribution, Inclusion removal

Galfan-coated full-locked coil rope is widely applied in long-span spatial structures because of its high strength and lightweight. However, the corrosion problem is relatively serious in the natatorium, which affects the structure’s durability. To deeply reveal the corrosion mechanism of Galfan-coated cable, this study first measured the natatorium on-site, and the results indicated that the natatorium environment can be simulated by a constant temperature and humidity environment in engineering. Then, the constant temperature and humidity corrosion test was carried out to simulate the corrosion of Galfan-coated cable with a certain amount of chloride ions on the surface, and the early corrosion rate was obtained. Later, the neutral salt spray accelerated corrosion test was carried out to predict the corrosion rate of the cable in the natatorium environment in the middle and late periods. The specimens included no-stress unprotected coating cable, high-stress unprotected coating cable, and high-stress protected coating cable. The results show that high stress will accelerate the corrosion, and a protective coating can effectively prevent the corrosion. Finally, the linear model, bilinear model, and bilinear model considering chloride ion accumulation were proposed to study the corrosion of the Galfan coating. The results show that the linear model overestimates the corrosion rate, and the bilinear model and bilinear model considering chloride ion accumulation are practical. Meanwhile, corresponding maintenance suggestions were given for the natatorium project to improve the structure's durability.

An increasing number of large-span space structures use flexible roofs to achieve a light and splendid architectural effect. When a flexible structural system such as a cable net is applied in a large-span stadium, the roof will deform significantly under the self-weight and wind load. Accessory structures of the roof such as catwalks, radial drainage pipes, circular drainage channels, and radial cable trenches need to cooperate with the large deformation of the roof to prevent damage caused by the large deformation of the roof. To thoroughly unveil the analysis and design method of an accessory structure, this paper first carried out the wind tunnel test to determine the wind load of the structure. Then, the gust response factors of each roof area and the dynamic amplification coefficient of the accessory structure considering the roof vibration were determined. Next, circular and radial catwalks were designed based on static analysis. A sliding joint was set in the accessory structure to adapt to the large deformation of the roof. Finally, a time history analysis of the catwalk was carried out to obtain the maximum deformation value of the sliding joint for the safety of the structure. The results demonstrate that the maximum deformation is less than the value given by the design and meets the specification.

We, the Editors and Publisher of the journal Artificial Cells, Nanomedicine, and Biotechnology, have retracted the following article:Guangfu Mu, Qian Liu, Si Wu, Yong Xia & Qing Fang (2019) Long noncoding RNA HAGLROS promotes the process of mantle cell lymphoma by regulating miR-100/ATG5 axis and involving in PI3K/AKT/mTOR signal. Artificial Cells, Nanomedicine, and Biotechnology, 47:1, 3649–3656, DOI: 10.1080/21691401.2019.1645151Since publication, concerns have been raised about the integrity of the data in the article. When approached for an explanation, the authors have been unable to verify their original data or answer our questions about research ethics and the informed consent process. In addition, two of the co-authors have alerted the Publisher that parts of the experiment were outsourced to a third party, and they do not believe the results to be credible. We also have concerns regarding the integrity of the authorship, as two co-authors have stated they did not consent to being listed as an author. We are therefore retracting this article and all authors listed in this publication have been informed.We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions.The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as ‘Retracted’.

The effects of genes on physiological and biochemical processes are interrelated and interdependent; it is common for genes to express pleiotropic control of complex traits. However, the study of gene expression and participating pathways in vivo at the whole-genome level is challenging. Here, we develop a coupled regulatory interaction differential equation to assess overall and independent genetic effects on trait growth. Based on evolutionary game theory and developmental modularity theory, we constructed multilayer, omnigenic networks of bidirectional, weighted, and positive or negative epistatic interactions using a forest poplar tree mapping population, which were organized into metagalactic, intergalactic, and local interstellar networks that describe layers of structure between modules, submodules, and individual single nucleotide polymorphisms, respectively. These multilayer interactomes enable the exploration of complex interactions between genes, and the analysis of not only differential expression of quantitative trait loci but also previously uncharacterized determinant SNPs, which are negatively regulated by other SNPs, based on the deconstruction of genetic effects to their component parts. Our research framework provides a tool to comprehend the pleiotropic control of complex traits and explores the inherent directional connections between genes in the structure of omnigenic networks.

Trait covariation during multiphasic growth is of crucial significance to optimal survival and reproduction during the entire life cycle. However, current analyses are mainly focused on the study of individual traits, but exploring how genes determine trait interdependence spanning multiphasic growth processes remains challenging. In this study, we constructed a nonlinear mixed mapping framework to explore the genetic mechanisms that regulate multiphasic growth changes between two complex traits and used this framework to study stem diameter and stem height in forest trees. The multiphasic nonlinear mixed mapping framework was implemented in system mapping, by which several key quantitative trait loci were found to interpret the process and pattern of stem wood growth by regulating the ecological interactions of stem apical and lateral growth. We quantified the timing and pattern of the vegetative phase transition between independently regulated, temporally coordinated processes. Furthermore, we visualized the genetic machinery of significant loci, including genetic effects, genetic contribution analysis, and the regulatory relationship between these markers in the network structure. We validated the utility of the new mapping framework experimentally via computer simulations. The results may improve our understanding of the evolution of development in changing environments.

Genes play an important role in community ecology and evolution, but how to identify the genes that affect community dynamics at the whole genome level is very challenging. Here, we develop a Holling type II functional response model for mapping quantitative trait loci (QTLs) that govern interspecific interactions. The model, integrated with generalized Lotka-Volterra differential dynamic equations, shows a better capacity to reveal the dynamic complexity of inter-species interactions than classic competition models. By applying the new model to a published mapping data from a competition experiment of two microbial species, we identify a set of previously uncharacterized QTLs that are specifically responsible for microbial cooperation and competition. The model can not only characterize how these QTLs affect microbial interactions, but also address how change in ecological interactions activates the genetic effects of the QTLs. This model provides a quantitative means of predicting the genetic architecture that shapes the dynamic behavior of ecological communities.

Abstract Introduction This study mainly investigated the role of miR‐199a‐5p in depression. Methods qRT‐PCR and western blotting were employed to detect the expressions of miR‐199a‐5p, CREB and BDNF. Sucrose preference test, forced swimming test, and tail suspension test were performed to evaluate depression‐related symptoms. MTT assays and flow cytometry were used to examine the cell reproduction and apoptotic cells of hippocampal neuron. Results The data demonstrated that the expression levels of miR‐199a‐5p in the cerebrospinal fluids and serums of depression patient and the hippocampus of chronic unpredictable mild stress (CUMS) mouse were significantly increased. However, the expressions of WNT2, p‐CREB, and BDNF were inhibited. In addition, miR‐199a‐5p‐inhibitor enhanced sucrose preferences of CUMS mouse and decreased immobile time in sucrose preference test and forced swimming test. Knockdown of WNT2 attenuated the effects of miR‐199a‐5p‐inhibitor on cell reproduction and apoptotic cells of hippocampal neuron and the expression of WNT2, p‐CREB, and BDNF. Conclusion MiR‐199a‐5p can target WNT2 to enhance the development of depression through regulation of the CREB/BDNF signaling. Trial registration: JNU‐Hos‐49284.