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Abstract Intervertebral disc degeneration (IDD), osteoarthritis (OA), and osteoporosis (OP) are common musculoskeletal disorders (MSDs) with similar age-related risk factors, representing the leading causes of disability. However, successful therapeutic development and translation have been hampered by the lack of clinically-relevant animal models. In this study, we investigated the potential suitability of the tree shrew, a small mammal with a close genetic relationship to primates, as a new animal model for MSDs. Age-related spontaneous IDD in parallel with a gradual disappearance of notochordal cells were commonly observed in tree shrews upon skeletal maturity with no sex differences, while age-related osteoporotic changes including bone loss in the metaphyses were primarily presented in aged females, similar to observations in humans. Moreover, in the osteochondral defect model, tree shrew cartilage exhibited behavior similar to that of humans, characterized by a more restricted self-healing capacity compared to the rapid spontaneous healing of joint surfaces observed in rats. The induced OA model in tree shrews was highly efficient and reproducible, characterized by gradual deterioration of articular cartilage, recapitulating the human OA phenotype to some degree. Surgery-induced IDD models were successfully established in tree shrews, in which the lumbar spine instability model developed slow progressive disc degeneration with more similarity to the clinical state, whereas the needle puncture model led to the rapid development of IDD with more severe symptoms. Taken together, our findings pave the way for the development of the tree shrew as a new animal model for the study of MSDs and aging.

Abstract Metabolic enzymes perform moonlighting functions during tumor progression, including the modulation of chemoresistance. However, the underlying mechanisms of these functions remain elusive. Here, utilizing a metabolic clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 knockout library screen, we observe that the loss of glutamate-cysteine ligase modifier subunit (GCLM), a rate-limiting enzyme in glutathione biosynthesis, noticeably increases the sensitivity of colorectal cancer (CRC) cells to platinum-based chemotherapy. Mechanistically, we unveil a noncanonical mechanism through which nuclear GCLM competitively interacts with NF-kappa-B (NF-κB)-repressing factor (NKRF), to promote NF-κB activity and facilitate chemoresistance. In response to platinum drug treatment, GCLM is phosphorylated by P38 MAPK at T17, resulting in its recognition by importin a5 and subsequent nuclear translocation. Furthermore, elevated expression of nuclear GCLM and phospho-GCLM correlate with an unfavorable prognosis and poor benefit from standard chemotherapy. Overall, our work highlights the essential nonmetabolic role and posttranslational regulatory mechanism of GCLM in enhancing NF-κB activity and subsequent chemoresistance.

Abstract Extracellular vesicles (EVs) are known to mediate cell communications and shape tumor microenvironment. Compared to the well-studied small EVs, the function of large microvesicles (MVs) during tumorigenesis is poorly understood. Here we show the proteome of MVs in Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC), and identify olfactomedin 4 (OLFM4) is induced by EBV infection and secreted via MVs to promote tumor progression through Hippo signaling. Specifically, OLFM4 is a target gene of the cGAS-STING pathway, and EBV infection activates cGAS-STING pathway and increases OLFM4 expression. Moreover, MV-carried OLFM4 binds with the extracellular cadherin domain of FAT1, thereby impairing its intracellular interaction with MST1 and leading to YAP activation in recipient cells. Together, our study not only reveals a regulatory mechanism though which viral infection is coupled via MVs with intercellular control of the Hippo signaling, but also highlights the OLFM4-Hippo axis as a therapeutic target for EBV-associated cancers.

Mitochondria are multitasking organelles involved in maintaining the cell homoeostasis. Beyond its well-established role in cellular bioenergetics, mitochondria also function as signal organelles to propagate various cellular outcomes. However, mitochondria have a self-destructive arsenal of factors driving the development of diseases caused by mitochondrial dysfunction. Extracellular vesicles (EVs), a heterogeneous group of membranous nano-sized vesicles, are present in a variety of bodily fluids. EVs serve as mediators for intercellular interaction. Exosomes are a class of small EVs (30–100 nm) released by most cells. Exosomes carry various cargo including microRNAs (miRNAs), a class of short noncoding RNAs. Recent studies have closely associated exosomal miRNAs with various human diseases, including diseases caused by mitochondrial dysfunction, which are a group of complex multifactorial diseases and have not been comprehensively described. In this review, we first briefly introduce the characteristics of EVs. Then, we focus on possible mechanisms regarding exosome-mitochondria interaction through integrating signalling networks. Moreover, we summarize recent advances in the knowledge of the role of exosomal miRNAs in various diseases, describing how mitochondria are changed in disease status. Finally, we propose future research directions to provide a novel therapeutic strategy that could slow the disease progress mediated by mitochondrial dysfunction.

Abstract Posaconazole enteric-coated tablet and oral suspension are two oral drugs in the treatment of invasive fungal infections (IFIs). This study compared the effectiveness and safety between posaconazole enteric-coated tablet and oral suspension, and provided a real world basis for the clinical practice. A retrospective cohort study was performed on IFIs patients treated with posaconazole enteric–coated tablet or oral suspension. The primary endpoints were in-hospital mortality, treatment discontinuation rate and clinical effective rate. The secondary endpoints were adverse events incidence (liver dysfunction, renal dysfunction and hypokalemia). One hundred and forty-four patients were totally included and divided into enteric-coated tablet group (n = 46) and oral suspension group (n = 98). There was no significant difference in effectiveness and safety between two groups. The female (OR = 0.130, P = 0.018) and diabetes mellitus (OR = 4.242, P = 0.003) were independently associated with combined in-hospital mortality/treatment discontinuation rate. The renal replacement therapy (OR = 10.071, P = 0.006), hypoalbuminemia (OR = 6.646, P = 0.002) and posaconazole duration (OR = 1.119, P = 0.002) were risk factors for liver dysfunction. The posaconazole enteric-coated tablet has comparable effectiveness and safety with oral suspension in IFIs, which need large-scale cases studies to confirm in the future.

Abstract This research uses CFD (computational fluid dynamics) to simulate an axial-flow pump and analyzes its internal flow dissipation. The results show that under different operating conditions, with increasing tip cascade density, the pump head gradually increases. With increasing tip cascade density, the pump efficiency gradually decreases under small discharge conditions, and the high-efficiency zone of the axial-flow pump gradually narrows when the pump is operated under large discharge conditions. Under the design operating conditions, the highest efficiency of the axial-flow pump reaches 86.15%. The total entropy generation of the impeller, guide vane, and outlet pipe decreases and then increases with increasing discharge. Meanwhile, the total entropy generation of the impeller is 3.37 W/K, which is the largest among different over-water flow components, accounting for 47%. The turbulence entropy generation (EGTD) ratios of the impeller, guide vane and outlet pipe are 42%, 59%, and 65% under the design operating conditions, respectively. Finally, the results of numerical simulation are reliable as verified by a model test. The research results have implications for improving the efficiency of axial-flow pumps.

Since inferior biomimetic fabrication and anti-thrombosis process always lead to the implantation failure of artificial vascular grafts, the development of bioactive platform which can promote endothelialization is fundamental in the research for blood vessel substitutes to overcome the low-efficiency or hyperplasia. To solve the limitation of insufficient autologous sources of small blood vessels, this study prepared a tri-layer small diameter vascular based on citrate, followed by covalently immobilizing of specific peptides to achieve in situ cells enrichment. The natural carbohydrate of carboxymethyl chitosan is creatively used as the inner layer of tubular graft, thus exerting the anti-thrombosis effect. Moreover, the gastrodin coating was employed to alleviate the inflammation response and increase the safety of this surgically implanted vascular scaffold. The synthesis process was characterized, its biocompatibility, hierarchically cell induction capacity, anticoagulant effect and the ability to promote neovascularization were evaluated. In such way, we hope to prepare a biodegradable small-diameter artificial vascular for the clinical application.

Abstract Resection of thoracic wall tumors results in significant defects in the chest wall, leading to various complications. In recent years, the use of three-dimensional (3D) printed titanium alloy prostheses in clinical practice has demonstrated enhanced outcomes in chest wall reconstruction surgery. A cohort of seven patients with sternal tumors was identified for this study. Following a helical CT scan, a digital model was generated for the design of the prosthesis. Subsequently, the tumors were then removed together with the affected sternum and ribs. The chest wall was then reconstructed using 3D-printed titanium alloy prosthesis for bone reconstruction, mesh for pleural reconstruction, and flap for soft tissue reconstruction. Patients were monitored for a period of one year post-surgery. In the seven cases examined, the tumors were found in various locations with varying degrees of invasion. Based on the scope of surgical resection and the size of the defect, 3D-printed titanium alloy prosthesis was custom-designed for chest wall reconstruction. Prior to bone reconstruction, pleural reconstruction was achieved with Bard Composix E/X Mesh, while soft tissue repair involved muscle flap and musculocutaneous flap procedures. A one-year follow-up assessment revealed that the utilization of the 3D-printed titanium alloy prosthesis led to secure fixation, favorable histocompatibility, and enhanced lung function. The findings demonstrate that the utilization of 3D printed titanium alloy prostheses represents a significant advancement in the field of chest wall reconstruction and thoracic surgical procedures.

Abstract Background Restoring the function of the ovary is important for chemotherapy-induced ovarian failure (COF) patients. Stem cell and extracellular vesicles (EVs) therapy show promise but need further improvement. Methods Human umbilical cord mesenchymal stem cells (hUC-MSCs) were primarily cultured and further three-dimensional (3D) cultured using an ultra-low attachment surface method. The expression levels of nutritional cytokines and immunomodulatory and stemness-related genes of 3D-cultured hUC-MSCs were analyzed. EVs were isolated by ultracentrifugation and characterized. Ovaries were decellularized with sodium dodecyl sulfate to obtain extracellular matrix (ECM). Lyophilized EVs from three-dimensional (2D) or 3D hUC-MSCs were mixed with ECM to prepare the 2D/3D-MSC-EVs-ECM gels. The therapeutic effect of the MSC-EVs-ECM gel on cyclophosphamide (CTX) -treated rats was analyzed through various tests. RNA sequencing was used to analyze the expression changes of genes before and after treatment. Results After culturing in ultra-low attachment dishes, hUC-MSCs aggregated into spheroids and significantly upregulated the expression levels of immunomodulatory and stemness-related genes. The total EVs yield was also upregulated (5.6-fold) after 3D culture. The cell viability of CTX-treated ovarian granulosa cells (OGCs) was significantly rescued by coculture with the 3D-MSC-EVs-ECM gel. Hormones indicative of ovarian function, AMH, E2, and FSH, were recovered in both the CTX + 2D-MSC-EVs-ECM gel group and the CTX + 3D-MSC-EVs-ECM gel group, while the apoptosis-related protein Bax was significantly downregulated. The 3D-MSC-EVs-ECM gel was more effective than the 2D-MSC-EVs-ECM gel. Significantly differentially expressed genes, such as Hbb-b1, Gpd1, and Sirpa, were detected by RNA sequencing. Hbb-b1 was increased in the ovaries of CTX-treated rats, and this increase was attenuated by injecting the 2D/3D-MSC-EVs-ECM gel. Gpd1 was increased after CTX treatment, and this increase was reversed by the 3D-MSC-EVs-ECM gel. Sirpa was decreased in the ovaries of CTX-treated rats, and this decrease was attenuated by injecting the 3D-MSC-EVs-ECM gel. Conclusions Our study demonstrated that the 3D-MSC-EVs-ECM gel is an efficient strategy for the recovery of ovarian function in CTX-induced ovarian failure.

The lungs, being the principal respiratory organs in humans, are highly vulnerable to occupational exposure hazards. The rapid industrialization and urbanization in China, coupled with the rise of new industries, have heightened the risk of lung-related occupational hazards for workers, thereby presenting substantial challenges to research in lung-related occupational toxicology. The emerging technology of lung organoids, a three-dimensional cell culture technique, has the potential to replicate human lung structure and function in a laboratory setting, enabling direct observation and assessment of various impacts. Furthermore, the organoid model's short cycles and high throughput play a critical role in the simulation of the occurrence and development of lung impairments and the screening and evaluation of potential therapeutic drugs for occupational lung diseases. As such, the utilization of lung-related organoid technology not only improves the assessment level of the health effects of lung-related occupational exposure, but also enhances researchers' understanding of the pathological mechanisms underlying lung diseases and aids in the development of prevention and treatment strategies, rendering it a valuable tool for investigating occupational lung diseases. This paper provided a comprehensive overview of the advancements in lung organoid models and their biomedical applications, particularly in the evaluation of the potential application in the heath effects of lung-related occupational exposures.

Abstract Background Sepsis-induced cardiomyopathy (SICM) is a common and life-threatening complication of sepsis, significantly contributing to elevated mortality. This study aimed to identify crucial indicators for the prompt and early assessment of SICM. Methods Patients diagnosed with sepsis or SICM within 24 h of intensive care unit (ICU) admission were enrolled in this prospective observational study. Patients were assigned to the training set, validation set and external test set. The primary endpoint was 7-day ICU mortality, and the secondary endpoint was 28-day ICU mortality. Three machine learning algorithms were utilized to identify relevant indicators for diagnosing SICM, incorporating 64 indicators including serum biomarkers associated with cardiac, renal, and liver function, lipid metabolism, coagulation, and inflammation. Internal and external validations were performed on the screening results. Patients were then stratified based on the cut-off value of the most diagnostically effective biomarker identified, and their prognostic outcomes were observed and analyzed. Results A total of 270 patients were included in the training and validation set, and 52 patients were included in the external test set. Age, sex, and comorbidities did not significantly differ between the sepsis and SICM groups (P > 0.05). The support vector machine (SVM) algorithm identified six indicators with an accuracy of 84.5%, the random forest (RF) algorithm identified six indicators with an accuracy of 81.9%, and the logistic regression (LR) algorithm screened out seven indicators. Following rigorous selection, a diagnostic model for sepsis-induced cardiomyopathy was established based on heart-type fatty acid binding protein (H-FABP) (OR 1.308, 95% CI 1.170–1.462, P

Abstract Fungal natural products from various species often feature hydroxamic acid motifs that have the ability to chelate iron. These compounds have an array of medicinally and ecologically relevant activities. Through genome mining, gene deletion in the host Aspergillus terreus, and heterologous expression experiments, this study has revealed that a nonribosomal peptide synthetase (NRPS) TamA and a specialized cytochrome P450 monooxygenase TamB catalyze the sequential biosynthetic reactions in the formation of terramides A-C, a series of diketopiperazines (DKPs) with hydroxamic acid motifs. Feeding experiments showed that TamB catalyzes an unprecedented di-hydroxylation of the amide nitrogens in the diketopiperazine core. This tailoring reaction led to the formation of two bidentate iron-binding sites per molecule with an unusual iron-binding stoichiometry. The structure of the terramide A-Fe complex was characterized by liquid chromatography-mass spectrometry (LC-MS), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy and electron paramagnetic resonance spectroscopy (EPR). Antimicrobial assays showed that the iron-binding motifs are crucial for the activity against bacteria and fungi. Murine infection experiments indicated that terramide production is crucial for the virulence of A. terreus and could be a potential antifungal drug target.

Objectives: Cancer cells undergo metabolic reprogramming to adapt to high oxidative stress, but little is known about how metabolic remodeling enables gastric cancer cells to survive stress associated with aberrant reactive oxygen species (ROS) production. Here, we aimed to identify the key metabolic enzymes that protect gastric cancer (GC) cells from oxidative stress.Methods: ROS level was detected by DCFH-DA probes. Multiple cell biological studies were performed to identify the underlying mechanisms. Furthermore, cell-based xenograft and patient-derived xenograft (PDX) model were performed to evaluate the role of MTHFD2 in vivo.Results: We found that overexpression of MTHFD2, but not MTHFD1, is associated with reduced overall and disease-free survival in gastric cancer. In addition, MTHFD2 knockdown reduces the cellular NADPH/NADP+ ratio, colony formation and mitochondrial function, increases cellular ROS and cleaved PARP levels and induces in cell death under hypoxia, a hallmark of solid cancers and a common inducer of oxidative stress. Moreover, genetic or pharmacological inhibition of MTHFD2 reduces tumor burden in both tumor cell lines and patient-derived xenograft-based models.Discussion: our study highlights the crucial role of MTHFD2 in redox regulation and tumor progression, demonstrating the therapeutic potential of targeting MTHFD2.

With the rapid increase in urban gas consumption, the frequency of maintenance and repair of gas pipelines has escalated, leading to a rise in safety accidents during these processes. The traditional manual supervision model presents challenges such as inaccurate monitoring results, incomplete risk factor analysis, and a lack of quantitative risk assessment. This research focuses on developing a dynamic risk assessment technology for gas emergency repair operations by integrating the monitoring outcomes of artificial olfactory for gas leakage information and video object recognition for visual safety factor monitoring data. To quantitatively evaluate the risk of the operation process, a three-dimensional risk assessment model combining gas leakage with risk-correlated sensitivity was established as well as a separate three-dimensional risk assessment model integrating visual risk factors with predictable risk disposition. Furthermore, a visual risk quantification expression mode based on the risk matrix-radar map method was introduced. Additionally, a risk quantification model based on the fusion of visual and olfactory results was formulated. The verification results of simulation scenarios based on field data indicate that the visual-olfactory fusion risk assessment method can more accurately reflect the dynamic risk level of the operation process compared to simple visual safety factor monitoring. The outcomes of this research can contribute to the identification of safety status and early warning of risks related to personnel, equipment, and environmental factors in emergency repair operations. Moreover, these results can be extended to other operational scenarios, such as oil and gas production stations and long-distance pipeline operations.

Abstract CD8+ T-cell exhaustion is a promising prognostic indicator of sepsis-induced acute respiratory distress syndrome (ARDS). Patients with sepsis-related ARDS had reduced levels of HSP90AA1. However, whether the changes in CD8+ T cells were related to HSP90α, encoded by the HSP90AA1 gene, was unclear. This study aimed to examine the regulatory mechanism of HSP90α and its impact on CD8+ T-cell exhaustion in lipopolysaccharide (LPS)-induced acute lung injury (ALI). In this study, by conducting a mouse model of ALI, we found that one week after LPS-induced ALI, CD8+ T cells showed exhaustion characteristics. At this time, proliferation and cytokine release in CD8+ T cells were reduced. The inhibitory costimulatory factors PD-1 and Tim-3, on the other hand, were enhanced. Meanwhile, the expression of HSP90α and STAT1 decreased significantly. The in vitro studies showed that HSP90α stimulation or inhibition affected the CD8+ T-cell exhaustion phenotype. Interference with STAT1 reduced the expression of HSP90α and impaired its regulation of CD8+ T cells. The Co-Immunoprecipitation results indicated that HSP90α can directly or indirectly bind to TOX to regulate TOX expression and downstream signal transduction. In summary, by inhibiting TOX-mediated exhaustion signaling pathways, HSP90α inhibited CD8+ T-cell exhaustion in ALI. The participation of STAT1 in the regulation of HSP90α was required.

Abstract The potential brain mechanism underlying resilience to socially transferred allodynia remains unknown. Here, we utilize a well-established socially transferred allodynia paradigm to segregate male mice into pain-susceptible and pain-resilient subgroups. Brain screening results show that ventral tegmental area glutamatergic neurons are selectively activated in pain-resilient mice as compared to control and pain-susceptible mice. Chemogenetic manipulations demonstrate that activation and inhibition of ventral tegmental area glutamatergic neurons bi-directionally regulate resilience to socially transferred allodynia. Moreover, ventral tegmental area glutamatergic neurons that project specifically to the nucleus accumbens shell and lateral habenula regulate the development and maintenance of the pain-resilient phenotype, respectively. Together, we establish an approach to explore individual variations in pain response and identify ventral tegmental area glutamatergic neurons and related downstream circuits as critical targets for resilience to socially transferred allodynia and the development of conceptually innovative analgesics.

Although rare earth zirconates (RE2Zr2O7) have garnered attention as viable candidates for thermal barrier coatings (TBCs), they suffer from low fracture toughness and accelerated calcium–magnesium–alumina–silicate (CMAS) melt corrosion at high service temperatures, which impedes their practical application. In this work, we developed a series of REAlO3/RE2Zr2O7 (RE = La, Nd, Sm, Eu, Gd, and Dy) composites with a eutectic composition that not only significantly enhanced the fracture toughness by more than 40% relative to that of RE2Zr2O7 but also exhibited improved resistance to CMAS corrosion. The increase in toughness arises from multiple mechanisms, such as ferroelastic toughening, fine-grain strengthening, and residual stress toughening, all of which trigger more crack defects and energy consumption. Additionally, the CMAS penetration depth of the REAlO3/RE2Zr2O7 composites is approximately 36% lower than that of RE2Zr2O7. Al–O constituents in composites can capture CaO, SiO2, and MgO in CMAS melts and increase their viscosity, resulting in enhanced CMAS corrosion resistance. The thermophysical properties of the REAlO3/RE2Zr2O7 composites were also investigated, and their coefficient of thermal expansion and thermal conductivity are comparable to those of 7–8 wt %Y2O3 partially stabilized ZrO2 (YSZ), indicating their potential as TBC materials.

Summary: Motor neurons are highly polarized, and their axons extend over great distances to form connections with myofibers via neuromuscular junctions (NMJs). Local translation at the NMJs in vivo has not been identified. Here, we utilized motor neuron-labeled RiboTag mice and the TRAP (translating ribosome affinity purification) technique to spatiotemporally profile the translatome at NMJs. We found that mRNAs associated with glucose catabolism, synaptic connection, and protein homeostasis are enriched at presynapses. Local translation at the synapse shifts from the assembly of cytoskeletal components during early developmental stages to energy production in adulthood. The mRNA of neuronal Agrin (Agrn), the key molecule for NMJ assembly, is present at motor axon terminals and locally translated. Disrupting the axonal location of Agrn mRNA causes impairment of synaptic transmission and motor functions in adult mice. Our findings indicate that spatiotemporal regulation of mRNA local translation at NMJs plays critical roles in synaptic transmission and motor functions in vivo.

BackgroundInflammaging, an immune status characterized by a sustained increase in pro-inflammatory markers and a decline in anti-inflammatory mechanisms, is a critical risk factor in the development of sarcopenia. Landscapes of the causal relationships between immunity and sarcopenia are needed to understand the mechanism of sarcopenia and provide novel treatments comprehensively.MethodsWe used Mendelian Randomization (MR) as the basic method in this study. By setting immune proteins, immune cells, and sarcopenia as exposures and outcomes alternatively, and then combining them in different directions, we potentially estimated their causal relationships and directions and subsequently mapped the comprehensive causal landscape based on this information efficiently. To further understand the network, we developed a method based on rank-sums to integrate multiple algorithms and identify the key immune cells and proteins.ResultsMore than 1,000 causal relationships were identified between immune cell phenotypes, proteins, and sarcopenia traits (p < 0.05), and the causal maps of these linkages were established. In the threshold of FDR < 0.05, hundreds of causal linkages were still significant. The final comprehensive map included 13 immune cell phenotypes and 8 immune proteins. The star factors in the final map included EM CD8br %CD8br, EM DN (CD4- CD8-) %DN, SIRT2, and so on.ConclusionBy reading the landscapes in this study, we may not only find the factors and the pathways that have been reported and proven but also identify multiple novel immunity cell phenotypes and proteins with enriched upstream and downstream pathways.

Abstract Esophageal adenocarcinoma is the most common histological subtype of esophageal cancer in Western countries and shows poor prognosis with rapid growth. EAC is characterized by a strong male predominance and racial disparity. EAC is up to fivefold more common among Whites than Blacks, yet Black patients with EAC have poorer survival rates. The racial disparity remains largely unknown, and there is limited knowledge of mutations in EAC regarding racial disparities. We used whole-exome sequencing to show somatic mutation profiles derived from tumor samples from 18 EAC male patients. We identified three molecular subgroups based on the pre-defined esophageal cancer-specific mutational signatures. Group 1 is associated with age and NTHL1 deficiency-related signatures. Group 2 occurs primarily in Black patients and is associated with signatures related to DNA damage from oxidative stress and NTHL1 deficiency-related signatures. Group 3 is associated with defective homologous recombination-based DNA often caused by BRCA mutation in White patients. We observed significantly mutated race related genes (LCE2B in Black, SDR39U1 in White) were (q-value

Abstract Background/Purpose Risk factors for re-bleeding and death after acute variceal bleeding (AVB) in cirrhotic HCC patients are not fully understood.We aimed to (1) explore how the combination of high-risk esophageal varices, HCC status, and portal vein tumor thrombus (i.e., HCC Portal Hypertension Imaging Score [HCCPHTIS]) helps predict increased risk of variceal re-bleeding and mortality; (2) assess predictability and reproducibility of the identified variceal re-bleeding rules. Methods This prospective study included 195 HCC patients with first-time AVB and liver cirrhosis, and conducted multivariable Cox regression analysis and Kaplan-Meier analysis. Receiver operating characteristic curve analysis was calculated to find the optimal sensitivity, specificity, and cutoff values of the variables. The reproducibility of the results obtained was verified in a different but related group of patients. Results 56 patients (28.7%) had re-bleeding within 6 weeks; HCCPHTIS was an independent risk factor for variceal re-bleeding after AVB (Odd ratio, 2.330; 95% confidence interval: 1.728–3.142, p 3 was 66.2%, sensitivity 83.9%, and specificity 82.3%. HCCPHTIS area under the curve was higher than Child-Pugh score (89% vs. 75%, p 4 was associated with increased risk of death within 6 weeks after AVB (p 3 is a strong predictor of variceal re-bleeding within the first 6 weeks. However, patients with HCCPHTIS > 4 were at increased risk of death within 6 weeks.

Abstract Plants are capable of altering root growth direction to curtail exposure to a saline environment (termed halotropism). The root cap that surrounds root tip meristematic stem cells plays crucial roles in perceiving and responding to environmental stimuli. However, how the root cap mediates root halotropism remains undetermined. Here, we identified a root cap-localized NAC transcription factor, SOMBRERO (SMB), that is required for root halotropism. Its effect on root halotropism is attributable to the establishment of asymmetric auxin distribution in the lateral root cap (LRC) rather than to the alteration of cellular sodium equilibrium or amyloplast statoliths. Furthermore, SMB is essential for basal expression of the auxin influx carrier gene AUX1 in LRC and for auxin redistribution in a spatiotemporally-regulated manner, thereby leading to directional bending of roots away from higher salinity. Our findings uncover an SMB-AUX1-auxin module linking the role of the root cap to the activation of root halotropism.

Abstract Background RNA secondary structure (RSS) can influence the regulation of transcription, RNA processing, and protein synthesis, among other processes. 3′ untranslated regions (3′ UTRs) of mRNA also hold the key for many aspects of gene regulation. However, there are often contradictory results regarding the roles of RSS in 3′ UTRs in gene expression in different organisms and/or contexts. Results Here, we incidentally observe that the primary substrate of miR159a (pri-miR159a), when embedded in a 3′ UTR, could promote mRNA accumulation. The enhanced expression is attributed to the earlier polyadenylation of the transcript within the hybrid pri-miR159a-3′ UTR and, resultantly, a poorly structured 3′ UTR. RNA decay assays indicate that poorly structured 3′ UTRs could promote mRNA stability, whereas highly structured 3′ UTRs destabilize mRNA in vivo. Genome-wide DMS-MaPseq also reveals the prevailing inverse relationship between 3′ UTRs’ RSS and transcript accumulation in the transcriptomes of Arabidopsis, rice, and even human. Mechanistically, transcripts with highly structured 3′ UTRs are preferentially degraded by 3′–5′ exoribonuclease SOV and 5′–3′ exoribonuclease XRN4, leading to decreased expression in Arabidopsis. Finally, we engineer different structured 3′ UTRs to an endogenous FT gene and alter the FT-regulated flowering time in Arabidopsis. Conclusions We conclude that highly structured 3′ UTRs typically cause reduced accumulation of the harbored transcripts in Arabidopsis. This pattern extends to rice and even mammals. Furthermore, our study provides a new strategy of engineering the 3′ UTRs’ RSS to modify plant traits in agricultural production and mRNA stability in biotechnology.

Abstract Abnormal inflammatory states in the brain are associated with a variety of brain diseases. The dynamic changes in the number and function of immune cells in cerebrospinal fluid (CSF) are advantageous for the early prediction and diagnosis of immune diseases affecting the brain. The aggregated factors and cells in inflamed CSF may represent candidate targets for therapy. The physiological barriers in the brain, such as the blood‒brain barrier (BBB), establish a stable environment for the distribution of resident immune cells. However, the underlying mechanism by which peripheral immune cells migrate into the brain and their role in maintaining immune homeostasis in CSF are still unclear. To advance our understanding of the causal link between brain diseases and immune cell status, we investigated the characteristics of immune cell changes in CSF and the molecular mechanisms involved in common brain diseases. Furthermore, we summarized the diagnostic and treatment methods for brain diseases in which immune cells and related cytokines in CSF are used as targets. Further investigations of the new immune cell subtypes and their contributions to the development of brain diseases are needed to improve diagnostic specificity and therapy.

With the background of carbon neutrality, the resource and energy utilization of excess sludge (ES) have become the focus of future research. The pyrolysis of ES can produce biochar and enrich phosphorus (P). In this paper, the existing forms and recovery efficiencies of P in biochar from ES (BCES) were investigated. The results showed that the total phosphorus (TP) content of BCES at 850 °C was 65.1 mg/g, and the inorganic phosphorus (IP) content was 64.2 mg/g. The TP content of BCES was two times heavier than that of ES. The main ingredient of ES was quartz (SiO2), while the main phases of BCES were quartz (SiO2) and aluminum phosphate (AlPO4) at 650 –850 °C, and P mainly existed in the form of AlPO4. When the pyrolysis temperature was 800 and 850 °C, two new minerals appeared: Ca5(PO4)3OH and CaZn2(PO4)2·2H2O. Based on the conditions of a leaching time of 150 min, a H2SO4 concentration of 0.2 mol/L, a stirring rate of 220 rpm and a liquid–solid ratio of 50 mL/g, the leaching efficiency of P in BCES was found to be 100%. The pyrolysis temperature had no effect on leaching efficiencies of P; however, a higher pyrolysis temperature promoted metal leaching content. ;

The high salinity, humidity, and oxygen-rich environments of coastal marine areas pose serious corrosion risks to metal structures, particularly in equipment such as ships, offshore platforms, and port facilities. With the development of artificial intelligence technologies, image recognition-based intelligent detection methods have provided effective support for corrosion monitoring in marine engineering structures. This study aims to explore the performance improvements of different modified YOLOv5 models in small-object corrosion detection tasks, focusing on five IoU-based improved loss functions and their optimization effects on the YOLOv5 model. First, the study utilizes corrosion testing data from the Zhoushan seawater station of the China National Materials Corrosion and Protection Science Data Center to construct a corrosion image dataset containing 1266 labeled images. Then, based on the improved IoU loss functions, five YOLOv5 models were constructed: YOLOv5-NWD, YOLOv5-Shape-IoU, YOLOv5-WIoU, YOLOv5-Focal-EIoU, and YOLOv5-SIoU. These models, along with the traditional YOLOv5 model, were trained using the dataset, and their performance was evaluated using metrics such as precision, recall, F1 score, and FPS. The results showed that YOLOv5-NWD performed the best across all metrics, with a 7.2% increase in precision and a 2.2% increase in F1 score. The YOLOv5-Shape-IoU model followed, with improvements of 4.5% in precision and 2.6% in F1 score. In contrast, the performance improvements of YOLOv5-Focal-EIoU, YOLOv5-SIoU, and YOLOv5-WIoU were more limited. Further analysis revealed that different IoU ratios significantly affected the performance of the YOLOv5-NWD model. Experiments showed that the 4:6 ratio yielded the highest precision, while the 6:4 ratio performed the best in terms of recall, F1 score, and confusion matrix results. In addition, this study conducted an assessment using four datasets of different sizes: 300, 600, 900, and 1266 images. The results indicate that increasing the size of the training dataset enables the model to find a better balance between precision and recall, that is, a higher F1 score, while also effectively improving the model’s processing speed. Therefore, the choice of an appropriate IoU ratio should be based on specific application needs to optimize model performance. This study provides theoretical support for small-object corrosion detection tasks, advances the development of loss function design, and enhances the detection accuracy and reliability of YOLOv5 in practical applications.

Stripe rust, induced by Puccinia striiformis f. sp. tritici (Pst), is one of the most destructive fungal diseases of wheat worldwide. Thinopyrum ponticum, a significant wild relative for wheat improvement, exhibits innate immunity to this disease. To transfer the stripe rust resistance gene from Th. ponticum to wheat, two translocation lines, SN21171 and SN52684, were produced through distant hybridization techniques. Disease evaluation results showed that these two lines were immune to Pst species CYR32 at the adult plant stage. Molecular cytogenetic analyses and specific intron-targeting markers amplification results revealed that SN21171 and SN52684 harbor several T3Eb-3DS·3DL and T1Eb-1BS·1BL translocation chromosomes. Furthermore, the comparison of the chromosome karyotype from two translocation lines and their recurrent parent YN15, revealed that structural variation occurred in chromosomes 2A, 5A, 2B, 4B, 5B, and 6B in SN21171 and chromosomes 5A, 3B, 4B, 5B, 6B, and 7B in SN52684. Agronomic trait assessments uncovered advantageous properties in both lines, with SN21171 matching the recurrent parent and SN52684 exhibiting elevated higher grain number per main spike and increased thousand grain weight. These two translocation lines and specific markers may apply to wheat stripe rust-resistance breeding.

The air injection method serves as a liquefaction mitigation technique to improve the liquefaction resistance of the foundations by decreasing the degree of saturation. To investigate the desaturation effect of this technique in various soil strata of the foundation, thin plate model tests were conducted, considering the impacts of gradation and relative density, to visualize the air migration process and distribution. The findings reveal the following: (1) The air migration process, delineated by air injection parameters, comprises four distinct phases, with stages II and III notably influenced by the pore structure; (2) air migration is governed by the pore throat dimensions, particle arrangement, and connectivity within the pore structure, exhibiting two predominant patterns: channel flow, primarily driven by inertial forces, and chamber flow, predominantly influenced by viscous and capillary forces; (3) referring to the air injection port, the gas phase distribution within the sand samples is consistent in the horizontal direction but not in the vertical direction. The concentration area and uniformity of the gas phase distribution are controlled by the pore structure. These results suggest potential enhancements in the positioning of air injection ports within complex soil layers, as well as improvements in the construction process, both aimed at optimizing the desaturation effect.

Portuguese oyster (Magallana angulata) is one of the most important shellfish species worldwide. Although significant improvements in growth have been achieved through artificial selection breeding, the genetic basis underlying these traits remains unclear. Thus, this study aimed to (i) estimate variation and heritability for growth-related traits and (ii) identify SNPs and candidate genes associated with growth traits in Portuguese oyster. Five growth-related traits, including shell height (SH), shell length (SL), shell width (SW), whole weight (WW), and soft tissue weight (STW), were measured and analyzed in 114 one-year-old individuals from a cultivated population in Fujian Province, China. Through whole-genome sequencing and genotyping, we obtained 8,183,713 high-quality SNPs. Based on the genomic relationship matrix, heritability for the five traits was estimated, ranging from 0.071 to 0.695. Through genome-wide association analysis (GWAS), a total of nine SNPs were identified as significantly or suggestively associated with one of the growth-related traits, each explaining phenotypic variation ranging from 14.13% to 18.56%. Differentially expressed genes (DEGs) between individuals with extreme phenotypes were identified using comparative transcriptome analysis, ranging from 868 to 2274 for each trait. By combining GWAS and comparative transcriptome analysis, a total of seven candidate genes were identified, with biological functions related to growth inhibition, stress response, cell cycle regulation, and immune defense. The associations between the candidate genes and the growth-related traits were validated by using single-marker association analysis in other populations. Based on SNPs in these candidate genes, 16 haplotypes associated with growth-related traits were obtained. This study contributes to a deeper understanding of the genetic mechanisms of growth traits, and provides a theoretical basis and genetic markers for the breeding of fast-growing strains of the Portuguese oyster.

Abstract Pooling operations, essential for neural networks, reduce feature map dimensions while preserving key features and enhancing spatial invariance. Traditional pooling methods often miss the feature maps' alternating currentcomponents. This study introduces a novel global pooling technique utilizing spectral self‐attention, leveraging the discrete cosine transform for spectral analysis and a self‐attention mechanism for assessing frequency component significance. This approach allows for efficient feature synthesis through weighted averaging, significantly boosting TOP‐1 accuracy with minimal parameter increase, outperforming existing models.

Hydrogel presents a three-dimensional polymer network with high water content. Over the past decade, hydrogel has developed from static material to intelligent material with controllable response. Various stimuli are involved in the formation of hydrogel network, among which photo-stimulation has attracted wide attention due to the advantages of controllable conditions, which has a good application prospect in the treatment of ophthalmic diseases. This paper reviews the application of photo-crosslink hydrogels in ophthalmology, focusing on the types of photo-crosslink hydrogels and their applications in ophthalmology, including drug delivery, tissue engineering and 3D printing. In addition, the limitations and future prospects of photo-crosslink hydrogels are also provided.

The Blasingame method is a valuable tool for analysing the diminishing production challenge in the presence of variable bottomhole pressure and diverse production conditions. It is essential to highlight that the Blasingame method views the closed reservoir as the outer boundary condition for its model. This paper introduces the concept of the equivalent well control radius and formulates the Blasingame method based on the fluid flow characteristics inherent in twin-well production, taking into account the influence of inter-well interference. This study provides an in-depth analysis of production variations in reservoirs with inter-well interference by examining Blasingame type-curve definitions of the dimensionless parameters. Additionally, it investigates key factors impacting production, including neighbouring wells’ production, distance, and opening time: variations in all three parameters lead to different levels of interference between wells, which manifests itself in the regularised production integral derivative curve with different lengths and heights of convexity. Numerical simulations employing orthogonality are conducted to validate the reliability of this method. The results of these simulations offer theoretical support for the precise evaluation of reservoirs facing similar challenges.

Abstract Background The growing demand for electrophysiology (EP) treatment in China presents a challenge for current EP care delivery systems. This study constructed a discrete event simulation (DES) model of an inpatient EP care delivery process, simulating a generalized inpatient journey of EP patients from admission to discharge in the cardiology department of a tertiary hospital in China. The model shows how many more patients the system can serve under different resource constraints by optimizing various phases of the care delivery process. Methods Model inputs were based on and validated using real-world data, simulating the scheduling of limited resources among competing demands from different patient types. The patient stay consists of three stages, namely: the pre-operative stay, the EP procedure, and the post-operative stay. The model outcome was the total number of discharges during the simulation period. The scenario analysis presented in this paper covers two capacity-limiting scenarios (CLS): (1) fully occupied ward beds and (2) fully occupied electrophysiology laboratories (EP labs). Within each CLS, we investigated potential throughput when the length of stay or operative time was reduced by 10%, 20%, and 30%. The reductions were applied to patients with atrial fibrillation, the most common indication accounting for almost 30% of patients. Results Model validation showed simulation results approximated actual data (137.2 discharges calculated vs. 137 observed). With fully occupied wards, reducing pre- and/or post-operative stay time resulted in a 1–7% increased throughput. With fully occupied EP labs, reduced operative time increased throughput by 3–12%. Conclusions Model validation and scenario analyses demonstrated that the DES model reliably reflects the EP care delivery process. Simulations identified which phases of the process should be optimized under different resource constraints, and the expected increases in patients served.

Automatic registration of unordered point clouds is the prerequisite for urban reconstruction. However, most of the existing technologies still suffer from some limitations. On one hand, most of them are sensitive to noise and repetitive structures, which makes them infeasible for the registration of large-scale point clouds. On the other hand, most of them dealing with point clouds with limited overlaps and unpredictable location. All these problems make it difficult for registration technology to obtain qualified results in outdoor point cloud. To overcome these limitations, this paper presents a grid graph-based point cloud registration (GGR) algorithm to align pairwise scans. First, point cloud is divided into a set of 3D grids. We propose a voting strategy to measure the similarity between two grids based on feature descriptor, transforming the superficial correspondence into 3D grid expression. Next, a graph matching is proposed to capture the spatial consistency from putative correspondences, and graph matching hierarchically refines the corresponding grids until obtaining point-to-point correspondences. Comprehensive experiments demonstrated that the proposed algorithm obtains good performance in terms of successful registration rate, rotation error, translation error, and outperformed the state-of-the-art approaches.

Abstract Background and objectives This study focused on changes in intestinal motility during different sleep stages based on long-term bowel sounds. Methods A modified higher order statistics algorithm was devised to identify the effective bowel sound segments. Next, characteristic values (CVs) were extracted from each bowel sound segment, which included 4 time-domain, 4 frequency-domain and 2 nonlinear CVs. The statistical analysis of these CVs corresponding to the different sleep stages could be used to evaluate the changes in intestinal motility during sleep. Results A total of 6865.81 min of data were recorded from 14 participants, including both polysomnographic data and bowel sound data which were recorded simultaneously from each participant. The average accuracy, sensitivity and specificity of the modified higher order statistics detector were 96.46 ± 2.60%, 97.24 ± 2.99% and 94.13 ± 4.37%. In addition, 217088 segments of effective bowel sound corresponding to different sleep stages were identified using the modified detector. Most of the CVs were statistically different during different sleep stages ( $$p

Coastal areas face severe corrosion issues, posing significant risks and economic losses to equipment, personnel, and the environment. YOLO v5, known for its speed, accuracy, and ease of deployment, has been employed for the rapid detection and identification of marine corrosion. However, corrosion images often feature complex characteristics and high variability in detection targets, presenting significant challenges for YOLO v5 in recognizing and extracting corrosion features. To improve the detection performance of YOLO v5 for corrosion image features, this study investigates two enhanced models: EfficientViT-NWD-YOLO v5 and Gold-NWD-YOLO v5. These models specifically target improvements to the backbone and neck structures of YOLO v5, respectively. The performance of these models for corrosion detection is analyzed in comparison with both YOLO v5 and NWD-YOLO v5. The evaluation metrics including precision, recall, F1-score, Frames Per Second (FPS), pre-processing time, inference time, non-maximum suppression time (NMS), and confusion matrix were used to evaluate the detection performance. The results indicate that the Gold-NWD-YOLO v5 model shows significant improvements in precision, recall, F1-score, and accurate prediction probability. However, it also increases inference time and NMS time, and decreases FPS. This suggests that while the modified neck structure significantly enhances detection performance in corrosion images, it also increases computational overhead. On the other hand, the EfficientViT-NWD-YOLO v5 model shows slight improvements in precision, recall, F1-score, and accurate prediction probability. Notably, it significantly reduces inference and NMS time, and greatly improves FPS. This indicates that modifications to the backbone structure do not notably enhance corrosion detection performance but significantly improve detection speed. From the application perspective, YOLO v5 and NWD-YOLO v5 are suitable for routine corrosion detection applications. Gold-NWD-YOLO v5 is better suited for scenarios requiring high precision in corrosion detection, while EfficientViT-NWD-YOLO v5 is ideal for applications needing a balance between speed and accuracy. The findings can guide decision making for corrosion health monitoring for critical infrastructure in coastal areas.

This paper is mainly devoted to studying the deployment problem of a multi-static radar system (MSRS) within a non-connected deployment region using multi-objective particle swarm optimization (MOPSO). By modeling and reformulating the problem, it can be represented as a multi-objective mixed integer programming (MOMIP), which eliminates the need for additional constraints. To enhance the algorithm performance, integer variables and continuous ones are treated separately employing multiple velocity formulas. The velocity formulas for integer variables are modified using the sigmoid function and genetic operation, leading to the proposal of two MSRS deployment algorithms, namely MOPSO-Sigmoid and MOPSO-Gene. To evaluate the performance of the proposed algorithms, they are compared with two existing MOPSO-based algorithms. The first algorithm is the MSRS deployment algorithm for the non-connected deployment region that addresses the additional constraint problem model. The second algorithm is based on an existing conventional MOPSO algorithm and addresses the equivalent MOMIP problem model. A numerical study demonstrates that MOPSO-Sigmoid and MOPSO-Gene exhibit promising efficiency and effectiveness.

The prediction of fuel consumption and Carbon Intensity Index (CII) of ships is crucial for optimizing decarbonization strategies in the maritime industry. This study proposes a ship fuel consumption prediction model based on the Long Short-Term Memory with Self-Attention Mechanism (SA-LSTM). The model is applied to a container ship of 2400 TEU to predict its hourly fuel consumption, hourly CII, and annual CII rating. Four different feature sets are selected from these data sources and are used as inputs for SA-LSTM and another ten models. The results demonstrate that the SA-LSTM model outperforms the other models in prediction accuracy. Specifically, the Mean Absolute Percentage Error (MAPE) for fuel consumption predictions using the SA-LSTM model is reduced by up to 20% compared to the XGBoost and by up to 12% compared to the LSTM model. Additionally, the SA-LSTM model achieves the highest accuracy in annual CII predictions.

To explore the effects of crushing processes on the rheological properties and edible quality of minced meat, blunt cutting tool and sharp cutting tool on two devices of beating machine and chopping machine were used to prepare minced meat. The pH value, salt soluble protein content, protein secondary structure, particle size distribution, color, stability and cooking loss, water holding capacity, texture characteristics and microstructure of minced meat gel were investigated. The results showed that the four crushing processes had different degrees of muscle fiber fragmentation, resulting in different properties of the low-fat minced meat and the resulting gel. Compared with the beater, the low-fat minced meat treated by the chopper had a higher G′ value in the temperature scanning. The low-fat minced meat beaten with blunt knife had the lowest viscosity and showed poor stability in frequency scanning. The high intensity cutting action of the chopper resulted in a lower end temperature and smaller particle size of the broken low-fat minced meat, and higher water holding capacity of the low-fat minced meat gel. Compared with the other three processes, the blunt knife chopped low-fat minced meat had the highest redness value (15.95), pH value (6.66), salt-soluble protein content (77.05 mg/mL), relative content of β-fold (43.71%), and the low-fat minced meat gel had the lowest cooking loss (17.48%), the highest hardness (4147.72 g), gumminess (2883.72), chewiness (2496.02 g), sensory scores, which may be attributed to the tighter microstructure of low-fat minced meat gel formed by this treatment with moderate muscle fragmentation. Therefore, the blunt chopping is suitable for the crushing production of low-fat minced meat, which can improve its salt-soluble protein content, relative content of β-sheet, redness, water holding capacity and texture properties.

Abstract Linear ubiquitination is a specific post-translational modification in which ubiquitin is linked through M1 residue to form multiple types of polyubiquitin chains on substrates in order to regulate cellular processes. LUBAC comprised by HOIP, HOIL-1L, and SHARPIN as a sole E3 ligase catalyzes the generation of linear ubiquitin chains, and it is simultaneously adjusted by deubiquitinases such as OTULIN and CYLD. Several studies have shown that gene mutation of linear ubiquitination in mice accompanied by different modalities of cell death would develop relative diseases. Cell death is a fundamental physiological process and responsible for embryonic development, organ maintenance, and immunity response. Therefore, it is worth speculating that linear ubiquitin mediated signaling pathway would participate in different diseases. The relative literature search was done from core collection of electronic databases such as Web of Science, PubMed, and Google Scholar using keywords about main regulators of linear ubiquitination pathway. Here, we summarize the regulatory mechanism of linear ubiquitination on cellular signaling pathway in cells with apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis. Intervening generation of linear ubiquitin chains in relative signaling pathway to regulate cell death might provide novel therapeutic insights for various human diseases.

Abstract Introduction The aim of this work is to determine the interocular differences in peripapillary retinal nerve fiber layer (p-RNFL) thickness and its associations among school children in Hong Kong. Methods We conducted a population-based study including 4034 children aged 6–8 years from the Hong Kong Children Eye Study (HKCES). All participants received comprehensive ocular examinations where p-RNFL thickness was measured using spectral-domain optical coherence tomography (SD-OCT). The degree of symmetry between both eyes was analyzed and represented by intraclass correlation coefficient (ICC) values. Multivariable linear regression analysis was used to investigate the associations between ocular and systemic factors with p-RNFL thickness difference. Results The study included 4034 children with a mean age of 7.61 ± 0.98 years. The mean global p-RNFL thickness was 106.60 ± 9.41 μm in right eyes and 105.99 ± 9.30 μm in left eyes. The ICC for global p-RNFL difference was 0.866 (95% CI 0.858–0.873, p

Abstract Traditional ecological restoration technology has many challenges in dealing with the greening of steep rock slopes, especially in the case of serious soil erosion. In order to overcome these problems, this study aims to organically combine the traditional protection and reinforcement technology with the new vegetation restoration technology, and put forward a new ecological protection technology of composite vegetation concrete to realize the comprehensive protection and ecological restoration of rocky slopes. In this paper, by analyzing the mechanism and existing problems of ecological protection of rocky slopes, the design requirements of composite vegetation concrete are studied in detail, and the related construction technology is expounded. In the experiment, the vegetation coverage and incidence were systematically analyzed, and the results showed that some samples showed high vegetation coverage and low incidence. Comprehensive consideration shows that the average vegetation coverage rate is 93.7%, and the average incidence rate is only 5.21%, which all meet the corresponding standards. The composite vegetation concrete technology has a wide application prospect in stone slope protection, which significantly improves the slope vegetation coverage and compressive strength, and effectively promotes the slope greening and ecological sustainable development. Through this study, we aim to convey to readers that the comprehensive method of combining traditional and innovative technologies can achieve encouraging results in solving the problem of ecological restoration of steep rock slopes, and provide useful reference for engineering practice in similar environments.

Abstract Colorectal cancer (CRC) patients with liver metastases usually obtain less benefit from immunotherapy, and the underlying mechanisms remain understudied. Here, we identify that fibrinogen-like protein 1 (FGL1), secreted from cancer cells and hepatocytes, facilitates the progression of CRC in an intraportal injection model by reducing the infiltration of T cells. Mechanistically, tumor-associated macrophages (TAMs) activate NF-ĸB by secreting TNFα/IL-1β in the liver microenvironment and transcriptionally upregulate OTU deubiquitinase 1 (OTUD1) expression, which enhances FGL1 stability via deubiquitination. Disrupting the TAM-OTUD1-FGL1 axis inhibits metastatic tumor progression and synergizes with immune checkpoint blockade (ICB) therapy. Clinically, high plasma FGL1 levels predict poor outcomes and reduced ICB therapy benefits. Benzethonium chloride, an FDA-approved antiseptics, curbs FGL1 secretion, thereby inhibiting liver metastatic tumor growth. Overall, this study uncovers the critical roles and posttranslational regulatory mechanism of FGL1 in promoting metastatic tumor progression, highlighting the TAM-OTUD1-FGL1 axis as a potential target for cancer immunotherapy.

Objective: Tianhuang Formula (THF) is a hospital formula summarized by Professor Jiao Guo's 30 years of clinical experience. Some studies have shown that it can alleviate dyslipidemia in the body. The purpose of this study is to confirm whether THF can improve non-alcoholic fatty liver diseases (NAFLD) in type 2 diabetic mice induced by high-fat diet (HFD)/streptomycin (STZ) and to clarify its potential mechanism. Methods: After induction of diabetes, mice were administrated with THF (60 ​mg/kg or 120 ​mg/kg) once daily for 10 weeks. Blood glucose (FBG), glucose tolerance, and insulin resistance (IR) were assayed by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Blood lipids, alanine transaminase (ALT), and aspartate transaminases (AST) were detected. Serum fasting insulin (INS) and adiponectin (APN) levels were measured using ELISA. Histological changes in liver and pancreatic islets were observed by H&E staining, followed by Oil Red O staining for liver lipid quantification and periodic acid-Schiff (PAS) staining to detect glycogen accumulation. Western blotting detected the levels of fatty cardiolipin synthase 1 (CRLS1), transcription factor activator 3 (ATF3), and carbohydrate-responsive element binding protein (ChREBP) in the liver. The mRNA transcripts of hepatic inflammatory factors, lipogenesis and lipolysis-related genes, and gluconeogenic enzyme-phosphoenolpyruvate carboxykinase (PEPCK), CRLS1, ATF3, and ChREBP mRNA levels were evaluated by RT-qPCR. Results: THF restored impaired glucose tolerance and insulin resistance, respectively. There was an improvement in HFD/STZ-induced liver and islet damage, high serum HDL-C and ANP levels, and a significant decrease in FBG, total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), FFA, INS, ALT, and AST, and lipid droplet counts in the T2DM mice treated with THF. CREBBP binding protein ATF3 mediated the insulin resistance signaling pathway, which regulated glucose and lipid metabolism in the liver. THF upregulated CRLS1, and ChREBP downregulated the expression of downstream ATF3 in the liver. RT-qPCR analysis also systemically indicated that THF suppressed the pathway and key regulators related to inflammation, lipid accumulation, and gluconeogenesis. Conclusion: Our findings demonstrated that THF ameliorated lipid profile and attenuated liver steatosis in T2DM mice through CRLS1-ATF3/ChREBP pathway activation.

To study the effect of dry ice on the performance of alkali-activated binders, we added dry ice to an alkali-activated slag (AAS). The addition amount was set to 5%, 10%, and 15% of the slag mass, depending on the amount of CO2 emitted by the material used in the preparation process. Microscopic experiments were performed to analyze the effect of dry ice on the hydration products of the AAS paste; transmission electron microscopy and scanning electron microscopy were used to observe the morphology of the hydration products. Furthermore, experimental tests for the compressive strength, ultrasonic pulse velocity, and electrical resistivity were performed. The results showed that compared with the content of the overall reaction products, the effect of dry ice on the reaction rate was more evident. The addition of dry ice slowed the hydration of the AAS, and the production of the hydration products, such as calcium aluminum silicate hydrate (C-A-S-H) gels, was significantly reduced in the early stage (1 d). Experiments on the strength showed that adding more than 5% dry ice degraded the early mechanical properties of the AAS. However, the mechanical properties of the AAS with dry ice added in the middle (3 and 7 d) and late (28 d) stages rapidly improved because the dry ice was added to the AAS to form potassium and calcium carbonate. In the middle (3 and 7 d) and late (28 d) stages, CO32− underwent a carbonation reaction to form carbonate compounds, enhancing the mechanical properties of the AAS.

With the development of globalization and artificial intelligence, as well as the outbreak of COVID-19, unmanned vehicles have played an important role in cargo distribution. In order to better analyze the research directions of unmanned vehicle distribution, this paper summarizes the models and algorithms of unmanned vehicle distribution optimization. The research results show that most of the studies have established the goal of optimizing the total costs or travel time. Many researchers have begun to study multi-objective optimization problems, but there are certain limitations, so some studies convert these problems into single-objective optimization for solving, such as converting time and energy consumption into cost, waiting time into distance, and time delay into penalty cost. With the development of unmanned vehicle distribution technology, in future research, a multi-objective model with the lowest cost, the shortest distance and the best security should be established and solved. Most studies have proposed heuristic algorithms for solving the unmanned vehicle distribution problem, and improved optimization solutions have been obtained. In order to ensure the diversity of solution methods, and give consideration to solution time and solution quality, hybrid methods with other algorithms will be a future research direction, for example, the combination of heuristic algorithm and exact algorithm. With the gradual deepening of research, integrated distribution of multiple types of unmanned equipment will become the focus of future research.

Abstract Background Obesity increases breast cancer risk and breast cancer-specific mortality, particularly for people with estrogen receptor (ER)-positive tumors. Body mass index (BMI) is used to define obesity, but it may not be the best predictor of breast cancer risk or prognosis on an individual level. Adult weight gain is an independent indicator of breast cancer risk. Our previous work described a murine model of obesity, ER-positive breast cancer, and weight gain and identified fibroblast growth factor receptor (FGFR) as a potential driver of tumor progression. During adipose tissue expansion, the FGF1 ligand is produced by hypertrophic adipocytes as a stimulus to stromal preadipocytes that proliferate and differentiate to provide additional lipid storage capacity. In breast adipose tissue, FGF1 production may stimulate cancer cell proliferation and tumor progression. Methods We explored the effects of FGF1 on ER-positive endocrine-sensitive and resistant breast cancer and compared that to the effects of the canonical ER ligand, estradiol. We used untargeted proteomics, specific immunoblot assays, gene expression profiling, and functional metabolic assessments of breast cancer cells. The results were validated in tumors from obese mice and breast cancer datasets from women with obesity. Results FGF1 stimulated ER phosphorylation independently of estradiol in cells that grow in obese female mice after estrogen deprivation treatment. Phospho- and total proteomic, genomic, and functional analyses of endocrine-sensitive and resistant breast cancer cells show that FGF1 promoted a cellular phenotype characterized by glycolytic metabolism. In endocrine-sensitive but not endocrine-resistant breast cancer cells, mitochondrial metabolism was also regulated by FGF1. Comparison of gene expression profiles indicated that tumors from women with obesity shared hallmarks with endocrine-resistant breast cancer cells. Conclusions Collectively, our data suggest that one mechanism by which obesity and weight gain promote breast cancer progression is through estrogen-independent ER activation and cancer cell metabolic reprogramming, partly driven by FGF/FGFR. The first-line treatment for many patients with ER-positive breast cancer is inhibition of estrogen synthesis using aromatase inhibitors. In women with obesity who are experiencing weight gain, locally produced FGF1 may activate ER to promote cancer cell metabolic reprogramming and tumor progression independently of estrogen.