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Abstract Background Human responses and acclimation to the environmental stresses of high altitude and low oxygen are multifaceted and regulated by multiple genes. However, the mechanism of how the body adjusts in a low-oxygen environment is not yet clear. Results Hence, we performed RNA sequencing (RNA-seq) and ATAC sequencing (ATAC-seq) to observe the changes of transcriptome and chromatin accessibility in the peripheral blood of eight individuals at 1 h post adaptation in a simulated plateau environment with 3500 m and 4500 m altitude, respectively. Differential expression analysis and the Boruta algorithm identified differentially expressed genes (DEGs) and differentially accessible regions (DARs) associated with hypoxia adaptation. Specifically, RNA-seq identified 93 and 7 DEGs after 1 h post adaptation with 3500 m altitude and 45 and 8 DEGs after 1 h adaptation with 4500 m. Additionally, ATAC-seq screened 12 and 4 DARs in 3500 m altitude adaption and 15 and 5 DARs in 4500 m altitude adaption. Moreover, the combined analysis of RNA-seq and ATAC-seq revealed that 10 hub genes were independently identified from the protein–protein interaction (PPI) network for each altitude. Gene enrichment analysis displayed that most hub genes were related with hypoxia pathways. Conclusions Our results can provide the reference for the early response of the organism to hypoxic adaptation.

Considering job resources of college teachers as a mediating variable, this study analyzed the relationship between job crafting and job engagement and established a model of the mechanism underlying the effects of job crafting on job engagement. This theoretical hypothesis model was empirically validated using 300 valid questionnaires completed by college teachers in Hebei Province, China, who were selected through convenience sampling. Job crafting directly affected job resources, and job resources exerted a direct effect on job engagement. However, job resources played a full mediating role in the relationship between job crafting and job engagement after it was added as a mediating variable.

1,3,5-Triamino-2,4,6-trinitrobenzene (TATB) is a highly insensitive energetic material used in applications where extreme safety is required primarily. Ensuring the safe use of TATB as planned relies on research into intrinsic behavior under shock loading, which needs further investigation. Here, we study the shock response in oriented supercells of the highly anisotropic TATB based on reactive molecular dynamics simulations and multi-scale shock technique. Results demonstrate that the mechanical response primarily consists of adiabatic compression and plastic deformation. The system is more susceptible to be compressed rather than plastic deformed when shocked direction to the molecular layer at a 45° angle, resulting in the most obvious initial temperature increase. The chemical reaction pathways are similar in our simulations. Under shock loading, polymerization occurs first and then decomposition begins. However, the overall chemical kinetics response intensifies, as the angle between the shock direction and molecular layer decreases. Nonetheless, the rate of decomposition does not strictly correlate with shock direction. Moreover, clusters evolution shows different reactivity based on shock direction and velocity, which makes anisotropy weak at high shock velocity.

Introduction: Pleural infections are a significant cause of mortality. Intrapleural fibrinolytic therapy (IPFT) utilising alteplase and dornase is a treatment option for patients unsuitable for surgery. The optimal dose of alteplase is unknown, and factors affecting treatment success in an Asian population are unclear. We sought to determine the factors affecting treatment success in Tan Tock Seng Hospital, Singapore and evaluate the efficacy of lower doses of IPFT. Method: A retrospective analysis of patients with pleural infections treated with IPFT between July 2016 and November 2023 was performed. Treatment success was defined as survival without surgery at 3 months. Data, including patient demographics; comorbidities; RAPID (renal, age, purulence, infection source and dietary factor) scores; and radiological characteristics, were extracted from medical records and analysed. Linear mixed effects model and logistic regression were performed to determine factors affecting treatment success. Results: A total of 131 cases were analysed. Of these, 51 (38.9%) reported positive pleural fluid culture, and the most common organism was Streptoccocus anginosus. Mean age was 65 years (standard deviation [SD] 15.5). Mean time from chest tube insertion to first dose of IPFT was 10.2 days (SD 11.5). Median starting dose of alteplase was 5 mg. Treatment success was reported in 112 cases (85.5%). There were no significant differences between the alteplase dose and radiological clearance. Patient age (odds ratio [OR] 0.94, confidence interval [CI] 0.89–0.98) and interval between chest tube insertion to first dose (OR 0.95, CI 0.91–0.99) were statistically significant variables for the treatment success. Conclusion: Lower starting doses of alteplase remain effective in the treatment of pleural infection. Early IPFT may result in better outcomes.

P2X receptors (P2X1–7) are non-selective cation channels involved in many physiological activities such as synaptic transmission, immunological modulation, and cardiovascular function. These receptors share a conserved mechanism to sense extracellular ATP. TNP-ATP is an ATP derivative acting as a nonselective competitive P2X antagonist. Understanding how it occupies the orthosteric site in the absence of agonism may help reveal the key allostery during P2X gating. However, TNP-ATP/P2X complexes (TNP-ATP/human P2X3 (hP2X3) and TNP-ATP/chicken P2X7 (ckP2X7)) with distinct conformations and different mechanisms of action have been proposed. Whether these represent species and subtype variations or experimental differences remains unclear. Here, we show that a common mechanism of TNP-ATP recognition exists for the P2X family members by combining enhanced conformation sampling, engineered disulfide bond analysis, and covalent occupancy. In this model, the polar triphosphate moiety of TNP-ATP interacts with the orthosteric site, while its TNP-moiety is deeply embedded in the head and dorsal fin (DF) interface, creating a restrictive allostery in these two domains that results in a partly enlarged yet ion-impermeable pore. Similar results were obtained from multiple P2X subtypes of different species, including ckP2X7, hP2X3, rat P2X2 (rP2X2), and human P2X1 (hP2X1). Thus, TNP-ATP uses a common mechanism for P2X recognition and modulation by restricting the movements of the head and DF domains which are essential for P2X activation. This knowledge is applicable to the development of new P2X inhibitors.

Abstract As one of the most prevalent tumors, colorectal cancer (CRC) owns complex pathogenesis and the high recurrence rate significantly influence the prognosis of patients with KRAS mutant CRC, to discovery the crosstalk among KEAP1‐NFE2L2 and oncogenic KRAS as the potential prognostic biomarkers in CRC, which might be used to develop novel and effective therapeutics. By using bioinformatics analysis, we explored and identified key genes as the predicted targets in the crosstalk among KEAP1 oncogenic signatures of KRAS mutation that were linked with development, metastasis, and poor prognosis in CRC. We further investigated the correlations between the clinical characteristics and expressions of prognostic genes among the KRAS and KEAP1‐related key hub genes in CRC, which as predicted targets to find the potential herbal ingredients in HERB database, further to verify the active herbal ingredients could regulate the key targets that related to KEAP1‐NFE2L2 in KRAS mutant CRC. The newest TCGA data reveals that the mutation of KRAS is found in 44% of CRC patients. In total, 28 genes were identified as differentially expressed genes (DEGs), and the hub genes such as CDKN2A, SPP1, FOS, BCL2L11, and HPSE were verified. Results indicated that key genes (SOX9, SPP1) significant correlation with the target prediction of the active herbal ingredients by molecular docking analysis. Furthermore, KEAP1, NFE2L2, SOX9 expression were decreased significantly with the treatment of potential ingredients. Furthermore, cyclopamine could enhance the sensitivity of HCT116 cells, downregulated the expression of SPP1, and induced activation of KEAP1‐NFE2L2 pathway, which cell death are characteristic features of apoptosis, and enhanced anticancer effect. Therefore, KEAP1‐related genes might be important oncogenic signatures in KRAS mutant CRC cells and cyclopamine was identified as a potential ingredient and regulated the predict targets of SOX9 and SPP1, may be expand the efficacy and range of novel and effective therapeutics.

Background: Fixed drug eruption (FDE) is a drug hypersensitivity reaction caused by antibiotics and non-steroidal anti-inflammatory drugs primarily. Antondine injection is a drug used to reduce fever, mainly composed of aminopyrine, antipyrine and barbiturate, and its adverse reactions include anaphylactic shock, epidermolysis, rash, agranulocytosis, etc. FDE caused by Antondine injection is an uncommon phenomenon, and the drug eruption caused by these ingredients has been reported in the current case report. However, the fatal severe fixed drug eruption caused by it has not been reported. Here, we report a case of severe PDE after treatment with Antondine, highlighting it’s necessary to avoid these medications with this ingredient when using antipyretic medications.

Objectives To assess the therapeutic effects and safety of Tongxie Yaofang (TXYF) granules vs placebo as an alternative treatment for diarrhoea-predominant irritable bowel syndrome (IBS-D). We hypothesised that TXYF would improve clinical responses among patients with IBS-D.Design A randomised, double-blind, placebo-controlled, phase II, superiority trial.Setting Outpatients attending the Fangshan Hospital, Beijing University of Chinese Medicine, Beijing, China.Participants 96 eligible participants included men and women ranging from late adolescence to middle adulthood (18–65 years), diagnosed with IBS-D according to the Rome IV criteria. In addition, they were required to have an irritable bowel syndrome symptom severity score (IBS-SSS) of at least 75.Interventions TXYF granules (3.7 g) twice daily (taken orally before meals) or placebo for 8 weeks.Primary and secondary outcomes The primary outcome was the response rate measured by the change in IBS-SSS compared with baseline at week 8. Secondary outcomes included stool frequency; stool consistency at weeks 4, 8 and 20; and quality of life, anxiety and depression at week 8; and safety was monitored throughout the trial.Results The TXYF and placebo groups each comprised 48 participants. The response rate was not significantly different at week 8 between the two groups (the unadjusted treatment effect estimate (intention-to-treat analysis) was 1.12 (95% CI (0.89, 1.41)), p=0.348). Both groups had a high and similar rate of symptom reduction (79.2% (38/48) vs 70.8% (34/48)). There were no statistically significant differences between the two groups on secondary outcomes, although both groups showed substantial improvements. Adverse events in the TXYF and placebo groups were one (sinus arrhythmia) and two (elevated transaminases, weakly positive faecal occult blood), respectively. No serious adverse events occurred.Conclusions Despite showing clinically meaningful improvements in IBS-D symptoms and a reasonable safety profile after 8 weeks, no significant differences were observed between the TXYF and placebo groups. This suggests that the severity of IBS-D symptoms in both treatment arms might have decreased over time, regardless of the treatment, and highlights the need to investigate the relationship between IBS-D and patient psychology. Future large-scale, rigorously designed trials with longer treatment and follow-up periods are essential to evaluate the therapeutic effects and safety of TXYF, and to explore the psychological factors.Trial registration number ISRCTN12453166.

Abstract Macrocycles are key tools for molecular recognition and self‐assembly. However, traditionally prevalent macrocyclic compounds exhibit specific cavities with diameters usually less than 1 nm, limiting their range of applications in supramolecular chemistry. The efficient synthesis of giant macrocycles remains a significant challenge because an increase in the monomer number results in cyclization‐entropy loss. In this study, we developed a low‐entropy‐penalty synthesis strategy for producing giant macrocycles in high yields. In this process, long and rigid monomers possessing two reaction modules were condensed with paraformaldehyde via Friedel–Crafts reaction. A series of giant macrocycles with cavities of sizes ranging from 2.0 to 4.7 nm were successfully synthesized with cyclization yields of up to 72%. Experimental results and theoretical calculations revealed that extending the monomer length rather than increasing the monomer numbers could notably reduce the cyclization‐entropy penalty and avoid configuration twists, thereby favoring the formation of giant macrocycles with large cavities. Significantly, the excellent self‐assembly capacity of these giant macrocycles promoted their assembly into organogels. The xerogels exhibited enhanced photoluminescence quantum efficiencies of up to 83.1%. Mechanism investigation revealed the excellent assembly capacity originated from the abundant π–π interactions sites of the giant macrocycles. The outstanding emission enhancement resulted from the restricted nonradiative decay processes of rotation/vibration and improved radiative decay process of fluorescence. This study provides an effective and general method for achieving giant macrocycles, thereby expanding the supramolecular toolbox for host–guest chemistry and assembly applications. Moreover, the intriguing assembly and photophysical properties demonstrate the feasibility of developing novel and unique properties by expanding the macrocycle size.

Abstract Osteoporosis is a metabolic bone disease that involves gradual loss of bone density and mass, thus resulting in increased fragility and risk of fracture. Inflammatory cytokines, such as tumour necrosis factor α (TNF‐α), inhibit osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), and several microRNAs are implicated in osteoporosis development. This study aimed to explore the correlation between TNF‐α treatment and miR‐27a‐3p expression in BMSC osteogenesis and further understand their roles in osteoporosis. An osteoporosis animal model was established using ovariectomized (OVX) mice. Compared with Sham mice, the OVX mice had a significantly elevated level of serum TNF‐α and decreased level of bone miR‐27a‐3p, and in vitro TNF‐α treatment inhibited miR‐27a‐3p expression in BMSCs. In addition, miR‐27a‐3p promoted osteogenic differentiation of mouse BMSCs in vitro, as evidenced by alkaline phosphatase staining and Alizarin Red‐S staining, as well as enhanced expression of the osteogenic markers Runx2 and Osterix. Subsequent bioinformatics analysis combined with experimental validation identified secreted frizzled‐related protein 1 (Sfrp1) as a downstream target of miR‐27a‐3p. Sfrp1 overexpression significantly inhibited the osteogenic differentiation of BMSCs in vitro and additional TNF‐α treatment augmented this inhibition. Moreover, Sfrp1 overexpression abrogated the promotive effect of miR‐27a‐3p on the osteogenic differentiation of BMSCs. Furthermore, the miR‐27a‐3p–Sfrp1 axis was found to exert its regulatory function in BMSC osteogenic differentiation via regulating Wnt3a–β‐catenin signalling. In summary, this study revealed that TNF‐α regulated a novel miR‐27a‐3p–Sfrp1 axis in osteogenic differentiation of BMSCs. The data provide new insights into the development of novel therapeutic strategies for osteoporosis.

Abstract Objective Neuromyelitis optica spectrum disorders (NMOSD) are rare inflammatory astrocytic diseases of the central nervous system (CNS). The roles of immune response gene‐1 (IRG1) and the IRG1–itaconic acid–NLRP3 inflammatory pathway in the pathogenesis of NMOSD and the effects of 4‐octyl itaconate (4‐OI) on the NLRP3 inflammatory pathway in NMOSD are unclear. This study aimed to determine the role of IRG1 and the activation status of the NLRP3 inflammatory pathway in acute‐onset NMOSD and to investigate the inhibitory effects of 4‐OI on NLRP3 inflammasome activation via the IRG1–itaconic acid–NLRP3 pathway in monocytes and macrophages by using in vitro models. Methods Peripheral blood mononuclear cells (PBMCs) and serum were collected from patients with acute NMOSDs and healthy controls (HC), followed by monocyte typing and detection of the expression of NLRP3‐related inflammatory factors. Subsequently, the effects of 4‐OI on the IRG1–itaconic acid–NLRP3 pathway were investigated in peripheral monocytes from patients with NMOSD and in macrophages induced by human myeloid leukemia mononuclear cells (THP‐1 cells) via in vitro experiments. Results Patients with acute NMOSD exhibited upregulated IRG1 expression. In particular, the upregulation of the expression of the NLRP3 inflammasome and proinflammatory factors was notable in monocytes in acute NMOSD patients. 4‐OI inhibited the activation of the IRG1–itaconic acid–NLRP3 inflammatory pathway in the PBMCs of patients with NMOSD. Interpretation 4‐OI could effectively inhibit NLRP3 signaling, leading to the inhibition of proinflammatory cytokine production in patients with NMOSD‐derived PBMCs and in a human macrophage model. Thus, 4‐OI and itaconate could have important therapeutic value for the treatment of NMOSD in the future.