Interdependency or submission to authority? The impacts of horizontal and vertical collectivist orientation on vaccine attitudes in mainland China.

Culture has a profound impact on preventive measures during the COVID-19 pandemic. Previous research has revealed that collectivism is associated with more effective responses to COVID-19 on the national or regional level. However, the impact of different components of collectivist orientation on vaccine attitudes remains insufficiently explored on the individual level. Two survey studies conducted in August 2021 in mainland China consistently found that individual-level horizontal collectivist orientation, rather than vertical collectivist orientation, was linked with more favourable vaccine attitudes. Specifically, Study 1 (N = 731) indicated that horizontal collectivist orientation was positive associated with vaccination intention indirectly via risk perception, and horizontal collectivist orientation was also positively associated with vaccination persuasion both directly and indirectly via risk perception. Study 2 (N = 1481), employing multilevel modelling, demonstrated that the link between horizontal collectivist orientation and confidence in vaccines remained robust regardless of provincial-level variations in socioeconomic development and cultural tightness. These findings convergently suggest that the positive vaccine attitudes among mainland Chinese are primarily driven by an amplified risk perception due to concern for others, rather than submission to authority.

Mechanism of ceramide synthase inhibition by fumonisin B1.

Ceramide synthases (CerSs) play crucial roles in sphingolipid metabolism and have emerged as promising drug targets for metabolic diseases, cancers, and antifungal therapy. However, the therapeutic targeting of CerSs has been hindered by a limited understanding of their inhibition mechanisms by small molecules. Fumonisin B1 (FB1) has been extensively studied as a potent inhibitor of eukaryotic CerSs. In this study, we characterize the inhibition mechanism of FB1 on yeast CerS (yCerS) and determine the structures of both FB1-bound and N-acyl-FB1-bound yCerS. Through our structural analysis and the observation of N-acylation of FB1 by yCerS, we propose a potential ping-pong catalytic mechanism for FB1 N-acylation by yCerS. Lastly, we demonstrate that FB1 exhibits lower binding affinity for yCerS compared to the C26- coenzyme A (CoA) substrate, suggesting that the potent inhibitory effect of FB1 on yCerS may primarily result from the N-acyl-FB1 catalyzed by yCerS, rather than through direct binding of FB1.

Highly efficient and stable adsorption of lithium from brine with microcapsules containing 1-phenylazo-2-naphthol and trioctylphosphine oxide.

Lithium extraction from salt lake brine is still challenging due to the existence of similar elements, e.g. sodium. In the present work, polysulfone (PSF) microcapsules containing 1-phenylazo-2-naphthol (HS) and trioctylphosphine oxide (TOPO) as extractants were successfully prepared by microfluidic technology for the separation of Li+ from brine with Li+ and Na+. The morphology, composition, and structure of HS-TOPO-based microcapsules were characterized systematically. The results showed that microcapsules consisting of 20 wt% (m m-1) polysulfone and 80 wt% (m m-1) 1-phenylazo-2-naphthol-trioctylphosphine oxide as the extractant, which was labeled as PSF/HS-TOPO-2/8, exhibited the best performance for Li+ adsorption. The separation factor (SF) of Li+ over Na+ is up to 653 and the adsorption capacity for Li+ in the simulated brine could reach 3.67 mg g-1 for microcapsules PSF/HS-TOPO-2/8, which demonstrated that Li+ can be separated with high selectivity. Besides, the kinetic results demonstrated that the adsorption followed quasi-secondary adsorption kinetic models, indicating that the adsorption mechanism of lithium by microcapsules involved chemisorption. After ten cycles of adsorption-elution, the maximum equilibrium adsorption capacity still remained at 87%. All these results demonstrate that PSF/HS-TOPO-2/8 microcapsules can be used as an efficient adsorber for the adsorption of Li+ from brine with high selectivity and stability.

Association of serum pertussis antibodies with acute asthma attacks in children.

Objective: The aim of this study was to examine the serum antibody levels against pertussis toxin (PT) in children experiencing an acute asthma attack and to explore the potential association between these levels and asthma. Methods: A prospective investigation was conducted, which involved 107 children with acute asthma attacks and 77 children diagnosed with bronchitis. The serum immunoglobulin G (IgG) antibody levels specific to PT were measured by using an in-house enzyme-linked immunosorbent assay. Based on the serum PT-IgG antibody levels, the children with asthma were categorized into three groups: non-pertussis infected, suspected pertussis infected, and recent pertussis infected. The clinical manifestations and pulmonary function of pediatric patients diagnosed with asthma were assessed and compared across various groups. Results: Of the total asthma group, 25 patients tested positive for PT-IgG, whereas only six patients in the bronchitis group were PT-IgG positive. The prevalence of recent pertussis infection was observed to be higher in the asthma group compared with the bronchitis group. Within the asthma group, those with recent pertussis infection exhibited a higher likelihood of experiencing wheezing and impaired lung function in comparison with the non-pertussis infection group. Conclusion: Pertussis infection is relatively common in children with asthma and correlates with the severity of asthma.

Development and therapeutic potential of DNA-dependent protein kinase inhibitors.

The deployment of DNA damage response (DDR) combats various forms of DNA damage, ensuring genomic stability. Cancer cells' propensity for genomic instability offers therapeutic opportunities to selectively kill cancer cells by suppressing the DDR pathway. DNA-dependent protein kinase (DNA-PK), a nuclear serine/threonine kinase, is crucial for the non-homologous end joining (NHEJ) pathway in the repair of DNA double-strand breaks (DSBs). Therefore, targeting DNA-PK is a promising cancer treatment strategy. This review elaborates on the structures of DNA-PK and its related large protein, as well as the development process of DNA-PK inhibitors, and recent advancements in their clinical application. We emphasize our analysis of the development process and structure-activity relationships (SARs) of DNA-PK inhibitors based on different scaffolds. We hope this review will provide practical information for researchers seeking to develop novel DNA-PK inhibitors in the future.

Construction of Iron-Scavenging Hydrogel via Thiol-Ene Click Chemistry for Antibiotic-Free Treatment of Bacterial Wound Infection.

Bacteria, especially drug-resistant strains, can quickly cause wound infections, leading to delayed healing and fatal risk in clinics. With the growing need for alternative antibacterial approaches that rely less on antibiotics or eliminate their use altogether, a novel antibacterial hydrogel named Ovtgel is developed. Ovtgel is formulated by chemically crosslinking thiol-modified ovotransferrin (Ovt), a member of the transferrin family found in egg white, with olefin-modified agarose through thiol-ene click chemistry. Ovt is designed to sequester ferric ions essential for bacterial survival and protect wound tissues from damages caused by the reactive oxygen species (ROS) generated in Fenton reactions. Experimental data have shown that Ovtgel significantly enhances wound healing by inhibiting bacterial growth and shielding tissues from ROS-induced harms. Unlike traditional antibiotics, Ovtgel targets essential trace elements required for bacterial survival in the host environment, preventing the development of drug resistance in pathogenic bacteria. Ovtgel exhibits excellent biocompatibility due to the homology of Ovt to mammalian transferrin. This hydrogel has the potential to serve as an effective antibiotic-free solution for combating bacterial infections.

Transformation and environmental risk of 90Sr and 137Cs under extreme rainstorm at a proposed nuclear facility site in China.

This paper explores the environmental hazards associated with nuclear facilities in arid regions, focusing on the rapid migration of radionuclides facilitated by flood runoff resulting from extreme rainstorms. Through a case study of a proposed nuclear facility site in China, the study developed a comprehensive model to calculate the transformation of 90Sr and 137Cs in flood and subsurface water during accidents. The methodology employs a combination of field tests, radionuclide adsorption tests, the SWAT model, and the HGS model to create a fully integrated model. This approach allows for the several complex couplings (radionuclide-flood runoff-subsurface water) that have not been previously examined in the reactive solute transport. The findings reveal that despite groundwater movement being relatively sluggish, 90Sr and 137Cs migrate downstream rapidly due to their transportation by floods, which permeate the Upper Pleistocene gravel aquifer along the route. The study underscores the importance of considering the migration of radionuclides carried by floods generated by extreme rainstorms, as it poses a significant risk that cannot be ignored.

Distinguishing Sanghuangporus from sanghuang-related fungi: a comparative and phylogenetic analysis based on mitogenomes.

The Chinese medicinal fungi "Sanghuang" have been long recognized for their significant and valued medicinal properties, as documented in ancient medical literature. However, in traditional folk medicine, various macrofungi sharing similar appearance, habitat, and therapeutic effects with Sanghuang were erroneously used. These Sanghuang-like fungi mainly belong to the Porodaedalea, Phellinus, and Inonotus genera within the Hymenochaetaceae family. Despite the establishment of the Sanghuangporus genus and the identification of multiple species, the emerging taxonomic references based on morphological, ITS, and mycelial structural features have been inadequate to differentiate Sanghuangporus and Sanghuang-like fungi. To address this limitation, this study presents the first comparative and phylogenetic analysis of Sanghuang-related fungi based on mitogenomes. Our results show that Sanghuangporus species show marked convergence in mitochondrial genomic features and form a distinct monophyletic group based on phylogenetic analyses of five datasets. These results not only deepen our understanding of Sanghuang-like fungi but also offer novel insights into their mitochondrial composition and phylogeny, thereby providing new research tools for distinguishing members of the Sanghuangporus genus. KEY POINTS: • Sanghuangporus, Inonotus, and Porodaedalea are monophyly in sanghuang-like species. • Mitogenome-based analysis exhibits high resolution in sanghuang-like genus. • The mitogenomes provide strong evidence for reclassifying Phellinus gilvus S12 as Sanghuangporus vaninii.

Mapping of spastic muscle activity after stroke: difference between passive stretch and active contraction.

BACKGROUND: Investigating the spatial distribution of muscle activity would facilitate understanding the underlying mechanism of spasticity. The purpose of this study is to investigate the characteristics of spastic muscles during passive stretch and active contraction by high-density surface electromyography (HD-sEMG). METHODS: Fourteen spastic hemiparetic subjects and ten healthy subjects were recruited. The biceps brachii (BB) muscle activity of each subject was recorded by HD-sEMG during passive stretch at four stretch velocities (10, 60, 120, 180˚/s) and active contraction at three submaximal contraction levels (20, 50, 80%MVC). The intensity and spatial distribution of the BB activity were compared by the means of two-way analysis of variance, independent sample t-test, and paired sample t-test. RESULTS: Compared with healthy subjects, spastic hemiparetic subjects showed significantly higher intensity with velocity-dependent heterogeneous activation during passive stretch and more lateral and proximal activation distribution during active contraction. In addition, spastic hemiparetic subjects displayed almost non-overlapping activation areas during passive stretch and active contraction. The activation distribution of passive stretch was more distal when compared with the active contraction. CONCLUSIONS: These alterations of the BB activity could be the consequence of deficits in the descending central control after stroke. The complementary spatial distribution of spastic BB activity reflected their opposite motor units (MUs) recruitment patterns between passive stretch and active contraction. This HD-sEMG study provides new neurophysiological evidence for the spatial relationship of spastic BB activity between passive stretch and active contraction, advancing our knowledge on the mechanism of spasticity. TRIAL REGISTRATION: ChiCTR2000032245.

Reciprocal regulation of T follicular helper cells and dendritic cells drives colitis development.

The immunological mechanisms underlying chronic colitis are poorly understood. T follicular helper (TFH) cells are critical in helping B cells during germinal center reactions. In a T cell transfer colitis model, a lymphoid structure composed of mature dendritic cells (DCs) and TFH cells was found within T cell zones of colonic lymphoid follicles. TFH cells were required for mature DC accumulation, the formation of DC-T cell clusters and colitis development. Moreover, DCs promoted TFH cell differentiation, contributing to colitis development. A lineage-tracing analysis showed that, following migration to the lamina propria, TFH cells transdifferentiated into long-lived pathogenic TH1 cells, promoting colitis development. Our findings have therefore demonstrated the reciprocal regulation of TFH cells and DCs in colonic lymphoid follicles, which is critical in chronic colitis pathogenesis.

NR4A1 transcriptionally regulates the differentiation of stem-like CD8+ T cells in the tumor microenvironment.

CD8+ T cells are rendered exhausted in tumor and chronic infection. Among heterogeneous exhausted T cells, a subpopulation of progenitor-like (Tpex) cells have been found important for long-term tumor or pathogen control and are also the main responders in immunotherapy. Using an RFP reporter mouse for the orphan nuclear receptor NR4A1, originally characterized as critical in T cell dysfunction, we discover that the reporter is highly expressed in Tpex cells in tumor and chronic infection. Enforced expression of Nr4a1 promotes Tpex cell accumulation, whereas tumor control is improved after Nr4a1 deletion, associated with increased effector function but decreased long-term maintenance of CD8+ T cells. Integrating chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) analysis, NR4A1 is found to bind and promote the expression of Tpex-related genes, as well as suppress terminal differentiation-associated genes. This study therefore has identified a key role of NR4A1 in Tpex regulation and provides a promising target for immunotherapy.

Dislocations deteriorate postoperative functional outcomes in supination-external rotation ankle fractures.

PURPOSE: To assess the relationship between dislocation and functional outcomes in supination-external rotation (SER) ankle fractures. METHODS: A retrospective case series study was performed on patients with ankle fractures treated surgically at a large trauma center from January 2015 to December 2021. The inclusion criteria were young and middle-aged patients of 18-65 years with SER ankle fractures that can be classified by Lauge-Hansen classification and underwent surgery at our trauma center. Exclusion criteria were serious life-threatening diseases, open fractures, fractures delayed for more than 3 weeks, fracture sites ≥2, etc. Then patients were divided into dislocation and no-dislocation groups. Patient demographics, injury characteristics, surgery-related outcomes, and postoperative functional outcomes were collected and analyzed. The functional outcomes of SER ankle fractures were assessed postoperatively at 1-year face-to-face follow-up using the foot and ankle outcome score (FAOS) and American orthopedic foot and ankle society score and by 2 experienced orthopedic physicians. Relevant data were analyzed using SPSS version 22.0 by Chi-square or t-test. RESULTS: During the study period, there were 371 ankle fractures. Among them, 190 (51.2%) were SER patterns with 69 (36.3%) combined with dislocations. Compared with the no-dislocation group, the dislocation group showed no statistically significant differences in gender, age composition, fracture type, preoperative complications with diabetes, smoking history, preoperative waiting time, operation time, and length of hospital stay (all p > 0.05), but a significantly higher Lauge-Hansen injury grade (p < 0.001) and syndesmotic screw fixation rate (p = 0.033). Moreover, the functional recovery was poorer, revealing a significantly lower FAOS in the sport/rec scale (p < 0.001). Subgroup analysis showed that among SER IV ankle fracture patients, FAOS was much lower in pain (p = 0.042) and sport/rec scales (p < 0.001) for those with dislocations. American orthopedic foot and ankle society score revealed no significant difference between dislocation and no-dislocation patients. CONCLUSION: Dislocation in SER ankle fractures suggests more severe injury and negatively affects functional recovery, mainly manifested as more pain and poorer motor function, especially in SER IV ankle cases.

Resolvin D1 delivery to lesional macrophages using antioxidative black phosphorus nanosheets for atherosclerosis treatment.

The buildup of plaques in atherosclerosis leads to cardiovascular events, with chronic unresolved inflammation and overproduction of reactive oxygen species (ROS) being major drivers of plaque progression. Nanotherapeutics that can resolve inflammation and scavenge ROS have the potential to treat atherosclerosis. Here we demonstrate the potential of black phosphorus nanosheets (BPNSs) as a therapeutic agent for the treatment of atherosclerosis. BPNSs can effectively scavenge a broad spectrum of ROS and suppress atherosclerosis-associated pro-inflammatory cytokine production in lesional macrophages. We also demonstrate ROS-responsive, targeted-peptide-modified BPNS-based carriers for the delivery of resolvin D1 (an inflammation-resolving lipid mediator) to lesional macrophages, which further boosts the anti-atherosclerotic efficacy. The targeted nanotherapeutics not only reduce plaque areas but also substantially improve plaque stability in high-fat-diet-fed apolipoprotein E-deficient mice. This study presents a therapeutic strategy against atherosclerosis, and highlights the potential of BPNS-based therapeutics to treat other inflammatory diseases.

BMI mediates the association of serum uric acid with bone health: a cross-sectional study of the National Health and Nutrition Examination Survey (NHANES).

BACKGROUND: The associations between serum uric acid and osteoporosis or osteopenia remain controversial, and few studies have explored whether BMI acts as a mediators in the association between the SUA and OP/ osteopenia. OBJECTIVE: To explore the relationship between serum uric acid and osteoporosis or osteopenia among US adults. METHODS: A cross-sectional study was conducted to examine the association between serum uric acid and osteoporosis or osteopenia from four cycles of NHANES. Binary logistic regression models and restricted cubic spline models were used to evaluate the association between serum uric acid and osteoporosis or osteopenia, and interaction analysis was used to test the differences between subgroups. Mediation analysis was utilized to investigate whether BMI acts as a mediator in the association between SUA and OP/ osteopenia. RESULTS: 12581 participants aged ≥ 18 years were included. A U-shape nonlinear relationship between SUA and osteoporosis or osteopenia in all people was found (P < 0.0001, P for nonlinear = 0.0287). There were significant interactions in age subgroups (P for interaction = 0.044), sex subgroups (P for interaction = 0.005), and BMI subgroups (P for interaction = 0.017). We further assessed the subgroups and found the optimal range of serum uric acid levels with a lower risk of osteoporosis or osteopenia was 357-535 µmol/L in males, 327-417 µmol/L in people aged ≥ 50 years, above 309 µmol/L in people aged < 50 years, 344-445 µmol/L in people with BMI ≥ 30, and above 308 µmol/L in people with BMI < 30. BMI fully mediated the association of SUA and OP/osteopenia, with a value of -0.0024(-0.0026--0.0021). These results were robust in sensitivity analyses. CONCLUSIONS: A complicated relationship between SUA and bone health in different populations was observed. Maintaining SUA within a specific range may be beneficial to bone health. In addition, BMI may play an important role in the association between SUA and bone health, but considering the limitations of this study, further prospective research is required.

Novel Bifunctional Conjugates Targeting PD-L1/PARP7 as Dual Immunotherapy for Potential Cancer Treatment.

Bifunctional conjugates targeting PD-L1/PARP7 were designed, synthesized, and evaluated for the first time. Compounds B3 and C6 showed potent activity against PD-1/PD-L1 interaction (IC50 = 0.426 and 0.342 µM, respectively) and PARP7 (IC50 = 2.50 and 7.05 nM, respectively). They also displayed excellent binding affinity with hPD-L1, approximately 100-200-fold better than that of hPD-1. Both compounds restored T-cell function, leading to the increase of IFN-γ secretion. In the coculture assay, B3 and C6 enhanced the killing activity of MDA-MB-231 cells by Jurkat T cells in a concentration-dependent manner. Furthermore, B3 and C6 displayed significant in vivo antitumor efficacy in a melanoma B16-F10 tumor mouse model, more than 5.3-fold better than BMS-1 (a PD-L1 inhibitor) and RBN-2397 (a PARP7i clinical candidate) at the dose of 25 mg/kg, without observable side effects. These results provide valuable insight and understanding for developing bifunctional conjugates for potential anticancer therapy.

Phylodynamics unveils invading and diffusing patterns of dengue virus serotype-1 in Guangdong, China from 1990 to 2019 under a global genotyping framework.

BACKGROUND: The strong invasiveness and rapid expansion of dengue virus (DENV) pose a great challenge to global public health. However, dengue epidemic patterns and mechanisms at a genetic scale, particularly in term of cross-border transmissions, remain poorly understood. Importation is considered as the primary driver of dengue outbreaks in China, and since 1990 a frequent occurrence of large outbreaks has been triggered by the imported cases and subsequently spread to the western and northern parts of China. Therefore, this study aims to systematically reveal the invasion and diffusion patterns of DENV-1 in Guangdong, China from 1990 to 2019. METHODS: These analyses were performed on 179 newly assembled genomes from indigenous dengue cases in Guangdong, China and 5152 E gene complete sequences recorded in Chinese mainland. The genetic population structure and epidemic patterns of DENV-1 circulating in Chinese mainland were characterized by phylogenetics, phylogeography, phylodynamics based on DENV-1 E-gene-based globally unified genotyping framework. RESULTS: Multiple serotypes of DENV were co-circulating in Chinese mainland, particularly in Guangdong and Yunnan provinces. A total of 189 transmission clusters in 38 clades belonging to 22 subgenotypes of genotype I, IV and V of DENV-1 were identified, with 7 Clades of Concern (COCs) responsible for the large outbreaks since 1990. The epidemic periodicity was inferred from the data to be approximately 3 years. Dengue transmission events mainly occurred from Great Mekong Subregion-China (GMS-China), Southeast Asia (SEA), South Asia Subcontinent (SASC), and Oceania (OCE) to coastal and land border cities respectively in southeastern and southwestern China. Specially, Guangzhou was found to be the most dominant receipting hub, where DENV-1 diffused to other cities within the province and even other parts of the country. Genome phylogeny combined with epidemiological investigation demonstrated a clear local consecutive transmission process of a 5C1 transmission cluster (5C1-CN4) of DENV-1 in Guangzhou from 2013 to 2015, while the two provinces of Guangdong and Yunnan played key roles in ongoing transition of dengue epidemic patterns. In contextualizing within Invasion Biology theories, we have proposed a derived three-stage model encompassing the stages of invasion, colonization, and dissemination, which is supposed to enhance our understanding of dengue spreading patterns. CONCLUSIONS: This study demonstrates the invasion and diffusion process of DENV-1 in Chinese mainland within a global genotyping framework, characterizing the genetic diversities of viral populations, multiple sources of importation, and periodic dynamics of the epidemic. These findings highlight the potential ongoing transition trends from epidemic to endemic status offering a valuable insight into early warning, prevention and control of rapid spreading of dengue both in China and worldwide.

Efficacy and Safety of Orally and Intravenously Administration of Tranexamic Acid in Patients with Elderly Femoral Neck Fracture.

OBJECTIVE: For elderly femoral neck fracture patients, anemia is one of the most common complications, increasing the risk of postoperative adverse events. Tranexamic acid (TXA) has been widely applied to the perioperative blood management. However, the optimal route of TXA administration in elderly femoral neck fracture remains unclear. The aim of this study is to evaluate the efficacy and safety of oral and intravenous (IV) application of TXA in elderly patients with femoral neck fracture undergoing total hip arthroplasty (THA) and hemiarthroplasty (HA). METHODS: All elderly patients aged over 65 years old diagnosed with femoral neck fracture admitted to the trauma orthopedics from August 1, 2020 to February 28, 2022 were enrolled in this prospective cohort study. Participants were divided into three groups: oral group: TXA 2g orally 2 h before incision; IV group: intravenous infusion of TXA 1g 15 min before incision; and control group: usual hemostatic method. The primary outcomes were total blood loss, allogeneic transfusion rate, and postoperative thromboembolic events. SPSS 23.0 (IBM, Armonk, NY, USA) was used for statistical analysis, and p ≤ 0.05 was considered statistically significant. RESULTS: A total of 100 patients were enrolled, including 32 cases in the oral group, 34 cases in the IV group and 34 cases in the control group. Compared with the control group, the total perioperative blood loss in the oral and IV groups was significantly decreased (763.92 ± 358.64 mL vs 744.62 ± 306.88 mL vs 1250.60 ± 563.37 mL, p = 0.048). No significant difference was identified between the oral and IV groups (p = 0.970). The rate of allogeneic transfusion was lower in the oral and IV groups than in the control group, but the difference had no statistical significant (6 vs 5 vs 12, p = 0.108), However, subgroup analysis showed that the IV and oral groups in patients who underwent THA have significant lower transfusion rate compared with the control group (1 vs 3 vs 7, p = 0.02). During 6 months follow-up, no thromboembolic events were identified. Two patients (one from the oral group and one from the control group) died of respiratory failure. The cost of blood management from the oral group was significantly lower than IV (p < 0.001) and control groups (p = 0.009). CONCLUSION: Elderly patients with femoral neck fracture undergoing THA can benefit from both IV and oral administration of tranexamic acid. The results of these two administration routes are similar in safety and effectiveness. A similar tendency was observed in patients undergoing HA. Oral TXA is more cost-benefit compared with intravenous applications.

CCDC6-RET fusion protein regulates Ras/MAPK signaling through the fusion- GRB2-SHC1 signal niche.

Rearranged during transfection (RET) rearrangement oncoprotein-mediated Ras/MAPK signaling cascade is constitutively activated in cancers. Here, we demonstrate a unique signal niche. The niche is a ternary complex based on the chimeric RET liquid-liquid phase separation. The complex comprises the rearranged kinase (RET fusion); the adaptor (GRB2), and the effector (SHC1). Together, they orchestrate the Ras/MAPK signal cascade, which is dependent on tyrosine kinase. CCDC6-RET fusion undergoes LLPS requiring its kinase domain and its fusion partner. The CCDC6-RET fusion LLPS promotes the autophosphorylation of RET fusion, with enhanced kinase activity, which is necessary for the formation of the signaling niche. Within the signal niche, the interactions among the constituent components are reinforced, and the signal transduction efficiency is amplified. The specific RET fusion-related signal niche elucidates the mechanism of the constitutive activation of the Ras/MAPK signaling pathway. Beyond just focusing on RET fusion itself, exploration of the ternary complex potentially unveils a promising avenue for devising therapeutic strategies aimed at treating RET fusion-driven diseases.

ß-Elemene Reverses Gefitinib Resistance in NSCLC Cells by Inhibiting lncRNA H19-Mediated Autophagy.

Lung cancer is a leading cause of mortality worldwide, especially among Asian patients with non-small cell lung cancer (NSCLC) who have epidermal growth factor receptor (EGFR) mutations. Initially, first-generation EGFR tyrosine kinase inhibitors (TKIs) are commonly administered as the primary treatment option; however, encountering resistance to these medications poses a significant obstacle. Hence, it has become crucial to address initial resistance and ensure continued effectiveness. Recent research has focused on the role of long noncoding RNAs (lncRNAs) in tumor drug resistance, especially lncRNA H19. ß-elemene, derived from Curcuma aromatic Salisb., has shown strong anti-tumor effects. However, the relationship between ß-elemene, lncRNA H19, and gefitinib resistance in NSCLC is unclear. This study aims to investigate whether ß-elemene can enhance the sensitivity of gefitinib-resistant NSCLC cells to gefitinib and to elucidate its mechanism of action. The impact of gefitinib and ß-elemene on cell viability was evaluated using the cell counting kit-8 (CCK8) assay. Furthermore, western blotting and qRT-PCR analysis were employed to determine the expression levels of autophagy-related proteins and genes, respectively. The influence on cellular proliferation was gauged through a colony-formation assay, and apoptosis induction was quantified via flow cytometry. Additionally, the tumorigenic potential in vivo was assessed using a xenograft model in nude mice. The expression levels of LC3B, EGFR, and Rab7 proteins were examined through immunofluorescence. Our findings elucidate that the resistance to gefitinib is intricately linked with the dysregulation of autophagy and the overexpression of lncRNA H19. The synergistic administration of ß-elemene and gefitinib markedly attenuated the proliferative capacity of resistant cells, expedited apoptotic processes, and inhibited the in vivo proliferation of lung cancer. Notably, ß-elemene profoundly diminished the expression of lncRNA H19 and curtailed autophagic activity in resistant cells, thereby bolstering their responsiveness to gefitinib. Moreover, ß-elemene disrupted the Rab7-facilitated degradation pathway of EGFR, facilitating its repositioning to the plasma membrane. ß-elemene emerges as a promising auxiliary therapeutic for circumventing gefitinib resistance in NSCLC, potentially through the regulation of lncRNA H19-mediated autophagy. The participation of Rab7 in this dynamic unveils novel insights into the resistance mechanisms operative in lung cancer, paving the way for future therapeutic innovations.

Leaching behaviour of 226Ra from uranium tailings and adsorption behaviour in geotechnical medias.

The leaching process of uranium tailings is a typical water-rock interaction. The release of 226Ra from uranium tailings depends on the nuclides outside the intrinsic properties of uranium tailings on the one hand, and is influenced by the water medium on the other. In this paper, a uranium tailings repository in southern China was used as a research object, and uranium tailings at different depths were collected by drilling samples and mixed to analyze the 226Ra occurrence states. Static dissolution leaching experiments of 226Ra under different pH conditions, solid-liquid ratio conditions, and ionic strength conditions were carried out, and the adsorption and desorption behaviours of 226Ra in five representative stratigraphic media were investigated. The results show that 226Ra has a strong adsorption capacity in representative strata, with adsorption distribution coefficient Kd values ranging from 1.07E+02 to 1.29E+03 (mL/g) and desorption distribution coefficients ranging from 4.97E+02 to 2.71E+03 (mL/g), but the adsorption is reversible. The 226Ra in uranium tailings exists mainly in the residual and water-soluble states, and the release of 226Ra from uranium tailings under different conditions is mainly from the water-soluble and exchangeable state fractions. Low pH conditions, low solid-liquid ratio conditions and high ionic strength conditions are favourable to the release of 226Ra from uranium tailings, so the release of 226Ra from uranium tailings can be reduced by means of adjusting the pH in the tailings and setting up a water barrier. The results of this research have important guiding significance for the management of existing uranium tailings ponds and the control of 226Ra migration in groundwater, which is conducive to guaranteeing the long-term safety, stability and sustainability of uranium mining sites.