Search

The study explores the effects of working practice in cultivating Chinese university teachers' professional identities. It collects data from questions delivered in a presentation forum and individual interviews. After analysing data the study gets the following findings. Firstly, the reasons for participants choosing to be university teachers include personal interests and job satisfaction. Secondly, after working for some years, participants' professional identities change significantly. They understand their position deeply, becoming more interested in their jobs, setting up more apparent professional goals or missions, and highlighting their moral levels and working ethics. Thirdly, working practice helps participants build clear professional plans. They expect to promote their teaching capabilities, communication abilities, and moral levels. Fourthly, working practice helps participants set up a strong sense of belongingness as university teachers. They care about other's opinions of their group. The findings illustrate that working practice can improve Chinese university teachers' professional identity, which can be explained by the collectivism of Chinese culture.

Abstract Purpose This prospective study aimed to compare the postoperative evaluation of the quadrant method measuring four points and Bernard method in femoral tunnel position evaluation on 3-Dimensional (3D) reconstructed computed tomography (CT) following the arthroscopic single-bundle anterior cruciate ligament (ACL) reconstruction. Methods Thirty-eight patients with ACL tears that were reconstructed using single-bundle ACL reconstruction between May 2021 and March 2023 were included in this study. Postoperative 3D CT images were obtained after the operation. The femoral tunnel position was measured by use of the quadrant method measuring four points and Bernard method. Results Average mean position of the femoral tunnel insertion center on the 3D CT image was at 26.16 ± 6.27% in the x-coordinate and at 24.36 ± 5.52% in the y-coordinate according to the Bernard method. Meanwhile, the position of the femoral insertion of the ACL measured by the quadrant method measuring four points was 24.2% ± 6.86% in the x-coordinate and 21.16% ± 5.14% in the y-coordinate. Conclusions Both the quadrant method measuring four points and Bernard method were effective in femoral tunnel position evaluation on 3D reconstructed CT. Application of the quadrant method measuring four points on 3D CT showed the advantage that measurement can be taken regardless of the shape of the bone tunnel.

Abstract Relationships between the visceral adiposity index (VAI) and type 2 diabetes mellitus (T2DM) have been underexplored. The purpose of this study is to explore association between VAI and T2DM in adults in the US. Based on the National Health and Nutrition Examination Survey 2007–2018, 11,214 participants aged 20 years or older were included in a cross-sectional study. Multifactorial logistic regression analysis and smoothed curve fitting analysis were performed to investigate links between VAI and the prevalence of T2DM, as well as the stability and incidence between subgroups. In a fully adjusted continuous model, the aggregate population risk of T2DM increased 0.43-fold with each 1-unit increase in VAI [odds ratio (OR) = 1.43; 95% confidence interval (CI) 1.35–1.50]. In the fully adjusted categorical model with VAI scores stratified by quartiles, results showed a higher T2DM advantage among participants in the second, third, and fourth quartiles (Q2: OR 1.35, 95% CI 1.06–1.71; Q3: OR 2.46, 95% CI 1.95–3.11; Q4: OR 4.42, 95% CI 3.55–05.50). Compared with Q1, the prevalence of T2DM in the total population increased 3.42-fold in Q4. The above results indicated that VAI was positively associated with the prevalence of T2DM, which was consistent and nonlinear with the smoothed curve-fitting analysis (P for non-linear = 0). Subgroup analyses after adjusting for covariates showed that keeping with the overall population results, it also was found that there was an interaction between sex and hypertension in the subgroups. VAI was positively associated with the prevalence of T2DM and was more prevalent in women, non-hypertensive than in men, hypertensive populations.

Abstract Machine learning can be used to define subtypes of psychiatric conditions based on shared biological foundations of mental disorders. Here we analyzed cross-sectional brain images from 4,222 individuals with schizophrenia and 7038 healthy subjects pooled across 41 international cohorts from the ENIGMA, non-ENIGMA cohorts and public datasets. Using the Subtype and Stage Inference (SuStaIn) algorithm, we identify two distinct neurostructural subgroups by mapping the spatial and temporal ‘trajectory’ of gray matter change in schizophrenia. Subgroup 1 was characterized by an early cortical-predominant loss with enlarged striatum, whereas subgroup 2 displayed an early subcortical-predominant loss in the hippocampus, striatum and other subcortical regions. We confirmed the reproducibility of the two neurostructural subtypes across various sample sites, including Europe, North America and East Asia. This imaging-based taxonomy holds the potential to identify individuals with shared neurobiological attributes, thereby suggesting the viability of redefining existing disorder constructs based on biological factors.

Abstract Metastatic breast cancer (mBC) poses a significant threat to women's health and is a major cause of malignant neoplasms in women. Human epidermal growth factor receptor (HER)3, an integral member of the ErbB/HER receptor tyrosine kinase family, is a crucial activator of the phosphoinositide-3 kinase/protein kinase B signaling pathway. HER3 overexpression significantly contributes to the development of resistance to drugs targeting other HER receptors, such as HER2 and epidermal growth factor receptors, and plays a crucial role in the onset and progression of mBC. Recently, numerous HER3-targeted therapeutic agents, such as monoclonal antibodies (mAbs), bispecific antibodies (bAbs), and antibody–drug conjugates (ADCs), have emerged. However, the efficacy of HER3-targeted mAbs and bAbs is limited when used individually, and their combination may result in toxic adverse effects. On the other hand, ADCs are cytotoxic to cancer cells and can bind to target cells through antibodies, which highlights their use in targeted HER3 therapy for mBC. This review provides an overview of recent advancements in HER3 research, historical initiatives, and innovative approaches in targeted HER3 therapy for metastatic breast cancer. Evaluating the advantages and disadvantages of current methods may yield valuable insights and lessons.

Abstract Background Hyperlipidemia damages vascular wall and serves as a foundation for diseases such as atherosclerosis, hypertension and stiffness. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is implicated in vascular dysfunction associated with hyperlipidemia-induced vascular injury. Sodium tanshinone IIA sulfonate (STS), a well-established cardiovascular protective drug with recognized anti-inflammatory, antioxidant, and vasodilatory properties, is yet to be thoroughly investigated for its impact on vascular relaxant imbalance induced by hyperlipidemia. Methods In this study, we treated ApoE-knockout (ApoE-/-) mouse with STS and assessed the activation of the NLRP3 inflammasome, expression of MMP2/9, integrity of elastic fibers, and vascular constriction and relaxation. Results Our findings reveal that STS intervention effectively preserves elastic fibers, significantly restores aortic relaxation function in ApoE-/- mice, and reduces their excessive constriction. Furthermore, STS inhibits the phosphorylation of spleen tyrosine kinase (SYK), suppresses NLRP3 inflammasome activation, and reduces MMP2/9 expression. Conclusions These results demonstrate that STS protects vascular relaxation against hyperlipidemia-induced damage through modulation of the SYK-NLRP3 inflammasome-MMP2/9 pathway. This research provides novel insights into the mechanisms underlying vascular relaxation impairment in a hyperlipidemic environment and uncovers a unique mechanism by which STS preserves vascular relaxation, offering valuable foundational research evidence for its clinical application in promoting vascular health.

Abstract Background FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is a common mutation type in acute myeloid leukemia (AML) and is usually associated with poor patient prognosis. With advancements in molecular diagnostics and the development of tyrosine kinase inhibitors (TKI), the overall survival (OS) of AML patients with FLT3-ITD mutations has been prolonged to some extent, but relapse and drug resistance are still substantial challenges. Ningetinib is a novel TKI against various kinases in relation to tumour pathogenesis and is undergoing clinical trials of lung cancer. In this study, we explored the antitumor activity of ningetinib against AML with FLT3 mutations both in vivo and in vitro. Methods Cell proliferation assays were performed in AML cell lines and Ba/F3 cells expressing various FLT3 mutations to validate the antileukemic activity of ningetinib in vitro. Immunoblot assays were used to verify the effect of ningetinib on the FLT3 protein and downstream pathways. Molecular docking and CETSA were used to validate the interaction of ningetinib with target proteins. The survival benefit of ningetinib in vivo was assessed in Ba/F3-FLT3-ITD-, MOLM13, Ba/F3-FLT3-ITD-F691L-, MOLM13-FLT3-ITD-F691L-induced leukemia mouse models. We also used patient-derived primary cells to determine the efficacy of ningetinib. Results Ningetinib inhibited cell proliferation, blocked the cell cycle, induced apoptosis and bound FLT3 to inhibit its downstream signaling pathways, including the STAT5, AKT and ERK pathways, in FLT3-ITD AML cell lines. In the mouse models with FLT3-ITD and FLT3-ITD-F691L mutation, ningetinib showed superior anti-leukemia activity to existing clinical drugs gilteritinib and quizartinib, significantly prolongating the survival of mice. In addition, ningetinib exhibited activity against patient-derived primary cells harboring FLT3-ITD mutations. Conclusion Overall, our study confirmed the therapeutic role of ningetinib in AML with FLT3-ITD mutations, providing a potential new option for clinically resistant patients.

Abstract Background Circadian rhythm (CR) disturbance is intricately associated with Parkinson’s disease (PD). However, the involvement of CR-related mechanisms in the pathogenesis and progression of PD remains elusive. Methods A total of 141 PD patients and 113 healthy participants completed CR-related clinical examinations in this study. To further investigate the CR-related mechanisms in PD, we obtained datasets (GSE7621, GSE20141, GSE20292) from the Gene Expression Omnibus database to identify differentially expressed genes between PD patients and healthy controls and further selected CR-related genes (CRRGs). Subsequently, the least absolute shrinkage and selection operator (LASSO) followed by logistic algorithms were employed to identify the hub genes and construct a diagnostic model. The predictive performance was evaluated by area under the curve (AUC), calibration curve, and decision curve analyses in the training set and external validation sets. Finally, RT‒qPCR and Western blotting were conducted to verify the expression of these hub genes in blood samples. In addition, Pearson correlation analysis was utilized to validate the association between expression of hub genes and circadian rhythm function. Results Our clinical observational study revealed that even early-stage PD patients exhibited a higher likelihood of experiencing sleep disturbances, nocturnal hypertension, reverse-dipper blood pressure, and reduced heart rate variability compared to healthy controls. Furthermore, 4 CR-related hub genes (AGTR1, CALR, BRM14, and XPA) were identified and subsequently incorporated as candidate biomarkers to construct a diagnostic model. The model showed satisfactory diagnostic performance in the training set (AUC = 0.941), an external validation set GSE20295 (AUC = 0.842), and our clinical centre set (AUC = 0.805). Additionally, the up-regulation of CALR, BRM14 and the down-regulation of AGTR1, XPA were associated with circadian rhythm disruption. Conclusion CR disturbance seems to occur in the early stage of PD. The diagnostic model based on CR-related genes demonstrated robust diagnostic efficacy, offering novel insights for future clinical diagnosis of PD and providing a foundation for further exploration into the role of CR-related mechanisms in the progression of PD.

Abstract Objective The aim of this study was to investigate the factors influencing good outcomes in patients receiving only intravenous tirofiban with endovascular thrombectomy for large vessel occlusion stroke. Methods Post hoc exploratory analysis using the RESCUE BT trial identified consecutive patients who received intravenous tirofiban with endovascular thrombectomy for large vessel occlusion stroke in 55 comprehensive stroke centers from October 2018 to January 2022 in China. Results A total of 521 patients received intravenous tirofiban, 253 of whom achieved a good 90-day outcome (modified Rankin Scale [mRS] 0–2). Younger age (adjusted odds ratio [aOR]: 0.965, 95% confidence interval [CI]: 0.947–0.982; p

Abstract Hybrid mapping is a powerful approach to efficiently identify and characterize genes regulated through mechanisms in cis. In this study, using reciprocal crosses of the phenotypically divergent Duroc and Lulai pig breeds, we perform a comprehensive multi-omic characterization of regulatory variation across the brain, liver, muscle, and placenta through four developmental stages. We produce one of the largest multi-omic datasets in pigs to date, including 16 whole genome sequenced individuals, as well as 48 whole genome bisulfite sequencing, 168 ATAC-Seq and 168 RNA-Seq samples. We develop a read count-based method to reliably assess allele-specific methylation, chromatin accessibility, and RNA expression. We show that tissue specificity was much stronger than developmental stage specificity in all of DNA methylation, chromatin accessibility, and gene expression. We identify 573 genes showing allele specific expression, including those influenced by parent-of-origin as well as allele genotype effects. We integrate methylation, chromatin accessibility, and gene expression data to show that allele specific expression can be explained in great part by allele specific methylation and/or chromatin accessibility. This study provides a comprehensive characterization of regulatory variation across multiple tissues and developmental stages in pigs.

Abstract Cancer stem cells (CSCs), a small subset of cells in tumors that are characterized by self-renewal and continuous proliferation, lead to tumorigenesis, metastasis, and maintain tumor heterogeneity. Cancer continues to be a significant global disease burden. In the past, surgery, radiotherapy, and chemotherapy were the main cancer treatments. The technology of cancer treatments continues to develop and advance, and the emergence of targeted therapy, and immunotherapy provides more options for patients to a certain extent. However, the limitations of efficacy and treatment resistance are still inevitable. Our review begins with a brief introduction of the historical discoveries, original hypotheses, and pathways that regulate CSCs, such as WNT/β-Catenin, hedgehog, Notch, NF-κB, JAK/STAT, TGF-β, PI3K/AKT, PPAR pathway, and their crosstalk. We focus on the role of CSCs in various therapeutic outcomes and resistance, including how the treatments affect the content of CSCs and the alteration of related molecules, CSCs-mediated therapeutic resistance, and the clinical value of targeting CSCs in patients with refractory, progressed or advanced tumors. In summary, CSCs affect therapeutic efficacy, and the treatment method of targeting CSCs is still difficult to determine. Clarifying regulatory mechanisms and targeting biomarkers of CSCs is currently the mainstream idea.

Abstract Background Burns cause serious physical and psychological harm to patients, placing a heavy burden on the global healthcare system. Our previous study detailed the epidemiological characteristics of burn injuries in Chinese inpatients from 2009 to 2018. Interestingly, the anatomic locations of burn injuries vary by gender, age, provinces, and outcomes among different causes. Therefore, this current study aims to analyze the characteristics of burn injuries in inpatients with various burn sites by collecting data in China from 2009 to 2018. This analysis will inform future healthcare system decisions and provide effective strategies. Methods Burns inpatients from 196 hospitals across 31 provinces in China were included in the study, covering the period from 2009 to 2018. The data collected encompassed information on gender, age, etiology, regions, clinical outcomes, and anatomical locations of the injuries. Data analysis was conducted using Microsoft Excel 2007. Results From 2009 to 2018, a total of 333,995 burns inpatients were recorded. The most vulnerable parts to burns were multiple burn sites (230,090, 68.89%). Women were more susceptible to lower limb burns (15,608, 14%), while men were more prone to eye injuries (8,387, 3.37%) and hand burns (6,119, 2.75%). The age group of 0–10 years was the most vulnerable to burns across all body areas, including internal organs. In China, individuals aged 20–50 years were at a higher risk of head and neck burns compared to other age groups. The Han population showed increased vulnerability to eye injuries (2.12 times higher than minorities), respiratory tract issues (2.09 times higher than minorities), and trunk burns (1.83 times higher than minorities), while being less susceptible to internal organ injuries (0.23 times fewer than minorities) and lower limb burns (0.78 times fewer than minorities). The southwest region had the highest proportion of burns inpatients with burns affecting single body parts, whereas the eastern area had the highest rates of respiratory tract burns (0.85%) and multiple burn sites (80.64%). Scalding was identified as the most common cause of burns, while flame burns (769, 55.81%) and chemical burns (438, 47.35%) were the main causes of respiratory tract and internal organ injuries, respectively. Conclusions This study provides an initial description of characteristics of burns inpatients with various anatomic locations of burns in China over the past decade. Our findings will contribute to the most up-to-date clinical evidence database for healthcare planning and prevention initiatives in both China and other countries.

Abstract Background Several studies have demonstrated the population-level effectiveness of oral PrEP in reducing the risk of HIV infection. However, oral PrEP utilization among MSM in China remains below 1%. While existing literature has primarily focused on oral PrEP preference and willingness, there is limited exploration of the underlying factors contributing to oral PrEP cessation in China. This study aims to fill this gap by investigating the factors associated with oral PrEP cessation among MSM in China. Methods Assisted by MSM community organizations, we collected 6,535 electronic questionnaires from 31 regions across China, excluding Taiwan, Hong Kong, and Macau. The questionnaire focused on investigating MSM's awareness, willingness, usage, and cessation of oral PrEP. Additionally, 40 participants were randomly chosen for key informant interviews. These qualitative interviews aimed to explore the reasons influencing MSM discontinuing oral PrEP. Results We eventually enrolled 6535 participants. Among the 685 participants who had used oral PrEP, 19.70% (135/685) ceased oral PrEP. The results indicated that individuals spending > ¥1000 on a bottle of PrEP (aOR = 2.999, 95% CI: 1.886–4.771) were more likely to cease oral PrEP compared to those spending ≤ ¥1000. Conversely, individuals opting for on-demand PrEP (aOR = 0.307, 95% CI: 0.194–0.485) and those using both daily and on-demand PrEP (aOR = 0.114, 95% CI: 0.058–0.226) were less likely to cease PrEP compared to those using daily PrEP. The qualitative analysis uncovered eight themes influencing oral PrEP cessation: (i) High cost and low adherence; (ii) Sexual inactivity; (iii) Lack of knowledge about PrEP; (iv) Trust in current prevention strategies; (v) Poor quality of medical service and counseling; (vi) PrEP stigma; (vii) Partner and relationship factors; (viii) Access challenges. Conclusions The cessation of oral PrEP among MSM in China is associated with various factors, including the cost of oral PrEP medication, regimens, individual perception of HIV risk, stigma, and the quality of medical services. It is recommended to provide appropriate regimens for eligible MSM and develop tailored combinations of strategies to enhance PrEP awareness and acceptance among individuals, medical staff, and the MSM community. The findings from this study can support the refinement of HIV interventions among MSM in China, contributing to efforts to reduce the burden of HIV in this population.

Currently, practical applications of shape memory alloy (SMA) solid elastocaloric refrigeration materials are limited by low elastocaloric effect (eCE), high applied stress, and large stress hysteresis (Δσhys). Here, we introduce a composition design strategy using Ti-doped Co–V-Ga SMAs to address these challenges. We combine first-principles calculations and experiments to verify this strategy. Our results show that the lattice distortion caused by the significant difference in atomic radius after Ti doping produces a solid solution strengthening effect inside the alloy, which significantly improves the superelasticity of the alloy, delays the plastic deformation of the austenite phase, and the volume fraction of martensitic transformation increases significantly. The newly developed Co51.7V31.3Ga16Ti1 bulk polycrystalline alloy exhibits a remarkable adiabatic temperature change (ΔTad) of −10 K at room temperature under a low stress of 400 MPa, a minimum Δσhys of 18 MPa, and a high coefficient of performance COPmat of 31.9. Importantly, the 100-cycle loading-unloading test at 350 MPa is done, and it reveals that the ΔTad for the Ti0 alloy was only 3.9 K, while it reached 6.2 K for the Ti1 alloy, marking a noteworthy 59 % performance enhancement. From the simplicity of the fabrication process to the comprehensive performance of the material, it exhibits a promising advantage for practical cooling applications This study presents a feasible design strategy for large-scale production of high-performance bulk polycrystalline alloys with high eCE, low stress, and Δσhys.

Bacillus protease, a microbial protease known for its diverse range, significant activity and extensive research, has been widely used in the food industry. This review covers various aspects, including the screening and selection of protease high-producing Bacillus strains, the construction of engineered bacteria, the optimization of fermentation conditions for protease production, and the application of Bacillus protease in the food industry, specifically with plant proteins and animal proteins as substrates. Moreover, the future research direction and development trend are forecasted. The purpose of this review is to serve as a scholarly resource for future investigation and practical utilization of Bacillus protease.

A type of integrated multiple-single-channel analyzer (IMSCA) is described. The IMSCA works with an input pulse of 2-20 pC, and it can be directly connected to a scintillation detector, which eliminates the need for a linear amplifier. It consists of 64 input ports, so 1–64 detectors can be set by users according to different requirements. Two energy regions for each input channel can be simultaneously analyzed. Another advantage of the IMSCA is that it integrates with a high-speed pulse signal acquisition card and transmits data to the computer through the network. The maximum pulse through-rate is 1.4 MHz, and linearity can reach 0.1%. This IMSCA has been successfully used in enrichment detecting of nuclear fuel rod.

BackgroundCold environments reduce work efficiency and increase the risk of frostbite. ObjectiveTo investigate the effects on cold protection and manual performance of rescue gloves in cold environments, and to preliminarily verify the feasibility of related quantitative characterization methods. MethodsAn experiment was conducted in a large and a small artificial climate chamber. 12 male right-handed university students were recruited. The experiment was divided into two parts, with 0-10 min as the baseline phase and 10-50 min as the test phase. Subjects sat quietly in a 16 ℃ large chamber, and hands were exposed to a small chamber at 0 ℃ either barely (control group) or with rescue gloves (experimental group). Skin temperatures of the five fingers (thumb, index finger, middle finger, ring finger, and little finger), as well as the dorsal and palm of the hands were measured. In addition, grip strength, manual dexterity, maximum finger flexion, and tactile sensitivity of the hands were measured as the indicators of manual performance. ResultsIn the control group, cold-induced vasodilation occurred when the skin temperature of the five fingers were lowered to about 10 ℃. The maximum rate of change in skin temperature of the control group was in the following order: thumb＞index finger＞middle finger＞little finger＞ring finger＞dorsal＞palm, 165.7 ℃·h−1 in the thumb, 80.0 and 89.9 ℃·h−1 in the palm and dorsal respectively. In addition, the minimum skin temperature of the thumb was 6.6 ℃. Compared with the control group: the rate of change of skin temperature in the experimentalgroup decreased by about 50%; the grip strength decreased by 15% after wearing the rescue gloves (P0.05). ConclusionThis study proved that the rescue gloves improved the thermal comfort of hands while better balancing the effect of cold exposure on manual performance. The quantitative characterization methods can evaluate the protective performance and manual performance of the rescue gloves, which provides a reliable theoretical foundation and reference basis for further experiments.

Objective To retrospectively explore the prognostic factors of uremic maintenance hemodialysis （MHD） patients with novel COVID-19 infection. Methods A total of 556 MHD patients on regular follow-ups were recruited. Baseline profiles and laboratory tests were recorded prior to contracting COVID-19 infection. Results There were 312 males and 244 females with an age of （52.37 ± 14.81） year and an MHD duration of （61.02 ± 43.90） months. Diabetic kidney disease（DKD） was a primary disease （n = 101, 18.1%） with top three complications of diabetes mellitus （DM）（n = 135, 16.3%）, cardiovascular disease （CVD）（n = 48, 6.6%） and stroke （n = 3, 0.5%）. Hemodialysis （n = 192, 34.5%） and peritoneal dialysis （PD）（n = 364, 65.5%） were performed. DM, hemodialysis, age and serum sodium level were risk factors for mortality after COVID-19 infection. And serum prealbumin level was a protective factor. Multivariate regression analysis revealed that MHD and age were independent risk factors for mortality. Cardiovascular disease, MHD, age and blood glucose level were risk factors for severe pneumonia after COVID-19 infection. And serum albumin level was a protective factor. Conclusion CVD and hyperglycemia are independent risk factors for severe pneumonia while age is an independent risk factor for severe pneumonia and mortality. Generally MHD patients have a higher risk of mortality than PD counterparts.

Abstract Mpox virus (MPXV) can cause mpox in humans. Due to its quick and wide spread in the past two years, mpox has turned into a significant public health concern. Helicase E5 is a multi-domain protein; its primer synthesis and DNA unwinding activity are required for genome uncoating and DNA replication of MPXV. However, the in vitro DNA unwinding activity has never been demonstrated. Here, we report the structural and biochemical studies of MPXV E5, showing that the full-length protein adopts an auto-inhibited conformation. Truncation of the N-terminus can recover the in vitro unwinding activity of E5 towards the forked DNA. Further structural analysis reveals that MPXV E5 shares a conserved mechanism in DNA unwinding and primer synthesis with the homologous proteins. These findings not only advance our understanding on the function of MPXV E5, but also provide a solid basis for the development of anti-poxvirus drugs.

Abstract KRAS mutations are highly prevalent in a wide range of lethal cancers, and these mutant forms of KRAS play a crucial role in driving cancer progression and conferring resistance to treatment. While there have been advancements in the development of small molecules to target specific KRAS mutants, the presence of undruggable mutants and the emergence of secondary mutations continue to pose challenges in the clinical treatment of KRAS-mutant cancers. In this study, we developed a novel molecular tool called tumor-targeting KRAS degrader (TKD) that effectively targets a wide range of KRAS mutants. TKD is composed of a KRAS-binding nanobody, a cell-penetrating peptide selectively targeting cancer cells, and a lysosome-binding motif. Our data revealed that TKD selectively binds to KRAS in cancer cells and effectively induces KRAS degradation via a lysosome-dependent process. Functionally, TKD suppresses tumor growth with no obvious side effects and enhances the antitumor effects of PD-1 antibody and cetuximab. This study not only provides a strategy for developing drugs targeting “undruggable” proteins but also reveals that TKD is a promising therapeutic for treating KRAS-mutant cancers.

Abstract Direct laser acceleration (DLA) of electrons in plasmas of near-critical density (NCD) is a very advancing platform for high-energy PW-class lasers of moderate relativistic intensity supporting Inertial Confinement Fusion research. Experiments conducted at the PHELIX sub-PW Nd:glass laser demonstrated application-promising characteristics of DLA-based radiation and particle sources, such as ultra-high number, high directionality and high conversion efficiency. In this context, the bright synchrotron-like (betatron) radiation of DLA electrons, which arises from the interaction of a sub-ps PHELIX laser pulse with an intensity of 1019 W/cm2 with pre-ionized low-density polymer foam, was studied. The experimental results show that the betatron radiation produced by DLA electrons in NCD plasma is well directed with a half-angle of 100–200 mrad, yielding (3.4 ± 0.4)·1010 photons/keV/sr at 10 keV photon energy. The experimental photon fluence and the brilliance agree well with the particle-in-cell simulations. These results pave the way for innovative applications of the DLA regime using low-density pre-ionized foams in high energy density research.

Abstract Background The neonatal mammalian heart exhibits considerable regenerative potential following injury through cardiomyocyte proliferation, whereas mature cardiomyocytes withdraw from the cell cycle and lose regenerative capacities. Therefore, investigating the mechanisms underlying neonatal cardiomyocyte proliferation and regeneration is crucial for unlocking the regenerative potential of adult mammalian heart to repair damage and restore contractile function following myocardial injury. Methods The Tudor staphylococcal nuclease (Tudor-SN) transgenic (TG) or cardiomyocyte-specific knockout mice (Myh6-Tudor-SN −/− ) were generated to investigate the role of Tudor-SN in cardiomyocyte proliferation and heart regeneration following apical resection (AR) surgery. Primary cardiomyocytes isolated from neonatal mice were used to assess the influence of Tudor-SN on cardiomyocyte proliferation in vitro. Affinity purification and mass spectrometry were employed to elucidate the underlying mechanism. H9c2 cells and mouse myocardia with either overexpression or knockout of Tudor-SN were utilized to assess its impact on the phosphorylation of Yes-associated protein (YAP), both in vitro and in vivo. Results We previously identified Tudor-SN as a cell cycle regulator that is highly expressed in neonatal mice myocardia but downregulated in adults. Our present study demonstrates that sustained expression of Tudor-SN promotes and prolongs the proliferation of neonatal cardiomyocytes, improves cardiac function, and enhances the ability to repair the left ventricular apex resection in neonatal mice. Consistently, cardiomyocyte-specific knockout of Tudor-SN impairs cardiac function and retards recovery after injury. Tudor-SN associates with YAP, which plays important roles in heart development and regeneration, inhibiting phosphorylation at Ser 127 and Ser 397 residues by preventing the association between Large Tumor Suppressor 1 (LATS1) and YAP, correspondingly maintaining stability and promoting nuclear translocation of YAP to enhance the proliferation-related genes transcription. Conclusion Tudor-SN regulates the phosphorylation of YAP, consequently enhancing and prolonging neonatal cardiomyocyte proliferation under physiological conditions and promoting neonatal heart regeneration after injury. Graphical Abstract

Abstract Background Currently, industrial fermentation of Botrytis cinerea is a significant source of abscisic acid (ABA). The crucial role of ABA in plants and its wide range of applications in agricultural production have resulted in the constant discovery of new derivatives and analogues. While modifying the ABA synthesis pathway of existing strains to produce ABA derivatives is a viable option, it is hindered by the limited synthesis capacity of these strains, which hinders further development and application. Results In this study, we knocked out the bcaba4 gene of B. cinerea TB-31 to obtain the 1′,4′-trans-ABA-diol producing strain ZX2. We then studied the fermentation broth of the batch-fed fermentation of the ZX2 strain using metabolomic analysis. The results showed significant accumulation of 3-hydroxy-3-methylglutaric acid, mevalonic acid, and mevalonolactone during the fermentation process, indicating potential rate-limiting steps in the 1′,4′-trans-ABA-diol synthesis pathway. This may be hindering the flow of the synthetic pathway. Additionally, analysis of the transcript levels of terpene synthesis pathway genes in this strain revealed a correlation between the bchmgr, bcerg12, and bcaba1-3 genes and 1′,4′-trans-ABA-diol synthesis. To further increase the yield of 1′,4′-trans-ABA-diol, we constructed a pCBg418 plasmid suitable for the Agrobacterium tumefaciens-mediated transformation (ATMT) system and transformed it to obtain a single-gene overexpression strain. We found that overexpression of bchmgr, bcerg12, bcaba1, bcaba2, and bcaba3 genes increased the yield of 1′,4′-trans-ABA-diol. The highest yielding ZX2 A3 strain was eventually screened, which produced a 1′,4′-trans-ABA-diol concentration of 7.96 mg/g DCW (54.4 mg/L) in 144 h of shake flask fermentation. This represents a 2.1-fold increase compared to the ZX2 strain. Conclusions We utilized metabolic engineering techniques to alter the ABA-synthesizing strain B. cinerea, resulting in the creation of the mutant strain ZX2, which has the ability to produce 1′,4′-trans-ABA-diol. By overexpressing the crucial genes involved in the 1′,4′-trans-ABA-diol synthesis pathway in ZX2, we observed a substantial increase in the production of 1′,4′-trans-ABA-diol.

Abstract Efficient seawater desalination is an effective way to solve the shortages of fresh water and energy but with limitations of the low fresh water production rate and high cost. Here, a hollow carbon fiber (HCF) wrapped by regular reduced graphene oxide (rGO) wave-like folds (rGO@HCF) is prepared on account of the differences in thermal shrinkage performance between graphene oxide (GO) and willow catkins fiber. Under one sun irradiation (1 kW m−2), the dry and wet surface temperature of the resulting evaporator reached up to 119.1 °C and 61.7 °C, respectively, and the water steam production rate reached 3.42 kg m−2 h−1. Also, for the outdoor experiment, the rGO@HCF exhibits good evaporator performance which reach up 27.8 kg m−2 day−1. Additionally, rGO@HCF also shows good seawater desalination performance and excellent durability for longtime work. DSC results indicate that the evaporation enthalpy of bulk water and adsorbed water decreased from 2503.92 to 1020.54 J g−1. The excellent evaporating performance is mainly attributed to the regular wave-like microstructure surface of the HCF, which can enhance the light absorption, reduced the vaporization enthalpy of the adsorption water. The findings not only introduce a novel approach for agricultural utilization, but also establish a crucial theoretical foundation for the design of regular wave-like microstructures.

Abstract Conjunctival melanoma (CoM) is a potentially devastating tumor that can lead to distant metastasis. Despite various therapeutic strategies for distant metastatic CoM, the clinical outcomes remain unfavorable. Herein, we performed single-cell RNA sequencing (scRNA-seq) of 47,017 cells obtained from normal conjunctival samples (n = 3) and conjunctival melanomas (n = 7). Notably, we noticed a higher abundance of cancer-associated fibroblasts (CAFs) in tumor microenvironment (TME), correlated with enhanced angiogenic capacity and increased VEGFR expression in distal metastatic CoM. Additionally, we observed a significant decrease in the proportion of total CD8+ T cells and an increase in the proportion of naive CD8+ T cells, contributing to a relatively quiescent immunological environment in distal metastatic CoM. These findings were confirmed through the analyses of 70,303 single-cell transcriptomes of 7 individual CoM samples, as well as spatially resolved proteomes of an additional 10 samples of CoMs. Due to the increase of VEGFR-mediated angiogenesis and a less active T cell environment in distal metastatic CoMs, a clinical trial (ChiCTR2100045061) has been initiated to evaluate the efficacy of VEGFR blockade in combination with anti-PD1 therapy for patients with distant metastatic CoM, showing promising tumor-inhibitory effects. In conclusion, our study uncovered the landscape and heterogeneity of the TME during CoM tumorigenesis and progression, empowering clinical decisions in the management of distal metastatic CoM. To our knowledge, this is the initial exploration to translate scRNA-seq analysis to a clinical trial dealing with cancer, providing a novel concept by accommodating scRNA-seq data in cancer therapy.

Abstract Background Dry eyes can cause discomfort. To treat dry eye disease, cyclosporine A (CsA) and Lifitegrast are two eye drugs approved by the U.S. Food and Drug Administration (FDA). However, frequent use of eye drops can be challenging and lead to poor compliance, especially in elderly patients. Therefore, this study aimed to develop a drug sustained-release vector and explore its therapeutic effect in animal models of dry eye. Methods Firstly, drug membranes loaded with both CsA and Lifitegrast using a carrier called poly(lactate-co-ε-caprolactone) (P(LLA-CL)) were prepared and evaluated for their physicochemical properties, release behavior in vitro, and safety in vivo. Next, a rabbit dry eye model using a 0.1% benzalkonium chloride (BAC) solution was developed and treated by drug-loaded micro membranes. We observed and recorded conjunctival hyperemia, corneal staining, corneal edema, corneal neovascularization, conjunctival goblet cells and hematoxylin and eosin (H&E) staining. Finally, we detected the MUC5AC and MMP-9 by immunofluorescence staining and enzyme-linked immunosorbent assay (ELISA). Results The composite film released both CsA and Lifitegrast for at least one month. Compared to the blank membrane group, conjunctival hyperemia, corneal fluorescein staining, corneal edema, corneal neovascularization and conjunctival goblet cells recovered faster in the drug membrane group, and the difference was statistically significant. At the molecular level, the drug membrane group showed an increase in mucin density and a significant anti-inflammatory effect. Conclusions The implantation of CsA/Lifitegrast loaded P(LLA-CL) membrane under the subconjunctival of the rabbit eye is safe. The study suggests that this subconjunctival administration could be developed into a minimally invasive delivery system to help patients with dry eye disease who require multiple daily eyedrops but have poor compliance.

Abstract Background Considering the age relevance of prostate cancer (PCa) and the involvement of the cGAS-STING pathway in aging and cancer, we aim to classify PCa into distinct molecular subtypes and identify key genes from the novel perspective of the cGAS-STING pathway. It is of significance to guide personalized intervention of cancer-targeting therapy based on genetic evidence. Methods The 430 patients with PCa from the TCGA database were included. We integrated 29 key genes involved in cGAS-STING pathway and analyzed differentially expressed genes and biochemical recurrence (BCR)-free survival-related genes. The assessments of tumor stemness and heterogeneity and tumor microenvironment (TME) were conducted to reveal potential mechanisms. Results PCa patients were classified into two distinct subtypes using AURKB, TREX1, and STAT6, and subtype 1 had a worse prognosis than subtype 2 (HR: 21.19, p

Abstract Osteoarthritis (OA) is the most common degenerative joint disorder that causes disability in aged individuals, caused by functional and structural alterations of the knee joint. To investigate whether metabolic drivers might be harnessed to promote cartilage repair, a liquid chromatography–mass spectrometry (LC–MS) untargeted metabolomics approach was carried out to screen serum biomarkers in osteoarthritic rats. Based on the correlation analyses, α-ketoglutarate (α-KG) has been demonstrated to have antioxidant and anti-inflammatory properties in various diseases. These properties make α-KG a prime candidate for further investigation of OA. Experimental results indicate that α-KG significantly inhibited H2O2-induced cartilage cell matrix degradation and apoptosis, reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), increased superoxide dismutase (SOD) and glutathione (GSH)/glutathione disulfide (GSSG) levels, and upregulated the expression of ETV4, SLC7A11 and GPX4. Further mechanistic studies observed that α-KG, like Ferrostatin-1 (Fer-1), effectively alleviated Erastin-induced apoptosis and ECM degradation. α-KG and Fer-1 upregulated ETV4, SLC7A11, and GPX4 at the mRNA and protein levels, decreased ferrous ion (Fe2+) accumulation, and preserved mitochondrial membrane potential (MMP) in ATDC5 cells. In vivo, α-KG treatment inhibited ferroptosis in OA rats by activating the ETV4/SLC7A11/GPX4 pathway. Thus, these findings indicate that α-KG inhibits ferroptosis via the ETV4/SLC7A11/GPX4 signaling pathway, thereby alleviating OA. These observations suggest that α-KG exhibits potential therapeutic properties for the treatment and prevention of OA, thereby having potential clinical applications in the future.

Abstract This multicentre, two-arm, phase 2 study aimed to explore the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy or apatinib in patients with initially unresectable stage II–III non-small-cell lung cancer (NSCLC). Eligible patients regardless of PD-L1 expression received neoadjuvant camrelizumab 200 mg and platinum-doublet chemotherapy every 3 weeks (arm A) or those with PD-L1-positive tumors received neoadjuvant camrelizumab and apatinib 250 mg once daily (arm B), for 2–4 cycles, followed by surgery. The primary endpoint was major pathological response (MPR) rate. Thirty patients in arm A and 21 in arm B were enrolled. Surgery rates were 50.0% (15/30) in arm A and 42.9% (9/21) in arm B, with all patients achieving R0 resections. Of these patients, the MPR and pathological complete response rates were both 20.0% (95% CI 4.3–48.1) in arm A and were 55.6% (95% CI 21.2–86.3) and 11.1% (95% CI 0.3–48.2) in arm B, respectively. The corresponding objective response rates were 33.3% (95% CI 11.8–61.6) and 55.6% (95% CI 21.2–86.3). With a median follow-up of 22.4 months (95% CI 19.0–26.0), the median event-free survival was not reached (NR; 95% CI 13.6-NR) in arm A and 16.8 months (95% CI 8.6-NR) in arm B. Grade 3 or above treatment-related adverse events occurred in eight (26.7%) patients in arm A and three (14.3%) in arm B. Biomarker analysis showed baseline TYROBP expression was predictive of treatment response in arm B. Neoadjuvant camrelizumab plus chemotherapy or apatinib exhibits preliminary efficacy and manageable toxicity in patients with initially unresectable stage II–III NSCLC.

Abstract New urbanization (NU) and ecological welfare performance (EWP) play pivotal roles in achieving sustainable urban development, with both emphasizing social equity and environmental management. Exploring the coordinated relationship between EWP and NU is invaluable for understanding the symbiotic interplay between humans and nature. We constructed a framework to elucidate the coupling mechanism of EWP and NU from the perspective of systems theory. We quantified the levels of NU and EWP utilizing the entropy weighting method and the super-efficient SBM method, respectively. Furthermore, we assessed the degree of coupling coordination between the two using the coupling coordination degree model (CCDM). Spatial and temporal evolution analysis was conducted, and factors influencing the degree of coupling coordination between EWP and NU were explored through a spatial–temporal geographically-weighted regression model (GTWR). The results indicate: (1) During the study period, the average annual increase in EWP in the study area was 2.59%, with a narrowing relative gap between cities. Conversely, the average annual increase in the level of NU was 7.6%, with demographic and economic dimensions carrying the highest weights. (2) The type of coupling coordination between EWP and NU transitions from basic coordination to moderate coordination, with the development of EWP lagging behind that of NU. (3) City size demonstrates a positive yet diminishing trend on the coupling coordination level, with economic development exerting the greatest influence and exhibiting a "V" trend, while the impact of green technology innovation diminishes negatively. Additionally, regional disparities are significant, with city size exhibiting a negative impact in areas of high population density and low economic levels, and green technology innovation showing notable polarization characteristics in core cities. These findings serve as a foundation for fostering coordinated ecological development amid the rapid urbanization process of the Chengdu–Chongqing Economic Circle.

Abstract Background Whether patients with cT1 − 2N1M0 breast cancer can benefit from postoperative radiotherapy (RT) after receiving neoadjuvant chemotherapy (NAC) has been controversial. Therefore, the purpose of this study was to explore whether postoperative RT can benefit this group of patients in terms of survival. Methods We used Surveillance, Epidemiology, and End Results (SEER) data to conduct a retrospective review of women with cT1 − 2N1M0 breast cancer diagnosed between 20 and 80 years of age who received NAC between 2010 and 2015. Our study compared the impact of postoperative RT on overall survival (OS) and cancer-specific survival (CSS) in breast cancer patients using propensity score matching (PSM) and performed subgroup analysis. Results This study finally included 1092 cT1 − 2N1M0 breast cancer patients. Regardless of the patient’s PSM status, postoperative RT was significantly associated with OS of cT1- 2N1M0 breast cancer patients who received NAC. Specifically, the 10-year OS rate was 78.7% before PSM matching, compared with 71.1% in patients who did not receive postoperative RT, and the difference was more significant after PSM matching, which was 83.1% and 71.1% respectively. However, postoperative RT did not significantly benefit CSS in patients with cT1 − 2N1M0 breast cancer who received NAC. The 10-year CSS rate was 81.4% VS 76.2% (P = 0.085) before PSM matching and 85.8% VS 76.2%(P = 0.076) after matching. Due to the intersection of OS and CSS curves, this restricted mean survival time (RMST) method was chosen as a supplement. After 60 months, the OS difference in RMST between the postoperative RT group and the non-radiotherapy (noRT) group was 7.37 months (95%CI: 0.54–14.21; P = 0.034), and the CSS difference was 5.18 months (95%CI: -1.31-11.68; P = 0.118). Subgroup analysis found that in patients with right-sided breast cancer, postoperative RT improved the patient’s OS (HR = 0.45, 95%CI: 0.21–0.95, P = 0.037) and CSS (HR = 0.42, 95%CI: 0.18–0.98, P = 0.045). Conclusions Our results showed that additional postoperative RT improved the OS of cT1 − 2N1M0 breast cancer patients who received NAC, but failed to improve their CSS. It is worth noting that in the subgroup analysis of patients with right-sided breast cancer, we observed significant improvements in OS and CSS. And further prospective studies are still needed to verify the effect of postoperative RT in different subgroups.

Fat content is an important trait in pig production. Adipose tissue and muscle are important sites for fat deposition and affect production efficiency and quality. To regulate the fat content in these tissues, we need to understand the mechanisms behind fat deposition. Laiwu pigs, a Chinese indigenous breed, have significantly higher fat content in both adipose tissue and muscle than commercial breeds such as Duroc. In this study, we analyzed the transcriptomes in adipose tissue and muscle of 21-d-old Laiwu and Duroc piglets. Results showed that there were 828 and 671 differentially expressed genes (DEG) in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), respectively. Functional enrichment analysis showed that these DEG were enriched in metabolic pathways, especially carbohydrate and lipid metabolism. Additionally, in the longissimus muscle (LM) and psoas muscle (PM), 312 and 335 DEG were identified, demonstrating enrichment in the cell cycle and metabolic pathways. The protein–protein interaction (PPI) networks of these DEG were analyzed and potential hub genes were identified, such as FBP1 and SCD in adipose tissues and RRM2 and GADL1 in muscles. Meanwhile, results showed that there were common DEG between adipose tissue and muscle, such as LDHB, THRSP, and DGAT2. These findings showed that there are significant differences in the transcriptomes of the adipose tissue and muscle between Laiwu and Duroc piglets (P

This study explores the potential of Artificial Intelligence (AI) in early screening and prognosis of Dry Eye Disease (DED), aiming to enhance the accuracy of therapeutic approaches for eye-care practitioners. Despite the promising opportunities, challenges such as diverse diagnostic evidence, complex etiology, and interdisciplinary knowledge integration impede the interpretability, reliability, and applicability of AI-based DED detection methods. The research conducts a comprehensive review of datasets, diagnostic evidence, and standards, as well as advanced algorithms in AI-based DED detection over the past five years. The DED diagnostic methods are categorized into three groups based on their relationship with AI techniques: (1) those with ground truth and/or comparable standards, (2) potential AI-based methods with significant advantages, and (3) supplementary methods for AI-based DED detection. The study proposes suggested DED detection standards, the combination of multiple diagnostic evidence, and future research directions to guide further investigations. Ultimately, the research contributes to the advancement of ophthalmic disease detection by providing insights into knowledge foundations, advanced methods, challenges, and potential future perspectives, emphasizing the significant role of AI in both academic and practical aspects of ophthalmology.

Small extracellular vesicles (sEVs) are known to be secreted by a vast majority of cells. These sEVs, specifically exosomes, induce specific cell-to-cell interactions and can activate signaling pathways in recipient cells through fusion or interaction. These nanovesicles possess several desirable properties, making them ideal for regenerative medicine and nanomedicine applications. These properties include exceptional stability, biocompatibility, wide biodistribution, and minimal immunogenicity. However, the practical utilization of sEVs, particularly in clinical settings and at a large scale, is hindered by the expensive procedures required for their isolation, limited circulation lifetime, and suboptimal targeting capacity. Despite these challenges, sEVs have demonstrated a remarkable ability to accommodate various cargoes and have found extensive applications in the biomedical sciences. To overcome the limitations of sEVs and broaden their potential applications, researchers should strive to deepen their understanding of current isolation, loading, and characterization techniques. Additionally, acquiring fundamental knowledge about sEVs origins and employing state-of-the-art methodologies in nanomedicine and regenerative medicine can expand the sEVs research scope. This review provides a comprehensive overview of state-of-the-art exosome-based strategies in diverse nanomedicine domains, encompassing cancer therapy, immunotherapy, and biomarker applications. Furthermore, we emphasize the immense potential of exosomes in regenerative medicine.

Abstract To counterbalance the abilities of global exploration and local exploitation of algorithm and enhance its comprehensive performance, a multi-objective particle swarm optimization with a competitive hybrid learning strategy (CHLMOPSO) is put forward. With regards to this, the paper first puts forward a derivative treatment strategy of personal best to promote the optimization ability of particles. Next, an adaptive flight parameter adjustment strategy is designed in accordance with the evolutionary state of particles to equilibrate the exploitation and exploration abilities of the algorithm. Additionally, a competitive hybrid learning strategy is presented. According to the outcomes of the competition, various particles decide on various updating strategies. Finally, an optimal angle distance strategy is proposed to maintain archive effectively. CHLMOPSO is compared with other algorithms through simulation experiments on 22 benchmark problems. The results demonstrate that CHLMOPSO has satisfactory performance.

Abstract Reduced hippocampal volume occurs in major depressive disorder (MDD), potentially due to elevated glucocorticoids from an overactivated hypothalamus–pituitary–adrenal (HPA) axis. To examine this in humans, hippocampal volume and hypothalamus (HPA axis) metabolism was quantified in participants with MDD before and after antidepressant treatment. 65 participants (n = 24 males, n = 41 females) with MDD were treated in a double-blind, randomized clinical trial of escitalopram. Participants received simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) before and after treatment. Linear mixed models examined the relationship between hippocampus/dentate gyrus volume and hypothalamus metabolism. Chi-squared tests and multivariable logistic regression examined the association between hippocampus/dentate gyrus volume change direction and hypothalamus activity change direction with treatment. Multiple linear regression compared these changes between remitter and non-remitter groups. Covariates included age, sex, and treatment type. No significant linear association was found between hippocampus/dentate gyrus volume and hypothalamus metabolism. 62% (38 of 61) of participants experienced a decrease in hypothalamus metabolism, 43% (27 of 63) of participants demonstrated an increase in hippocampus size (51% [32 of 63] for the dentate gyrus) following treatment. No significant association was found between change in hypothalamus activity and change in hippocampus/dentate gyrus volume, and this association did not vary by sex, medication, or remission status. As this multimodal study, in a cohort of participants on standardized treatment, did not find an association between hypothalamus metabolism and hippocampal volume, it supports a more complex pathway between hippocampus neurogenesis and hypothalamus metabolism changes in response to treatment.

Abstract Background Members of the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain containing (NLRP) family regulate various physiological and pathological processes. However, none have been shown to regulate actin cap formation or spindle translocation during the asymmetric division of oocyte meiosis I. NLRP4E has been reported as a candidate protein in female fertility, but its function is unknown. Methods Immunofluorescence, reverse transcription polymerase chain reaction (RT-PCR), and western blotting were employed to examine the localization and expression levels of NLRP4E and related proteins in mouse oocytes. small interfering RNA (siRNA) and antibody transfection were used to knock down NLRP4E and other proteins. Immunoprecipitation (IP)-mass spectrometry was used to identify the potential proteins interacting with NLRP4E. Coimmunoprecipitation (Co-IP) was used to verify the protein interactions. Wild type (WT) or mutant NLRP4E messenger RNA (mRNA) was injected into oocytes for rescue experiments. In vitro phosphorylation was employed to examine the activation of steroid receptor coactivator (SRC) by NLRP4E. Results NLRP4E was more predominant within oocytes compared with other NLRP4 members. NLRP4E knockdown significantly inhibited actin cap formation and spindle translocation toward the cap region, resulting in the failure of polar body extrusion at the end of meiosis I. Mechanistically, GRIN1, and GANO1 activated NLRP4E by phosphorylation at Ser429 and Thr430; p-NLRP4E is translocated and is accumulated in the actin cap region during spindle translocation. Next, we found that p-NLRP4E directly phosphorylated SRC at Tyr418, while p-SRC negatively regulated p-CDC42-S71, an inactive form of CDC42 that promotes actin cap formation and spindle translocation in the GTP-bound form. Conclusions NLRP4E activated by GRIN1 and GANO1 regulates actin cap formation and spindle translocation toward the cap region through upregulation of p-SRC-Tyr418 and downregulation of p-CDC42-S71 during meiosis I.

Abstract CircRNAs are covalently closed, single-stranded RNA that form continuous loops and play a crucial role in the initiation and progression of tumors. Cancer stem cells (CSCs) are indispensable for cancer development; however, the regulation of cancer stem cell-like properties in gastric cancer (GC) and its specific mechanism remain poorly understood. We elucidate the specific role of Circ-0075305 in GC stem cell properties. Circ-0075305 associated with chemotherapy resistance was identified by sequencing GC cells. Subsequent confirmation in both GC tissues and cell lines revealed that patients with high expression of Circ-0075305 had significantly better overall survival (OS) rates than those with low expression, particularly when treated with postoperative adjuvant chemotherapy for GC. In vitro and in vivo experiments confirmed that overexpression of Circ-0075305 can effectively reduce stem cell-like properties and enhance the sensitivity of GC cells to Oxaliplatin compared with the control group. Circ-0075305 promotes RPRD1A expression by acting as a sponge for corresponding miRNAs. The addition of LF3 (a β-catenin/TCF4 interaction antagonist) confirmed that RPRD1A inhibited the formation of the TCF4–β-catenin transcription complex through competitive to β-catenin and suppressed the transcriptional activity of stem cell markers such as SOX9 via the Wnt/β-catenin signaling pathway. This leads to the downregulation of stem cell-like property-related markers in GC. This study revealed the underlying mechanisms that regulate Circ-0075305 in GCSCs and suggests that its role in reducing β-catenin signaling may serve as a potential therapeutic candidate.

Abstract Background Bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) remains a devastating clinical complication seriously affecting the therapeutic outcome of preterm infants. Hence, early prevention and timely diagnosis prior to pathological change is the key to reducing morbidity and improving prognosis. Our primary objective is to utilize machine learning techniques to build predictive models that could accurately identify BPD infants at risk of developing PH. Methods The data utilized in this study were collected from neonatology departments of four tertiary-level hospitals in China. To address the issue of imbalanced data, oversampling algorithms synthetic minority over-sampling technique (SMOTE) was applied to improve the model. Results Seven hundred sixty one clinical records were collected in our study. Following data pre-processing and feature selection, 5 of the 46 features were used to build models, including duration of invasive respiratory support (day), the severity of BPD, ventilator-associated pneumonia, pulmonary hemorrhage, and early-onset PH. Four machine learning models were applied to predictive learning, and after comprehensive selection a model was ultimately selected. The model achieved 93.8% sensitivity, 85.0% accuracy, and 0.933 AUC. A score of the logistic regression formula greater than 0 was identified as a warning sign of BPD-PH. Conclusions We comprehensively compared different machine learning models and ultimately obtained a good prognosis model which was sufficient to support pediatric clinicians to make early diagnosis and formulate a better treatment plan for pediatric patients with BPD-PH.

Abstract Background Acute pancreatitis (AP) is a common acute digestive system disorder, with patients often turning to TikTok for AP-related information. However, the platform’s video quality on AP has not been thoroughly investigated. Objective The main purpose of this study is to evaluate the quality of videos about AP on TikTok, and the secondary purpose is to study the related factors of video quality. Methods This study involved retrieving AP-related videos from TikTok, determining, and analyzing them based on predefined inclusion and exclusion criteria. Relevant data were extracted and compiled for evaluation. Video quality was scored using the DISCERN instrument and the Health on the Net (HONcode) score, complemented by introducing the Acute Pancreatitis Content Score (APCS). Pearson correlation analysis was used to assess the correlation between video quality scores and user engagement metrics such as likes, comments, favorites, retweets, and video duration. Results A total of 111 TikTok videos were included for analysis, and video publishers were composed of physicians (89.18%), news media organizations (13.51%), individual users (5.41%), and medical institutions (0.9%). The majority of videos focused on AP-related educational content (64.87%), followed by physicians’ diagnostic and treatment records (15.32%), and personal experiences (19.81%). The mean scores for DISCERN, HONcode, and APCS were 33.05 ± 7.87, 3.09 ± 0.93, and 1.86 ± 1.30, respectively. The highest video scores were those posted by physicians (35.17 ± 7.02 for DISCERN, 3.31 ± 0.56 for HONcode, and 1.94 ± 1.34 for APCS, respectively). According to the APCS, the main contents focused on etiology (n = 55, 49.5%) and clinical presentations (n = 36, 32.4%), followed by treatment (n = 24, 21.6%), severity (n = 20, 18.0%), prevention (n = 19, 17.1%), pathophysiology (n = 17, 15.3%), definitions (n = 13, 11.7%), examinations (n = 10, 9%), and other related content. There was no correlation between the scores of the three evaluation tools and the number of followers, likes, comments, favorites, and retweets of the video. However, DISCERN (r = 0.309) and APCS (r = 0.407) showed a significant positive correlation with video duration, while HONcode showed no correlation with the duration of the video. Conclusions The general quality of TikTok videos related to AP is poor; however, the content posted by medical professionals shows relatively higher quality, predominantly focusing on clinical presentations and etiologies. There is a discernible correlation between video duration and quality ratings, indicating that a combined approach incorporating the guideline can comprehensively evaluate AP-related content on TikTok.

Achieving a balance between convergence and diversity and their mutual enhancement is a complex task in the process of algorithm improvement. This is crucial because it is directly related to the effectiveness of the algorithm in obtaining accurate and uniformly distributed Pareto frontiers. Although significant progress has been made in particle swarm algorithms, exploring new approaches is necessary. In this paper, we construct a projection plane (projection line in 2D) based on the extreme values of the non-dominated solutions, select a set of uniform reference points on the projection plane, and then project the non-dominated solutions onto the constructed projection plane to form projection points. The reference points and projection points on the projection plane are thus utilized to guide the updating of the population as well as the maintenance of the external archive, a strategy that enhances the algorithm's global exploration and local exploitation capabilities. Secondly, we aggregate the target values of particles into a single scalar value and combine the idea of particle fusion to design a scheme for the particle selection of individual optimal particles. This paper further improves the algorithm's overall performance by using the information between populations to select individual optimal particles. Lastly, it is evaluated against a number of multi-objective algorithms that are currently in use and perform well on 22 test problems. The findings demonstrate that the algorithm this paper proposes performs better when solving multi-objective problems.