Picosecond Spin Current Generation from Vicinal Metal-Antiferromagnetic Insulator Interfaces.

We report the picosecond spin current generation from the interface between a heavy metal and a vicinal antiferromagnet insulator Cr_{2}O_{3} by laser pulses at room temperature and zero magnetic field. It is converted into a detectable terahertz emission in the heavy metal via the inverse spin Hall effect. The vicinal interfaces are apparently the source of the picosecond spin current, as evidenced by the proportional terahertz signals to the vicinal angle. We attribute the origin of the spin current to the transient magnetic moment generated by an interfacial nonlinear magnetic-dipole difference-frequency generation. We propose a model based on the in-plane inversion symmetry breaking to quantitatively explain the terahertz intensity with respect to the angles of the laser polarization and the film azimuth. Our work opens new opportunities in antiferromagnetic and ultrafast spintronics by considering symmetry breaking.

Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU): Trial Satisfaction and Attitudes towards Future Clinical Trials.

BACKGROUND: Clinical trial satisfaction is increasingly important for future trial designs and is associated with treatment adherence and willingness to enroll in future research studies or to recommend trial participation. In this post-trial survey, we examined participant satisfaction and attitudes toward future clinical trials in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU). METHODS: We developed an anonymous, participant satisfaction survey tailored to participants enrolled in the DIAN-TU-001 double-blind clinical trial of solanezumab or gantenerumab and requested that all study sites share the survey with their trial participants. A total of 194 participants enrolled in the trial at 24 study sites. We utilized regression analysis to explore the link between participants' clinical trial experiences, their satisfaction, and their willingness to participate in upcoming trials. RESULTS: Survey responses were received over a sixteen-month window during 2020-2021 from 58 participants representing 15 study sites. Notably, 96.5% of the survey respondents expressed high levels of satisfaction with the trial, 91.4% would recommend trial participation, and 96.5% were willing to enroll again. Age, gender, and education did not influence satisfaction levels. Participants reported enhanced medical care (70.7%) and pride in contributing to the DIAN-TU trial (84.5%). Satisfaction with personnel and procedures was high (98.3%). Respondents had a mean age of 48.7 years, with most being from North America and Western Europe, matching the trial's demographic distribution. Participants' decisions to learn their genetic status increased during the trial, and most participants endorsed considering future trial participation regardless of the DIAN-TU-001 trial outcome. CONCLUSION: Results suggest that DIAN-TU-001 participants who responded to the survey exhibited high motivation to participate in research, overall satisfaction with the clinical trial, and willingness to participate in research in the future, despite a long trial duration of 4-7 years with detailed annual clinical, cognitive, PET, MRI, and lumbar puncture assessments. Implementation of features that alleviate barriers and challenges to trial participation is like to have a high impact on trial satisfaction and reduce participant burden.

Sampling time for different matrices in stress assessment of farmed Atlantic salmon post-smolt.

The sustainability of commercial aquaculture production depends critically on prioritizing fish welfare management. Besides monitoring welfare parameters such as fish behaviour and water quality, fish stress level can also provide a reliable measure of the welfare status of farmed fish. Cortisol and 5 of its metabolites (5ß-THF, cortisone, 5ß-DHE, 5ß-THE, ß-cortolone) were previously identified by the authors as suitable stress biomarkers of farmed Atlantic salmon. Based on this knowledge, the present study aimed to investigate the time-related dynamics of these metabolites in plasma, skin mucus, bile and faeces over a 72 h- period. The objective was to determine the optimal sampling time for each matrix and to understand the clearance pathway of these metabolites following stress. An experiment was carried out using a total of 90 Atlantic salmon with an average weight of 438 (±132) g. The average sea temperature was 6.9 °C during the experimental period. A control group of 10 fish was first collected before the remaining 80 fish were submitted to a stress of netting and subsequent relocation into two separate cages. From each of these two stress groups, 10 fish were sampled at 1h, 2h, 4h, 6h and 12h, 24h, 48h, 72h after the stress event respectively. The concentrations of cortisol and its metabolites were measured at each of the sampling timepoint. The results demonstrated that plasma cortisol metabolites reached the highest concentration 4h after stress and remained elevated despite the slight decrease for the remaining timepoints. The peak level was observed at 12h post stress in skin mucus and 24h in bile and faeces. The findings suggest that these timepoints are the optimal for sampling Atlantic salmon post-smolt following stressful events in acute stress studies. Furthermore, the results reveal that analysing cortisol and its metabolites, both in free and conjugated forms, rather than free cortisol provides greater flexibility as their concentrations are less affected by sampling procedure. This study confirms the appropriateness of skin mucus and faeces as less-invasive sample matrices for fish stress evaluation and provides a basis for further developing low invasive tools for monitoring the welfare of farmed salmonid.

Changes and significance of the fibrinolytic system following two pulmonary thromboembolisms in a rabbit model.

In this study, we examined the changes in the fibrinolytic system in a rabbit model of two acute pulmonary thromboembolisms (PTE). Fourteen healthy adult New Zealand white rabbits were divided into three groups: the single PTE group (five rabbits), the double PTE group (five rabbits), and the control group (four rabbits). A rabbit model of acute pulmonary embolism was established, and immunohistochemistry and polymerase chain reaction (PCR) were performed on tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) in plasma, and pulmonary embolism tissue. Plasma results: 1) t-PA levels: one hour following the initial modeling, the levels of t-PA in the modeling groups were significantly lower than those in the control group (P<0.05). In addition, the t-PA levels in the double PTE group were found to be lower after the modeling, as compared to the pre-modeling period (P<0.05). One hour after the second modeling, the double PTE group had lower t-PA levels compared to the control group (P<0.05). However, t-PA rebounded two hours after modeling in the double PTE group. One week after the second modeling, the double PTE group had higher t-PA levels compared to the other two groups (P<0.05). 2) PAI-1 results: one hour after the initial modeling, PAI-1 levels in the two modeling groups were lower compared to the pre-modeling period and control groups (P<0.05). Two hours following modeling, PAI-1 levels in both modeling groups were lower compared to the control group (P<0.05). PAI-1 levels were lower in the double PTE group one and two hours after the second modeling compared to the other two groups and pre-modeling period (P<0.05). 3) The immunohistochemistry results: the expression of PAI-1 decreased in the two modeling groups, while t-PA expression increased compared to the control group. 4) PCR results: t-PA mRNA expression did not differ among the three groups. The PAI-1 mRNA expression was lower in the two PTE groups compared to the control group. We conclude that in the early stages of PTE, the local fibrinolytic activity of the thrombus is increased, which is favorable for thrombolysis. However, as the thrombus persists, the activity of the fibrinolytic system is inhibited, contributing to the development of chronic thromboembolic pulmonary hypertension.

[Prognostic value of skeletal muscle measured by CT at the T4 level in advanced EGFR-positive non-small cell lung cancer patients treated with ecotinib].

Objective: To investigate the prognostic value of skeletal muscle measured by CT at the level of the fourth thoracic vertebra (T4) in advanced epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) patients treated with ecotinib. Methods: The study retrospectively reviewed clinical and pathological characteristics of 176 patients with advanced EGFR-positive NSCLC who received ecotinib and underwent chest CT scans at Wuhan Union Hospital between January 2017 and October 2020. Among them, 70 were male and 106 were female, with ages ranging from 27 to 80 (58.6±10.6) years. As of August 21, 2021, the median follow-up duration was 19.2 months (95%CI: 15.3 to 23.7 months). The optimal cut-off value of skeletal muscle density (T4-SMD) on CT images at the T4 level were determined using X-tile software. Kaplan-Meier analysis and log-rank test were used to plot progression-free survival curves. Cox proportional hazards regression models were employed to analyze factors influencing 1-year progression-free survival (PFS), and a nomogram prognostic model was constructed accordingly. Receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA) were utilized to evaluate the predictive value of the nomogram. Results: The T4-SMD [M (Q1,Q3)] of 176 patients was 42.56 (37.05, 45.93) HU. Patients were divided into low T4-SMD group (n=122) and high T4-SMD group (n=54) based on the cut-off value (The values for males and females were 49.44 and 41.41 HU, respectively) of T4-SMD. The median PFS time and 1-year PFS rate in the low T4-SMD group were significantly lower than those in the high T4-SMD group [10.4 (95%CI: 9.3-11.8) vs 13.7 (95%CI: 11.1-18.5) months, 36.1% vs 59.3%, respectively, P=0.034]. Eastern Cooperative Oncology Group performance status (HR=3.308, 95%CI: 1.183-9.247, P=0.023), lactate dehydrogenase level (HR=1.852, 95%CI: 1.037-3.307, P=0.037), systemic immune-inflammation index (HR=1.772, 95%CI: 1.019-3.080, P=0.043), and T4-SMD (HR=0.563, 95%CI: 0.325-0.974, P=0.040) were prognostic factors for 1-year PFS in advanced EGFR-positive NSCLC patients treated with ecotinib. A nomogram for predicting 1-year PFS of advanced EGFR-positive NSCLC patients treated with ecotinib was constructed based on the four indicators selected by multivariate Cox regression analysis. The area under the ROC curve of the nomogram was 0.775 (95%CI: 0.676-0.874). The calibration curve showed good consistency between the predicted and actual 1-year PFS. DCA demonstrated good clinical prediction effectiveness of the nomogram. Conclusion: Low T4-SMD is a prognostic risk factor for patients with advanced EGFR-positive NSCLC receiving icotinib therapy.

Plasma electron acceleration driven by a long-wave-infrared laser.

Laser-driven plasma accelerators provide tabletop sources of relativistic electron bunches and femtosecond x-ray pulses, but usually require petawatt-class solid-state-laser pulses of wavelength λL ~ 1 µm. Longer-λL lasers can potentially accelerate higher-quality bunches, since they require less power to drive larger wakes in less dense plasma. Here, we report on a self-injecting plasma accelerator driven by a long-wave-infrared laser: a chirped-pulse-amplified CO2 laser (λL ≈ 10 µm). Through optical scattering experiments, we observed wakes that 4-ps CO2 pulses with < 1/2 terawatt (TW) peak power drove in hydrogen plasma of electron density down to 4 × 1017 cm-3 (1/100 atmospheric density) via a self-modulation (SM) instability. Shorter, more powerful CO2 pulses drove wakes in plasma down to 3 × 1016 cm-3 that captured and accelerated plasma electrons to relativistic energy. Collimated quasi-monoenergetic features in the electron output marked the onset of a transition from SM to bubble-regime acceleration, portending future higher-quality accelerators driven by yet shorter, more powerful pulses.

[A retrospective study of postoperative adjuvant therapy following immunotherapy combined with targeted therapy and sequential curative surgical procedures for initially unresectable hepatocellular carcinoma].

Objective: To report the clinical efficacy of adjuvant therapy based on pathological results following immunotherapy combined with targeted therapy and sequential curative surgical procedures in patients with initially unresectable hepatocellular carcinoma. Methods: This is a retrospective case series study. Data from 100 patients who underwent adjuvant therapy based on pathological results following immunotherapy combined with targeted therapy and sequential curative surgical procedures with long-term survival were collected from December 2018 to December 2022 at the Faculty of Hepato-Pancreato-Biliary Surgery, First Medical Center, Chinese People's Liberation Army General Hospital. According to inclusion and exclusion criteria, 47 cases were included, among which patients who met the discontinuation criteria and maintained a drug-free tumor-free status. Thirty-nine male and eight female patients were included, with an age of (54.2±18.8)years(range:38 to 73 years) at initial diagnosis. At the time of initial diagnosis, 43 cases (91.5%) were classified as Barcelona Clinic Liver Cancer(BCLC) stage C. Survival curves were made using Kaplan Meier method. Results: Forty-seven patients underwent R0 resection, all achieved a drug-free tumor-free state through postoperative adjuvant therapy based on pathological examination results. Thirty-six patients(76.6%) maintained a drug-free tumor-free survival status for more than 6 months,28 patients(59.6%) for more than 12 months,and 8 patients(17.0%) for more than 24 months. The longest drug-free tumor-free survival in this cohort reached 48 months. The median follow-up time in this study was 32 months. After diagnosis, the overall survival rates at 1- and 3- years were 97.7%(95%CI:93.4% to 100%) and 90.7%(95%CI:82.5% to 99.8%). The postoperative recurrence-free survival rates at 1- and 3- years were 91.0%(95%CI:83.0% to 99.8%) and 71.3%(95%CI:58.7% to 86.5%). Conclusions: The adjuvant therapy based on pathological results following immunotherapy combined with targeted therapy and sequential curative surgical approach provides long-term survival benefits for patients with initially unresectable hepatocellular carcinoma. Standardized adjuvant therapy maybe sustain long-term tumor-free status,and achieve drug-free tumor-free survival.

First Measurement of η Meson Production in Neutrino Interactions on Argon with MicroBooNE.

We present a measurement of η production from neutrino interactions on argon with the MicroBooNE detector. The modeling of resonant neutrino interactions on argon is a critical aspect of the neutrino oscillation physics program being carried out by the DUNE and Short Baseline Neutrino programs. η production in neutrino interactions provides a powerful new probe of resonant interactions, complementary to pion channels, and is particularly suited to the study of higher-order resonances beyond the Δ(1232). We measure a flux-integrated cross section for neutrino-induced η production on argon of 3.22±0.84(stat)±0.86(syst) 10^{-41} cm^{2}/nucleon. By demonstrating the successful reconstruction of the two photons resulting from η production, this analysis enables a novel calibration technique for electromagnetic showers in GeV accelerator neutrino experiments.

[Application of optical coherence tomography in the evaluation of cervical lesions: a multicenter study].

Objective: To explore the value of optical coherence tomography (OCT) imaging system in evaluating cervical lesions in vivo. Methods: A total of 1 214 patients with cervical lesions were collected from January 2020 to December 2021 in the Third Affiliated Hospital of Zhengzhou University, Maternal and Chlid Heaith Hospital of Gushi County, Xinyang City, Henan Province, and Maternal and Chlid Heaith Hospital of Sui County, Shangqiu City, Henan Province. The age of the patients was (38.9±10.5) years (range: 16-77 years). All patients underwent in vivo cervical OCT examination and cervical biopsy pathology examination, and summarized the OCT image features of in vivo cervical lesions. Using the pathological diagnosis as the "gold standard", the accuracy, specificity, sensitivity, positive predictive value (PPV) and negative predictive value (NPV) of OCT image interpretation results were evaluated, as well as the consistency of OCT image diagnosis and pathological diagnosis. At the same time, the in vivo cervical OCT imaging system, as a newly developed screening tool, was compared with the traditional combined screening of human papillomavirus (HPV) and Thinprep cytologic test (TCT), to assess the screening effect. Results: By comparing the OCT images of the cervix in vivo with the corresponding HE images, the OCT image characteristics of the normal cervix and various types of cervical lesions in vivo were summarized. The accuracy, sensitivity, specificity, PPV and NPV of OCT image in the diagnosis of high-grade squamous intraepithelial lesion (HSIL) and above (HSIL+) were 93.4%, 88.5%, 95.0%, 85.0% and 96.2%, respectively. The accuracy, sensitivity, specificity, PPV and NPV of OCT for low-grade squamous intraepithelial lesion (LSIL) were 84.7%, 61.7%, 96.3%, 89.3% and 83.2%, respectively. The consistency between OCT image diagnosis and pathological diagnosis was strong (Kappa value was 0.701).The accuracy, sensitivity and specificity of OCT screening, HPV and TCT combined screening were 83.7% vs 64.9% (χ²=128.82, P<0.001), 77.8% vs 64.5% (χ²=39.01, P<0.001), 91.8% vs 65.4% (χ²=98.12, P<0.001), respectively. The differences were statistically significant. Conclusions: OCT imaging system has high sensitivity and specificity in the evaluation of cervical lesions in vivo, and has the characteristics of non-invasive, real-time and high efficiency. OCT examination is expected to become an effective method for the diagnosis of cervical lesions and cervical cancer screening.

Stationary striations in plasma, created by a short microwave pulse in a waveguide filled with a neutral gas.

It was observed experimentally that after crossing a waveguide filled with a neutral gas a short powerful microwave pulse leaves a periodic glow of plasma along the waveguide, persisting for several tens of nanoseconds. A theoretical model is presented which in combination with numerical simulations proposes a possible explanation for this phenomenon.

[A prospective study of association between physical activity and ischemic stroke in adults].

Objective: To explore the prospective associations between physical activity and incident ischemic stroke in adults. Methods: Data of China Kadoorie Biobank study in Tongxiang of Zhejiang were used. After excluding participants with cancers, strokes, heart diseases and diabetes at baseline study, a total of 53 916 participants aged 30-79 years were included in the final analysis. The participants were divided into 5 groups according to the quintiles of their physical activity level. Cox proportional hazard regression models was used to calculate the hazard ratios (HR) for the analysis on the association between baseline physical activity level and risk for ischemic stroke. Results: The total physical activity level in the participants was (30.63±15.25) metabolic equivalent (MET)-h/d, and it was higher in men [(31.04±15.48) MET-h/d] than that in women [(30.33±15.07) MET-h/d] (P<0.001). In 595 526 person-years of the follow-up (average 11.4 years), a total of 1 138 men and 1 082 women were newly diagnosed with ischemic stroke. Compared to participants with the lowest physical activity level (<16.17 MET-h/d), after adjusting for socio-demographic factors, lifestyle, BMI, waist circumference, and SBP, the HRs for the risk for ischemic stroke in those with moderate low physical activity level (16.17-24.94 MET-h/d), moderate physical activity level (24.95-35.63 MET-h/d), moderate high physical activity level (35.64-43.86 MET-h/d) and the highest physical activity level (≥43.87 MET-h/d) were 0.93 (95%CI: 0.83-1.04), 0.87 (95%CI: 0.76-0.98), 0.82 (95%CI: 0.71-0.95) and 0.76 (95%CI: 0.64-0.89), respectively. Conclusion: Improving physical activity level has an effect on reducing the risk for ischemic stroke.

Heat Stroke Induces Pyroptosis in Spermatogonia via the cGAS-STING Signaling Pathway.

To explore the mechanism whereby cGAS-STING pathway regulates the pyroptosis of cryptorchidism cells, with a view to finding a new strategy for clinically treating cryptorchidism-induced infertility. Spermatogonial GC-1 cells were heat stimulated to simulate the heat hurt microenvironment of cryptorchidism. The cell viability was assayed by CCK-8, and cellular DNA damage was detected by gamma-H2AX immunofluo-rescence assay. Flow cytometry was employed to assess pyroptosis index, while western blot, ELISA and PCR were used to examine the expressions of pyroptosis-related proteins (Caspase-1, IL-1beta, NLRP3) and cGAS-STING pathway proteins (cGAS, STING). After STING silencing by siRNA, the expressions of pyroptosis-related proteins were determined. Pyroptosis occurred after heat stimulation of cells. Morphological detection found cell swelling and karyopyknosis. According to the gamma-H2AX immunofluorescence (IFA) assay, the endonuclear green fluorescence was significantly enhanced, the gamma-H2AX content markedly increased, and the endonuclear DNA was damaged. Flow cytometry revealed a significant increase in pyroptosis index. Western blot and PCR assays showed that the expressions of intracellular pyrogenic proteins like Caspase-1, NLRP3 and GSDMD were elevated. The increased STING protein and gene expressions in cGAS-STING pathway suggested that the pathway was intracellularly activated. Silencing STING protein in cGAS-STING pathway led to significantly inhibited pyroptosis. These results indicate that cGAS-STING pathway plays an important role in heat stress-induced pyroptosis of spermatogonial cells. After heat stimulation of spermatogonial GC-1 cells, pyroptosis was induced and cGAS-STING pathway was activated. This study can further enrich and improve the molecular mechanism of cryptorchidism.

CT respiratory motion synthesis using joint supervised and adversarial learning.

Objective.Four-dimensional computed tomography (4DCT) imaging consists in reconstructing a CT acquisition into multiple phases to track internal organ and tumor motion. It is commonly used in radiotherapy treatment planning to establish planning target volumes. However, 4DCT increases protocol complexity, may not align with patient breathing during treatment, and lead to higher radiation delivery.Approach.In this study, we propose a deep synthesis method to generate pseudo respiratory CT phases from static images for motion-aware treatment planning. The model produces patient-specific deformation vector fields (DVFs) by conditioning synthesis on external patient surface-based estimation, mimicking respiratory monitoring devices. A key methodological contribution is to encourage DVF realism through supervised DVF training while using an adversarial term jointly not only on the warped image but also on the magnitude of the DVF itself. This way, we avoid excessive smoothness typically obtained through deep unsupervised learning, and encourage correlations with the respiratory amplitude.Main results.Performance is evaluated using real 4DCT acquisitions with smaller tumor volumes than previously reported. Results demonstrate for the first time that the generated pseudo-respiratory CT phases can capture organ and tumor motion with similar accuracy to repeated 4DCT scans of the same patient. Mean inter-scans tumor center-of-mass distances and Dice similarity coefficients were 1.97 mm and 0.63, respectively, for real 4DCT phases and 2.35 mm and 0.71 for synthetic phases, and compares favorably to a state-of-the-art technique (RMSim).Significance.This study presents a deep image synthesis method that addresses the limitations of conventional 4DCT by generating pseudo-respiratory CT phases from static images. Although further studies are needed to assess the dosimetric impact of the proposed method, this approach has the potential to reduce radiation exposure in radiotherapy treatment planning while maintaining accurate motion representation. Our training and testing code can be found athttps://github.com/cyiheng/Dynagan.

The application of the modified Snodgrass technique in hypospadias surgery.

OBJECTIVE: We aimed to explore the effectiveness of the modified tubularized incised plate urethroplasty (Snodgrass Technique) in hypospadias surgery. PATIENTS AND METHODS: A study was conducted on 50 pediatric patients with hypospadias treated in our hospital from May 2020 to May 2023. The patients were divided into two groups based on the condition of their urethral plate; 22 patients were included in the study group and 28 patients were included in the control group. The control group underwent the traditional Snodgrass technique, while the study group received the modified Snodgrass technique. The two groups were compared in terms of treatment efficacy, preoperative and postoperative 6-month Hypospadias Objective Scoring Evaluation (HOSE) scores, surgical data, and postoperative complications. RESULTS: The operation time for the study group was longer than that of the control group, and the intraoperative blood loss was less, but the differences were not statistically significant (p > 0.05). The success rate of surgery in the study group was 95.45% (21/22), compared to 71.43% (20/28) in the control group, showing a statistically significant difference (p < 0.05). The maximum urinary flow rate at 3 and 6 months postoperatively was significantly higher in the study group than in the control group (p < 0.05). The time to maximum flow (TQmax) and post-void residual (PVR) at 3 and 6 months postoperatively were significantly lower in the study group (p < 0.05). A total of 3 patients in the cohort developed urethral fistulas, all between 0.10 cm x 0.10 cm and 0.15 cm x 0.15 cm in size. By instructing the patients to apply pressure to the fistula during urination, all fistulas closed between 3 and 6 months postoperatively. The incidence of postoperative complications was 4.55% in the study group and 28.57% in the control group, a difference that was statistically significant (p < 0.05). CONCLUSIONS: The modified Snodgrass technique shows significant therapeutic effectiveness in hypospadias surgery, substantially increasing the success rate and reducing postoperative complications in pediatric patients, making it suitable for widespread application.

[Porphyromonas gingivalis outer membrane vesicles activate Toll-like receptor 2 to promote osteoclast differentiation by carrying lipopolysaccharide].

Objective: To investigate the effects of Porphyromonas gingivalis derived outer membrane vesicles (Pg OMV) on osteoclast differentiation of macrophages and its underlying mechanisms. Methods: The morphology and the size distribution of Pg OMV were analyzed by transmission electron microscopy and nanoparticle tracing analysis, respectively. The osteoclast precursors were treated with 1, 3 and 10 mg/L Pg OMV (1, 3 and 10 mg/L OMV treatment group) or phosphate buffer solution (PBS)(control group). The formation of osteoclasts was analyzed by tartrate-resistant acid phosphase (TRAP) staining and F-actin staining and real-time quantitative PCR (RT-qPCR) were used to detect the expression of Fos and matrix metallopeptidase 9 (MMP9). Polymyxin B (PMB) was used to block lipopolysaccharide (LPS) and then Pg OMV was used to treat osteoclast precursor (PMB-OMV treatment group), and OMV treatment group was used as control. TRAP and F-actin staining were used to observe the formation of osteoclasts and actin rings. The effect of Pg OMV on the expression of Toll-like receptor (TLR) 2 and TLR4 in preosteoclasts was detected by Western blotting. The osteoclast precursors were pretreated with 10, 50, 100 and 200 µmol/L C29, an inhibitor of TLR2, and then treated with Pg OMV(OMV+10, 50, 100 and 200 µmol/L C29 treatment group) and OMV treatment group without C29 pretreatment was control. TRAP and F-actin staining were used to observe the formation of osteoclasts and actin rings. The osteoclast precursor cells were treated with OMV (OMV treatment group) and OMV incubated with PMB (PMB-OMV treatment group) and the expression of TLR2 in osteoclast precursor was detected by Western blotting. Results: Pg OMV showed classical vesicular structures, and the average particle size of Pg OMV were 179.2 nm. A large number of actin rings were observed in the 3 and 10 mg/L OMV treatment groups. The percentages of TRAP-positive osteoclast area in 3 mg/L OMV treatment group [(22.6±2.1)%] and 10 mg/L OMV treatment group [(32.0±2.3)%] were significantly increased compared with control group [(4.9±0.5)%] (P<0.001). Compared with the control group (1.000±0.029), the mRNA relative expression of Fos in 3 mg/L OMV treatment group (1.491±0.114) and 10 mg/L OMV treatment group (1.726±0.254) was significantly increased (P=0.013, P=0.001). Compared with the control group (1.007±0.148), the mRNA relative expression of MMP9 in the group of 10 mg/L OMV (2.232±0.097) was significantly increased (P<0.001). Actin ring formation was less in PMB-OMV treatment groups than in OMV treatment groups. The proportion of TRAP-positive osteoclasts area [(14.8±3.8)%] in PMB-OMV treatment group was significantly lower than OMV treatment group [(31.5±6.7) %] (P=0.004). The relative expression of TLR2 in OMV treatment group (1.359±0.134) was significantly higher than that in the control group (1.000±0.000) (t=4.62, P=0.044). Compared with the OMV treatment group [(29.4±1.7)%], 50, 100 and 200 µmol/L C29 significantly decreased the formation of osteoclasts [(24.0±1.7)%, (18.5±2.1)%, (9.1±1.3) %] (P=0.026, P<0.001, P<0.001). TLR2 protein expression in PMB-OMV group (0.780±0.046) was significantly lower than that in OMV group (1.000±0.000)(t=8.32, P=0.001). Conclusions: Pg OMV can promote osteoclast differentiation by carrying LPS, TLR2 plays an important role in Pg OMV mediated osteoclast differentiation.

Search for Heavy Neutral Leptons in Electron-Positron and Neutral-Pion Final States with the MicroBooNE Detector.

We present the first search for heavy neutral leptons (HNLs) decaying into νe^{+}e^{-} or νπ^{0} final states in a liquid-argon time projection chamber using data collected with the MicroBooNE detector. The data were recorded synchronously with the NuMI neutrino beam from Fermilab's main injector corresponding to a total exposure of 7.01×10^{20} protons on target. We set upper limits at the 90% confidence level on the mixing parameter |U_{µ4}|^{2} in the mass ranges 10≤m_{HNL}≤150 MeV for the νe^{+}e^{-} channel and 150≤m_{HNL}≤245 MeV for the νπ^{0} channel, assuming |U_{e4}|^{2}=|U_{τ4}|^{2}=0. These limits represent the most stringent constraints in the mass range 35

Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) ß, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

[The mechanism of NRF2 inhibiting ROS induced autophagy to reduce ovarian granulosa cells damage].

This study explores the effects and possible mechanisms of nuclear factor E2 related factor 2 (NRF2) on ovarian granulosa cells, providing a scientific basis to prevent premature ovarian failure. An ovarian cell injury model was constructed by treating human ovarian granulosa cell (KGN cell) with 4-Vinylcyclohexene dioxide (VCD). Firstly, KGN cells were treated with different concentrations of VCD, and cell counting kit 8 (CCK-8) was used to detect ovarian cell proliferation. After determining IC50 by CCK8, the levels of estradiol and progesterone in the cell supernatant were detected using enzyme-linked immunosorbent assay (ELISA), reactive oxygen species (ROS) assay kit was used to detect the content of ROS in ovarian cells, real-time fluorescence quantitative polymerase chain reaction (qRT PCR) was used to detect the mRNA expression level of NRF2, and Western blot was used to detect the protein expression level of NRF2. Further, NRF2 silence (siNRF2) and overexpression (NRF2-OE) cell models were constructed through lentivirus transfection, and the effects of regulating NRF2 on VCD treated cell models were investigated by detecting hormone levels, oxidative stress indicators (ROS, SOD, GSH-Px), and autophagy (LC3B level). The results showed that VCD intervention inhibited the proliferation of ovarian granulosa cells in a time-dependent and dose-dependent manner (F>100, P<0.05), with an IC50 of 1.2 mmol/L at 24 hours. After VCD treatment, the level of estradiol in the cell supernatant decreased from (56.32±10.18) ng/ml to (24.59±8.75) ng/ml (t=5.78, P<0.05). Progesterone decreased from (50.25±7.03) ng/ml to (25.13±6.67) ng/ml (t=6.54, P<0.05). After VCD treatment, the SOD of cells decreased from (44.47±7.71) ng/ml to (30.92±4.97) ng/ml (t=3.61, P<0.05). GSH-Px decreased from (68.51±10.17) ng/ml to (35.19±6.59) ng/ml (t=5.73, P<0.05). Simultaneously accompanied by an increase in autophagy and a decrease in NRF2. This study successfully constructed KGN cell models that silenced NRF2 and overexpressed NRF2. Subsequently, this study treated each group of cells with VCD and found that the cell proliferation activity of the siNRF2 group was significantly reduced (t=8.37, P<0.05), while NRF2-OE could reverse the cell activity damage caused by VCD (t=3.37, P<0.05). The siNRF2 group had the lowest level of estradiol (t=5.78, P<0.05), while NRF2-OE could reverse the decrease in cellular estradiol levels caused by VCD (t=5.58, P<0.05). The siNRF2 group had the lowest progesterone levels (t=3.02, P<0.05), while NRF2-OE could reverse the decrease in cellular progesterone levels caused by VCD (t=2.41, P<0.05). The ROS level in the siNRF2 group was the highest (t=2.86, P<0.05), NRF2-OE could reverse the increase in ROS caused by VCD (t=3.14, P<0.05), the SOD enzyme content in the siNRF2 group was the lowest (t=2.98, P<0.05), and NRF2-OE could reverse the decrease in SOD enzyme content caused by VCD (t=4.72, P<0.05). The GSH-Px enzyme content in the siNRF2 group was the lowest (t=3.67, P<0.05), and NRF2-OE could reverse the decrease in antioxidant enzyme content caused by VCD (t=2.71, P<0.05). The LC3B level was highest in the siNRF2 group (t=2.45, P<0.05), and NRF2-OE was able to reverse the LC3B elevation caused by VCD (t=9.64, P<0.05). In conclusion, NRF2 inhibits ROS induced autophagy, thereby playing a role in reducing ovarian granulosa cell damage, which may be a potential target for premature ovarian failure.

Functional Selection of Tau Oligomerization-Inhibiting Aptamers.

Pathological hyperphosphorylation and aggregation of microtubule-associated Tau protein contribute to Alzheimer's Disease (AD) and other related tauopathies. Currently, no cure exists for Alzheimer's Disease. Aptamers offer significant potential as next-generation therapeutics in biotechnology and the treatment of neurological disorders. Traditional aptamer selection methods for Tau protein focus on binding affinity rather than interference with pathological Tau. In this study, we developed a new selection strategy to enrich DNA aptamers that bind to surviving monomeric Tau protein under conditions that would typically promote Tau aggregation. Employing this approach, we identified a set of aptamer candidates. Notably, BW1c demonstrates a high binding affinity (Kd=6.6 nM) to Tau protein and effectively inhibits arachidonic acid (AA)-induced Tau protein oligomerization and aggregation. Additionally, it inhibits GSK3ß-mediated Tau hyperphosphorylation in cell-free systems and okadaic acid-mediated Tau hyperphosphorylation in cellular milieu. Lastly, retro-orbital injection of BW1c tau aptamer shows the ability to cross the blood brain barrier and gain access to neuronal cell body. Through further refinement and development, these Tau aptamers may pave the way for a first-in-class neurotherapeutic to mitigate tauopathy-associated neurodegenerative disorders.

[Quantitative analysis of risk assessment indicators for re-introduction of imported malaria in China].

OBJECTIVE: To quantitatively analyze the risk indicators of re-introduction of imported malaria in China and their weighting coefficients, so as to investigate the difference in the contribution of risk indicators included in the current risk assessment framework for re-introduction of imported malaria in China to the risk assessment of re-introduction of imported malaria. METHODS: Publications pertaining to the risk assessment framework for re-introduction of imported malaria in China that reported the risk indicators and their weighting coefficients were retrieved in PubMed, Web of Science, CNKI, Wanfang Data, and VIP with terms of "malaria", "re-introduction/re-transmission/re-establishment", "risk assessment/risk evaluation/risk prediction" from the inception of the database through 3 August 2023, and literature search was performed in Google Scholar to ensure the comprehensiveness of the retrieval. Basic characteristics of included studies were extracted using pre-designed information extraction forms by two investigators, and data pertaining to risk indicators of re-introduction of imported malaria were cross-checked by these two investigators. The risk indicators included in the risk assessment framework for re-introduction of imported malaria in China and their weighting coefficients were visualized with the Nightingale's rose diagrams using the software R 4.2.1, and the importance of risk indictors was evaluated with the frequency of risk indicators included in the risk assessment framework and the ranking of weighting coefficients of risk indicators. In addition, the capability of risk indicators screened by different weighting methods was compared by calculating the ratio of the maximum to the minimum of the weighting coefficients of the risk indicators screened by different weighting methods. RESULTS: A total of 2 138 publications were retrieved, and following removal of duplications and screening, a total of 8 publications were included in the final analysis. In these 8 studies, 8 risk assessment frameworks for re-introduction of imported malaria in China and 52 risk indicators of re-introduction of imported malaria were reported, in which number of imported malaria cases (n = 8) and species of malaria vectors were more frequently included in the risk assessment frameworks (n = 8), followed by species of imported malaria parasites (n = 6) and population density of local malaria vectors (n = 6), and species of local malaria vectors (n = 6), number of imported malaria cases (n = 5) and species of imported malaria parasites had the three highest weighting coefficients (n = 4). The weighting methods included expert scoring method, combination of expert scoring method and analytic hierarchy process, and combination of expert scoring method and entropy weight method in these 8 studies, and the ratios of the maximum to the minimum of the weighting coefficients of the risk indicators screened by the expert scoring method were 1.143 to 2.241, while the ratios of the maximum to the minimum of the weighting coefficients of the risk indicators screened by combination of the expert scoring method and analytic hierarchy process were 34.970 to 162.000. CONCLUSIONS: Number of imported malaria cases, species of imported malaria parasites, species of local malaria vectors and population density of local malaria vectors are core indicators in the current risk assessment framework for re-introduction of imported malaria in China. Combination of the expert scoring method and analytic hierarchy process is superior to the expert scoring method alone for weighting the risk indicators.