Search

Abstract Background Previous investigations identified a connection between air pollution and kidney diseases. Nevertheless, there is a lack of comprehensive evidence on the long-term risks posed by air pollution with respect to acute kidney injury (AKI) and AKI-related death. Methods This prospective cohort analysis included 414,885 UK Biobank (UKB) participants who did not exhibit AKI at the study’s outset. AKI was defined based on ICD-10 codes recorded for hospitalized patients. Cox proportional hazards models were used to assess the association between prolonged exposure to air pollutants (particulate matter with diameters of 2.5 micrometers or less (PM2.5), between 2.5 and 10 micrometers (PM2.5−10), and 10 micrometers or less (PM10), along with nitrogen dioxide (NO2) and nitrogen oxides (NOx)) and the risk of AKI and AKI-related death, adjusting for potential confounders including sex, age, ethnicity, education, income, lifestyle factors, and relevant clinical covariates. Restricted cubic splines were applied to evaluate non-linear dose-response relationships, and stratified analyses were performed to explore potential effect modification across subgroups. Results Over an average follow-up duration of 11.7 years, 14,983 cases of AKI and 326 cases of AKI-related death were diagnosed. Quartile analysis showed individuals exposed to higher levels of these air pollutants had a significantly higher risk of developing AKI and AKI-related death compared to those in the lowest quartile (all P 0.05). Sensitivity analyses confirmed the robustness of our findings. Conclusion Our study reveals a direct association between prolonged air pollution exposure and elevated risks of both AKI and AKI-related death. These findings offer scientific validation for the adoption of environmental and public health measures directed towards the reduction of air pollution. Such initiatives could potentially ease the impact associated with AKI and AKI-related death.

Abstract Typhoons are one of the most important weather systems that can cause severe ozone (O3) pollution in eastern China. While the effects of individual typhoons on O3 concentrations have been extensively studied, the effects of consecutive northward typhoons and the underlying mechanisms remain unclear, partly due to the complex processes involved. Here, Typhoons Maysak and Haishen, two consecutive northward typhoons in 2020, are selected to investigate their impact on the O3 pollution in eastern China. The results show that consecutive northward typhoons not only produced and maintained meteorological conditions conducive to O3 generation (e.g., elevated temperatures and intensified solar radiation), but also facilitated local accumulation and cross-regional transport of O3. These factors jointly led to a 30% increase in O3 concentration in eastern China with a prolonged period of O3 pollution. Our work underscores the significance of complex meteorological conditions in O3 pollution occurrences during extreme weather events, advancing our understanding of how consecutive northward typhoons affect air quality.

Abstract Malaria is one of the major health threats in Africa, and the risk of transmission is projected to be exacerbated by global warming. Rwanda experienced an 11-fold increase in malaria incidence from 2011 to 2015 despite extensive funding and implementation of control measures. Here, we focus on Rwanda as a case study and simulate monthly malaria incidence between 2010 and 2015, employing an ensemble learning method. Next, we project future malaria prevalence using shared socio-economic pathways (SSP2-4.5 and SSP5-8.5). We find that the projected increases in temperature and precipitation may shift malaria transmission risk to the highlands of western and northern Rwanda. These two regions that currently experience low malaria transmission. The seasonal effects of malaria incidence may be less apparent from January to June, and the peak season for malaria transmission in the highlands could occur one month earlier. Our findings highlight the impacts of climate change on malaria epidemics in Rwanda, which have implications for other world regions.

Abstract Cavity optomechanical systems have enabled precision sensing of magnetic fields, by leveraging the optical resonance-enhanced readout and mechanical resonance-enhanced response. Previous studies have successfully achieved mass-produced and reproducible microcavity optomechanical magnetometry (MCOM) by incorporating Terfenol-D thin films into high-quality (Q) factor whispering gallery mode (WGM) microcavities. However, the sensitivity was limited to 585 pT Hz−1/2, over 20 times inferior to those using Terfenol-D particles. In this work, we propose and demonstrate a high-sensitivity and mass-produced MCOM approach by sputtering a FeGaB thin film onto a high-Q SiO2 WGM microdisk. Theoretical studies are conducted to explore the magnetic actuation constant and noise-limited sensitivity by varying the parameters of the FeGaB film and SiO2 microdisk. Multiple magnetometers with different radii are fabricated and characterized. By utilizing a microdisk with a radius of 355 μm and a thickness of 1 μm, along with a FeGaB film with a radius of 330 μm and a thickness of 1.3 μm, we have achieved a remarkable peak sensitivity of 1.68 pT Hz−1/2 at 9.52 MHz. This represents a significant improvement of over two orders of magnitude compared with previous studies employing sputtered Terfenol-D film. Notably, the magnetometer operates without a bias magnetic field, thanks to the remarkable soft magnetic properties of the FeGaB film. Furthermore, as a proof of concept, we have demonstrated the real-time measurement of a pulsed magnetic field simulating the corona current in a high-voltage transmission line using our developed magnetometer. These high-sensitivity magnetometers hold great potential for various applications, such as magnetic induction tomography and corona current monitoring.

Abstract Most of the van der Waals homo- and hetero-junctions of group VIB two-dimensional (2D) transition-metal dichalcogenides (TMDs; MoS2, WS2, MoSe2, and WSe2) show indirect energy band gaps which hinders some of their applications especially in optoelectronics. In the current work, we demonstrate that most of the bilayers and even few-layers consisting of group VIB TMDs can have direct gaps by efficient weakening of their interlayer interactions via real and/or energy spaces tuning, which is based on insights from quantitative analyses of interlayer electronic hybridizations. Real space tuning here means introducing large-angle rotational misalignment between layers, which has been realized in a very recent experiment; and, energy space tuning means introducing energy mismatch between layers which can be introduced efficiently by different means thanks to the small vertical dielectric constant of 2D semiconducting TMDs. The efficient tuning in both real and energy spaces proposed here paves an avenue for indirect-direct gap regulation of homo- and hetero-junctions of TMDs and other 2D semiconductors. Notably, both tuning can be permanently preserved and hence our work is of great significance for the diverse applications of 2D semiconductors.

Abstract Transcription-blocking lesions (TBLs) stall elongating RNA polymerase II (Pol II), which then initiates transcription-coupled repair (TCR) to remove TBLs and allow transcription recovery. In the absence of TCR, eviction of lesion-stalled Pol II is required for alternative pathways to address the damage, but the mechanism is unclear. Using Protein-Associated DNA Damage Sequencing (PADD-seq), this study reveals that the p97-proteasome pathway can evict lesion-stalled Pol II independently of repair. Both TCR and repair-independent eviction require CSA and ubiquitination. However, p97 is dispensable for TCR and Pol II eviction in TCR-proficient cells, highlighting repair’s prioritization over repair-independent eviction. Moreover, ubiquitination of RPB1-K1268 is important for both pathways, with USP7’s deubiquitinase activity promoting TCR without abolishing repair-independent Pol II release. In summary, this study elucidates the fate of lesion-stalled Pol II, and may shed light on the molecular basis of genetic diseases caused by the defects of TCR genes.

Abstract Inherited non-hemolytic anemia is a group of rare bone marrow disorders characterized by erythroid defects. Although concerted efforts have been made to explore the underlying pathogenetic mechanisms of these diseases, the understanding of the causative mutations are still incomplete. Here we identify in a diseased pedigree that a gain-of-function mutation in toll-like receptor 8 (TLR8) is implicated in inherited non-hemolytic anemia. TLR8 is expressed in erythroid lineage and erythropoiesis is impaired by TLR8 activation whereas enhanced by TLR8 inhibition from erythroid progenitor stage. Mechanistically, TLR8 activation blocks annexin A2 (ANXA2)-mediated plasma membrane localization of STAT5 and disrupts EPO signaling in HuDEP2 cells. TLR8 inhibition improves erythropoiesis in RPS19 +/− HuDEP2 cells and CD34+ cells from healthy donors and inherited non-hemolytic anemic patients. Collectively, we identify a gene implicated in inherited anemia and a previously undescribed role for TLR8 in erythropoiesis, which could potentially be explored for therapeutic benefit in inherited anemia.

Abstract The hypercoagulable state is a hallmark for patients with multiple myeloma (MM) and is associated with disease progression. Activated platelets secrete exosomes and promote solid tumor growth. However, the role of platelet-derived exosomes in MM is not fully clear. We aim to study the underlying mechanism of how platelet-derived exosomes promote MM cell growth. Flow cytometry, Western blot, proteome analysis, co-immunoprecipitation, immunofluorescence staining, and NOD/SCID mouse subcutaneous transplantation model were performed to investigate the role of exosomal LRG1 on multiple myeloma cell growth. Peripheral blood platelets in MM patients were in a highly activated state, and platelet-rich plasma from MM patients significantly promoted cell proliferation and decreased apoptotic cells in U266 and RPMI8226 cells. Leucine-rich-alpha-2-glycoprotein 1 (LRG1) was significantly enriched in MM platelet-derived exosomes. Blocking LRG1 in recipient cells using LRG1 antibody could significantly eliminate the proliferation-promoting effect of platelet-derived exosomes on MM cells. And high exosomal LRG1 was associated with poor prognosis of patients with MM. Mechanistic studies revealed that LRG1 interacted with Olfactomedin 4 (OLFM4) to accelerate MM progression by activating the epithelial-to-mesenchymal transition (EMT) signaling pathway and promoting angiogenesis. Our results revealed that blocking LRG1 is a promising therapeutic strategy for the treatment of MM.

Summary: Background: The high price of HPV vaccines remains a significant barrier to vaccine accessibility in China, hindering the country’s efforts toward cervical cancer elimination and exacerbating health inequity. We aimed to inform HPV vaccine price negotiations by identifying threshold prices that ensure that a government-funded HPV vaccination programme is cost-effective or cost-saving. Methods: We used a previously validated transmission model to estimate the health and economic impact of HPV vaccination over a 100-year time horizon from a healthcare payer perspective. Threshold analysis was conducted considering different settings (national, rural, and urban), cervical cancer screening scenarios (cytology-based or HPV DNA-based, with different paces of scale-up), vaccine types (four types available in China), vaccine schedules (two-dose or one-dose), mode of vaccination (routine vaccination with or without later switching to high-valency vaccines), willingness-to-pay thresholds, and decision-making criteria (cost-effective or cost-saving). Furthermore, we examined the budget impact of introducing nationwide vaccination at the identified threshold prices. Findings: Using the current market price, national routine HPV vaccination with any currently available vaccine is unlikely cost-effective. Under a two-dose schedule, the prices of the four available HPV vaccine types cannot exceed $26–$36 per dose (44.1%–80.2% reduction from current market prices) depending on vaccine type to ensure the cost-effectiveness of the national programme. Adopting vaccination at threshold prices would require an annual increase of 72.18%–96.95% of the total annual National Immunization Programme (NIP) budget in China. A cost-saving routine vaccination programme requires vaccine prices of $5–$10 per dose (depending on vaccine type), producing a 21.38%–34.23% increase in the annual NIP budget. Adding the second dose is unlikely to be cost-effective compared to a one-dose schedule, with the threshold price approaching or even falling below zero. Rural pilot vaccination programmes require lower threshold prices compared with a national programme. Interpretation: Our study could inform vaccine price negotiation and thus facilitate nationwide scale-up of current HPV vaccination pilot programmes in China. The evidence may potentially be valuable to other countries facing HPV introduction barriers due to high costs. This approach may also be adapted for other contexts that involve the introduction of a pricy vaccine. Funding: CAMS Innovation Fund for Medical Sciences (CIFMS); Bill & Melinda Gates Foundation.

The effect of methylprotodioscin (MPD), a steroidal saponin obtained from medicinal plants, on myocardial infarction (MI) remains elusive. In this study, HL-1 and AC16 cells were subjected to injury induced by hypoxic environment, and a mouse model of MI was established by ligating the left anterior descending. MPD significantly increased viabilities and proliferations, improved the stability of MMP, reduced ROS and inflammatory factor levels in hypoxia cardiomyocytes. Moreover, MPD significantly improved cardiac functions, increased the ventricular ejection fraction and short axis shortening rate of mice with MI, reduced the infarction area, alleviated oxidative stress and increased ATPase activities. Then, differentially expressed proteins (DEPs) were discovered and evaluated using tandem mass tag (TMT)-based proteomics and bioinformatics approaches. Compared with sham group, there were 420 DEPs in the cardiac tissue of MI group, likewise, 163 DEPs in MPD group were identified compared to MI group. By validating, the expression of COX6C was elevated in MI group and declined in MPD groups, consistent with the TMT-based proteomics results. Correspondingly, p-NF-κB expression was downregulated, while Nrf2 and SOD expressions were upregulated by MPD. Moreover, si-COX6C transfection blocked the regulatory effects of MPD on COX6C-mediated inflammation and oxidative stress in MI. Our findings indicate that MPD, a naturally occurring active ingredient, could effectively improve cardiac function. Its ability may result from regulating COX6C to reduce oxidative stress and suppress inflammation, suggesting that MPD is very attractive for the treatment of MI.

Abstract Calcium oxalate (CaOx) kidney stones are common and recurrent, lacking pharmacological prevention. Randall's plaques (RPs), calcium deposits in renal papillae, serve as niduses for some CaOx stones. This study explores the role of osteogenic‐like cells in RP formation resembling ossification. CaP crystals deposit around renal tubules, interstitium, and blood vessels in RP tissues. Human renal interstitial fibroblasts (hRIFs) exhibit the highest osteogenic‐like differentiation potential compared to chloride voltage‐gated channel Ka positive tubular epithelial cells, aquaporin 2 positive collecting duct cells, and vascular endothelial cells, echoing the upregulated osteogenic markers primarily in hRIFs within RP tissues. Utilizing RNA‐seq, osteomodulin (OMD) is found to be upregulated in hRIFs within RP tissues and hRIFs following osteogenic induction. Furthermore, OMD colocalizes with CaP crystals and calcium vesicles within RP tissues. OMD can enhance osteogenic‐like differentiation of hRIFs in vitro and in vivo. Additionally, crystal deposits are attenuated in mice with Omd deletion in renal interstitial fibroblasts following CaOx nephrocalcinosis induction. Mechanically, a positive feedback loop of OMD/BMP2/BMPR1A/RUNX2/OMD drives hRIFs to adopt osteogenic‐like fates, by which OMD induces osteogenic‐like microenvironment of renal interstitium to participate in RP formation. We identify OMD upregulation as a pathological feature of RP, paving the way for preventing CaOx stones.

ObjectiveDeveloping and validating a clinical prediction nomogram of 28-day mortality in critically ill patients with acute gastrointestinal injury (AGI).MethodsFirstly, the construction of a clinical prediction model was developed using data obtained from a prospective observational study from May 2023 to April 2024. Then, data from a prospective multicenter observational study conducted in the intensive care units of 12 teaching hospitals in 2014 were utilized to independently and externally validate the clinical prediction model developed in the first part. We first screened the covariates of the development cohort by univariate cox regression, and then carried out cox regression analysis on the development cohort by backward stepwise regression to determine the optimal fitting model. Subsequently, a nomogram was derived from this model.ResultsA total of 1102 and 379 patients, 28-day mortality occurred in 20.3% and 15.8% of patients respectively, were included in the development and validation cohort, respectively. We developed a nomogram in critically ill patients with AGI and the AGI grade, APACHE II score, Mechanical ventilation (MV), Feeding intolerance (FI) and daily calorie intake (DCI) in 72 h, were independent predictors of 28-day mortality, with the OR of the AGI grade was 1.910 (95% CI, 1.588–2.298; P < 0.001), the OR of APACHE II score was 1.099 (95% CI, 1.069–1.130; P < 0.001), the OR of MV was 1.880 (95% CI, 1.215–2.911; P = 0.005), the OR of FI was 3.453 (95% CI, 2.414–4.939; P < 0.001) and the DCI > 0.7 or < 0.5 of calorie target is associated with increased 28-day mortality, with OR of 1.566 (95% CI, 1.024–2.395; P = 0.039) and 1.769 (95% CI, 1.170–2.674; P = 0.007), respectively. Independent external validation of the prediction model was performed. This model has good discrimination and calibration. The DCA and CIC also validated the good clinical utility of the nomogram.ConclusionThe prediction of 28-day mortality can be conveniently facilitated by the nomogram that integrates AGI grade, APACHE II score, MV, FI and DCI in 72 h in critically ill patients with AGI.

Finding water resources is a crucial objective of lunar missions. However, both hydroxyl (OH) and natural water (H2O) have been reported to be scarce on the Moon. We propose a potential method for obtaining water on the Moon through H2O formation via endogenous reactions in lunar regolith (LR), specifically through the reaction FeO/Fe2O3 + H → Fe + H2O. This process is demonstrated using LR samples brought back by the Chang’E-5 mission. FeO and Fe2O3 are lunar minerals containing Fe oxides. Hydrogen (H) retained in lunar minerals from the solar wind can be used to produce water. The results of this study reveal that 51–76 mg of H2O can be generated from 1 g of LR after melting at temperatures above 1,200 K. This amount is ∼10,000 times the naturally occurring OH and H2O on the Moon. Among the five primary minerals in LR returned by the Chang’E-5 mission, FeTiO3 ilmenite contains the highest amount of H, owing to its unique lattice structure with sub-nanometer tunnels. For the first time, in situ heating experiments using a transmission electron microscope reveal the concurrent formation of Fe crystals and H2O bubbles. Electron irradiation promotes the endogenous redox reaction, which is helpful for understanding the distribution of OH on the Moon. Our findings suggest that the hydrogen retained in LR is a significant resource for obtaining H2O on the Moon, which is helpful for establishing a scientific research station on the Moon.

Abstract The wet bulb temperature (Tw) has gained considerable attention as a crucial indicator of heat-related health risks. Here we report south-to-north spatially heterogeneous trends of Tw in China over 1979-2018. We find that actual water vapor pressure (Ea) changes play a dominant role in determining the different trend of Tw in southern and northern China, which is attributed to the faster warming of high-latitude regions of East Asia as a response to climate change. This warming effect regulates large-scale atmospheric features and leads to extended impacts of the South Asia high (SAH) and the western Pacific subtropical high (WPSH) over southern China and to suppressed moisture transport. Attribution analysis using climate model simulations confirms these findings. We further find that the entire eastern China, that accommodates 94% of the country’s population, is likely to experience widespread and uniform elevated thermal stress the end of this century. Our findings highlight the necessity for development of adaptation measures in eastern China to avoid adverse impacts of heat stress, suggesting similar implications for other regions as well.

Abstract This study aimed to explore the changes of pharmacokinetic parameters after meropenem in patients with abdominal septic shock after gastrointestinal perforation, and to simulate the probability of different dosing regimens achieving different pharmacodynamic goals. The study included 12 patients, and utilized high performance liquid chromatography-tandem mass spectrometry to monitor the plasma concentration of meropenem. The probability of target attainment (PTA) for different minimum inhibitory concentration (MIC) values and %fT > 4MIC was compared among simulated dosing regimens. The results showed that in 96 blood samples from 12 patients, the clearance (CL) of meropenem in the normal and abnormal creatinine clearance subgroups were 7.7 ± 1.8 and 4.4 ± 1.1 L/h, respectively, and the apparent volume of distribution (Vd) was 22.6 ± 5.1 and 17.2 ± 5.8 L, respectively. 2. Regardless of the subgroup, 0.5 g/q6h infusion over 6 h regimen achieved a PTA > 90% when MIC ≤ 0.5 mg/L. 1.0 g/q6h infusion regimen compared with other regimen, in most cases, the probability of making PTA > 90% is higher. For patients at low MIC, 0.5 g/q6h infusion over 6 h may be preferable. For patients at high MIC, a dose regimen of 1.0 g/q6 h infusion over 6 h may be preferable. Further research is needed to confirm this exploratory result.

This study utilized a modified split Hopkinson pressure bar apparatus to subject polypropylene fiber-reinforced foamed concrete (PPFRFC) to substantial deformation loading at high temperatures and strain rates. Based on experimental results, the study systematically investigated the coupled effects of temperature and strain rate on the dynamic mechanical behavior of PPFRFC across a broad range of strain rates (0.001 s−1 to 1300 s−1) and temperatures (25 °C–600 °C). The findings revealed that elevated temperatures significantly affected various mechanical parameters including peak stress, plateau stress, elastic modulus, densification strain, dynamic increase factor (DIF), and energy absorption. Notably, with increasing temperature, the strain rate amplified the peak stress, plateau stress, and energy absorption, whereas its influence on the elastic modulus diminished. Microstructural examination revealed the absence of notable cracks in the pore walls after high-temperatures exposure. However, degradation of the cement matrix results in a loose skeleton structure within the pore walls, leading to a considerable reduction in material strength. Finally, a constitutive model was developed, considering the coupling effects of temperature and strain rate. This model accurately describes the mechanical response of the PPFRFC across various stages, including the elastic, plateau, and densification stages, as well as the stress drop behavior in the transition stage. Moreover, it effectively reflects the influence of strain rate and temperature coupling effects on the material's mechanical properties.

Abstract Meteorological conditions exert influences on sport performances via complex processes. Previous studies conventionally investigate the effects of weather conditions on marathon performance by following events held at the same places, which brings large uncertainties due to the changed participants. Via following each athlete to eliminate these uncertainties, we show that elite athletes’ marathon-running performance tends to monotonically worsen as ambient temperature rises except when it is extremely cold based on the best 16 athletes from each of the sex continents. It worsens by 0.56 (0.39 for men and 0.71 for women) min/°C when it rises beyond 15 °C. Theoretical analysis based on global marathon performance and weather observation datasets shows that more than half of this effect is mediated by reduced oxygen partial density as warmer temperature expands air and increases vapor pressure for both the men and women athletes, which is confirmed by the methods of Baron–Kenny. This atmospheric thermodynamic mechanism has not been emphasized previously. We also show that world-top athletes’ marathon performance approximately linearly worsens as ambient pressure decreases and slightly worsens as relative humidity rises if not extremely wet. These results substantially differ from the previous ones following the events instead of each athlete. Multi-variable changes in climate system are projected to slow Olympic marathon athletes by 2.51 and 1.06 min by the end of the 21st century in relative to 2020 under the high and intermediate emission scenario, respectively. Therefore, future progression of marathon performance is likely to be substantially slowed or even halted by climate changes without efficient greenhouse gas mitigation.

Abstract Understanding both positive and negative impacts of climate change is essential for comprehensively assessing and well adapting to the impacts of changing climate. Conventionally, climate warming is revealed to negatively impact human activities. Here, we reveal that human beings’ performance in anaerobic sports may benefit from climate warming. Using global weather observation and athletes’ performance datasets, we show that world-top athletes’ performances in nearly all athletics anaerobic events (i.e., sprints, jumps and throws) substantially improve as ambient temperature rises. For example, 100 m performance monotonically improves by 0.26 s as ambient temperature rises from 11.8° to 36.4 °C. Using Coupled Model Intercomparison Project Phase 6 datasets, we further show that global warming can substantially improve world-top athletes’ performance in eleven of the thirteen Olympics athletics anaerobic events by 0.27%–0.88% and 0.14–0.48% under high-emission and medium-emission scenarios, respectively, during 1979–2100. Among them, the improvements for 100 m are 0.59% (0.063 s) and 0.32% (0.034 s), respectively. Mechanism analysis shows that the warmed ambient atmosphere can improve competitors’ performance through expanding the air and thus reducing the air resistance to the competitors and throwing implements for hummer throw and all the sprints, hurdling and jumps. Quantitative analysis estimates that this thermodynamic process is essential for the impacts of warmed ambient atmosphere on the performances in these events as physiological processes are.

The Ornstein-Uhlenbeck (OU) process was used to simulate random perturbations in the environment. Considering the influence of telegraph noise and jump noise, a stochastic Gilpin-Ayala nonautonomous competition model driven by the mean-reverting OU process with finite Markov chain and Lévy jumps was established, and the asymptotic behaviors of the stochastic Gilpin-Ayala nonautonomous competition model were studied. First, the existence of the global solution of the stochastic Gilpin-Ayala nonautonomous competition model was proven by the appropriate Lyapunov function. Second, the moment boundedness of the solution of the stochastic Gilpin-Ayala nonautonomous competition model was discussed. Third, the existence of the stationary distribution of the solution of the stochastic Gilpin-Ayala nonautonomous competition model was obtained. Finally, the extinction of the stochastic Gilpin-Ayala nonautonomous competition model was proved. The theoretical results were verified by numerical simulations.

Abstract Purpose This study aimed to investigate the imaging repeatability of self-service fundus photography compared to traditional fundus photography performed by experienced operators. Design Prospective cross-sectional study. Methods In a community-based eye diseases screening site, we recruited 65 eyes (65 participants) from the resident population of Shanghai, China. All participants were devoid of cataract or any other conditions that could potentially compromise the quality of fundus imaging. Participants were categorized into fully self-service fundus photography or traditional fundus photography group. Image quantitative analysis software was used to extract clinically relevant indicators from the fundus images. Finally, a statistical analysis was performed to depict the imaging repeatability of fully self-service fundus photography. Results There was no statistical difference in the absolute differences, or the extents of variation of the indicators between the two groups. The extents of variation of all the measurement indicators, with the exception of the optic cup area, were below 10% in both groups. The Bland–Altman plots and multivariate analysis results were consistent with results mentioned above. Conclusions The image repeatability of fully self-service fundus photography is comparable to that of traditional fundus photography performed by professionals, demonstrating promise in large-scale eye disease screening programs.

Abstract Background The differential expression, biological function, and ceRNA regulatory mechanism of lncRNA XIST in bladder cancer (BC) were investigated, and its clinical values for the early diagnosis of bladder cancer patients were elucidated. Methods qRT-PCR was employed to detect the expression patterns of lncRNA XIST, miR-129-5p and TNFSF10. The biological functions were measured by CCK8 assay, wound healing assay and transwell assay. Bioinformatics analysis and Dual-Luciferase reporter assay were employed to evaluate the interactions between the lncRNA XIST, miR-129-5p and TNFSF10. Results LncRNA XIST and TNFSF10 were highly expressed and miR-129-5p was low expressed (P

Recent years have witnessed a spurt of progress in China’s tourism industry, contributing greatly to the economy, culture, and ecology. Cultural relics and historic sites boast significant value in terms of tourism, economic, ecological service, cultural, and scientific research value, yet the intentional destruction makes it a serious problem threatening human natural and cultural heritage. So far, there is no scientific and standardized method to assess the value of the damaged cultural relics and historic sites and the corresponding ecological compensation. This study fills up a critical gap in developing a new ecological damage assessment method for the intentional destruction of cultural relics and monuments by taking the graffiti of Taishan Mountain, a World Heritage Site in China, as an example. The method consists of four steps: (1) selecting the assessment indicators based on the characteristics of cultural relics and historic sites, (2) obtaining the evaluation weights of the indicators by conducting a questionnaire survey among experts and the public, (3) determining the spatial distribution of the protected areas and the damage grade of the cultural relics and historic sites by using GIS and remote sensing techniques, and (4) calculating the economic value of the damaged cultural relics and historic sites by using the market price method, the travel cost method, and the contingent valuation method. The results show that the total value of ecological damage in the case was 70,588.07 yuan ($9958.11), which was successfully accepted by both parties involved in the case.

Summary: Prioritizing electric power system decarbonization is crucial for meeting global carbon neutrality targets. However, the role of energy technology cost reduction driven by innovation in advancing carbon neutrality in the electric power system has not been well studied. To fill this gap, an integrated investment planning and operation model is developed to simulate the carbon neutral pathway in the electric power system over a 30-year period from 2020 to 2050. The learning curves with different learning rates are incorporated into the model to represent different energy technology innovation scenarios. According to our results, the advanced innovation scenario is projected to achieve carbon neutrality in the electric power system five years earlier compared with the conservative innovation scenario, with a cost savings of 465 billion CNY. In addition, both inter-regional and intra-regional collaboration facilitate the achievement of carbon neutrality in the electric power system at a reduced cost. Science for society: Reducing carbon emissions and achieving carbon neutrality is a critical global challenge. Previous studies have formulated pathways for energy transition in the electric power system to meet carbon reduction targets. However, many of them overlook the role of energy technology cost reduction driven by innovation in advancing carbon neutrality in the electric power system. In this study, an integrated investment planning and operation model is developed to simulate the transition pathway in the electric power system from 2020 to 2050 toward carbon neutrality under different innovation scenarios. Our results reveal that carbon neutrality can be achieved earlier and more cost effectively in the advanced energy technology innovation scenario. Furthermore, expanding both inter-regional and intra-regional transmission capacities can facilitate the achievement of carbon neutrality in the electric power system at a reduced cost.

Selenium (Se), is an essential trace element in the diet of fish and aquatic animals needed for growth, thyroid hormone metabolism, antioxidant activity, and immunity. Thus, this study has evaluated the dietary selenium yeast (Se-yeast) impact on the growth performance, antioxidant capacity, and gut bacterial community of zebrafish, Danio rerio. The fish with an average weight of 0.247 g ± 0.005 were distributed in 12 glass aquariums. 30 fish per aquarium in three replicates per group were exposed to different dietary Se-yeast concentrations: 0.3 mg/kg (control), 0 mg/kg, 3 mg/kg, and 30 mg/kg for three weeks. The result indicated a higher body weight gain and specific growth rate in the 3 mg/kg group in all groups. Se significantly accumulated in the liver, muscle, gill, and gut. The antioxidant genes superoxide dismutase 1 (SOD1), catalase (CAT), and glutathione peroxidase 1 (GPx1), and the gut marker genes: solute carrier family 15 member 1b (slc15a1b), fatty acid binding protein 2 (fabp2), cytochrome P450 family 8 subfamily B member 1 (cyp8b1), and cytochrome P450 family 3 subfamily A, polypeptide 65 (cyp3a65) were significantly expressed in the gut tissue. The 16 s rRNA sequencing showed a significant difference at phyla Proteobacteria, Fusobacteria, Firmicutes, and Actinobacteria and Cetobacterium, Aeromonas, mycobacterium, and Lactobacillus at the genus level. It was concluded that dietary Se 3 mg/kg can promote growth performance and antioxidant status, furthermore, dietary Se yeast has a significant impact on the gut microbiota of D. rerio.

Exploring and discovering novel circRNAs is one of the ways to develop innovative drugs for the diagnosis and treatment of myocardial ischemia-reperfusion injury (MI/RI). In the work, some dysregulated circRNAs were found by microarray screening analysis in AC16 cells, and hsa_circRNA_104852 named circMIRIAF was screened, which was up-regulated in AC16 cells damaged by hypoxia-reoxygenation injury (H/RI). The comprehensive analysis of ceRNA network revealed the potential relationship of circMIRIAF/miR-544/WDR12. Then, the results of interaction research confirmed that circMIRIAF acted as sponge of miR-544 to positively regulate WDR12 protein expression. Further, the validation results indicate that miR-544 silencing increased the expression of WDR12, and WDR12 activated Notch1 signal to aggravate H/RI of AC16 cells and MI/RI of mice via regulating oxidative stress and inflammation. Furthermore, silencing circMIRIAF caused the decreased circMIRIAF levels and the increased miR-544 levels in cardiomyocytes, while excessive miR-544 inhibited WDR12 expression to alleviate the disorder. On the contrary, excessive circMIRIAF increased WDR12 expression by adsorbing miR-544 to exacerbate H/RI in AC16 cells. In addition, circMIRIAF siRNA reversed the aggravation of H/RI in cells caused by WDR12 overexpression. Overall, circMIRIAF can serve as a drug target or treating MI/RI, and circMIRIAF could sponge miR-544 and enhance WDR12 expression to aggravate MI/RI, which may provide a novel therapeutic strategy for MI/RI treatment.

Summary: Trichodesmium is one of the dominant dinitrogen (N2) fixers in the ocean, influencing global carbon and nitrogen cycles through biochemical reactions. Although its photosynthetic activity fluctuates rapidly, the physiological or ecological advantage of this fluctuation is unclear. We develop a metabolic model of Trichodesmium that can perform daytime N2 fixation. We examined (1) the effect of the duration of switches between photosynthetic and non-photosynthetic cellular states and (2) the effect of the presence and absence of N2 fixation in photosynthetic states. Results show that a rapid switch between photosynthetic and non-photosynthetic states increases Trichodesmium growth rates by improving metabolic efficiencies due to an improved balance of C and N metabolism. This provides a strategy for previous paradoxical observations that all Trichodesmium cells can contain nitrogenase. This study reveals the importance of fluctuating photosynthetic activity and provides a mechanism for daytime N2 fixation that allows Trichodesmium to fix N2 aerobically in the global ocean.

By using the Ornstein-Uhlenbeck (OU) process to simulate random disturbances in the environment, and considering the influence of jump noise, a stochastic Gilpin-Ayala mutualism model driven by mean-reverting OU process with Lévy jumps was established, and the asymptotic behaviors of the stochastic Gilpin-Ayala mutualism model were studied. First, the existence of the global solution of the stochastic Gilpin-Ayala mutualism model is proved by the appropriate Lyapunov function. Second, the moment boundedness of the solution of the stochastic Gilpin-Ayala mutualism model is discussed. Third, the existence of the stationary distribution of the solution of the stochastic Gilpin-Ayala mutualism model is obtained. Finally, the extinction of the stochastic Gilpin-Ayala mutualism model is proved. The theoretical results were verified by numerical simulations.

AIM: To observe the effects of N-acetylserotonin (NAS) administration on retinal ischemia-reperfusion (RIR) injury in rats and explore the underlying mechanisms involving the high mobility group box 1 (HMGB1)/receptor for advanced glycation end-products (RAGE)/nuclear factor-kappa B (NF-κB) signaling pathway. METHODS: A rat model of RIR was developed by increasing the pressure of the anterior chamber of the eye. Eighty male Sprague Dawley were randomly divided into five groups: sham group (n=8), RIR group (n=28), RIR+NAS group (n=28), RIR+FPS-ZM1 group (n=8) and RIR+NAS+ FPS-ZM1 group (n=8). The therapeutic effects of NAS were examined by hematoxylin-eosin (H&E) staining, and retinal ganglion cells (RGCs) counting. The expression of interleukin 1 beta (IL-1β), HMGB1, RAGE, and nod-like receptor 3 (NLRP3) proteins and the phosphorylation of nuclear factor-kappa B (p-NF-κB) were analyzed by immunohistochemistry staining and Western blot analysis. The expression of HMGB1 protein was also detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: H&E staining results showed that NAS significantly reduced retinal edema and increased the number of RGCs in RIR rats. With NAS therapy, the HMGB1 and RAGE expression decreased significantly, and the activation of the NF-κB/NLRP3 pathway was antagonized along with the inhibition of p-NF-κB and NLRP3 protein expression. Additionally, NAS exhibited an anti-inflammatory effect by reducing IL-1β expression. The inhibitory of RAGE binding to HMGB1 by RAGE inhibitor FPS-ZM1 led to a significant decrease of p-NF-κB and NLRP3 expression, so as to the IL-1β expression and retinal edema, accompanied by an increase of RGCs in RIR rats. CONCLUSION: NAS may exhibit a neuroprotective effect against RIR via the HMGB1/RAGE/NF-κB signaling pathway, which may be a useful therapeutic target for retinal disease.

Abstract Temperature distribution in transformer windings is a crucial factor that influences the safe operation, and lifespan of an insulating system in an oil‐immersed power transformer. Thermal hydraulic network modelling (THNM) has been the subject of numerous studies because of its lower computation cost as compared to a computational fluid dynamics (CFD) simulation. This study proposes improvements to THNM, with primary focus on non‐uniformity of temperatures in the entry and exit vertical oil ducts, and the feasibility of using a piecewise fitting formula for Nusselt number (Nu) of convection heat transfer coefficient in transformer windings. The deviation of hot spot temperature was 0.3°C, and the location of hot spot for CFD and THNM was 34th disc and 35th disc, respectively. The calculation time of CFD and THNM was about 34 h and 35 s under the same computer hardware situations. This provides an acceptable THNM method for the rapid prediction of transformer hot spot temperature and location at low costs for digital twin.

Abstract Studying complex relaxation behaviors is of critical importance for understanding the nature of glasses. Here we report a Kovacs-like memory effect in glasses, manifested by non-monotonic stress relaxation during two-step high-to-low strains stimulations. During the stress relaxation process, if the strain jumps from a higher state to a lower state, the stress does not continue to decrease, but increases first and then decreases. The memory effect becomes stronger when the atomic motions become highly collective with a large activation energy, e.g. the strain in the first stage is larger, the temperature is higher, and the stimulation is longer. The physical origin of the stress memory effect is studied based on the relaxation kinetics and the in-situ synchrotron X-ray experiments. The stress memory effect is probably a universal phenomenon in different types of glasses.

Abstract The tumor suppressor p53 (p53) is regulated by murine double minute 2 (Mdm2) and its homologous MdmX in maintaining the basal level of p53. Overexpressed Mdm2/MdmX inhibits cellular p53 activity, which is highly relevant to cancer occurrence. Coiled-coil domain-containing protein 106 (CCDC106) has been identified as a p53-interacting partner. However, the molecular mechanism of the p53/Mdm2/MdmX/CCDC106 interactions is still elusive. Here, we show that CCDC106 functions as a signaling regulator of the p53-Mdm2/MdmX axis. We identified that CCDC106 directly interacts with the p53 transactivation domain by competing with Mdm2 and MdmX. CCDC106 overexpression downregulates the cellular level of p53 and Mdm2/MdmX, and decreased p53 reversibly downregulates the cellular level of CCDC106. Our work provides a molecular mechanism by which CCDC106 regulates the cellular levels of p53 and Mdm2/MdmX.

To predict the behavior of aromatic contaminants (ACs) in complex soil–plant systems, this study developed machine learning (ML) models to estimate the root concentration factor (RCF) of both traditional (e.g., polycyclic aromatic hydrocarbons, polychlorinated biphenyls) and emerging ACs (e.g., phthalate acid esters, aryl organophosphate esters). Four ML algorithms were employed, trained on a unified RCF dataset comprising 878 data points, covering 6 features of soil–plant cultivation systems and 98 molecular descriptors of 55 chemicals, including 29 emerging ACs. The gradient-boosted regression tree (GBRT) model demonstrated strong predictive performance, with a coefficient of determination (R2) of 0.75, a mean absolute error (MAE) of 0.11, and a root mean square error (RMSE) of 0.22, as validated by five-fold cross-validation. Multiple explanatory analyses highlighted the significance of soil organic matter (SOM), plant protein and lipid content, exposure time, and molecular descriptors related to electronegativity distribution pattern (GATS8e) and double-ring structure (fr_bicyclic). An increase in SOM was found to decrease the overall RCF, while other variables showed strong correlations within specific ranges. This GBRT model provides an important tool for assessing the environmental behaviors of ACs in soil–plant systems, thereby supporting further investigations into their ecological and human exposure risks.

Bilayer and few-layer MoS_{2} show intrinsically higher electronic quality and substantially improved device performance than monolayer, and high-quality MoS_{2} wafers with controlled layer number have been grown. In addition, MoS_{2} has different polymorphs such as the semiconducting H phase and semimetallic distorted T (dT) phase, and vertically stacked dT-/H-MoS_{2} metal-semiconductor junctions (MSJs) have been synthesized. However, the contact mechanism of dT-/H (few layer)-MoS_{2} MSJs remains to be elucidated, and p-type ohmic contact to MoS_{2} is difficult to realize due to the high ionization energy of MoS_{2}. In the current work, we reveal a mechanism of two-dimensional (2D) semiconductors (2DSCs) layer-number-assisted metal-semiconductor (SC) interface engineering for Schottky barrier height (SBH) reduction and p-type ohmic contact is achieved based on this mechanism; 2DSCs here mean H (few layer)-MoS_{2} and metal-SC interfaces are the dT-/H-MoS_{2} interfaces with increasing 2DSC layers. Specifically speaking, the mechanism is as follows: (1) two competing effects coexist, namely, the interface dipole (ΔV) at the metal-SC interface and the quasibonding (QB) between all adjacent layers, with ΔV (QB) increasing (decreasing) SBH; (2) the effect of QB beats ΔV and hence the overall effect is decreasing SBH at the metal-SC interface; and (3) the SBH reduction effect increases with increasing 2DSC layers. The mechanism of 2DSC layer-number-assisted metal-SC interface engineering should apply also for other 2DSCs with a suitable metal and hence our current work paves an avenue for ohmic contact to few-layer 2DSCs by the accumulated interlayer QBs that widely present in 2DSCs.

Myocardial infarction (MI) is the primary cause of cardiac mortality. Esculentoside A (EsA), a triterpenoid saponin, has anti-inflammatory and antioxidant activities. However, its effect on MI remains unknown. In this study, the protective effect and mechanisms of EsA against MI were investigated. EsA significantly alleviated hypoxia-induced HL-1 cell injury, including increasing cell viability, inhibiting reactive oxygen species (ROS) production, mitochondrial membrane potential (MMP) and lactate dehydrogenase (LDH) leakage. In mouse MI model by left coronary artery (LAD) ligating, EsA obviously restored serum levels of creatine kinase isoenzymes (CK-MB), cardiac troponin I (cTnI), superoxide dismutase (SOD) and malondialdehyde (MDA). In addition, the cardioprotective effect of EsA was further confirmed by infarct size, electrocardiogram and echocardiography. Mechanistically, the targeted binding relationship between EsA and C-X-C motif chemokine receptor 2 (CXCR2) was predicted by molecular docking and dynamics, and validated by small molecule pull-down and surface plasmon resonance tests. EsA inhibited CXCR2 level both in vitro and in vivo, correspondingly alleviated oxidative stress by suppressing NOX1 and NOX2 and relieved inflammation through inhibiting p65 and p-p65. It demonstrated that EsA could play a cardioprotective role by targeting CXCR2. However, the effect of EsA against MI was abolished in combination with CXCR2 overexpression both in vitro and in vivo. This study revealed that EsA showed excellent cardioprotective activities by targeting CXCR2 to alleviate oxidative stress and inflammation in MI. EsA may function as a novel CXCR2 inhibitor and a potent candidate for the prevention and intervention of MI in the future.

Summary: The Hunga Tonga-Hunga Ha’apai (HTHH) volcano eruption received worldwide attention due to its magnitude and potential effects on environment and climate. However, the operational sulfur dioxide (SO2) products mis-estimated SO2 emissions under volcanic conditions due to large uncertainties in the assumptions of SO2 plume altitude. That might have occurred in previous volcanic eruptions and misled understanding of the evolution of sulfate aerosols in the atmosphere and their impact on global climate. Here, we simultaneously retrieved the volcanic SO2 and its plume altitude from the Troposphere Monitoring Instrument (TROPOMI) and the Environment Monitoring Instrument-2 (EMI-2), exploring the SO2 burden, distribution, and evolution from January 14 to 17. We captured multiple eruptions with the second eruption emitting far more SO2 than the first. Total emissions exceeded 900 kt, significantly higher than those from operational products. Our inferred emission fluxes and injection heights offer valuable references for climate modeling and submarine volcano studies.

Background Learning and memory impairment is a common dysfunction after stroke, which seriously affects the overall recovery of patients. Electroacupuncture at Shenting and Baihui has definite efficacy in patients with cognitive dysfunction after stroke, but its mechanism of action remains uncertain. Objective To observe the effect of electroacupuncture on hippocampal neuronal protection and brain-derived nerve growth factor (BDNF) /tyrosine receptor kinase B (TrkB) /phosphatidylinositol-3-hydroxykinase (PI3K) /protein kinase B (Akt) signaling pathway in rats with learning and memory impairment after middle cerebral artery occlusion reperfusion (MCAO/R) . Methods A total of 60 8-week-old healthy male SD rats were selected from May 2021 to March 2022, and 24 rats were divided into the blank group (n=12) and sham operation group (n=12), and the other 36 rats were constructed as MCAO/R model. The 24 rats with successful modeling were randomly divided into the model group (n=12) and electroacupuncture group (n=12). The electroacupuncture treatment was performed at Shenting and Baihui points in the electroacupuncture group. Zea-Longa score was used to observe the degree of neurological impairment in each group. Spatial probe test was used to evaluate the spatial learning and memory ability of the rats. TTC staining was used to observe the volume of brain infarction in rats. RT-PCR was used to measure the mRNA levels of BDNF, TrkB, PI3K and Akt, Western blotting was used to detect the protein levels of BDNF and TrkB and the levels of p-PI3K/PI3K and p-Akt/Akt. Results Zea-Longa score of the model group and electroacupuncture group was significantly different from the blank group and sham operation group at 2 h after surgery (P

Background: Cannabinoid compounds have been approved as prescription drugs for treating various human ailments. However, the production using both microbial and plant-based sources is time-consuming and expensive because their yield is extremely low. Tetraketide synthase (TKS), the key enzyme in the biosynthesis of cannabinoid compounds, produces only 4% of the intermediate compound olivetolic acid. However, it may be possible to rearrange the carbon metabolic flux of TKS using genetic methods to increase the overall yields of cannabinoid compounds. In this context, protein engineering is an economically beneficial and viable solution to improve the catalytic activity of TKS. However, the ability to produce enzyme variants significantly exceeds the capacity to screen and identify high producers, creating a bottleneck in the enzyme engineering process. Results: This study constructed an Escherichia coli-based biosensor workflow for detecting the byproduct pentyl diacetic acid lactone (PDAL). Rational design was used to generate E. coli strains with mutant regulatory protein AraC and an altered effector PDAL to control the transcription of gfp and kanamycin. The developed biosensor could detect PDAL at the concentrations of the operational range from microbial cell culture and cell-free catalytic system. Conclusions: The E. coli-based biosensor developed in this study efficiently detected PDAL with high throughput and low cost.How to cite: Gao M, Zhang Y, Xue L, et al. Screening microbially produced pentyl diacetic acid lactone using an Escherichia coli biosensor workflow. Electron J Biotechnol 2023;66. https://doi.org/10.1016/j.ejbt.2023.09.002.

Chalkiness is one of the most important agronomic traits in rice breeding, which directly affects the quality of rice seed. In this study, we identified a chalkiness endosperm mutant, chalk-h, from N-methyl-N-nitrosourea (MNU)-induced japonica rice cultivar Hwacheong (HC). Compared with wild type (WT)-HC, chalk-h showed severe chalkiness in the endosperm, yellowish green leaves, as well as reduced plant height. Scanning electron microscopy (SEM) analysis showed that starch grains in the chalk-h mutant were irregular in size and loosely arranged, with large gaps between granules, forming ovoid or orbicular shapes. MutMap analysis revealed that the phenotype of chalk-h is controlled by a single recessive gene LOC_Os11g39670 encoding seryl-tRNA synthetase, which is renamed as CHALK-H. A point mutation occurs in chalk-h on the sixth exon (at nucleotide 791) of CHALK-H, in which adenine (A) is replaced by thymidine (T), resulting in an amino acid codon change from glutamine (Glu) to valine (Val). The chalk-h mutant exhibited a heat-sensitive phenotype from the 3-leaf stage, including yellow-green leaves and reduced pigment content. The transcriptional expression of starch synthesis-related genes was down-regulated in the chalk-h mutants compared to WT-HC at different grain-filling stages. With an increase in temperature, the expression of photosynthesis-related genes was down-regulated in the chalk-h mutant compared to WT-HC. Overexpression of CHALK-H rescued the phenotype of chalk-h, with endosperm and leaf color similar to those of WT-HC. Our findings reveal that CHALK-H is a causative gene controlling chalkiness and leaf color of the chalk-h mutant. CHALK-H is the same gene locus as TSCD11, which was reported to be involved in chloroplast development under high temperature. We suggest that CHALK-H/TSCD11 plays important roles not only in chloroplast development, but also in photosynthesis and starch synthesis during rice growth and development, so it has great application potential in rice breeding for high quality and yield.

Abstract In recent years, to improve air quality, significant efforts have been made to reduce regional aerosols including China, Europe and North America, which have potential impacts on climate. In this study, fast and slow climate responses in China to changes in domestic and foreign anthropogenic emissions of aerosols and precursors from 2013 to 2019 are investigated using the Community Earth System Model version 1 (CESM1). Aerosol emissions changes, especially reductions in China, North America and Europe, during 2013–2019 resulted in surface air temperature increases across the Northern Hemisphere. Global aerosol changes induce a regional warming of 0.2 °C in China, equally contributed by domestic and foreign emissions changes. China’s domestic emission reductions lead to a regional average temperature rise of 0.1°C, primarily driven by rapid atmospheric adjustments over eastern China. Foreign aerosol changes, particularly reductions in North America and Europe, also contributed to a 0.1°C warming in China through slow oceanic processes. This warming in China induced by foreign aerosol changes is due to a teleconnection between the aerosol-induced anomalous regional warming in Eastern U.S.-North Atlantic Ocean-Europe and the downstream East Asian climate through anomalous wave trains propagation. The comparable influence of domestic and foreign aerosol changes on climate in China underscores the importance of international collaboration in climate mitigation endeavors.

Abstract Background High-copper diets have been widely used to promote growth performance of pigs, but excess copper supplementation can also produce negative effects on ecosystem stability and organism health. High-copper supplementation can damage the intestinal barrier and disturb the gut microbiome community. However, the specific relationship between high-copper-induced intestinal damage and gut microbiota or its metabolites is unclear. Objective Using fecal microbiota transplantation and metagenomic sequencing, responses of colonic microbiota to a high-copper diet was profiled. In addition, via comparison of specific bacteria and its metabolites rescue, we investigated a network of bacteria-metabolite interactions involving conversion of specific metabolites as a key mechanism linked to copper-induced damage of the colon. Results High copper induced colonic damage, Lactobacillus extinction, and reduction of SCFA (acetate and butyrate) concentrations in pigs. LefSe analysis and q-PCR results confirmed the extinction of L. johnsonii. In addition, transplanting copper-rich fecal microbiota to ABX mice reproduced the gut characteristics of the pig donors. Then, L. johnsonii rescue could restore decreased SCFAs (mainly acetate and butyrate) and colonic barrier damage including thinner mucus layer, reduced colon length, and tight junction protein dysfunction. Given that acetate and butyrate concentrations exhibited a positive correlation with L. johnsonii abundance, we investigated how L. johnsonii exerted its effects by supplementing acetate and butyrate. L. johnsonii and butyrate administration but not acetate could correct the damaged colonic barrier. Acetate administration had no effects on butyrate concentration, indicating blocked conversion from acetate to butyrate. Furthermore, L. johnsonii rescue enriched a series of genera with butyrate-producing ability, mainly Lachnospiraceae NK4A136 group. Conclusions For the first time, we reveal the microbiota-mediated mechanism of high-copper-induced colonic damage in piglets. A high-copper diet can induce extinction of L. johnsonii which leads to colonic barrier damage and loss of SCFA production. Re-establishment of L. johnsonii normalizes the SCFA-producing pathway and restores colonic barrier function. Mechanistically, Lachnospiraceae NK4A136 group mediated conversion of acetate produced by L. johnsonii to butyrate is indispensable in the protection of colonic barrier function. Collectively, these findings provide a feasible mitigation strategy for gut damage caused by high-copper diets. Video Abstract

Abstract Preventing tau aggregation is a potential therapeutic strategy in Alzheimer’s disease and other tauopathies. Recently, liquid–liquid phase separation has been found to facilitate the formation of pathogenic tau conformations and fibrillar aggregates, although many aspects of the conformational transitions of tau during the phase transition process remain unknown. Here, we demonstrate that the tau aggregation inhibitor methylene blue promotes tau liquid–liquid phase separation and accelerates the liquid-to-gel transition of tau droplets independent of the redox activity of methylene blue. We further show that methylene blue inhibits the conversion of tau droplets into fibrils and reduces the cytotoxicity of tau aggregates. Although gelation slows down the mobility of tau and tubulin, it does not impair microtubule assembly within tau droplets. These findings suggest that methylene blue inhibits tau amyloid fibrillization and accelerates tau droplet gelation via distinct mechanisms, thus providing insights into the activity of tau aggregation inhibitors in the context of phase transition.

Abstract Nonsteroidal anti-inflammatory drugs compose one of the most widely used classes of medications, but the risks for early development remain controversial, especially in the nervous system. Here, we utilized zebrafish larvae to assess the potentially toxic effects of nonsteroidal anti-inflammatory drugs and found that sulindac can selectively induce apoptosis of GABAergic neurons in the brains of zebrafish larvae brains. Zebrafish larvae exhibit hyperactive behaviour after sulindac exposure. We also found that akt1 is selectively expressed in GABAergic neurons and that SC97 (an Akt1 activator) and exogenous akt1 mRNA can reverse the apoptosis caused by sulindac. Further studies showed that sulindac binds to retinoid X receptor alpha (RXRα) and induces autophagy in GABAergic neurons, leading to activation of the mitochondrial apoptotic pathway. Finally, we verified that sulindac can lead to hyperactivity and selectively induce GABAergic neuron apoptosis in mice. These findings suggest that excessive use of sulindac may lead to early neurodevelopmental toxicity and increase the risk of hyperactivity, which could be associated with damage to GABAergic neurons.

Nitroreductase (NTR) is an enzyme expressed at an abnormally high level in solid tumors, which is associated with the hypoxia level in tumors. The establishment of a high-performance and convenient fluorescent platform for the fast monitoring of NTR is of pivotal importance. Herein, a novel host–guest complex was created by encapsulating a fluorescent substrate GP-NTR within a metal–organic capsule Zn-MPB that included a NADH mimic for the detection of hypoxia via responding to nitroreductase (NTR) with fast responsiveness and good fluorescence imaging. Notably, the double-substrate process was streamlined to a single–substrate process by the host–guest supramolecular method in the catalytic process of NTR, which enabled the reaction to be independent of the cofactor NADH supply and shortened the distance between the substrate and the active site of NTR. The increasing fluorescence intensity of Zn-MPB⊃GP-NTR exhibits a linear relationship with NTR concentration and shows a fast response toward NTR in solution in tens of seconds. Zn-MPB⊃GP-NTR also displays high sensitivity to NTR with a low detection limit of 6.4 ng/mL. Cells and in vivo studies have confirmed that Zn-MPB⊃GP-NTR could be successfully applied for the fast imaging of NTR in NTR-overexpressed tumor cells and tumor-bearing animals. The host–guest platform not only provides a new avenue for the design and optimization of a fluorescence detection platform for the rapid and quantitative detection of NTR activity, but also offers an imaging tool for the early diagnosis of hypoxia-related tumors.

By constructing a complex network model grounded in time series analysis, this study delves into the intricate relationships between the stock markets of 18 countries worldwide. Utilizing 31 distinct time series distance functions to formulate the network, we employ Hamming distance to quantify the resemblance between networks derived from different distance functions. By modulating the network density through distance percentiles (p=0.1, 0.3, 0.5), we demonstrate the similarity of various distance functions across multiple density levels. Our findings reveal that certain distance functions exhibit high degrees of similarity across varying network densities, suggesting their potential for mutual substitution in network construction. Furthermore, the centroid network identified via hierarchical cluster analysis highlights the similarities between the stock markets of different nations, mirroring the intricate interconnections within the global financial landscape. The insights gained from this study offer crucial perspectives for comprehending the intricate network structure of global financial time series data, paving the way for further analysis and prediction of global financial market dynamics.