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Abstract Background Understanding the mechanism behind sepsis-associated encephalopathy (SAE) remains a formidable task. This study endeavors to shed light on the complex cellular and molecular alterations that occur in the brains of a mouse model with SAE, ultimately unraveling the underlying mechanisms of this condition. Methods We established a murine model using intraperitoneal injection of lipopolysaccharide (LPS) in wild type and Anxa1 −/− mice and collected brain tissues for analysis at 0-hour, 12-hour, 24-hour, and 72-hour post-injection. Utilizing advanced techniques such as single-nucleus RNA sequencing (snRNA-seq) and Stereo-seq, we conducted a comprehensive characterization of the cellular responses and molecular patterns within the brain. Results Our study uncovered notable temporal differences in the response to LPS challenge between Anxa1−/− (annexin A1 knockout) and wild type mice, specifically at the 12-hour and 24-hour time points following injection. We observed a significant increase in the proportion of Astro-2 and Micro-2 cells in these mice. These cells exhibited a colocalization pattern with the vascular subtype Vas-1, forming a distinct region known as V1A2M2, where Astro-2 and Micro-2 cells surrounded Vas-1. Moreover, through further analysis, we discovered significant upregulation of ligands and receptors such as Timp1-Cd63, Timp1-Itgb1, Timp1-Lrp1, as well as Ccl2-Ackr1 and Cxcl2-Ackr1 within this region. In addition, we observed a notable increase in the expression of Cd14-Itgb1, Cd14-Tlr2, and Cd14-C3ar1 in regions enriched with Micro-2 cells. Additionally, Cxcl10-Sdc4 showed broad upregulation in brain regions containing both Micro-2 and Astro-2 cells. Notably, upon LPS challenge, there was an observed increase in Anxa1 expression in the mouse brain. Furthermore, our study revealed a noteworthy increase in mortality rates following Anxa1 knockdown. However, we did not observe substantial differences in the types, numbers, or distribution of other brain cells between Anxa1−/− and wildtype mice over time. Nevertheless, when comparing the 24-hour post LPS injection time point, we observed a significant decrease in the proportion and distribution of Micro-2 and Astro-2 cells in the vicinity of blood vessels in Anxa1−/− mice. Additionally, we noted reduced expression levels of several ligand-receptor pairs including Cd14-Tlr2, Cd14-C3ar1, Cd14-Itgb1, Cxcl10-Sdc4, Ccl2-Ackr1, and Cxcl2-Ackr1. Conclusions By combining snRNA-seq and Stereo-seq techniques, our study successfully identified a distinctive cellular colocalization, referred to as a special pathological niche, comprising Astro-2, Micro-2, and Vas-1 cells. Furthermore, we observed an upregulation of ligand-receptor pairs within this niche. These findings suggest a potential association between this cellular arrangement and the underlying mechanisms contributing to SAE or the increased mortality observed in Anxa1 knockdown mice.

Throughout pregnancy, maternal thyroid-related hormones are transported to the fetus via the placenta to allow normal fetal growth and development and are particularly important in the first and second trimesters of pregnancy. During maternal-fetal transport, in addition to thyroid-related hormones, thyroid-stimulating hormone receptor antibodies and antithyroid drugs can enter the fetus and interfere with development of the fetal thyroid gland and endocrine function, potentially leading to hyperthyroidism or hypothyroidism in the fetus or newborn. Several basic studies have been performed to demonstrate the important role of thyroid-related hormones in fetal and neonatal bone development. Ultrasound can assess neonatal skeletal maturity and bone development safely, rapidly, and effectively. This review aims to communicate the latest knowledge about maternal and fetal thyroid function in both normal and pathological pregnancies and summarize the latest advances in the potential effects of abnormal maternal thyroid function on bone development in the fetus and neonate. Finally, it discusses recent advances in research on ultrasound in the assessment of fetal and neonatal bone development.

Aiming at the special ultra-high purity (UHP) requirements of AISI 316L stainless steel used in semiconductor equipment, a strategy of vacuum C deoxidization pretreatment plus Mg–Ca composite treatment was proposed in this work. The effects of this strategy on cleanness and inclusion modification were systematically investigated by experimental observations and thermodynamic calculations. The results demonstrated that this strategy significantly reduced the O and S contents to 0.0005 wt% and 0.0007 wt%, respectively. The main inclusions after vacuum C deoxidization were large-sized Al2O3·SiO2 and MnS. After Mg treatment, the oxide inclusions were gradually modified into MgO·Al2O3 and MgO, while the sulfide inclusion was still MnS. After additional Ca treatment, the inclusions were further modified into finer CaO, MgO, CaO·MgO, and CaS. Moreover, this strategy remarkably decreased the number and size of the inclusions. The best level was that all inclusions were smaller than 2 μm, and the proportion of inclusions smaller than 1 μm was as high as 75.47%. Meanwhile, the evolution mechanism of inclusions during different treatments was clarified in this work. Finally, the optimum process for preparing UHP AISI 316L stainless steel was proposed as vacuum C deoxidation plus 0.002 wt% Mg and 0.0016 wt% Ca composite treatment.

Abstract Digital twin network (DTN) as an emerging network paradigm, have garnered growing attention. For large-scale networks, a crucial problem is how to effectively map physical networks onto the infrastructure platform of DTN. To address this issue, we propose a heuristic method of the adaptive boundary whale optimization algorithm (ABWOA) to solve the digital twin network construction problem, improving the efficiency and reducing operational costs of DTN. Extensive comparison experiments are conducted between ABWOA and various algorithms such as genetic algorithm, particle swarm optimization, artificial bee colony, differential evolution algorithm, moth search algorithm and original whale optimization algorithm. The experimental results show that ABWOA is superior to other algorithms in terms of solution quality, convergence speed, and time cost. It can solve the digital twin network construction problem more effectively.

Nanocrystalline NiTi shape memory alloys (SMAs) generally possess outstanding biocompatibility, good corrosion resistance, high cyclic stability and superior fatigue resistance. Nanocrystalline NiTi SMAs are frequently made into the components by experiencing plastic deformation at moderate temperatures in order to prevent nanocrystalline grains from growing up at high temperatures. Therefore, it is of great significance to investigate plastic deformation of nanocrystalline NiTi SMAs at moderate temperature by combining crystal plasticity finite element method (CPFEM) with experiment. In the present work, a CPFEM is employed for studying strengthening mechanism of nanocrystalline Ni50·3Ti49.7 SMA during hot deformation at 400 °C, where statistically stored dislocation (SSD) and geometrically necessary dislocation (GND) densities are integrated into the crystal plasticity constitutive model to account for strain gradients based on dislocation slip. The results show that nanocrystalline Ni50·3Ti49.7 SMA exhibits a strong size effect during plastic deformation at 400 °C, where yield stress along with SSD and GND densities increases with the decrease of grain size. It is evident that grain boundary strengthening and dislocation strengthening play an important role in size effect of nanocrystalline Ni50·3Ti49.7 SMA. The occurrence of grain rotation is induced by significant plastic strain gradients and high dislocation densities. With the increase of plastic strain, grain rotation results in the decrease of average grain boundary misorientation and activates additional available slip systems to+ accommodate the deformation, thereby leading to the decrease of the GND density and the increase of SSD density.

Abstract Dexmedetomidine (Dex) has been used in surgery to improve patients' postoperative cognitive function. However, the role of Dex in stress-induced anxiety-like behaviors and cognitive impairment is still unclear. In this study, we tested the role of Dex in anxiety-like behavior and cognitive impairment induced by acute restrictive stress and analyzed the alterations of the intestinal flora to explore the possible mechanism. Behavioral and cognitive tests, including open field test, elevated plus-maze test, novel object recognition test, and Barnes maze test, were performed. Intestinal gut Microbe 16S rRNA sequencing was analyzed. We found that intraperitoneal injection of Dex significantly improved acute restrictive stress-induced anxiety-like behavior, recognition, and memory impairment. After habituation in the environment, mice (male, 8 weeks, 18–23 g) were randomly divided into a control group (control, N = 10), dexmedetomidine group (Dex, N = 10), AS with normal saline group (AS + NS, N = 10) and AS with dexmedetomidine group (AS + Dex, N = 10). By the analysis of intestinal flora, we found that acute stress caused intestinal flora disorder in mice. Dex intervention changed the composition of the intestinal flora of acute stress mice, stabilized the ecology of the intestinal flora, and significantly increased the levels of Blautia (A genus of anaerobic bacteria) and Coprobacillus. These findings suggest that Dex attenuates acute stress-impaired learning and memory in mice by maintaining the homeostasis of intestinal flora.

High silicon steel has excellent soft magnetic properties, but a poor plasticity limits its practical application seriously. In this research, a novel FeSiCrNi alloy short for Fe-6.5Si–2Cr–12Ni (wt%) was designed and deformed via the local canning compression process at room temperature. It was shown that the FeSiCrNi alloy presents a relatively high plasticity in a triaxial compressive stress state. Geometrically necessary dislocations ensure the compatibility of plastic deformation for FeSiCrNi alloy. There are a small number of η and γ textures inside the FeSiCrNi sample. The intensity of η texture nearly keeps steady, while the intensity of γ texture increases slightly with the level of plastic deformation increasing. Additionally, the intensity of {112} copper texture increases with the increase of plastic deformation. Lath structures dominate the inhomogeneous plastic deformation of FeSiCrNi alloy and then integrate with the phase α-Fe. The main deformation mechanism of FeSiCrNi alloy is dislocation slip rather than twinning which has not been observed yet. The order degree of FeSiCrNi alloy continuously decreases, and deformation bands, dislocation walls and dislocation cells are successively formed, as the compression proceeds. It is feasible to produce FeSiCrNi components in cold forming process.

Abstract Using computational tools, bulk transcriptomics can be deconvoluted to estimate the abundance of constituent cell types. However, existing deconvolution methods are conditioned on the assumption that the whole study population is served by a single reference panel, ignoring person-to-person heterogeneity. Here, we present imply, a novel algorithm to deconvolute cell type proportions using personalized reference panels. Simulation studies demonstrate reduced bias compared with existing methods. Real data analyses on longitudinal consortia show disparities in cell type proportions are associated with several disease phenotypes in Type 1 diabetes and Parkinson’s disease. imply is available through the R/Bioconductor package ISLET at https://bioconductor.org/packages/ISLET/ .

Abstract Background Postoperative cognitive dysfunction (POCD) is a common neurological complication of anesthesia and surgery in aging individuals. Neuroinflammation has been identified as a hallmark of POCD. However, safe and effective treatments of POCD are still lacking. Itaconate is an immunoregulatory metabolite derived from the tricarboxylic acid cycle that exerts anti-inflammatory effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we investigated the effects and underlying mechanism of 4-octyl itaconate (OI), a cell-permeable itaconate derivative, on POCD in aged mice. Methods A POCD animal model was established by performing aseptic laparotomy in 18-month-old male C57BL/6 mice under isoflurane anesthesia while maintaining spontaneous ventilation. OI was intraperitoneally injected into the mice after surgery. Primary microglia and neurons were isolated and treated to lipopolysaccharide (LPS), isoflurane, and OI. Cognitive function, neuroinflammatory responses, as well as levels of gut microbiota and their metabolites were evaluated. To determine the mechanisms underlying the therapeutic effects of OI in POCD, ML385, an antagonist of Nrf2, was administered intraperitoneally. Cognitive function, neuroinflammatory responses, endogenous neurogenesis, neuronal apoptosis, and Nrf2/extracellular signal-related kinases (ERK) signaling pathway were evaluated. Results Our findings revealed that OI treatment significantly alleviated anesthesia/surgery-induced cognitive impairment, concomitant with reduced levels of the neuroinflammatory cytokines IL-1β and IL-6, as well as suppressed activation of microglia and astrocytes in the hippocampus. Similarly, OI treatment inhibited the expression of IL-1β and IL-6 in LPS and isoflurane-induced primary microglia in vitro. Intraperitoneal administration of OI led to alterations in the gut microbiota and promoted the production of microbiota-derived metabolites associated with neurogenesis. We further confirmed that OI promoted endogenous neurogenesis and inhibited neuronal apoptosis in the hippocampal dentate gyrus of aged mice. Mechanistically, we observed a decrease in Nrf2 expression in hippocampal neurons both in vitro and in vivo, which was reversed by OI treatment. We found that Nrf2 was required for OI treatment to inhibit neuroinflammation in POCD. The enhanced POCD recovery and promotion of neurogenesis triggered by OI exposure were, at least partially, mediated by the activation of the Nrf2/ERK signaling pathway. Conclusions Our findings demonstrate that OI can attenuate anesthesia/surgery-induced cognitive impairment by stabilizing the gut microbiota and activating Nrf2 signaling to restrict neuroinflammation and promote neurogenesis. Boosting endogenous itaconate or supplementation with exogenous itaconate derivatives may represent novel strategies for the treatment of POCD.

Abstract Realization of higher-order multistates with mutual interstate switching in ferroelectric materials is a perpetual drive for high-density storage devices and beyond-Moore technologies. Here we demonstrate experimentally that antiferroelectric van der Waals CuInP2S6 films can be controllably stabilized into double, quadruple, and sextuple polarization states, and a system harboring polarization order of six is also reversibly tunable into order of four or two. Furthermore, for a given polarization order, mutual interstate switching can be achieved via moderate electric field modulation. First-principles studies of CuInP2S6 multilayers help to reveal that the double, quadruple, and sextuple states are attributable to the existence of respective single, double, and triple ferroelectric domains with antiferroelectric interdomain coupling and Cu ion migration. These findings offer appealing platforms for developing multistate ferroelectric devices, while the underlining mechanism is transformative to other non-volatile material systems.

Precipitates always have a complex effect on the hot work hardening and recrystallization softening of materials. In this work, the dual effect of V-microalloying on hot deformation behavior and microstructure evolution of high nitrogen martensitic stainless steel (HNMSS) was investigated by hot compression experiments, modeling study and microstructure characterization. The results showed that V-microalloying enhanced the flow stresses and activation energy of 0.2V steel due to the fine grain strengthening effect and the blocking effect of dynamic precipitation on dislocation movement and grain boundary migration. On the other hand, the recrystallization model and deformed microstructure indicated the more intense dynamic recrystallization (DRX) softening effect in 0.2V steel, inducing the faster decrease of flow stress after the peak stress. V-microalloying promoted the dynamic precipitation of HNMSS during hot deformation, which reduced the size and increased the number of precipitates in 0.2V steel. The fine precipitates hindered dislocation movement, promoted dislocation accumulation and entanglement, formed a particle deformation zone (PDZ) with high dislocation density and large orientation gradient, and then induced the occurrence of particle-stimulated nucleation (PSN). In addition, the dislocation cells evolved from dislocation entanglement were also favorable nucleation sites for DRX.

Protein phosphorylation is an important link in a variety of signaling pathways, and most of the important life processes in cells involve protein phosphorylation. Based on the amino acid residues of phosphorylated proteins, protein kinases can be categorized into the following families: serine/threonine protein kinases, tyrosine-specific protein kinases, histidine-specific protein kinases, tryptophan kinases, and aspartate/glutamyl protein kinases. Of all the protein kinases, most are serine/threonine kinases, where serine/threonine protein kinases are protein kinases that catalyze the phosphorylation of serine or threonine residues on target proteins using ATP as a phosphate donor. The current socially accepted classification of serine/threonine kinases is to divide them into seven major groups: protein kinase A, G, C (AGC), CMGC, Calmodulin-dependent protein kinase (CAMK), Casein kinase (CK1), STE, Tyrosine kinase (TKL) and others. After decades of research, a preliminary understanding of the specific classification and respective functions of serine/threonine kinases has entered a new period of exploration. In this paper, we review the literature of the previous years and introduce the specific signaling pathways and related therapeutic modalities played by each of the small protein kinases in the serine/threonine protein kinase family, respectively, in some common cardiovascular system diseases such as heart failure, myocardial infarction, ischemia-reperfusion injury, and diabetic cardiomyopathy. To a certain extent, the current research results, including molecular mechanisms and therapeutic methods, are fully summarized and a systematic report is made for the prevention and treatment of cardiovascular diseases in the future.

Aggregate grading design is the foundation of concrete mix proportion design. Existing aggregate grading design methods are based on the tightest accumulation theory of homogeneous natural aggregates. However, this method has not been applied to mixed recycled aggregate (MRA) containing coal gangue brick aggregate (CGBA) (hereinafter referred to as MRA) due to significant differences in physical and mechanical properties. In this study, we subjected five types of MRA (initial particle size: 19–26.5 mm) to confined crushing, sieving, and grading composition analysis, then configured recycled concrete. We investigated the determination method of the optimal gradation of MRA, summarized the composition, particle distribution characteristics, and fractal characterization of the optimal gradation. This study focused on analyzing the factors that affect the compressive strength of recycled concrete, as well as examining the mix proportion design method. The results reveal that the optimal gradation of MRA can be determined using the five-stage loading method for approach minimum porosity. Our analysis of MRA gradation suggests that the mix proportion design of recycled concrete should be determined by considering the porosity of optimal gradation and the surplus volume coefficient of slurry. Finally, we determined that the water-binder (W/B) ratio is the primary factor that affects the compressive strength, while the CGBA’s intrinsic strength has a minimal impact. The replacement ratio of CGBA primarily affects the porosity of MRA and the W/B ratio, indirectly reducing recycled concrete’s compressive strength. Based on our findings, we recommend that the replacement ratio of CGBA should not exceed 50%. This study can promote the recycling of recycled concrete containing CGBA.

Crop yields are related to N fertilizer management, and also depend on local precipitation. Varying precipitation levels with long-term meteorological data have not been considered to optimize nitrogen (N) strategies in previous studies on the Loess Plateau of China. In this study, Root Zone Water Quality Model 2 (RZWQM2) was calibrated and validated using data from multi-year experiments and used to assess and optimize N management strategies for winter wheat cultivation. Results showed that the basal dressing fertilizer with 120 kg N ha-1 together with the topdressing of 67–77 kg N ha-1 was recommended in regions with 443 mm average annual precipitation. For those with 364 mm and 290 mm average annual precipitation, the basal dressing fertilizer with 90 kg N ha-1 together with the topdressing of 67–77 kg N ha-1 and the basal dressing with 90 kg N ha-1 together with the topdressing fertilizer of 13–23 kg N ha-1 were recommended, respectively. Compared with farmers’ practice (i.e., the single basal dressing), although decreasing the total rate by 12–18 kg N ha-1, the optimized N strategies (i.e., the basal fertilizer together with one-time topdressing) can effectively promote grain N uptake, nitrogen harvest index, and agronomic efficiency of N. It also maintained similar grain yield, evapotranspiration, and crop water productivity. The minimum precipitation threshold was around 300 mm, where the topdressing N fertilizer had little influence on grain yield, evapotranspiration, and grain N uptake. Additionally, the largest advantage of optimized N strategies was saving N fertilizer and reducing the environment footprint of wheat production. However, the crop production under the optimized N strategies was more sensitive to the precipitation variation than that under farmers’ practice. Thus, if climate continues to change following historical data, greater harvest fluctuations are expected under optimized N strategies. To cope with the evolving climate change, optimized N strategies should be integrated with other management measures for smallholder farming households on the Loess Plateau.

Addressing the challenges in detecting surface defects on ceramic disks, such as difficulty in detecting small defects, variations in defect sizes, and inaccurate defect localization, we propose an enhanced YOLOv5s algorithm. Firstly, we improve the anchor frame structure of the YOLOv5s model to enhance its generalization ability, enabling robust defect detection for objects of varying sizes. Secondly, we introduce the ECA attention mechanism to improve the model's accuracy in detecting small targets. Under identical experimental conditions, our enhanced YOLOv5s algorithm demonstrates significant improvements, with precision, F1 scores, and mAP values increasing by 3.1 %, 3 %, and 4.5 % respectively. Moreover, the accuracy in detecting crack, damage, slag, and spot defects increases by 0.2 %, 4.7 %, 5.4 %, and 1.9 % respectively. Notably, the detection speed improves from 232 frames/s to 256 frames/s. Comparative analysis with other algorithms reveals superior performance over YOLOv3 and YOLOv4 models, showcasing enhanced capability in identifying small target defects and achieving real-time detection.

Closed-loop neuromodulation with intelligence methods has shown great potentials in providing novel neuro-technology for treating neurological and psychiatric diseases. Development of brain-machine interactive neuromodulation strategies could lead to breakthroughs in precision and personalized electronic medicine. The neuromodulation research tool integrating artificial intelligent computing and performing neural sensing and stimulation in real-time could accelerate the development of closed-loop neuromodulation strategies and translational research into clinical application. In this study, we developed a brain-machine interactive neuromodulation research tool (BMINT), which has capabilities of neurophysiological signals sensing, computing with mainstream machine learning algorithms and delivering electrical stimulation pulse by pulse in real-time. The BMINT research tool achieved system time delay under 3 ms, and computing capabilities in feasible computation cost, efficient deployment of machine learning algorithms and acceleration process. Intelligent computing framework embedded in the BMINT enable real-time closed-loop neuromodulation developed with mainstream AI ecosystem resources. The BMINT could provide timely contribution to accelerate the translational research of intelligent neuromodulation by integrating neural sensing, edge AI computing and stimulation with AI ecosystems.

Summary: Global warming will change the photosynthesis and transpiration of plants greatly and ultimately affect water use efficiency (WUE). Here, we present a protocol to investigate the response of maize WUE to the coupling effect of CO2 and temperature at ear stage using a specialized designed gradient. We describe steps for plant culture, parameter measurements, model fitting, and statistical analysis. This protocol holds potential for studying the response of WUE and CO2 adaptation across various plant species.For complete details on the use and execution of this protocol, please refer to Sun et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

As a crucial event in the process of China’s trade cooperation and openness, the Belt and Road Initiative (BRI) relies on the logistics as the foundational industry for its sustainable development. This study measures the green logistics efficiency (GLE) of BRI partner countries using panel data from 2013 to 2019 and evaluates the BRI’s impact on their GLE. We find that: (1) The GLE of BRI partner countries is generally low, with only 15.9% achieving effectiveness. High-income countries have notably higher GLE than middle-income ones. (2) The GLE of BRI partner countries shows an upward trend annually, especially in middle-income countries, which are closing the gap with high-income countries. (3) The BRI has a significant positive impact on the GLE growth of partner countries. Heterogeneity analysis reveals that this growth effect is more pronounced in middle-income countries. These results indicate and enhance the understanding of GLE among BRI partner countries and addresses some skepticism regarding BRI’s sustainable development.

Abstract Background Distant metastasis is the major cause of lung adenocarcinoma (LUAD)-associated mortality. However, molecular mechanisms involved in LUAD metastasis remain to be fully understood. While the role of long non-coding RNAs (lncRNAs) in cancer development, progression, and treatment resistance is being increasingly appreciated, the list of dysregulated lncRNAs that contribute to LUAD pathogenesis is also rapidly expanding. Methods Bioinformatics analysis was conducted to interrogate publicly available LUAD datasets. In situ hybridization and qRT-PCR assays were used to test lncRNA expression in human LUAD tissues and cell lines, respectively. Wound healing as well as transwell migration and invasion assays were employed to examine LUAD cell migration and invasion in vitro. LUAD metastasis was examined using mouse models in vivo. RNA pulldown and RNA immunoprecipitation were carried out to test RNA–protein associations. Cycloheximide-chase assays were performed to monitor protein turnover rates and Western blotting was employed to test protein expression. Results The expression of the lncRNA LINC01559 was commonly upregulated in LUADs, in particular, in those with distant metastasis. High LINC01559 expression was associated with poor outcome of LUAD patients and was potentially an independent prognostic factor. Knockdown of LINC01559 diminished the potential of LUAD cell migration and invasion in vitro and reduced the formation of LUAD metastatic lesions in vivo. Mechanistically, LINC01559 binds to vimentin and prevents its ubiquitination and proteasomal degradation, leading to promotion of LUAD cell migration, invasion, and metastasis. Conclusion LINC01559 plays an important role in LUAD metastasis through stabilizing vimentin. The expression of LINC01559 is potentially an independent prognostic factor of LUAD patients, and LINC01559 targeting may represent a novel avenue for the treatment of late-stage LUAD.

The detection of fine-grained objects in remote sensing images has been recognized as a challenging issue, which cannot be well addressed by the existing deep learning-based methods due to their inadaptability to multi-scale objects, slow convergence speed, and limitations to scarce datasets. To cope with the above issue, we propose a deep convolutional neural network (CNN)-based detection method for multi-scale fine-grained objects in complex remote sensing scenarios. Specifically, we adopt a deep CNN with a residual structure as the backbone network, to extract deep-level details from the image. Besides, we introduce a multi-scale region generation network to overcome the limitations of fixed receptive field convolution kernels and enable multi-scale object detection. Lastly, we replace fully connected layers in the fully convolutional region classification network with $1\times 1$ convolutional layer to enhance detection efficiency and detection speed. To overcome the limitation of scarce datasets, we conducted experiments on the FAIR1M dataset, which is currently the largest fine-grained object detection dataset in the remote sensing field. Simulation results show that the proposed detection method achieves the highest average precision (35.86%) among all benchmarks and outperforms the classic Faster R-CNN-based method by 3.44%. Furthermore, our method demonstrates significantly improved detection speed compared to the Faster R-CNN-based methods.

Climate change is one of the foremost challenges confronting the contemporary world. Carbon and water cycles and their interconnections of ecosystems are playing a pivotal role in assessing the impacts of climate change on ecosystems. The Qinling Mountains of China represent a focal area for research on global climate change and regional adaptation strategies. Based on historical and CMIP6 (Coupled Model Intercomparison Project Phase 6) future climatic data, the Biome-BGC model, which was sufficiently optimized with the Biome-BGC-PEST package, was used to simulate the historical and future trends of GPP (Gross primary productivity), ET (Evapotranspiration), and WUE (Ecosystem water use efficiency) in the Qinling Mountains, so as to elucidate the dynamics and spatiotemporal variations of carbon and water fluxes amidst climate change. The results showed that the GPP, ET, and WUE of the Qinling Mountains heterogeneously distributed in space, due to the dramatic disparities in carbon and water fluxes among different vegetation types in the Qinling Mountains. Among the various vegetation types, evergreen needle-leaved forest had the highest annual mean value of WUE. In the historical period of 1979-2018, deciduous broad-leaved forest had the highest annual mean value of GPP and ET, while evergreen needle-leaved forest would dominate in the future (2021-2100). For the annual GPP and ET flux variations, different vegetation cover types followed varying peak patterns in the Qinling Mountains. Deciduous broad-leaved forest, evergreen needle-leaved forest, and shrub meadow showed ’single-peak’ pattern annually, whereas the crop area displayed ’double-peak’ pattern due to the different growing seasons of crops. There also were temporal variations for the carbon and water fluxes within the same vegetation type. Future projections suggested a continuous increase in GPP and ET fluxes, underscoring the consistent role of the Qinling Mountains in water resource conservation and carbon sink amid evolving climatic conditions.

BackgroundTuberculosis (TB) is recognized as a significant global public health concern. Still, there remains a dearth of comprehensive evaluation regarding the specific indicators and their influencing factors of delay for adolescents and young adults.MethodsAll notified pulmonary TB (PTB) patients in Jiaxing City were collected between 2005 and 2022 from China’s TB Information Management System. Logistic regression models were conducted to ascertain the factors that influenced patient and health system delays for PTB cases, respectively. Furthermore, the impact of the COVID-19 pandemic on local delays has been explored.ResultsFrom January 1, 2005 to December 31, 2022, a total of 5,282 PTB cases were notified in Jiaxing City, including 1,678 adolescents and 3,604 young adults. For patient delay, female (AOR: 1.18, 95%CI: 1.05–1.32), PTB complicated with extra-pulmonary TB (AOR: 1.70, 95% CI: 1.28–2.26), passive case finding (AOR: 1.46, 95% CI: 1.07–1.98) and retreatment (AOR: 1.52, 95% CI: 1.11–2.09) showed a higher risk of delay. For health system delay, minorities (AOR: 0.69, 95% CI: 0.53–0.90) and non-students (AOR: 0.83, 95% CI: 0.71–0.98) experienced a lower delay. Referral (AOR: 1.46, 95% CI: 1.29–1.65) had a higher health system delay compared with clinical consultation. Furthermore, county hospitals (AOR: 1.47, 95% CI: 1.32–1.65) and etiological positive results (AOR: 1.46, 95% CI: 1.30–1.63) were associated with comparatively high odds of patient delay. Contrarily, county hospitals (AOR: 0.88, 95% CI: 0.78–1.00) and etiological positive results (AOR: 0.67, 95% CI: 0.59–0.74) experienced a lower health system delay. Besides, the median of patient delay, health system delay, and total delay during the COVID-19 pandemic were significantly lower than that before.ConclusionIn general, there has been a noteworthy decline in the notification rate of PTB among adolescents and young adults in Jiaxing City while the declining trend was not obvious in patient delay, health system delay, and total delay, respectively. It also found factors such as gender, case-finding method, and the hospital level might influence the times of seeking health care and diagnosis in health agencies. These findings will provide valuable insights for refining preventive and treatment strategies for TB among adolescents and young adults.

Fe-6.5 wt% Si high silicon steel alloy presents excellent soft magnetic performances, but a poor plasticity limits its industrial application seriously. In this work, a novel FeSiCrNi alloy with the chemical composition of Fe-6.5Si-2Cr-12Ni (wt%) is designed and subjected to thermomechanical processing including local canning compression at room temperature and annealing at elevated temperatures. It is observed that microstructures of FeSiCrNi specimens with a compression degree of 70 % are dominated by dislocation cells. The microstructural evolution is transformed from static recovery to static recrystallization when FeSiCrNi specimens are annealed from 400 to 700 °C. Grains with high strain energy are successively nucleated via the integration of subgrain boundaries at 600 °C and a pronounced growth of recrystallized grains occurs at 700 °C. In particular, microtextures of the FeSiCrNi alloy essentially consist of γ-fiber ({111}∥ND) and λ-fiber ({100}∥ND) textures during recovery and recrystallization. The intensity of λ-fiber texture is weakened with increasing annealing temperature, while the intensity of γ-fiber which is composed of {111} 〈112〉 and {111} 〈110〉 textures is strengthened. The intensity of {111} 〈112〉 texture within the recrystallized FeSiCrNi grains reaches the maximum value at 700 °C.

Exposure to cadmium (Cd), a toxic heavy metal classified as an environmental endocrine disruptor, can exert significant toxicity in both animals and humans. However, the potential effects of Cd exposure on socioemotional behaviors are still poorly understood, as are the underlying mechanisms. In the present study, employing a series of behavioral tests as well as 16 S rRNA sequencing analysis, we investigated the long-term effects of Cd exposure on socioemotional behaviors and their associated mechanisms in mice based on the brain–gut interaction theory. The results showed that postweaning exposure to Cd reduced the ability to resist depression, decreased social interaction, subtly altered sexual preference, and changed the composition of the gut microbiota in male mice during adolescence. These findings provided direct evidence for the deleterious effects of exposure to Cd in the postweaning period on socioemotional behaviors later in adolescence, and suggested that these effects of Cd exposure may be linked to changes in the gut microbiota.

Abstract Quorum sensing (QS) is a crucial regulatory mechanism controlling bacterial signalling and holds promise for novel therapies against antimicrobial resistance. In Gram-positive bacteria, such as Streptococcus pneumoniae, ComA is a conserved efflux pump responsible for the maturation and secretion of peptide signals, including the competence-stimulating peptide (CSP), yet its structure and function remain unclear. Here, we functionally characterize ComA as an ABC transporter with high ATP affinity and determined its cryo-EM structures in the presence or absence of CSP or nucleotides. Our findings reveal a network of strong electrostatic interactions unique to ComA at the intracellular gate, a putative binding pocket for two CSP molecules, and negatively charged residues facilitating CSP translocation. Mutations of these residues affect ComA’s peptidase activity in-vitro and prevent CSP export in-vivo. We demonstrate that ATP-Mg2+ triggers the outward-facing conformation of ComA for CSP release, rather than ATP alone. Our study provides molecular insights into the QS signal peptide secretion, highlighting potential targets for QS-targeting drugs.

Abstract Unavoidable nonmetallic inclusions generated in the steelmaking process are fatal defects that often cause serious corrosion failure of steel, leading to catastrophic accidents and huge economic losses. Over the past decades, extensive efforts have been made to address this difficult issue, but none of them have succeeded. Here, we propose a strategy of wrapping deleterious inclusions with corrosion-resistant niobium armour (Z phase). After systematic theoretical screening, we introduce minor Nb into duplex stainless steels (DSSs) to form inclusion@Z core-shell structures, thus isolating the inclusions from corrosive environments. Additionally, both the Z phase and its surrounding matrix possess excellent corrosion resistance. Thus, this strategy effectively prevents corrosion caused by inclusions, thereby doubly improving the corrosion resistance of DSSs. Our strategy overcomes the long-standing problem of “corrosion failure caused by inclusions”, and it is verified as a universal technique in a series of DSSs and industrial production.

In this study, a high nitrogen martensitic stainless bearing steel with ultra-high strength and excellent toughness combination treated by quenching-cryogenic cooling-partitioning-tempering (Q-C-P-T) process was obtained. The yield strength, ultimate tensile strength, uniform elongation and the impact energy of the sample after partitioning at 200 °C for 1 h followed by tempering at 400 °C for 1 h are up to 2034 MPa, 2217 MPa, 5.83% and 58.73 J respectively. The microstructure characterization shows that the interstitial atoms of C and N in martensite diffuse into adjacent austenite during the partitioning process, resulting in the high stability of austenite. Strain-induced martensitic transformation was suppressed in maximum, effectively avoiding the formation of hard martensite enriched in C/N and dimensional instability caused by volume expansion of martensitic transformation, which is crucial for bearing steels. And nano-scale precipitates in the martensite matrix effectively compensate for the strength loss of the martensite caused by lower solid solution of carbon and nitrogen, thus obtaining excellent comprehensive mechanical properties. This work paves a new way for the development of advanced bearing steels.

Abstract Background Endovascular recanalization in patients with symptomatic nonacute intracranial large artery occlusion (ILAO) has been reported to be feasible, but technically challenging. This study aimed to determine the predictors of successful endovascular recanalization in patients with symptomatic nonacute ILAO. Methods The outcomes of endovascular recanalization attempts performed in 70 consecutive patients showing symptomatic nonacute ILAO with hemodynamic cerebral ischemia between January 2016 to December 2022 were reviewed. Potential variables, including clinical and radiological characteristics related to technical success, were collected. Univariate analysis and multivariate logistic regression were performed to identify predictors of successful recanalization for nonacute ILAO. Results Technically successful recanalization was achieved in 57 patients (81.4%). The periprocedural complication rate was 21.4% (15 of 70), and the overall 30-day morbidity and mortality rates were 7.1% (5 of 70) and 2.9% (2 of 70), respectively. Univariate analysis showed that successful recanalization was associated with occlusion duration, stump morphology, occlusion length, slow distal antegrade flow sign, and the presence of bridging collateral vessels. Multivariate analysis showed that occlusion duration ≤ 3 months (odds ratio [OR]: 22.529; 95% confidence interval [CI]: 1.636-310.141), tapered stump (OR: 7.498; 95% CI: 1.533–36.671), and occlusion length

Abstract Linked climate and crop simulation models are widely used to assess the impact of climate change on agriculture. However, it is unclear how ensemble configurations (model composition and size) influence crop yield projections and uncertainty. Here, we investigate the influences of ensemble configurations on crop yield projections and modeling uncertainty from Global Gridded Crop Models and Global Climate Models under future climate change. We performed a cluster analysis to identify distinct groups of ensemble members based on their projected outcomes, revealing unique patterns in crop yield projections and corresponding uncertainty levels, particularly for wheat and soybean. Furthermore, our findings suggest that approximately six Global Gridded Crop Models and 10 Global Climate Models are sufficient to capture modeling uncertainty, while a cluster-based selection of 3-4 Global Gridded Crop Models effectively represents the full ensemble. The contribution of individual Global Gridded Crop Models to overall uncertainty varies depending on region and crop type, emphasizing the importance of considering the impact of specific models when selecting models for local-scale applications. Our results emphasize the importance of model composition and ensemble size in identifying the primary sources of uncertainty in crop yield projections, offering valuable guidance for optimizing ensemble configurations in climate-crop modeling studies tailored to specific applications.

Temperature compensatory effect, which quantifies the increase in cumulative air temperature from soil temperature increase caused by mulching, provides an effective method for incorporating soil temperature into crop models. In this study, compensated temperature was integrated into the AquaCrop model to investigate the capability of the compensatory effect to improve assessment of the promotion of maize growth and development by plastic film mulching (PM). A three-year experiment was conducted from 2014 to 2016 with two maize varieties (spring and summer) and two mulching conditions (PM and non-mulching (NM)), and the AquaCrop model was employed to reproduce crop growth and yield responses to changes in NM, PM, and compensated PM. A marked difference in soil temperature between NM and PM was observed before 50 days after sowing (DAS) during three growing seasons. During sowing–emergence and emergence–tasseling, the increase in air temperature was proportional to the compensatory coefficient, with spring maize showing a higher compensatory temperature than summer maize. Simulation results for canopy cover (CC) were generally in good agreement with the measurements, whereas predictions of aboveground biomass and grain yield under PM indicated large underestimates from 60 DAS to the end of maturity. Simulations of spring maize biomass and yield showed general increase based on temperature compensation, accompanied by improvement in modeling accuracy, with RMSEs decreasing from 2.5 to 1.6 t ha−1 and from 4.1 t to 3.4 t ha−1. Improvement in biomass and yield simulation was less pronounced for summer than for spring maize, implying that crops grown during low-temperature periods would benefit more from the compensatory effect. This study demonstrated the effectiveness of the temperature compensatory effect to improve the performance of the AquaCrop model in simulating maize growth under PM practices.

Abstract Background Perioperative neurocognitive disorder (PND) is a key complication affecting older individuals after anesthesia and surgery. Failure to translate multiple pharmacological therapies for PND from preclinical studies to clinical settings has necessitated the exploration of novel therapeutic strategies. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) treatment has emerged as a promising therapeutic strategy for treating neurodegenerative diseases and has the potential to translate basic science into clinical practice. In this study, we investigated the effects and underlying mechanism of hUC-MSCs on PND in aged mice. Methods hUC-MSCs were isolated from an infant umbilical cord and identified using flow cytometry and differentiation assays. We established PND model by undergoing aseptic laparotomy under isoflurane anesthesia maintaining spontaneous ventilation in eighteen-month-old male C57BL/6 mice. hUC-MSCs were slowly injected into mice by coccygeal vein before anesthesia. Cognitive function, systemic and neuroinflammatory responses, neuroplasticity, endogenous neurogenesis, and brain-derived neurotrophic factor (BDNF) were assessed. To determine the brain mechanisms underlying by which hUC-MSCs mediate their neuroprotective effects in PND, K252a, an antagonist of BDNF receptor, was administered intraperitoneally before surgery. Hippocampal BDNF/TrkB/CREB signaling pathway and metabolomic signatures were evaluated. Results hUC-MSC treatment ameliorated the learning and memory impairment in aged mice with PND. The downstream effects were the suppression of systemic and hippocampal inflammation and restoration of neurogenesis and neuroplasticity dysregulation. Interestingly, the level of mature BDNF, but not that of proBDNF, was increased in the hippocampus after hUC-MSC treatment. Further analysis revealed that the improved cognitive recovery and the restoration of neurogenesis and neuroplasticity dysregulation elicited by exposure to hUC-MSCs were, at least partially, mediated by the activation of the BDNF/TrkB/CREB signaling pathway. Untargeted metabolomic further identified lipid metabolism dysfunction as potential downstream of the BDNF/TrkB/CREB signaling pathway in hUC-MSC-mediated neuroprotection for PND. Conclusions Our study highlights the beneficial effects of hUC-MSC treatment on PND and provides a justification to consider the potential use of hUC-MSCs in the perioperative period.

Abstract Apple Valsa canker (AVC) has caused significant losses worldwide, especially in East Asia. Various fungal species from the genus Cytospora/Valsa can infect tree bark and cause tissue rot, and Valsa mali (Vm) is responsible for the most severe tree branch deaths and yield losses. Since AVC was first reported in Japan in 1903, the pathogen species, biological characteristics, infection and pathogenesis, spore dissemination, and disease cycle have been intensively investigated. Based on the new cognition of the disease dynamics, the disease control strategy has shifted from scraping diseased tissue to protecting the bark from infection. In this review, we summarize new knowledge of the Vm infection process mediated by various kinds of virulence factors, including cell wall degrading enzymes, toxins, effectors, microRNA-like RNAs, and pathogenic signaling regulators. We also introduce progress in evaluating germplasm resources and identifying disease response-related genes in apples. In addition, we elaborate current understanding of spore dissemination and disease cycles in orchards and disease prevention techniques. Finally, we provide recommendations for developing more cost-effective strategies for controlling AVC by applying genetic resistance and biological fungicides.

Abstract This study aims to investigate the beneficial effects of surface retaining elements (SREs) on the mechanical behaviors of bolted rock and roadway stability. 3D printing (3DP) technology is utilized to create rock analogue prismatic specimens for conducting this investigation. Uniaxial compression tests with acoustic emission (AE) and digital image correlation techniques have been conducted on 3DP specimens bolted with different SREs. The results demonstrate that the strength and modulus of elasticity of the bolted specimens show a positive correlation with the area of the SRE; the AE characteristics of the bolted specimens are higher than those of the unbolted specimen, but they decrease with an increase in SRE area, thus further improving the integrity of the bolted specimens. The reinforcement effect of SREs on the surrounding rock of roadways is further analyzed using numerical modelling and field test. The results provide a better understanding of the role of SREs in rock bolting and the optimization of rock bolting design. Furthermore, they verify the feasibility of 3DP for rock analogues in rock mechanics tests.

This study examines the impact of climate change on winter wheat production in Henan Province. The analysis, under the utilization of GLASS LAI data, focuses on shifts in the planting areas of winter wheat. In addition, a comprehensive assessment of the spatiotemporal trends in meteorological factors during the winter wheat growth period has also been conducted. The findings reveal a fluctuating increase in accumulated temperature across Henan Province, ranging from 3145 °C to 3424 °C and exhibiting a gradual rise from north to south. In particular, precipitation patterns from 1980 to 2019 showed limited significant trends, while notable abrupt changes were observed in 1983, 2004, 2009, and 2016. Geographically, southwestern Henan Province experiences greater precipitation than the northeast. Moreover, a fluctuating downward trend in sunshine hours has been observed, gradually decreasing from north to south. The study further highlights an increase in winter wheat planting frequency in the northwestern region of Luoyang and the northeastern part of Zhumadian, contrasted by a decrease in Zhengzhou and Kaifeng. Accumulated temperature is positively correlated with the expansion of winter wheat planting areas (R2 = 0.685), while sunshine hours exert a suppressive effect (R2 = 0.637). Among meteorological factors, accumulated temperature emerges as the most crucial determinant, followed by precipitation, with sunshine hours having a relatively minor influence. Yield demonstrates a positive association with accumulated temperature (R2 = 0.765) and a negative correlation with sunshine hours (R2 = −0.614). This finding is consistent with the impact of meteorological factors on winter wheat production. The results of this study enhance the understanding of how the underlying mechanisms of climate change impact crop yields.

Due to dramatic increases in data traffic over the last decade, there has been growing interest in enhancing system performance levels in data communications and networking [...]

The structural, electronic, magnetic, and optical properties of Co-doped 10–20-atom silver clusters are investigated by GGA/PBE via the density functional theory. The Ag–Co clusters form core–shell structures with a Co atom in the center. Co atom doping modulates electronic properties like energy gap, molecular softness, global hardness, electronegativity, and electrophilicity index. For the optical spectra of the Ag–Co clusters, the energy of their spectra overall exhibits little change with increasing numbers of atoms; the strongest peaks are roughly distributed at 3.5 eV, and the intensity of their spectra overall is strengthened. Raman and vibrational spectra reflect structural changes with Co atom addition. The addition of the Co atom alters magnetic moments of specific Ag–Co clusters, while others remain unchanged.

BackgroundEndovascular treatment of severe intracranial atherosclerotic stenosis (ICAS) using coronary drug-eluting stents (DESs) significantly reduces the risk of in-stent restenosis (ISR) and stroke recurrence. However, there are few reports regarding the treatment of ICAS with intracranial dedicated DES. Herein, we present our experience with the feasibility, safety, and medium-term follow-up outcomes of a novel intracranial DES, named NOVA stent, in patients with symptomatic severe ICAS (≥70%).MethodsFrom December 2021 to May 2022, patients with symptomatic severe ICAS who underwent implantation of the NOVA stent in our institution were retrospectively analyzed for procedural results, perioperative complications, imaging and clinical follow-up outcomes.ResultsTwenty-four patients, 16 (66.7%) with anterior circulation lesions and 8 (33.3%) with posterior circulation lesions, were enrolled. All patients with intracranial ICA (n = 6), middle cerebral artery (n = 10), basilar artery (n = 3), intracranial vertebral artery (n = 3), and the vertebrobasilar junction (n = 2) stenosis were treated successfully using NOVA stents. The severity of stenosis ranged from 75 to 96% (mean 85.9%) before treatment and this was reduced to 0 to 20% (mean 8.6%) immediately after stent placement. Symptomatic distal embolism occurred in one case; however, there were no other perioperative complications. The mean follow-up duration was 12.2 ± 1.06 months. No symptomatic ischemic events occurred during follow-up. Follow-up cerebral angiography was performed in 22 of 24 patients (91.7%), and significant ISR occurred in one patient (4.2%).ConclusionOur results demonstrate that implantation of the novel intracranial DES NOVA in severe ICAS is feasible, safe, and effective in selected cases, reducing the incidence of ISR, and showing excellent midterm clinical outcomes, providing a promising option for ICAS treatment.

Recently, novel biotechnologies to quantify RNA modifications became an increasingly popular choice for researchers who study epitranscriptome. When studying RNA methylations such as N6-methyladenosine (m6A), researchers need to make several decisions in its experimental design, especially the sample size and a proper statistical power. Due to the complexity and high-throughput nature of m6A sequencing measurements, methods for power calculation and study design are still currently unavailable. In this work, we propose a statistical power assessment tool, magpie, for power calculation and experimental design for epitranscriptome studies using m6A sequencing data. Our simulation-based power assessment tool will borrow information from real pilot data, and inspect various influential factors including sample size, sequencing depth, effect size, and basal expression ranges. We integrate two modules in magpie: (i) a flexible and realistic simulator module to synthesize m6A sequencing data based on real data; and (ii) a power assessment module to examine a set of comprehensive evaluation metrics.

Purpose: MicroRNAs (miRs) play multiple roles during cutaneous squamous cell carcinoma (CSCC) progression. Previous studies suggest miR-124 could inhibit cancer development in CSCC. Methods: Obtained 63 pairs of CSCC and adjacent tissues for analysis. Cultured HaCaT and two CSCC cell lines (A431 and SCL-1) in DMEM (10 % FBS). Transfected cells using Lipofectamine 2000 with various miR-124 mimics, inhibitors, or Snail family transcriptional repressor 2 (SNAI2) expression plasmid. Performed a series of assays, including real-time quantitative PCR, Western blot, CCK8, wound healing, transwell, and luciferase reporter gene assay, to examine the effects of miR-124 on CSCC cells. Results: An evident downregulation of miR-124 in CSCC tissues, which was related to advanced disease stage and nodal metastasis. Overexpressing miR-124 could reduce the proliferation, migration, and invasion abilities of CSCC cells. It was verified that miR-124 targets the SNAI2 in CSCC cells. Moreover, ectopic expression of SNAI2 rescued the suppressive effects on CSCC cells induced by miR-124 overexpression. Furthermore, miR-124 increased cell sensitivity to cisplatin. Besides, SNAI2 is a critical factor in the immune-related aspects of CSCC and its modulation may influence the response to immunotherapy. Conclusion: We demonstrate that miR-124 inhibits CSCC progression through downregulating SNAI2, and thus it may be a molecular candidate for treating CSCC in the clinic.

Viral infectious diseases significantly threaten the sustainability of freshwater fish aquaculture. The lack of studies on epidemic transmission patterns and mechanisms inhibits the development of containment strategies from the viewpoint of veterinary public health. This study raises an epidemic mathematical model considering water transmission with the aim of analyzing the transmission process more accurately. The basic reproduction number R0 was derived by the model parameter including the water transmission coefficient and was used for the analysis of the virus transmission. Spring viremia of carp virus (SVCV) and zebrafish were used as model viruses and animals, respectively, to conduct the transmission experiment. Transmission through water was achieved by connecting two aquarium tanks with a water channel but blocking the fish movement between the tanks. With the collected experimental data, we determined the optimal hybrid machine learning algorithm to analyze the transmission process using an established mathematical model. In addition, future transmission was predicted and validated using the epidemic model and an optimal algorithm. Finally, the sensitivity of model parameters and the simulations of R0 variation were performed based on the modified complex epidemic model. This study is of significance in providing theoretical guidance for minimizing R0 by manipulating model parameters with containment measures. More importantly, since the modified model and algorithm demonstrated better performance in handling freshwater fish transmission problems, this study advances the future application of transmissible disease modeling with larger datasets in freshwater fish aquaculture.

Summary: Viral inclusion bodies (VIBs) are subcellular structures required for efficient viral replication. How type II grass carp reovirus (GCRV-II), the mainly prevalent strain, forms VIBs is unknown. In this study, we found that GCRV-II infection induced punctate VIBs in grass carp ovary (GCO) cells and that non-structural protein 38 (NS38) functioned as a participant in VIB formation. Furthermore, VP56 and VP35 induced VIBs and recruited other viral proteins via the N-terminal of VP56 and the middle domain of VP35. Additionally, we found that the newly synthesized viral RNAs co-localized with VP56 and VP35 in VIBs during infection. Taken together, VP56 and VP35 induce VIB formation and recruit other viral proteins and viral RNAs to the VIBs for viral replication, which helps identify new targets for developing anti-GCRV-II drugs to disrupt viral replication.

ABSTRACTHeterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) plays an important role in regulating the replication of many viruses. However, it remains elusive whether and how hnRNPA1 regulates fish virus replication. In this study, the effects of twelve hnRNPs on the replication of snakehead vesiculovirus (SHVV) were screened. Three hnRNPs, one of which was hnRNPA1, were identified as anti-SHVV factors. Further verification showed that knockdown of hnRNPA1 promoted, while overexpression of hnRNPA1 inhibited, SHVV replication. SHVV infection reduced the expression level of hnRNPA1 and induced the nucleocytoplasmic shuttling of hnRNPA1. Besides, we found that hnRNPA1 interacted with the viral phosphoprotein (P) via its glycine-rich domain, but not with the viral nucleoprotein (N) or large protein (L). The hnRNPA1-P interaction competitively disrupted the viral P-N interaction. Moreover, we found that overexpression of hnRNPA1 enhanced the polyubiquitination of the P protein and degraded it through proteasomal and lysosomal pathways. This study will help understanding the function of hnRNPA1 in the replication of single-stranded negative-sense RNA viruses and providing a novel antiviral target against fish rhabdoviruses.

Abstract Background Cervical cancer is and will remain to be an important health problem in China, especially with an increasing proportion of younger patients who has more specific needs. In China, surgery to remove tumor burden followed by postoperative treatment with radiotherapy and chemotherapy based on clinicopathologic factors may be the best choice for stages IB3 and IIA2 patients. Radical hysterectomy in cervical cancer has been a classic landmark surgery in gynecology. The current trial is designed to evaluate whether there is a difference between laparoscopic RH and abdominal RH in cervical cancer (stages IB3 and IIA2) patient survival under stringent operation standards and consistent surgical oncologic principles. This paper reports the rationale, design, and implementation of the trial. Methods/design This is an investigator-initiated, prospective, randomized, open, blinded endpoint (PROBE) controlled trial. A total of 1104 patients with stage IB3 and IIA2 cervical cancer will be enrolled over a period of 3 years. Patients are randomized (1:1) to either the laparoscopic RH or the abdominal RH group. Patients will then be followed up for at least 5 years. The primary end point will be 5-year overall survival, and secondary endpoints include 5-year progression-free survival, recurrence, and quality of life measurements. Discussion The study results will provide more convincing evidence-based information for stages IB3 and IIA2 cervical cancer patients and their gynecologic cancer surgeons in their choice of surgical method. Trial registration ClinicalTrials.gov, NCT04939831 , retrospectively registered on 25 June 2021.

Abstract We propose a statistical framework ISLET to infer individual-specific and cell-type-specific transcriptome reference panels. ISLET models the repeatedly measured bulk gene expression data, to optimize the usage of shared information within each subject. ISLET is the first available method to achieve individual-specific reference estimation in repeated samples. Using simulation studies, we show outstanding performance of ISLET in the reference estimation and downstream cell-type-specific differentially expressed genes testing. We apply ISLET to longitudinal transcriptomes profiled from blood samples in a large observational study of young children and confirm the cell-type-specific gene signatures for pancreatic islet autoantibody. ISLET is available at https://bioconductor.org/packages/ISLET .

Abstract Objective This systematic review and meta-analysis study aimed to evaluate the effectiveness of probiotics supplementation on glycaemic control in patients with type 2 diabetes mellitus (T2DM) based on the data from the randomised clinical trials (RCTs). Methods PubMed, Web of Sciences, Embase, and Cochrane Library were searched from the inception to October 2022, and RCTs about probiotics and T2DM were collected. The standardised mean difference (SMD) with 95% confidence interval (CI) was used to estimate the effects of probiotics supplementation on glycaemic control related parameters, e.g. fasting blood glucose (FBG), insulin, haemoglobin A1c (HbA1c), and homeostasis model of assessment of insulin resistance (HOMA-IR). Results Thirty RCTs including 1,827 T2MD patients were identified. Compared with the placebo group, the probiotics supplementation group had a significant decrease in the parameters of glycaemic control, including FBG (SMD = − 0.331, 95% CI − 0.424 to − 0.238, P effect

Stimulator of interferon gene (STING) functions importantly as antiviral adaptor protein during the innate immune activation. The role of the dimerization domain (DD) of STING remains obscure although other domains of this molecule have been studied extensively. To clarify the mechanism of black carp STING (bcSTING) in the innate immunity, bcSTING-ΔDD (bcSTING without DD) and bcSTING-ΔCTT (bcSTING without CTT domain) were constructed and analyzed in this manuscript. The reporter assays revealed that the induced transcription of IFN promoters mediated by bcSTING-ΔDD were much higher than that of the wild type bcSTING; however, bcSTING-ΔCTT almost lost the activities to trigger the interferon (IFN) promoters transcription. The mRNA transcriptional levels of IFN and interferon stimulated genes (ISGs) in EPC cells expressing bcSTING-ΔDD were obviously higher than those of EPC cells expressing wild type bcSTING; however, the transcriptional levels of the above cytokines of EPC cells expressing bcSTING-ΔCTT were basically the same as those of control cells. EPC cells overexpressing bcSTING-DD showed stronger antiviral activity than those overexpressing wild-type bcSTING. Furthermore, the co-immunoprecipitation assay identified the self-interaction between bcSTING-ΔDD molecules. And it was interesting that the affinity between bcSTING-ΔDD and bcTBK1 was obviously stronger than that between bcTBK1 and wild-type bcSTING. Thus, our data suggests that DD of black carp STING plays a negative regulatory role in STING-mediated antiviral immunity, which provides a new perspective for further researching the function of fish STING in the innate immunity.

Ischemic stroke (IS), chronic obstructive pulmonary disease (COPD) and diabetes mellitus (DM) account for a large burden of premature deaths. However, few studies have investigated the associations between fine particular matter (PM2.5) components and mortality of IS, COPD and DM. We aimed to examine these associations in Beijing, China. Data on daily mortality, air pollutants and meteorological factors from 2008 to 2011 in Beijing were collected. Daily concentrations of five PM2.5 components, namely, sulfate ion (SO42−), ammonium ion (NH4+), nitrate ion (NO3−), organic matter (OM) and black carbon (BC), were obtained from the Tracking Air Pollution (TAP) database in China. The association between PM2.5 components and daily deaths was explored using a quasi-Poisson regression with the distributed lag nonlinear model (DLNM). The average daily concentrations of SO42−, NH4+, NO3−, OM and BC were 11.24, 8.37, 12.00, 17.34 and 3.32 μg/m3, respectively. After adjusting for temperature, relative humidity, pressure, particulate matter less than 10 μm in aerodynamic diameter (PM10), nitrogen dioxide (NO2) and sulfur dioxide (SO2), an IQR increase in OM at lag day 2 and lag day 6 was associated with an increased DM mortality risk (RR 1.038; 95% CI: 1.005–1.071) and COPD mortality risk (RR 1.013; 95% CI: 1.001–1.026). An IQR increase in BC at lag day 0 and lag day 6 was associated with increased COPD mortality risk (RR 1.228; 95% CI: 1.017–1.48, RR 1.059; 95% CI: 1.001–1.121). Cumulative exposure to SO42− and NH4+ was associated with an increased mortality risk for IS, with the highest effect found for lag of 0–7 days (RR 1.085; 95% CI: 1.010–1.167, RR 1.083; 95% CI: 1.003–1.169). These effects varied by sex and age group. This study demonstrated associations of short-term exposure to PM2.5 components with increased risk of IS, COPD and DM mortality in the general population. Our study also highlighted susceptible subgroups.