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Abstract Background Osteoporosis, a systemic skeletal disease, seriously affects the quality of life in postmenopausal women. As one type of cathepsin K (CatK) inhibitor, odanacatib (ODN) is a fresh medication for osteoporosis. Considering the potential of ODN, we further examined the effect and safety of ODN for postmenopausal osteoporosis (PMOP) with a meta-analysis. Methods PubMed, EMBASE, Cochrane Library, and Web of Science were searched for eligible studies from inception to December 29th, 2023. After that, we conducted a comprehensive meta-analysis following PRISMA guidelines. Risk of bias was meticulously investigated with the Cochrane Collaboration’s tool. Efficacy was assessed with bone mineral density (BMD) at different sites (lumbar spine, trochanter, radius, femoral neck) and biomarkers of bone turnover (P1NP, uNTx/Cr, s-CTx, BSAP). Safety was evaluated by analyzing total, serious, other, and skin adverse events (AEs). Results Four random clinical trials (RCTs) were involved in our research. All trials were rated as having high quality and met the eligibility criteria. In the current research, ODN was found to elevate BMD at lumbar spine, femoral neck, total hip, trochanter and forearm, while it decreased the levels of serum C-telopeptides of type I collagen (s-CTx) as well as urinary N-telopeptide/creatinine ratio (uNTx/Cr). No significant differences were observed in AEs between the ODN group and the control group. Conclusions ODN is a promising alternative for the treatment of PMOP on account of its excellent efficacy and credible safety. Unclear links between ODN and cardiovascular AEs require further research to clarify.

The influence of different bottom blowing processes on the flow field and dead zone distribution of molten steel was simulated using Fluent software， taking the 130 ton ladle as the research object.The results showed that when the center distance decreased from 0.65R to 0.50R， the average flow velocity of the molten steel decreased from 0.24 m/s to 0.05 m/s， and the proportion of low flow velocity areas significantly increased. The steel flow at the two wall ends was slow， and the average flow velocity at the interface of slag and molten steel decreased from 0.18 m/s to 0.009 m/s. The proportion of dead zones increased from 7% to 25%， and the overall stirring effect decreased； When the center angle of the permeable brick increased from 85° to 180°， the average flow velocity of the molten steel decreases to 0.09 m/s， the average flow velocity at the interface of slag and molten steel was 0.05 m/s， and the dead zone volume ratio increased to 28%； With the amount of argon blowing increased， the flow rate of the molten steel significantly accelerated， the dead zone volume further decreased， and the mixing time of the molten steel gradually shortened. At 200 L/min， the average flow rate increased to 0.43 m/s， and the average flow rate at the horizontal interface of slag and molten steel was 0.32 m/s. There was no slag entrapment phenomenon， and the mixing time of the molten steel was 300 seconds. In summary， it is determined that the optimal solution is an argon flow rate of 200 L/min for breathable brick 1 and 210 L/min for breathable brick 2.under the following conditions： the diameter of the two breathable bricks is 165 mm， the angle of breathable brick is 85°， the center distance of breathable is 0.65 R， the thickness of slag layer thickness is 100 mm， the thickness of air layer is 400 mm ， and bottom blowing time is 600 s.

Acute pancreatitis (AP) is a potentially fatal condition with no targeted treatment options. Although inhibiting xanthine oxidase (XO) in the treatment of AP has been studied in several experimental models and clinical trials, whether XO is a target of AP and what its the main mechanism of action is remains unclear. Here, we aimed to re-evaluate whether XO is a target aggravating AP other than merely generating reactive oxygen species that trigger AP. We first revealed that XO expression and enzyme activity were significantly elevated in the serum and pancreas of necrotizing AP models. We also found that allopurinol and febuxostat, as purine-like and non-purine XO inhibitors, respectively, exhibited protective effects against pancreatic acinar cell death in vitro and pancreatic damage in vivo at different doses and treatment time points. Moreover, we observed that conditional Xdh overexpression aggravated pancreatic necrosis and severity. Further mechanism analysis showed that XO inhibition restored the hypoxia-inducible factor 1-alpha (HIF-1α)-regulated lactate dehydrogenase A (LDHA) and NOD-like receptor family pyrin domain containing 3 (NLRP3) signaling pathways and reduced the enrichment of 13C6-glucose to 13C3-lactate. Lastly, we observed that clinical circulatory XO activity was significantly elevated in severe cases and correlated with C-reactive protein levels, while pancreatic XO and urate were also increased in severe AP patients. These results together indicated that proper inhibition of XO might be a promising therapeutic strategy for alleviating pancreatic necrosis and preventing progression of severe AP by downregulating HIF-1α-mediated LDHA and NLRP3 signaling pathways.

Abstract Depressive symptoms occur commonly in Alzheimer’s disease (AD). Although abnormalities in the amygdala-frontal circuit have been linked to emotional dysregulation and cognitive impairment, the neurological basis underlying these associations in AD patients with depressive symptoms (ADD) is unclear. We aimed to investigate the relationship between the amygdala-frontal circuit and depressive symptoms and cognitive function in ADD. We recruited 60 ADD, 60 AD patients without depressive symptoms (ADND), and 60 healthy controls (HC). Functional connectivity (FC) maps of the bilateral amygdala were compared. Fractional anisotropy (FA) of the amygdala-frontal circuit connected by the uncinate fasciculus (UF) was calculated using automated fiber quantification (AFQ). In addition, mediation analysis was performed to explore the effects of the amygdala-frontal circuit on the relationship between depressive symptoms and cognitive function. We found decreased bilateral amygdala FC with the inferior frontal gyrus (IFG) in the ADD group compared to the ADND and HC groups. Moreover, FA in the left frontal UF (nodes 64–97) was significantly lower in the ADD group than ADND group. Notably, amygdala-based FC with IFG and the left frontal UF FA mediated the relationship between depressive symptoms and cognitive function in ADD, with mediating effects ranging between 15 and 18%. Our study is the first to demonstrate the mediating effect of functional and microstructural abnormalities in the amygdala-frontal circuit in ADD. The findings suggest that the amygdala-frontal circuit may underlie emotional dysregulation in ADD, providing potential targets for treatment strategies.

Abstract How disruptions to normal cell differentiation link to tumorigenesis remains incompletely understood. Wilms tumor, an embryonal tumor associated with disrupted organogenesis, often harbors mutations in epigenetic regulators, but their role in kidney development remains unexplored. Here, we show at single-cell resolution that a Wilms tumor-associated mutation in the histone acetylation reader ENL disrupts kidney differentiation in mice by rewiring the gene regulatory landscape. Mutant ENL promotes nephron progenitor commitment while restricting their differentiation by dysregulating transcription factors such as Hox clusters. It also induces abnormal progenitors that lose kidney-associated chromatin identity. Furthermore, mutant ENL alters the transcriptome and chromatin accessibility of stromal progenitors, resulting in hyperactivation of Wnt signaling. The impacts of mutant ENL on both nephron and stroma lineages lead to profound kidney developmental defects and postnatal mortality in mice. Notably, a small molecule inhibiting mutant ENL’s histone acetylation binding activity largely reverses these defects. This study provides insights into how mutations in epigenetic regulators disrupt kidney development and suggests a potential therapeutic approach.

Introduction: The level of atmospheric CO2 has continuously been increasing and the resulting greenhouse effects are receiving attention globally. Carbon removal from the atmosphere occurs naturally in various ecosystems. Among them, saline environments contribute significantly to the global carbon cycle. Carbonate deposits in the sediments of salt lakes are omnipresent, and the biological effects, especially driven by halophilic microalgae and bacteria, on carbonate formation remain to be elucidated. Objectives: The present study aims to characterize the carbonates formed in saline environments and demonstrate the mechanisms underlying biological-driven CO2 removal via microalgal-bacterial consortium. Methods: The carbonates naturally formed in saline environments were collected and analyzed. Two saline representative organisms, the photosynthetic microalga Dunaliella salina and its mutualistic halophilic bacteria Nesterenkonia sp. were isolated from the inhabiting saline environment and co-cultivated to study their biological effects on carbonates precipitation and isotopic composition. During this process, electrochemical parameters and Ca2+ flux, and expression of genes related to CaCO3 formation were analyzed. Genome sequencing and metagenomic analysis were conducted to provide molecular evidence. Results: The results showed that natural saline sediments are enriched with CaCO3 and enrichment of genes related to photosynthesis and ureolysis. The co-cultivation stimulated 54.54% increase in CaCO3 precipitation and significantly promoted the absorption of external CO2 by 49.63%. A pH gradient was formed between the bacteria and algae culture, creating 150.22 mV of electronic potential, which might promote Ca2+ movement toward D. salina cells. Based on the results of lab-scale induction and 13C analysis, a theoretical calculation indicates a non-negligible amount of 0.16 and 2.3 Tg C/year carbon sequestration in China and global saline lakes, respectively. Conclusion: The combined effects of these two typical representative species have contributed to the carbon sequestration in saline environments, by promoting Ca2+ influx and increase of pH via microalgal and bacterial metabolic processes.

The continuous cooling expansion curve of 18CrNiMo7-6 wind power steel was tested by using a Gleeble-3800 thermal simulator at a cooling rate of 0. 1-30 ℃/s. The static continuous cooling transformation curve （CCT curve） of 18CrNiMo7-6 wind power steel was plotted by using metallographic hardness method. The microstructure transformation law of 18CrNiMo7-6 wind power steel under different cooling rate conditions was analyzed. The experimental results show that the Ac1 phase transition temperature of 18CrNiMo7-6 wind power steel is 765 ℃， and the Ac3 phase transition tempera ture is 843 ℃. When the cooling rate is less than 0. 5 ℃/s， the microstructure of the experimental steel is ferrite and pearlite， and high-temperature phase transformation occurs； At a cooling rate of 0. 5-1 ℃/s， ferrite disappears and plate-like martensite is initially formed； Starting from 2 ℃/s， the microstructure is mainly bainite and martensite， with both medium temperature and low temperature phase transformations occurring simultaneously； After 10 ℃/s， the bainite content de creases and the martensite content increases with the increase of cooling rate； When the cooling rate is greater than 20 ℃/s， the microstructure is entirely martensitic with only low-temperature phase transformation occurring； During the process of increasing the cooling rate from 0. 1 ℃/s to 30 ℃/s， the hardness of the wind power steel shows an upward trend.

Allergic diseases like asthma, allergic rhinitis and dermatitis pose a significant global health burden, driving the search for novel therapies. The NLRP3 inflammasome, a key component of the innate immune system, is implicated in various inflammatory diseases. Upon exposure to allergens, NLRP3 undergoes a two-step activation process (priming and assembly) to form active inflammasomes. These inflammasomes trigger caspase-1 activation, leading to the cleavage of pro-inflammatory cytokines (IL-1β and IL-18) and GSDMD. This process induces pyroptosis and amplifies inflammation. Recent studies in humans and mice strongly suggest a link between the NLRP3 inflammasome, IL-1β, and IL-18, and the development of allergic diseases. However, further research is needed to fully understand NLRP3’s specific mechanisms in allergies. This review aims to summarize the latest advances in NLRP3 activation and regulation. We will discuss small molecule drugs and natural products targeting NLRP3 as potential therapeutic strategies for allergic diseases.

Glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) are putative non-amyloid biomarkers indicative of ongoing inflammatory and neurodegenerative disease processes. Hence, this study aimed to demonstrate the relationship between plasma biomarkers (GFAP and NfL) and 18F-AV-1451 tau PET images, and to explore their effects on cognitive function. Ninety-one participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database and 20 participants from the Shanghai Action of Prevention Dementia for the Elderly (SHAPE) cohort underwent plasma biomarker testing, 18F-AV-1451 tau PET scans and cognitive function assessments. Within the ADNI, there were 42 cognitively normal (CN) individuals and 49 with mild cognitive impairment (MCI). Similarly, in the SHAPE, we had 10 CN and 10 MCI participants. We calculated the standardized uptake value ratios (SUVRs) for the regions of interest (ROIs) in the 18F-AV-1451 PET scans. Using plasma biomarkers and regional SUVRs, we trained machine learning models to differentiate between MCI and CN subjects with ADNI database and validated in SHAPE.Results showed that eight selected variables (including left amygdala SUVR, right amygdala SUVR, left entorhinal cortex SUVR, age, education, plasma NfL, plasma GFAP, plasma GFAP/ NfL) identified by LASSO could differentiate between the MCI and CN individuals, with AUC ranging from 0.783 to 0.926. Additionally, cognitive function was negatively associated with the plasma biomarkers and tau deposition in amygdala and left entorhinal cortex. Increased tau deposition in amygdala and left entorhinal cortex were related to increased plasma biomarkers. Moreover, tau pathology mediated the effect of plasma biomarkers level on the cognitive decline. The present study provides valuable insights into the association among plasma markers (GFAP and NfL), regional tau deposition and cognitive function. This study reports the mediation effect of brain regions tau deposition on the plasma biomarkers level and cognitive function, indicating the significance of tau pathology in the MCI patients.

Photovoltaic power generation and energy storage technology are current hotspots in the clean energy industry. As a core piece of equipment, an inverter is subjected to higher demands for its voltage regulation range and output performance. A differential boost inverter features a boosting function not found in traditional inverters, effectively widening the input voltage range, with characteristics of a single-stage structure and simple modulation. However, the differential boost inverter faces the issue of high common-mode voltage. Considering that the magnitude of the common-mode voltage changes with different modulation methods, a novel modulation strategy with a flexible common-mode voltage is proposed, which can effectively suppress the common-mode voltage under the same gain without affecting the output power quality. This article first introduces the topology, working principle, and traditional modulation methods of the differential boost inverter. Then, the new modulation strategy is defined, and the gain equation is derived. The new modulation method’s applicable scenarios are discussed and compared to other modulation methods based on the gain curve, concluding that the new method has advantages in terms of common-mode voltage amplitude and power quality under low boost gain. Finally, the effectiveness of the proposed method is verified through simulation and experiments.

The epithelial barrier serves as a critical defense mechanism separating the human body from the external environment, fulfilling both physical and immune functions. This barrier plays a pivotal role in shielding the body from environmental risk factors such as allergens, pathogens, and pollutants. However, since the 19th century, the escalating threats posed by environmental pollution, global warming, heightened usage of industrial chemical products, and alterations in biodiversity have contributed to a noteworthy surge in allergic disease incidences. Notably, allergic diseases frequently exhibit dysfunction in the epithelial barrier. The proposed epithelial barrier hypothesis introduces a novel avenue for the prevention and treatment of allergic diseases. Despite increased attention to the role of barrier dysfunction in allergic disease development, numerous questions persist regarding the mechanisms underlying the disruption of normal barrier function. Consequently, this review aims to provide a comprehensive overview of the epithelial barrier’s role in allergic diseases, encompassing influencing factors, assessment techniques, and repair methodologies. By doing so, it seeks to present innovative strategies for the prevention and treatment of allergic diseases.

The Junggar Basin is rich in oil and gas resources, with huge exploration potential, which is one of the main arenas of increasing oil and gas reserve and producing in China. In recent years, CNPC has made major breakthroughs in exploration in the Junggar Basin, revealing the orderly symbionic distribution pattern of conventional and conventional oil and gas. In order to further learn from the oil and gas achievements and exploration and development experience in neighboring areas and the new geological theories, for formulating SINOPEC's oil and gas exploration strategy in the Junggar Basin, the potential and distribution characteristics of the oil and gas resources in the Junggar Basin are systematically analyzed in this paper and it is pointed out that no enough attention is paid to natural gas and unconventional petroleum. The key breakthrough direction and exploration strategy of SINOPEC in the Junggar Basin are put forward in the paper after reviewing the major exploration breakthroughs in multiple fields, multiple strata, and multiple types in recent years and combining with the oil and gas geolo-gical conditions and exploration practice of SINOPEC's mining rights area. The research reveals that the Junggar Basin has entered a new period of exploration dominated by the middle and lower assemblage, and the exploration ideas must be adjusted accordingly. We must insist on the transformation from early outside-source exploration to intra-source and near-source exploration, and from early conventional petroleum exploration to both conventional and unconventional petroleum exploration. In order to make big exploration breakthrough of SINOPEC and realize the target of increasing reserves and production in the near and medium term in the Junggar Basin as soon as possible, four exploration strategies are proposed in the paper, including further figuring out the resources, establishing an integrated research team of conventional and unconventional petroleum, strengthening the joint research of geological and engineering integration, and increasing the support of risk exploration.

Abstract To understand the epidemiological and genetic characteristics of B19V, a multiple-province surveillance of patients with febrile rash illnesses (FRIs) were conducted in China during 2009 ~ 2021. The clinical specimens of 3,820 FRI patients were collected and tested for B19V DNA. A total of 99 (2.59%) patients were positive for B19V, and 49 (49.49%) were children under 5 years old. B19V infections occurred throughout the year without obvious seasonal pattern. Ten NS1-VP1u sequences and seven genome sequences were obtained in this study, identified as subgenotype 1a. Combined with the globally representative genome sequences, no temporal and geographic clustering trends of B19V were observed, and there was no significant correlation between B19V sequences and clinical manifestations. The evolutionary rate of the B19V genome was 2.30 × 10–4 substitutions/site/year. The number of negative selection sites was higher than that of positive selection sites. It was the first to comprehensively describe the prevalence patterns and evolutionary characteristics of B19V in FRI patients in China. B19V played the role in FRI patients. Children under 5 years old were the main population of B19V infection. Subgenotype 1a was prevalent in FRI patients in China. B19V showed a high mutation rate, while negative selection acted on the genome.

Abstract Background Obesity has been confirmed to be associated with infertility. However, the association between metabolically healthy obesity (MHO), a subset of obesity with no metabolic abnormalities, and female infertility has not yet been investigated. This study aimed to examine the association between MHO and the risk of female infertility among United States. Methods This study utilized a cross-sectional design and included 3542 women aged 20–45 years who were selected from the National Health and Nutrition Examination Survey (NHANES) 2013–2020 database. The association between MHO and the risk of infertility was evaluated using risk factor–adjusted logistic regression models. Results Higher BMI and WC were associated with increased infertility risk after adjusting for potential confounding factors (OR (95% CI): 1.04(1.02, 1.06), P = 0.001; OR (95% CI): 1.02 (1.01, 1.03), P

The lower play of the Junggar Basin has huge oil and gas potential, which is the most important strategic succession field for oil and gas exploration. Large-scale delta sand bodies are developed in Permian and Triassic in the four sags in the hinterland, in which new discoveries of oil and gas have been made in succession. In order to reveal the sedimentary characteristics, sedimentary model, and distribution patterns of sand bodies in the hinterland, the studies on basin prototype, sequence framework, paleogeomorphic restoration and sedimentary system were systematically carried out based on a large number of newly drilled cores, logging and geophysical data. The results show that: the development background of large depression lake basin can be identified in the development period of the Upper Permian-Lower Triassic shallow water braided river delta in the hinterland of the basin, and the study area has the characteristics of flat terrain, small slope, sufficient material supply, extremely shallow and frequently turbulent water bodies, alternating oxidation and reduction environments, and overall oxidation environment during the sedimentation period. The shallow braided river delta is characterized by coarse grain size, low impurity content, medium texture maturity, long distance transportation, strong hydrodynamic scouring, cross bedding and parallel bedding. The advantageous water system in the sedimentation period of the Upper Wuerhe and Baikouquan formations in the hinterland mainly comes from the northwest and northeast, and extends from north to south as a whole, with three provenance systems developed, namely Wuerhe provenance, Karamay provenance and Kelameily provenance. The terrain within the basin has obvious zoning characteristics, forming four facies belts namely fan delta area, braided river delta plain area, front area and lake area, thus forming a shallow water braided river delta sedimentary pattern of "large plain, small front" in the hinterland, where plain area and front area are favorable sand body development zones.

The lower play (Permian to Triassic) in the hinterland is the most important strategic succession field for oil and gas exploration in the Junggar Basin. Multiple wells have been drilled into high-quality clastic rock reservoirs below 6 000 m, greatly breaking through the deadline of buried depth of traditional clastic rock effective reservoirs. It has been made clear that the development status and pore evolution process are the key issues that determine whether oil and gas can be accumulated. Taking typical drilling wells in the hinterland as an example, this paper comprehensively analyzed the petrology, physical properties and pore structure characteristics of deep and ultra-deep clastic reservoirs in the hinterland of the Junggar Basin from a qualitative and quantitative perspective, and quantitatively restored the pore evolution process by integrating the microscopic analysis of rock thin sections, porosity and permeability tests, image analysis technology, quantitative characterization of porosity evolution, temperature measurement of inclusions, basin modeling and other methods. The results show that the clastic rock in the lower play of the hinterland is mainly developed in the Permian Upper Wuerhe Formation, Triassic Baikouquan Formation and Triassic Kelamayi Formation, of which the sand in the Triassic Baikouquan Formation is the most developed, followed by the Permian Upper Wuerhe Formation and Triassic Kalamayi Formation. There is little difference in rock types among different layers, which mainly composed of lithic sandstone with a small amount of feldspar lithic sandstone. The composition of rock debris is mainly medium-basic volcanic rock debris, with low content of feldspar and quartz, and the sum of them is generally less than 20%. The Kelamayi Formation is dominated by primary pores with the best reservoir property and the highest porosity of 13.18%. The Upper Wuerhe Formation and Baikouquan Formation are dominated by secondary corrosion pores, and the corrosion materials are mainly medium-basic volcanic debris, laumontite cement and a small amount of feldspar. The reservoir properties of them are not as good as those of the Kelamayi Formation. The pore evolution of the Kelamayi Formation has experienced weak compaction (21.08% pore reduction by compaction), weak cementation (2.88% pore reduction by cementation), and weak corrosion (1.4% pore increase by corrosion). Today's high porosity is mainly due to the large amount of preservation of primary pores under weak compaction and late weak cementation. The Baikouquan Formation and Upper Wuerhe Formation have undergone strong compaction (26.60% and 26.43% pore reduction by compaction, respectively), strong cementation (7.43% and 11% pore reduction by cementation, respectively), and strong corrosion (6.32% and 4.21% pore increase by corrosion, respectively). Secondary corrosion is the main way for them to increase porosity, but it is insufficient to compensate for the porosity reduction effect of strong compaction and cementation, resulting in lower porosity in the two formations.

The Shawan Sag is one of the important exploration areas in the hinterland of the Junggar Basin. In order to better clarify the source of crude oil from the Permian, Jurassic and Cretaceous reservoirs in the sag and identify hydrocarbon accumulation processes and enrichment pattern, the authors conducted a carbon isotope and biomarker analysis on the typical crude oil samples from the eastern Shawan Sag in this study, and further carried out crude oil classification and oil-source correlation based on the analysis of geochemical characteristics of crude oil. The results indicate that the crude oil from different strata in the eastern Shawan Sag can be divided into three types. The first type mainly occurs in the Permian and Jurassic reservoirs, and its whole oil δ13C value and Pr/Ph ratio range from -31.0‰ to -29.0‰ and from 1.0 to 2.0, respectively. The relative contents of αααR regular sterane display the characteristics of C27 < C28 < C29, and the terpanes are mainly characterized by C20 < C21>C23 TT and C24TeT/C26TT < 1, with the gammacerane index lower than 0.30. This type of crude oil is mainly derived from the source rocks in the Middle Permian Lower Wuerhe Formation. In the oil samples from the Upper Permian Upper Wuerhe Formation, Ts content is below the detection limit, the β-carotane/C30 hopane ratio is greater than 1, and the tricyclic terpane distribution displays the characteristics of C20>C21>C23TT. The distribution fraction of methyl phenanthrene reflects that the crude oil is in the stage of high-maturity evolution. All these indicate the mixing of crude oil generated in the Lower Permian source rocks. The second type occurs in the Middle Jurassic reservoirs. The whole oil δ13C value and individual n-alkanes δ13C value are higher than -29.0‰. The Pr/Ph ratio is relatively higher, ranging from 2.0 to 2.5, with C24TeT/C26TT>1, which indicate that this type of crude oil is mainly derived from the Jurassic source rocks. The third type occurs in the Lower Cretaceous reservoirs, and its whole oil δ13C value and Pr/Ph ratio are lower than -31.0‰ and 1.0, respectively. The αααR regular sterane contents display the characteristics of C27≈C28

Background & Aims: The steatotic grafts have been applied in liver transplantation frequently owing to the high incidence of non-alcoholic fatty liver disease. However, fatty livers are vulnerable to graft injury. Myeloid-derived suppressor cell (MDSC) recruitment during liver graft injury promotes tumour recurrence. Lipid metabolism exerts the immunological influence on MDSCs in tumour progression. Here, we aimed to explore the role and mechanism of inflammasome activation in MDSCs induced by lipid metabolism during fatty liver graft injury and the subsequent effects on tumour recurrence. Methods: MDSC populations and nucleotide-binding oligomerisation domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome levels were investigated in a clinical cohort and a rat liver transplantation model. The mechanism of NLRP3 activation by specific fatty acids was explored in mouse hepatic ischaemia/reperfusion injury (IRI) with tumour recurrence model and in vitro studies. Results: MDSC populations and NLRP3 levels were increased with higher tumour recurrent rate in patients using steatotic grafts. NLRP3 was upregulated in MDSCs with lipid accumulation post mouse fatty liver IRI. Mechanistically, arachidonic acid was discovered to activate NLRP3 inflammasome in MDSCs through fatty acid transport protein 2 (FATP2), which was identified by screening lipid uptake receptors. The mitochondrial dysfunction with enhanced reactive oxygen species bridged arachidonic acid uptake and NLRP3 activation in MDSCs, which subsequently stimulated CD4+ T cells producing more IL-17 in fatty liver IRI. Blockade of FATP2 inhibited NLRP3 activation in MDSCs, IL-17 production in CD4+ T cells, and the tumour recurrence post fatty liver IRI. Conclusions: During fatty liver graft injury, arachidonic acid activated NLRP3 inflammasome in MDSCs through FATP2, which subsequently stimulated CD4+ T cells producing IL-17 to promote tumour recurrence post transplantation. Impact and implications: The high incidence of non-alcoholic fatty liver disease resulted in the frequent application of steatotic donors in liver transplantation. Our data showed that the patients who underwent liver transplantation using fatty grafts experienced higher tumour recurrence. We found that arachidonic acid activated NLRP3 inflammasome in MDSCs through FATP2 during fatty liver graft injury, which led to more IL-17 secretion of CD4+ T cells and promoted tumour recurrence post transplantation. The inflammasome activation by aberrant fatty acid metabolism in MDSCs bridged the acute-phase fatty liver graft injury and liver tumour recurrence.

Vaccination with the primary two-dose series of SARS-CoV-2 mRNA protects against infection with the ancestral strain, and limits the presentation of severe disease after re-infection by multiple variants of concern (VOC), including Omicron, despite the lack of a strong neutralizing response to these variants. We compared antibody responses in serum samples collected from mRNA-1273 (Moderna) vaccinated subjects to identify mechanisms of immune escape and cross-protection. Using pseudovirus constructs containing domain-specific amino acid changes representative of Omicron BA.1, combined with domain competition and RBD-antibody depletion, we showed that RBD antibodies were primarily responsible for virus neutralization and variant escape. Antibodies to NTD played a less significant role in antibody neutralization but acted along with RBD to enhance neutralization. S2 of Omicron BA.1 had no impact on neutralization escape, suggesting it is a less critical domain for antibody neutralization; however, it was as capable as S1 at eliciting IgG3 responses and NK-cell mediated, antibody-dependent cell cytotoxicity (ADCC). Antibody neutralization and ADCC activities to RBD, NTD, and S1 were all prone to BA.1 escape. In contrast, ADCC activities to S2 resisted BA.1 escape. In conclusion, S2 antibodies showed potent ADCC function and resisted Omicron BA.1 escape, suggesting that S2 contributes to cross-protection against Omicron BA.1. In line with its conserved nature, S2 may hold promise as a vaccine target against future variants of SARS-CoV-2.

Abstract Targeted anticancer drugs block cancer cell growth by interfering with specific signaling pathways vital to carcinogenesis and tumor growth rather than harming all rapidly dividing cells as in cytotoxic chemotherapy. The Response Evaluation Criteria in Solid Tumor (RECIST) system has been used to assess tumor response to therapy via changes in the size of target lesions as measured by calipers, conventional anatomically based imaging modalities such as computed tomography (CT), and magnetic resonance imaging (MRI), and other imaging methods. However, RECIST is sometimes inaccurate in assessing the efficacy of targeted therapy drugs because of the poor correlation between tumor size and treatment-induced tumor necrosis or shrinkage. This approach might also result in delayed identification of response when the therapy does confer a reduction in tumor size. Innovative molecular imaging techniques have rapidly gained importance in the dawning era of targeted therapy as they can visualize, characterize, and quantify biological processes at the cellular, subcellular, or even molecular level rather than at the anatomical level. This review summarizes different targeted cell signaling pathways, various molecular imaging techniques, and developed probes. Moreover, the application of molecular imaging for evaluating treatment response and related clinical outcome is also systematically outlined. In the future, more attention should be paid to promoting the clinical translation of molecular imaging in evaluating the sensitivity to targeted therapy with biocompatible probes. In particular, multimodal imaging technologies incorporating advanced artificial intelligence should be developed to comprehensively and accurately assess cancer-targeted therapy, in addition to RECIST-based methods.

Abstract Background In seed plants, the ovule is the precursor to the seed. The process of ovule development and differentiation is regulated by multiple factors, including starch metabolism and endogenous hormones. Castanea henryi produces nuts with high nutritional value. However, the high proportion of empty buds restricts the commercial use of the tree. Previous studies have shown that the empty bud phenotype is closely related to ovule abortion. If none of the ovules in the ovary expand rapidly and develop in 7–8 weeks after pollination, an empty bud will form. Therefore, we studied the development and molecular mechanisms underlying single seed formation in C. henryi. Results We found that 49 days after pollination (DAP) is a critical period for the formation of fertile and abortive ovules. The morphology and starch distribution of the fertile and abortive ovules differed significantly at 49 DAP. The fertile ovules were smooth and round in appearance, with a large amount of starch. In contrast, abortive ovules were smaller with only a small amount of starch. The embryo sac of the abortive ovule proceeded to develop abnormally, and the entire ovule lacked starch. We identified 37 candidate genes involved in metabolism with potential roles in the regulation of starch levels. Three ADP-glucose pyrophosphorylase (AGPase) genes, one granule-bound starch synthase (GBSS) gene, and two beta-amylase genes could affect starch accumulation. The levels of auxin, cytokinins, gibberellins, and jasmonic acid in fertile ovules were higher than those in abortive ovules. In addition, the levels of endogenous abscisic acid and salicylic acid in abortive ovules were higher than those in fertile ovules of the same age, consistent with the expression patterns of genes related to the synthesis of abscisic and salicylic acid and signal transduction. We identified and mapped the differentially expressed genes associated with hormone synthesis and signal transduction. Conclusions These results improve our general understanding of the molecular mechanisms underlying single seed development in C. henryi and the phenomenon of empty buds, providing directions for future research.

A bandwidth-tunable multiband microwave photonic filter (MPF) using a strongly coupled microring resonator (MRR) with optical phase modulation is demonstrated theoretically and experimentally. Two notches of the MRR adjacent to the optical carrier break the intrinsic balance of the phase-modulated signal and then two sub-MPFs are formed thanks to the conversion from phase modulation to intensity modulation (PM-IM). The frequency responses of the two sub-MPFs are superimposed to form a passband with a fixed center frequency. Due to the periodicity of the MRR transmission spectrum, multiple passbands separated by a certain spacing appear in the frequency domain and combine to form a multiband MPF, whose bandwidth can be adjusted by tuning the wavelength of the carrier. The tunable bandwidth and shape factors ranging from 0.73 GHz to 2.73 GHz and 5.06 to 1.38 are experimentally performed. The number of passbands can be reconfigured. The proposed multiband MPF has the potential to be employed in modern multi-standard wireless communication systems.

Optical beamforming in microwave photonics is promising for supporting broadband wireless communications. However, the current optical beamforming lacks freedom because of the fixed connection between radio frequency (RF) signal and antenna elements (AEs). This manuscript tackles this challenge by proposing a dynamical optical beamforming architecture that reconfigures the antenna subarray for signal transmission depending on the number of signals to be transmitted. The proposed architecture employs an optical switching and distributing network (SDN) to realize a flexible connection between signals and AEs. An instance of the proposed architecture in photonic integrated circuits, which enables three working modes and transmits four RF signals through sixteen AEs, was presented and numerically simulated. The optical field distribution and beam pattern plots illustrated the operational principle and validated the feasibility of the proposed SDN architecture. Furthermore, the impact of the introduced architecture on the signal amplitude–phase consistency and the comparison of the proposed dynamic architecture and conventional fixe architectures are analyzed and discussed. The results indicate that the proposed architecture exhibits variable beamforming gain with lower hardware complexity.

Castanea henryi is a monoecious woody food tree species whose yield and industrialization potential are limited by its low female-to-male flower ratio. Here, the male flowers on the male inflorescence of C. henryi were converted to female flowers by triple applications of exogenous cytokinin (CK) (N-(2-chloro-4-pyridyl)-N’-phenylurea, CPPU). To study the role of exogenous CK in flower sex determination, cytological and transcriptomic analyses were performed on samples from the five stages after CK treatment. Cytological analysis showed that stage 3 (nine days after the last CK treatment) was the critical stage in the differential development of the pistil primordium and stamen primordium. On this basis, one key module and two modules with significant positive correlations with stage 3 were identified by weighted gene co-expression network analysis (WGCNA), combined with transcriptome data. The CK and GA biosynthesis- and signaling-related genes, three transcription factor (TF) families, and 11 floral organ identity genes were identified in the related modules. In particular, the TFs WRKY47, ERF021, and MYB4, and floral organ identity genes AGL11/15, DEF, and SEP1 with large differences are considered to be critical regulators of sex determination in C. henryi. Based on these results, a genetic regulatory network for exogenous CK in the sex determination of flowers in C. henryi is proposed. This study contributes to the understanding of the role of CK in the sex regulation of flowers and provides new insights into the regulatory network of sex determination in C. henryi.

Summary: Background: Mental symptoms have been shown to be associated with dementia. As the most common neuropsychiatric disorder, it is unclear whether and why anxiety increases the risk of cognitive progression in elderly. Methods: The aim of this study was to investigate the longitudinal effects of anxiety on cognitive impairment in non-dementia elderly and to explore the underlying biological processes using multi-omics including microarray-based transcriptomics, mass spectrometry-based proteomics and metabolomics, cerebrospinal fluid (CSF) biochemical markers, and brain diffusion tensor imaging (DTI). The Alzheimer's Disease Neuroimaging Initiative (ADNI), Chinese Longitudinal Healthy Longevity Survey (CLHLS) and Shanghai Mental Health Centre (SMHC) cohorts were included. Findings: Anxiety was found to increase the risk of subsequent cognitive progression in the ADNI, and a similar result was observed in the CLHLS cohort. Enrichment analysis indicated activated axon/synapse pathways and suppressed mitochondrial pathways in anxiety, the former confirmed by deviations in frontolimbic tract morphology and altered levels of axon/synapse markers, and the latter supported by decreased levels of carnitine metabolites. Mediation analysis revealed that anxiety's effect on the longitudinal cognition was mediated by brain tau burden. Correlations of mitochondria-related expressed genes with axon/synapse proteins, carnitine metabolites, and cognitive changes were found. Interpretation: This study provides cross-validated epidemiological and biological evidence that anxiety is a risk factor for cognitive progression in non-dementia elderly, and that axon/synapse damage in the context of energy metabolism imbalance may contribute to this phenomenon. Funding: The National Natural Science Foundation of China (82271607, 81971682, and 81830059) for data analysis and data collection.

Hand, foot and mouth disease, caused by enterovirus A71 (EV-A71) infection, is common in children in China. Here, the authors estimate EV-A71 incidence and seroprevalence using data from two longitudinal cohorts and find that, despite high infection rates, a large proportion of children under 6 are susceptible.

Abstract Background A major hand-foot-and-mouth disease (HFMD) pathogen, coxsackievirus A16 (CVA16), has predominated in several of the last 10 years and caused the largest number of HFMD outbreaks between 2011 and 2018 in China. We evaluated the efficacy of maternal anti-CVA16 antibody transfer via the placenta and explored the dynamics of maternal and natural infection-induced neutralizing antibodies in children. Methods Two population-based longitudinal cohorts in southern China were studied during 2013–2018. Participants were enrolled in autumn 2013, including 2475 children aged 1–9 years old and 1066 mother-neonate pairs, and followed for 3 years. Blood/cord samples were collected for CVA16-neutralizing antibody detection. The maternal antibody transfer efficacy, age-specific seroprevalence, geometric mean titre (GMT) and immune response kinetics were estimated. Results The average maternal antibody transfer ratio was 0.88 (95% CI 0.80–0.96). Transferred maternal antibody levels declined rapidly (half-life: 2.0 months, 95% CI 1.9–2.2 months). The GMT decayed below the positive threshold (8) by 1.5 months of age. Due to natural infections, it increased above 8 after 1.4 years and reached 32 by 5 years of age, thereafter dropping slightly. Although the average duration of maternal antibody-mediated protection was < 3 months, the duration extended to 6 months on average for mothers with titres ≥ 64. Conclusions Anti-CVA16 maternal antibodies are efficiently transferred to neonates, but their levels decline quickly. Children aged 0–5 years are the main susceptible population and should be protected by CVA16 vaccination, with the optimal vaccination time between 1.5 months and 1 year of age.

The receptor-binding domain (RBD) of the SARS-CoV-2 spike is a primary target of neutralizing antibodies and a key component of licensed vaccines. Substantial mutations in RBD, however, enable current variants to escape immunogenicity generated by vaccination with the ancestral (WA1) strain. Here, we produce and assess self-assembling nanoparticles displaying RBDs from WA1 and BA.5 strains by using the SpyTag:SpyCatcher system for coupling. We observed both WA1- and BA.5-RBD nanoparticles to degrade substantially after a few days at 37 °C. Incorporation of nine RBD-stabilizing mutations, however, increased yield ~five-fold and stability such that more than 50% of either the WA1- or BA.5-RBD nanoparticle was retained after one week at 37 °C. Murine immunizations revealed that the stabilized RBD-nanoparticles induced ~100-fold higher autologous neutralization titers than the prefusion-stabilized (S2P) spike at a 2 μg dose. Even at a 25-fold lower dose where S2P-induced neutralization titers were below the detection limit, the stabilized BA.5-RBD nanoparticle induced homologous titers of 12,795 ID50 and heterologous titers against WA1 of 1767 ID50. Assessment against a panel of β-coronavirus variants revealed both the stabilized BA.5-RBD nanoparticle and the stabilized WA1-BA.5-(mosaic)-RBD nanoparticle to elicit much higher neutralization breadth than the stabilized WA1-RBD nanoparticle. The extraordinary titer and high neutralization breadth elicited by stabilized RBD nanoparticles from strain BA.5 make them strong candidates for next-generation COVID-19 vaccines.

Membrane fouling is a key factor limiting the application of a membrane bioreactor (MBR), and membrane-surface modification holds the potential to control membrane fouling and solves this problem. In the research, novel nanocomposite membranes were designed and fabricated using antimicrobial copper nanoparticles (CuNPs) coupled with powdered active carbon (PAC) to mitigate membrane fouling. The successful coating was confirmed by SEM, XRD, and FTIR analysis. Compared with a pristine membrane, the functionalization of CuNPs and PAC improved the hydrophilicity of the modified membrane but led to a lower permeate flux. The result of antimicrobial adhesion experiments showed that the modified M-CuOC displayed high antibacterial activity with the bacteria count decreased by 72%. In MBR operation, the modified M-CuOC leads to the removal efficiency of chemical oxygen demand (COD) increasing to 93%, with better filtration performance under a lower TMP rise. The fouling-resistance analysis demonstrated that, although the intrinsic membrane resistance of modified M-CuOC slightly increased, the reversible and irreversible fouling resistances obviously decreased by 45% and 90%. Moreover, the membrane flux recovery efficiency of the modified M-CuOC also increased by 35%. Overall, these results indicated that, in addition to an improvement in antifouling performance, the functionalization of CuNPs and PAC also enhanced the membrane flux recovery efficiency, revealing a good antifouling potential in a practical application.

IntroductionPrevious literatures have mainly explored the impact of the experience of power on impulsive buying, but have ignored the impacts of the expectations of power. The purpose of this research is to delineates a two-facet portrait of power in the role of affecting purchase impulsiveness by proposing a theoretical extension from the experience of power to the expectations of power.MethodsFour laboratory experiments were developed that used ANOVA to verify the hypothesis. A moderated mediation path model was established including the experience of power, product attribute, the expectations of power, deservingness, and purchasing impulsiveness as observed variables.ResultsThe results revealed that powerless consumers are more likely to impulsively buy hedonic products; while powerful consumers prefer to impulsively buy utilitarian products. However, when focusing on the expectations of power, powerless consumers feel a lower perception of deservingness, which reduces their impulse to buy hedonic products. In contrast, when powerful consumers imagine how powerful people should behave in consumption, they will experience a higher sense of deservingness and increase purchasing impulsiveness for hedonic products. The underlying mechanism is that deservingness plays a mediation role in the three-way interaction impacts of the experience of power, product attribute, and the expectations of power on purchasing impulsiveness.ConclusionThe current research formulates a new theoretical perspective on the relationship between power and purchasing impulsiveness. An experience-expectation model of power is presented that proposes consumers’ purchasing impulsiveness can be affected both by the experience of power and the expectations of power.

Alzheimer’s disease (AD) is the most common form of dementia and a significant social and economic burden. Estrogens can exert neuroprotective effects and may contribute to the prevention, attenuation, or even delay in the onset of AD; however, long-term estrogen therapy is associated with harmful side effects. Thus, estrogen alternatives are of interest for countering AD. Naringin, a phytoestrogen, is a key active ingredient in the traditional Chinese medicine Drynaria. Naringin is known to protect against nerve injury induced by amyloid beta-protein (Aβ) 25–35, but the underlying mechanisms of this protection are unclear. To investigate the mechanisms of naringin neuroprotection, we observed the protective effect on Aβ25–35-injured C57BL/6J mice’s learning and memory ability and hippocampal neurons. Then, an Aβ25–35 injury model was established with adrenal phaeochromocytoma (PC12) cells. We examined the effect of naringin treatment on Aβ25–35-injured PC12 cells and its relationship with estrogen receptor (ER), phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT), and glycogen synthase kinase (GSK)-3β signaling pathways. Estradiol (E2) was used as a positive control for neuroprotection. Naringin treatment resulted in improved learning and memory ability, the morphology of hippocampal neurons, increased cell viability, and reduced apoptosis. We next examined the expression of ERβ, p-AKT (Ser473, Thr308), AKT, p-GSK-3β (Ser9), GSK-3β, p-Tau (Thr231, Ser396), and Tau in PC12 cells treated with Aβ25–35 and either naringin or E2, with and without inhibitors of the ER, PI3K/AKT, and GSK-3β pathways. Our results demonstrated that naringin inhibits Aβ25–35-induced Tau hyperphosphorylation by modulating the ER, PI3K/AKT, and GSK-3β signaling pathways. Furthermore, the neuroprotective effects of naringin were comparable to those of E2 in all treatment groups. Thus, our results have furthered our understanding of naringin’s neuroprotective mechanisms and indicate that naringin may comprise a viable alternative to estrogen therapy.