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ABSTRACT: Accurate genomic predictions of breeding values for traits included in the selection indexes are paramount for optimizing genetic progress in populations under selection. The size of the reference populations is a major factor influencing the accuracy of genomic predictions, which is even more important for lowly heritable traits, such as fertility and reproduction indicators. Combining data from different geographical regions or countries can be beneficial for genomic prediction of these lowly heritable traits. Therefore, the objectives of this study were to (1) evaluate the benefits of performing across-regional genomic evaluations for reproduction traits in Chinese Holstein cattle and (2) assess the feasibility of validating genomic predictions across environments based on reaction norm models (RNM) and the linear regression (LR) method after accounting for genotype-by-environment interactions. Phenotypic records from 194,574 cows collected across 47 farms located in 2 regions of China were used for this study. The reference and validation populations were defined based on birth year for applying the LR validation method. The traits evaluated included: interval from first to last insemination (IFL), conception rate at the first insemination (CR_f), and number of inseminations (NS) recorded in heifers and first-parity cows. The results indicated that combining data from different regions resulted in greater genomic prediction accuracies compared with using data from single regions, with increases ranging from 2.74% to 93.81%. This improvement was particularly notable for the region with the least amount of available data, where the increases ranged from 26.49% to 93.81%. Furthermore, the predictive abilities could be validated for all studied traits based on the LR method across different environments when fitting RNM. The prediction accuracies and bias of genomic breeding values based on RNM were better than regular single-trait animal models in extreme climatic conditions for IFL and NS, whereas limited increases in predictive abilities were observed for CR_f. Across-regional genomic prediction by RNM can account for genotype-by-environment interactions, potentially increase the accuracy of genomic prediction, and predict the performances of individuals in the environments with limited phenotypic data available.

Abstract Acute rejection (AR) is a significant complication in liver transplantation, impacting graft function and patient survival. Kupffer cells (KCs), liver-specific macrophages, can polarize into pro-inflammatory M1 or anti-inflammatory M2 phenotypes, both of which critically influence AR outcomes. Angiopoietin-like 4 (ANGPTL4), a secretory protein, is recognized for its function in regulating inflammation and macrophage polarization. This study investigates the effects of ANGPTL4 on KC polarization through cellular interactions between hepatocytes (HCs) and KCs. Using a rat orthotopic liver transplantation model, we observed reduced ANGPTL4 expression during AR, whereas increased ANGPTL4 levels were linked to immune tolerance. Administration of ANGPTL4 recombinant protein improved liver function, suppressed inflammation, and promoted M2 polarization of KCs. Co-culture experiments demonstrated that hepatocyte-derived ANGPTL4 significantly modulates KC polarization and inflammatory responses, mainly by inhibiting the NF-κB signaling pathway. The results emphasize the promise of ANGPTL4 as a therapeutic target to reduce AR and improve liver transplant outcomes by influencing hepatocyte-KC interactions.

Guvermectin, a purine nucleoside natural product produced by the genus Streptomyces, has recently been registered as a new biopesticide to boost rice yield. Despite its economic and agricultural significance, the regulatory mechanisms of guvermectin biosynthesis remain essentially unknown, hindering industrial production and widespread agricultural application. Here, we examined the roles of two LacI family regulators, gvmR and gvmR2, located within and adjacent to the guvermectin biosynthesis cluster, respectively, in guvermectin production in Streptomyces caniferus NEAU6. GvmR activated the expression of the guvermectin cluster by binding to the promoters of gvmR, gvmA, and O1, while GvmR2 repressed the guvermectin cluster via competitive binding to promoters containing GvmR-binding sites, specifically, a 14-bp palindromic sequences: 5′-RTCATWCGYATGAY-3′ (R = G/A, W = A/T, Y = T/C). Moreover, GvmR indirectly activates the expression of gvmR2 while GvmR2 feedback inhibits gvmR transcription, suggesting a functional interaction between the two regulators for coordinating guvermectin production. Overexpression of gvmR via the T7 RNA polymerase-T7 promoter system in the gvmR2 mutant significantly elevated guvermectin production by 125 % (from 631 mg L−1 to 1422 mg L−1), compared to the parental strain NEAU6. This suggested that combinatorial manipulation of gvmR and gvmR2 is useful for improving guvermectin production. These findings enrich our knowledge of the regulatory network for guvermectin biosynthesis, and offer key targets and effective strategies for high-titer guvermectin production.

Abstract Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a liver disease that is strongly associated with chronic low-grade inflammation. Stage 3 of MASLD is characterized by excessive formation of connective tissues, commonly referred to as liver fibrosis. Although numerous inflammatory markers have been identified and extensively studied, including the tumor necrosis factor-α and interleukin-6 have been studied [Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol. 2015;62(1 Suppl):S47–64], the lymphocyte-to-high-density lipoprotein ratio (LHR) as a new biomarker that has not been sufficiently studied. This study aims to investigate the relationship between LHR levels and MASLD, determine its potential as a predictive marker for steatosis and fibrosis stages. Methods This was a population-based study using data from 15,560 participants in the 2017–2020 National Health and Nutrition Examination Survey (NHANES) database. The study aimed to explore the relationship between LHR and MASLD. The disease progression was tracked by continuously measuring CAP and liver stiffness measurements. Participants who exhibited a median Controlled Attenuation Parameter (CAP) of 248 dB/m or higher were deemed to have hepatic steatosis. The LHR was calculated by dividing the lymphocyte count by the high-density lipoprotein cholesterol (HDL-C) level. Multivariate linear regression models were employed to explore the linear association between LHR and MASLD. Fitted smoothing curves and threshold effect analysis were employed to display nonlinear relationships. A two-part linear regression model was employed to estimate threshold effects. Subgroup analyses were conducted to determine the consistency of this association across various demographic groups. Results A total of 6,950 adults aged 18 years and older were enrolled in the study, with an average age of 48.15 ± 17.10 years (49.14% male, 50.86% female). The adjusted multiple logistic regression analysis revealed a significant positive correlation between LHR and MASLD (OR: 1.64, 95% CI: 1.40–1.92). Using the complex two-piece linear regression model, we observed an inverted L-shaped association between LHR and CAP, suggesting a critical inflection point at -2.58. Subgroup analyses indicated a pronounced association of the LHR index with obese individuals (OR: 1.96, 95% CI: 1.66–2.32) and females (OR: 1.76, 95% CI: 1.25–2.46). There was no significant association between LHR and clinically significant fibrosis. Conclusion The LHR index is positively correlated with MASLD among US adults. Therefore, LHR may be a robust marker for early screening, diagnosis, and monitoring of treatment efficacy in clinical practice.

Abstract By targeting the essential viral RNA-dependent RNA polymerase (RdRP), nucleoside analogs (NAs) have exhibited great potential in antiviral therapy for RNA virus-related diseases. However, most ribose-modified NAs do not present broad-spectrum features, likely due to differences in ribose-RdRP interactions across virus families. Here, we show that HNC-1664, an adenosine analog with modifications both in ribose and base, has broad-spectrum antiviral activity against positive-strand coronaviruses and negative-strand arenaviruses. Importantly, treatment with HNC-1664 demonstrate anti-SARS-CoV-2 efficacy in infected K18-human ACE2 mice, with reduced viral titer and mortality, as well as improved lung injury. Enzymology data demonstrate that HNC-1664 inhibits RNA synthesis mainly at the pre-catalysis stage. The cryo-EM structures of HNC-1664-bound RdRP-RNA complexes from both SARS-CoV-2 and LASV reveal an unusual base pairing mode of HNC-1664 in part due to its base modification, thus revealing its great potency in binding but not catalysis. Under certain circumstances, 1664-TP can be slowly incorporated by RdRP through regular Watson-Crick base pairing, as evidenced by enzymology data and an HNC-1664-incorporated crystal structure of the RdRP-RNA complex. Overall, HNC-1664 achieves broad-spectrum characteristics by favoring an alternative base pairing strategy to non-catalytically block RNA synthesis, providing a novel concept for the rational development of NA drugs.

A Mg-19Gd binary alloy with exceptionally good synergy of strength and ductility has been fabricated by conventional hot extrusion and aging. The aged alloy with a specific bimodal-grained structure achieves a yield strength of 482 MPa and an ultimate tensile strength of 535 MPa with a good elongation of 5%. The high strength arises from the high number density of β′ precipitates and a strong texture, while the good ductility is related to the excellent deformation ability of fine dynamic recrystallized grains and the compatible ability of slips within elongated grains, activated by the high density of I1 stacking faults inside.

Sleep disorders can lead to various diseases, so good sleep plays an important role in maintaining the physiological and psychological health of all living organisms. Compared with traditional medicines, dietary intake has a higher safety factor in improving sleep and does not cause drug dependence in people. This article first summarizes the functional factors related to regulating sleep from three aspects: excitatory and inhibitory neurotransmitters, immune cytokines, and gut microbiota. Secondly, the mechanisms of action of different sleep regulating factors are reviewed. Finally, the dietary sources of different sleep regulating factors are summarized, in order to provide theoretical support for the industrialization and commercialization of functional foods for improving sleep in the future.

Abstract Background Cardiovascular disease (CVD) has become the leading cause of competitive mortality in female breast cancer (BC). Regular aerobic exercise (AE) has been widely accepted as an effective intervention to reduce cardiovascular risk in a variety of different clinical conditions. This study is aimed at evaluating the efficacy and safety of AE on cardiovascular risk factors in female BC and assessing the quality of the synthesized evidence. Methods We searched five English databases (Cochrane Library, PubMed, Embase, Scopus, and Web of Science) from inception to January 2023. Randomized controlled trials (RCTs) and cohort trials studying the effects of AE intervention on cardiovascular disease risk in female breast cancer were included. We used Stata 16 for data synthesis, Risk of Bias 2, and the Newcastle–Ottawa Scale for methodological quality evaluation and assessed the certainty of the synthesized evidence in the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Results Forty RCTs and 6 cohort trials involving 44,877 BC patients showed AE reduced the incidence of CVD events by 29.4% [risk ratio (RR) = 0.706, 95% confidence interval (CI) (0.659, 0.757), low certainty] and coronary artery disease events by 36% [RR = 0.640, 95% CI (0.561, 0.729), low certainty]. AE improved LVEF, and reduced weight and hip circumference. The subgroup analysis results showed that nonlinear AE increased VO2max by 5.354 ml·kg·min−1 [mean difference (MD) = 5.354, 95% CI (2.645, 8.062), very low certainty] and reduced fat mass by 4.256 kg [MD = 4.256, 95% CI (-3.839, -0.094), very low certainty]. While linear AE reduced low-density lipoprotein cholesterol (LDL-C) by 8.534 mg/dL [MD = -8.534, 95% CI (-15.511, -1.557), low certainty]. The sensitivity analysis results showed that each trial did not affect the impact index of the highly heterogeneous outcomes. Conclusions Our study indicates that AE has a positive effect in reducing cardiovascular risk factors. The individualization principle of AE deserves more attention in the future. This will provide new ideas to reduce CVD events and improve the quality of life in female BC patients. However, further research on AE in female BC should take into account long-term and well-designed administration to draw definitive conclusions.

Abstract Degradation is the most immediate threat to biodiversity and sustainable livelihoods of global pastoral grasslands. However, we are still uncertain why grassland degradation is enhanced by the land policy of grassland parcellation. We hypothesized that spatial redundancy of the grazing system, that is, parcellation accelerates land fragmentation and reduces spatial redundancy, leads to land degradation. This study aimed to clarify the relationship between households, livestock and grassland management under the grassland contract policy, and to determine the causes and consequences of grassland fragmentation and degradation. We interviewed households who received land under the grassland contract policy in typical pastoral areas of the Qinghai–Tibetan Plateau, and then, we employed binary logistic regressions, multinomial logistic regressions and fuzzy‐set qualitative comparative analyses to examine the relationship between spatial redundancy and grassland–livestock balance. A very significant (p

In this work, we compared the effects of bimodal microstructure and heterogeneous microstructure on the mechanical properties and strengthening mechanisms of ZK60 alloy. The bimodal microstructure is composed of coarse un-dynamically recrystallized (un-DRXed) grains with strong basal texture and fine dynamically recrystallized (DRXed) grains with weak texture, while the heterogeneous microstructure is composed of coarse DRXed grains and fine DRXed grains. The result suggests that high-density dislocations and high-density precipitates have significant contribution to the strength. The high-density dislocations in un-DRXed grains cause the formation of an uneven distribution of precipitates in the ZK60 alloy which results in the high yield strength of 305 MPa, ultimate tensile strength of 344 MPa and elongation of 12% in the bimodal-structured ZK60 alloy. In comparison, the heterogeneous-structured ZK60 alloy lacks the strengthening effect from high-density dislocations and precipitates, and a lower YS of 226 MPa, and UTS of 305 MPa are achieved. The result also indicates the weak texture, low density of dislocations, low density of precipitates, and stronger ability of storing dislocations in coarse grains for heterogeneous microstructure are helpful to the ductility. Thus, HE sample exhibits higher elongation of 23% than BI sample. The finding shed light on the microstructure designing of high-performance Mg alloys.

Abstract There is a growing interest in the health impacts of PM2.5 originating from landscape fires. We conducted a time-series study to investigate the association between daily exposure to landscape fire PM2.5 and hospital admissions for cardiovascular events in 184 major Chinese cities. We developed a machine learning model combining outputs from chemical transport models, meteorological information and observed air pollution data to determine daily concentrations of landscape fire PM2.5. Furthermore, we fitted quasi-Poisson regression to evaluate the link between landscape fire PM2.5 concentrations and cardiovascular hospitalizations in each city, and conducted random-effects meta-analysis to pool the city-specific estimates. Here we show that, on a national scale, a rise of 1-μg/m3 in landscape fire PM2.5 concentrations is positively related to a same-day 0.16% (95% confidence interval: 0.01%–0.32%) increase in hospital admissions for cardiovascular disease, 0.28% (0.12%–0.44%) for ischemic heart disease, and 0.25% (0.02%–0.47%) for ischemic stroke. The associations remain significant even after adjusting for other sources of PM2.5. Our findings indicate that transient elevation in landscape fire PM2.5 levels may increase risk of cardiovascular diseases.

Abstract Floods are widespread and dangerous natural hazards worldwide. It is essential to grasp the causes of floods to mitigate their severe effects on people and society. The key drivers of flood susceptibility in rapidly urbanizing areas can vary depending on the specific context and require further investigation. This research developed an index system comprising 10 indicators associated with factors and environments that lead to disasters, and used machine learning methods to assess flood susceptibility. The core urban area of the Yangtze River Delta served as a case study. Four scenarios depicting separate and combined effects of climate change and human activity were evaluated using data from various periods, to measure the spatial variability in flood susceptibility. The findings demonstrate that the extreme gradient boosting model outperformed the decision tree, support vector machine, and stacked models in evaluating flood susceptibility. Both climate change and human activity were found to act as catalysts for flooding in the region. Areas with increasing susceptibility were mainly distributed to the northwest and southeast of Taihu Lake. Areas with increased flood susceptibility caused by climate change were significantly larger than those caused by human activity, indicating that climate change was the dominant factor influencing flood susceptibility in the region. By comparing the relationship between the indicators and flood susceptibility, the rising intensity and frequency of extreme precipitation as well as an increase in impervious surface areas were identified as important reasons of heightened flood susceptibility in the Yangtze River Delta region. This study emphasized the significance of formulating adaptive strategies to enhance flood control capabilities to cope with the changing environment.

Abstract Cellular communication network factor 2 (CCN2) is a secreted extracellular matrix-associated protein, and its aberrantly increased expression has been implicated in a diversity of diseases involving pathological processes of fibrosis, chronic inflammation, or tissue injury, which has promoted the evaluation of CCN2 as therapeutic targets for multiple disorders. However, human phenotypes associated with CCN2 deficiency have remained enigmatic; variants in CCN2 have not yet been associated with a human phenotype. Here, we collected families diagnosed with spondyloepimetaphyseal dysplasia (SEMD), and screened candidate pathogenic genes for families without known genetic causes using next-generation sequencing. We identified a monoallelic variant in signal peptide of CCN2 (NM_001901.2: c.65 G > C [p.Arg22Pro]) as the cause of SEMD in 14 subjects presenting with different degree of short stature, premature osteoarthritis, and osteoporosis. Affected subjects showed decreased serum CCN2 levels. Cell lines harboring the variant displayed decreased amount of CCN2 proteins in culture medium and an increased intracellular retention, indicating impaired protein secretion. And the variant weakened the stimulation effect of CCN2 on osteogenesis of bone marrow mesenchymal stem cells. Zebrafish ccn2a knockout model and osteoblast lineage-specific Ccn2-deficient mice (Ccn2 fl/fl ;Prx1 Cre ) partially recapitulated the phenotypes including low bone mass observed in affected subjects. Pathological mechanism implicated in the skeletal abnormality in Ccn2 fl/fl ;Prx1 Cre mice involved decreased bone formation, increased bone resorption, and abnormal growth plate formation. Collectively, our study indicate that monoallelic variants in CCN2 lead to a human inherited skeletal dysplasia, and highlight the critical role of CCN2 in osteogenesis in human.

Abstract Background The integration of high-risk human papilloma virus (HPV) DNA into the human genome has been implicated in cervical carcinogenesis and head and neck squamous cell cancer. However, its role in lung squamous cell carcinoma is not well understood. In addition, tuberculosis (TB) and lung cancer(LC) share similar clinical symptoms and imaging features, increasing the risk of misdiagnosis. Case Presentation The patient presented with a 16-month history of hemoptysis, chest pain, and occasional fatigue, without fever, chills, or history of mechanical damage or autoimmune diseases. Examination revealed normal vital signs and laboratory parameters, except for a positive interferon-gamma release assay indicating tuberculosis infection. Bronchoscopic examinations identified congestion and edema of the tracheal wall, along with a tiny lesion in the right wall of the trachea. She had been misdiagnosed with tuberculosis. However, the diagnosis of squamous cell carcinoma was eventually confirmed by endoscopic biopsy. The patient’s macrogenomic second-generation sequencing (mNGS) of the bronchoscopic biopsy specimen was positive for HPV-16.The patient’s sex partner tested positive for HPV-16 in penile scrapings, indicating HPV transmission through oral sex. Conclusions This case highlights the potential for HPV infection acquired through oral sex to lead to lung squamous cell carcinoma. It emphasizes the importance of considering HPV-associated malignancies in patients with respiratory symptoms who engage in oral sexual behaviors.

Abstract Background This study was to analyze the roles of red blood cell distribution width (RDW), anion gap (AG) levels and their combined effects on the risk of acute kidney injury (AKI) following cardiac surgery. Methods This cohort study extracted the data of 1951 participants aged ≥ 18 years with the assessment of AKI after cardiac surgery during ICU stay from MIMIC-IV database between 2008 and 2019. Receiver operator characteristic (ROC) curve was used to determine the optimal cut-off value AG and RDW. The associations between AG, RDW, and the combined effects of AG and effects were evaluated via univariable and multivariable Logistic models. Odds ratio (OR) with 95% confidence interval (CI) were imputed. Results Among all the participants, 831 participants had AKI, and 1120 did not have AKI. ROC curves revealed that the optimum cut of points of AG and RDW were 12.75 mmol/L, and 13.65%, respectively. Increased risk of AKI was found in patients after cardiac surgery with AG > 12.75 mmol/L (OR = 1.44, 95%CI 1.15–1.80) or RDW > 13.65% group (OR = 1.23, 95%CI 1.01–1.50). In comparison to subjects with AG ≤ 12.75 mmol/L and RDW ≤ 13.65%, AG > 12.75 mmol/L and RDW ≤ 13.65% (OR = 1.42, 95%CI 1.07–1.89), and AG > 12.75 mmol/L and RDW > 13.65% (OR = 1.75, 95%CI 1.24–2.47) were associated with increased odds of AKI in patients after cardiac surgery. Conclusions AG and RDW had combined effects on risk of AKI in patients after cardiac surgery, which might offer an insight for the management of patients after cardiac surgery.

Abstract The clustering algorithm is an effective method for developing energy efficiency routing protocol for wireless sensor networks (WSNs). In clustered WSNs, cluster heads must handle high traffic, thus consuming more energy. Therefore, forming balanced clusters and selecting optimal cluster heads are significant challenges. The paper proposes a sector clustering algorithm based on K-means called KMSC. KMSC improves efficiency and balances the cluster size by employing symmetric dividing sectors in conjunction with K-means. For the selection of cluster heads (CHs), KMSC uses the residual energy and distance to calculate the weight of the node, then selects the node with the highest weight as CH. A hybrid single-hop and multi-hop communication is utilized to reduce long-distance transmissions. Furthermore, the impact of the number of sectors, the threshold for clustering, and the network size on the performance of KMSC has been explored. The simulation results show that KMSC outperforms EECPK-means, K-means, TSC, LSC, and SEECP in terms of FND, HND, and LND.

Abstract Background Macrophage-based cell therapy is promising in solid tumors, but the efficient acquisition of macrophages remains a challenge. Induced pluripotent stem cell (iPSC)-induced macrophages are a valuable source, but time-consuming and costly. The application of reprogramming technologies allows for the generation of macrophages from somatic cells, thereby facilitating the advancement of cell-based therapies for numerous malignant diseases. Methods The composition of CD45+ myeloid-like cell complex (MCC) and induced macrophage (iMac) were analyzed by flow cytometry and single-cell RNA sequencing. The engraftment capacity of CD45+ MCC was evaluated by two transplantation assays. Regulation of c-Myc on MafB was evaluated by ChIP-qPCR and promoter reporter and dual luciferase assays. The phenotype and phagocytosis of iMac were explored by flow cytometry and immunofluorescence. Leukemia, breast cancer, and patient-derived tumor xenograft models were used to explore the anti-tumor function of iMac. Results Here we report on the establishment of a novel methodology allowing for reprogramming fibroblasts into functional macrophages with phagocytic activity by c-Myc overexpression. Fibroblasts with ectopic expression of c-Myc in iPSC medium rapidly generated CD45+ MCC intermediates with engraftment capacity as well as the repopulation of distinct hematopoietic compartments. MCC intermediates were stably maintained in iPSC medium and continuously generated functional and highly pure iMac just by M-CSF cytokine stimulation. Single-cell transcriptomic analysis of MCC intermediates revealed that c-Myc up-regulated the expression of MafB, a major regulator of macrophage differentiation, to promote macrophage differentiation. Characterization of the iMac activity showed NF-κB signaling activation and a pro-inflammatory phenotype. iMac cells displayed significantly increased in vivo persistence and inhibition of tumor progression in leukemia, breast cancer, and patient-derived tumor xenograft models. Conclusions Our findings demonstrate that c-Myc alone is enough to reprogram fibroblasts into functional macrophages, supporting that c-Myc reprogramming strategy of fibroblasts can help circumvent long-standing obstacles to gaining “off-the-shelf” macrophages for anti-cancer immunotherapy.

In this work, the influence of Mn and Ca doping on the microstructure and mechanical properties of Mg–3Zn, Mg–3Zn-0.5Mn, and Mg–3Zn-0.5Mn-1.2Ca alloys is systematically investigated. The addition of Mn elements is shown to exert no obvious effect on the microstructure of as-cast, as-homogenized, and extruded Mg–3Zn alloys. In contrast, the introduction of Ca into the extruded Mg–3Zn-0.5Mn alloy promotes the formation of nano-sized compounds and enhances grain refinement compared to the other two alloys. The extruded Mg–3Zn-0.5Mn alloy exhibits the higher yield strength (YS, 155 MPa) and ultimate tensile strength (UTS, 183 MPa) but the lower elongation (13%) than the extruded Mg–3Zn alloy (YS of 130 MPa, UTS of 175 MPa, and elongation of 25%). The improved strength of the extruded Mg–3Zn-0.5Mn alloy is mainly attributed to the refined grains, while both the lack of twinning deformation and strong texture result in ductility loss. The most optimal combination of strength and ductility is achieved in an extruded Mg–3Zn-0.5Mn-1.2Ca alloy (YS of 180 MPa, UTS of 250 MPa, and elongation of 26%). This suggests that fine grains and high volume fraction of nano-sized MgZn2 compounds contribute mainly to the strength of Mg–3Zn-0.5Mn-1.2Ca alloy. Although the grain refinement also facilitates the suppression of twinning in the extruded Mg–3Zn-0.5Mn-1.2Ca alloy, the weak texture and fine homogeneous grains are conducive to the high ductility.

Abstract Background Liver fibrosis can progress to end-stage cirrhosis and liver cancer. Mesenchymal stem cells (MSCs) were considered the most promising therapeutic strategy, but most of the MSCs injected intravenously traditionally are trapped in the lungs, rapidly reducing their survival ability. MSC spheroids cultured in 3D have shown higher tolerance to fluid shear stress and better survival than dissociated MSCs. Simulating the route of orthotopic liver transplantation, transplanting MSC spheroids into the liver via hepatic portal vein may impact superior therapeutic effects. Methods In the present study, human umbilical cord-derived MSC spheroids (hUC-MSCsp) were transplanted into rhesus monkey models of liver fibrosis via B-ultrasound-guided percutaneous portal vein puncture with minimized body invasion. The therapeutic effect is evaluated through hematology, ultrasound, and pathology. To study the effect of hUC-MSCsp on gene expression in rhesus monkeys with liver injury, transcriptome sequencing analysis was performed on the livers of rhesus monkeys. The distribution of transplanted hUC-MSCsp was traced with RNA scope technology. Results We found that hUC-MSCsp significantly restored liver function, including ALT, AST, ALB, GLOB and bilirubin. hUC-MSCsp also significantly reduced liver collagen deposition and inflammatory infiltration, and promote dismission of liver ascites. Subsequently, the therapeutic effects were further validated in TGF-β1/Smad pathway by global transcription profile. The distribution of transplanted hUC-MSCsp were also tracked, and we found that hUC-MSCsp distributed in the liver in a sphere status at 1 h after transplantation. After 16 days, the hUC-MSCsp were dispersed into dissociated cells that were predominantly distributed in the spleen, and a significant number of dissociated cells were still present in the liver. Conclusions This study reveals the distributions of transplanted hUC-MSCsp after liver portal vein transplantation, and provides a novel approach and new insights into the molecular events of potential molecular events underlying the treatment of liver fibrosis with hUC-MSCsp.

To examine how different harvesting periods affect the storage quality of 'Satsuma' plum fruits, this study analyzed 13 quality and physiological metrics post-harvest and utilized principal component analysis (PCA) and mathematical models to assess (0±0.5)℃ low temperature storage quality across three different harvesting periods (100 d after flowering, 103 d after flowering, 106 d after flowering). The results showed that harvesting at 103 days after full bloom led to the best preservation effect. Additionally, the hardness and total acidity of plum fruit decreased by 37.37% and 27.06% respectively until the end of the storage period, which was the slowest. Furthermore, changes in relative conductivity, anthocyanins, total soluble solids, malondialdehyde, total phenols, and flavonoids were relatively smooth. The activity of polyphenol oxidase was low, while peroxidase, superoxide dismutase, and catalase activities were high, specifically catalase activities. After conducting PCA analysis, it was determined that PC1, PC2, and PC3 accurately capture 87.472% of the relevant information. These results suggested that varying harvesting periods would have significant impacts on all indicators. The mathematical model analysis revealed that the plum fruits harvested at 100, 103, and 106 days after bloom, and stored for 56 days, had comprehensive scores of 1.06, 0.99, and 2.69, respectively. Lower comprehensive scores indicated better quality, so the order of preservation effect was as follows: 103 days after bloom>100 days after bloom>106 days after bloom. The study provides a theoretical framework for evaluating postharvest preservation and quality of plum fruits, along with technical parameters to enable timely harvesting.

Abstract Fludarabine (FA) is still considered as a first-line chemotherapy drug for hematological tumors related to B lymphocytes. However, it is worth noting that the non-specific distribution and non-different cytotoxicity of FA may lead to irreversible consequences such as central nervous system damage such as blindness, coma, and even death. Therefore, it is very important to develop a system to targeting delivery FA. In preliminary studies, it was found that B lymphoma cells would specific highly expressing the sialic acid-binding immunoglobulin-like lectin 2 (known as CD22). Inspired by the specific recognition of sialic acid residues and CD22, we have developed a supramolecular prodrug based on polysialic acid, an endogenous biomacromolecule, achieving targeted-therapy of B-cell non-Hodgkin’s lymphoma (B-NHL). Specifically, the prepared hydrophobic reactive oxygen species-responsive FA dimeric prodrug (F2A) interacts with the TPSA, which polysialic acid were modified by the thymidine derivatives, through non-covalent intermolecular interactions similar to “Watson–Crick” base pairing, resulting in the formation of nanoscale supramolecular prodrug (F@TPSA). Cell experiments have confirmed that F@TPSA can be endocytosed by CD22+ B lymphoma cells including Raji and Ramos cells, and there is a significant difference of endocytosis in other leukocytes. Furthermore, in B-NHL mouse model, compared with FA, F@TPSA is determined to have a stronger tumor targeting and inhibitory effect. More importantly, the distribution of F@TPSA in vivo tends to be enriched in lymphoma tissue rather than nonspecific, thus reducing the leukopenia of FA. The targeted delivery system based on PSA provides a new prodrug modification strategy for targeted treatment of B-NHL. Graphical abstract

Abstract Porcine reproductive and respiratory syndrome virus (PRRSV) is a severe disease with substantial economic consequences for the swine industry. The DEAD-box helicase 3 (DDX3X) is an RNA helicase that plays a crucial role in regulating RNA metabolism, immunological response, and even RNA virus infection. However, it is unclear whether it contributes to PRRSV infection. Recent studies have found that the expression of DDX3X considerably increases in Marc-145 cells when infected with live PRRSV strains Ch-1R and SD16; however, it was observed that inactivated viruses did not lead to any changes. By using the RK-33 inhibitor or DDX3X-specific siRNAs to reduce DDX3X expression, there was a significant decrease in the production of PRRSV progenies. In contrast, the overexpression of DDX3X in host cells substantially increased the proliferation of PRRSV. A combination of transcriptomics and metabolomics investigations revealed that in PRRSV-infected cells, DDX3X gene silencing severely affected biological processes such as ferroptosis, the FoxO signalling pathway, and glutathione metabolism. The subsequent transmission electron microscopy (TEM) imaging displayed the typical ferroptosis features in PRRSV-infected cells, such as mitochondrial shrinkage, reduction or disappearance of mitochondrial cristae, and cytoplasmic membrane rupture. Conversely, the mitochondrial morphology was unchanged in DDX3X-inhibited cells. Furthermore, silencing of the DDX3X gene changed the expression of ferroptosis-related genes and inhibited the virus proliferation, while the drug-induced ferroptosis inversely promoted PRRSV replication. In summary, these results present an updated perspective of how PRRSV infection uses DDX3X for self-replication, potentially leading to ferroptosis via various mechanisms that promote PRRSV replication.

Phosphorylation, the most extensive and pleiotropic form of protein posttranslation modification, is central to cellular signal transduction. Throughout the extensive co-evolution of plant hosts and viruses, modifications to phosphorylation have served multiple purposes. Such modifications highlight the evolutionary trajectories of viruses and their hosts, with pivotal roles in regulation and refinement of host-virus interactions. In plant hosts, protein phosphorylation orchestrates immune responses, enhancing the activities of defense-related proteins such as kinases and transcription factors, thereby strengthening pathogen resistance in plants. Moreover, phosphorylation influences the interactions between host and viral proteins, altering viral spread and replication within host plants. In the context of plant viruses, protein phosphorylation controls key aspects of the infection cycle, including viral protein functionality and the interplay between viruses and host plant cells, leading to effects on viral accumulation and dissemination within plant tissues. Explorations of the nuances of protein phosphorylation in plant hosts and their interactions with viruses are particularly important. This review provides a systematic summary of the biological roles of the proteins of plant viruses carrying diverse genomes in regulating infection and host responses through changes in the phosphorylation status. [Figure: see text] Copyright © 2024 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Southern China encountered two rounds of rainfall/snowfall and freezing weather accompanied by intensive lightning flashes from January 31 to February 5 and February 18-25,2024 (hereinafter referred to as "0131" and "0218" events,respectively). In this paper,three-dimensional lightning location data,CLDAS-V2.0 precipitation product,and infrared cloud image data of Himawari-9 satellite are used to analyze and compare the temporal and spatial distribution of cloud-to-ground (CG) flashes,the number of return strokes and the cumulative probability distribution of lightning current during these two events. The relationship between CG flashes with precipitation and satellite blackbody brightness temperature (TBB) is also investigated. The results are as follows. (1) More than 130,000 CG lightning flashes were detected in the two events,with positive and negative CG lightning strokes being more than 20,000 and 110,000,respectively. The CG flashes of the two events showed a nocturnal pattern,with the peak of the positive CG distribution lagging behind the total CG flashes and negative CG flashes by about 1-2 h. The probability of large current events generated by positive CG flashes was greater than that of negative CG flashes. (2) In the "0131" event,the large value of CG flash density appeared in the southern part of Guizhou and the junction of Guizhou,Chongqing,and Hubei provinces; In the "0218" event,the large value of CG density occurred in the eastern part of Hubei,the northern part of Jiangxi,Anhui,Jiangsu and most of Zhejiang. (3) The spatial and temporal distribution of precipitation and CG flashes during the "0131" event was inconsistent. The peak precipitation was concentrated in the daytime,with the precipitation mainly appearing in southeastern Hunan,Jiangxi,Anhui,and southern Jiangsu,and most of Zhejiang and Fujian. During the "0218" event,the spatial and temporal distribution of precipitation and CG flashes were consistent,with the peak of CG flashes being 2 h later than the peak of precipitation. (4) In both events,the distribution of CG flashes well indicated the convection regions. The CG flashes were mainly distributed in the southern tail of the convective cloud cluster,where the TBB gradient was large. Convective merging may lead to a jump in the frequency of CG flashes at the merging area. Almost no CG flashes were detected in the core of the cold clouds,where convection developed most vigorously. The CG flash density in both events increased first and then decreased with the increase of TBB.

The prevalence of collaborative learning in online virtual environments is on the rise. It is vital to investigate the effect of emotional interaction on the learning engagement of students. The university students who participated in 16 h of online collaborative learning responded to an anonymous survey. The instruments included Collaborative Learning Emotional Interaction Scale, Loneliness Scale, Positive and Negative Rumination Scale, and Learning Engagement Scale. The mediating and moderating roles of variables were tested. Both positive and negative emotional interactions in online collaborative learning positively predicted learning engagement. Positive emotional interaction can inversely predict loneliness, while negative emotional interaction has a positive effect on loneliness. Loneliness inversely predicts learning engagement. In the low level of positive rumination, loneliness has a significant inhibitory effect on learning engagement, and the effect is much greater than that in the high level of positive rumination. In online collaborative learning, loneliness mediates the effect of learners' emotional interaction on learning engagement. The level of positive rumination moderated the connection between loneliness and learning engagement, the second part of the mediation model. We can begin by increasing learners' positive rumination and reducing the detrimental impact of negative emotional interaction and isolation on learning engagement in online collaborative learning.

Ischemia brain injury is closely associated with the gut microbiota. Polysaccharides, as a typical prebiotic, have been extensively employed in stroke treatment. In our previous study, Pueraria lobata polysaccharide (PLP-3) with antioxidant activity was prepared via water extraction and alcohol precipitation combined with ultrasonic degradation. In this study, the effects of PLP-3 on ischemia brain injury and its regulatory effects on the gut microbiota were further investigated. The results demonstrated that PLP-3 effectively reduced the infarct area, improves neurological function, and alleviates neuronal damage of cerebral ischemia injury. Mechanistically, PLP-3 significantly reduces serum LPS levels in MCAO mice, inhibiting TLR-4 activation in brain tissue and thereby reducing IL-1β and TNF-α levels. Meanwhile, PLP-3 significantly repaired the intestinal barrier injury by increasing the expression of tight junction proteins (ZO-1 and Occludin) and increasing the number of goblet cells. Additionally, the structure and composition of gut microbiota in MCAO mice after PLP-3 intervention, were also significantly changed, especially the enrichment of Lactobacillus and the reduction of Corynebacterium and Staphylococcus. At the same time, short chain fatty acid, metabolites of gut microbiota, were also significantly increased and significantly correlated with the abundance of Lactobacillus. Moreover, LC-MS untargeted metabolomics revealed that PLP-3 significantly improves the intestinal metabolic profile after cerebral ischemia injury, upregulating the amino acid biosynthesis pathway and enriching amino acids such as glutamine and arginine, as well as neuroprotective flavonoids such as fisetin and liquiritigenin. These results suggested that PLP-3 could protect mice from cerebral ischemia–reperfusion injury by regulating gut microbiota and repairing gut barrier, inhibiting brain LPS/TLR4/MyD88 inflammatory pathway, therefore we provide a theoretical basis for PLP-3 as a functional food to prevent ischemic brain injury.

BackgroundIgA nephropathy (IgAN) is a leading cause of renal failure, but its pathogenesis remains unclear, complicating diagnosis and treatment. The invasive nature of renal biopsy highlights the need for non-invasive diagnostic biomarkers. Bulk RNA sequencing (RNA-seq) of urine offers a promising approach for identifying molecular changes relevant to IgAN.MethodsWe performed bulk RNA-seq on 53 urine samples from 11 untreated IgAN patients and 11 healthy controls, integrating these data with public renal RNA-seq, microarray, and scRNA-seq datasets. Machine learning was used to identify key differentially expressed genes, with protein expression validated by immunohistochemistry (IHC) and drug-target interactions explored via molecular docking.ResultsUrine RNA-seq analysis revealed differential expression profiles, from which TYROBP and HCK were identified as key biomarkers using machine learning. These biomarkers were validated in both a test cohort and an external validation cohort, demonstrating strong predictive accuracy. scRNA-seq confirmed their cell-specific expression patterns, correlating with renal function metrics such as GFR and serum creatinine. IHC further validated protein expression, and molecular docking suggested potential therapeutic interactions with IgAN treatments.ConclusionTYROBP and HCK are promising non-invasive urinary biomarkers for IgAN. Their predictive accuracy, validated through machine learning, along with IHC confirmation and molecular docking insights, supports their potential for both diagnostic and therapeutic applications in IgAN.

SignificanceBurning mouth syndrome (BMS) is a chronic orofacial pain disorder that seriously affects quality of life of patients. In recent years, Low-level laser therapy (LLLT) has been regarded as an important innovation in pain management, but there is insufficient evidence of its effectiveness in patients with painful BMS. This study aimed to evaluate the efficacy of LLLT for immediate pain relief due to BMS.MethodsThis retrospective study included 94 BMS patients that were treated with an intraoral semiconductor laser (635 nm, 100 mW/cm2). Pain was self-assessed before and immediately after LLLT sessions using a 0-to-10 visual analogue scale (VAS). Paired-samples t-test and multivariable binary logistic regression were used to analyze overall efficacy and its influencing factors.ResultsAfter standardized LLLT session, 71.3% of patients reported an immediate pain decrease. Compared to pre-LLLT treatment, the VAS immediately post-LLLT was significantly reduced (P

Introduction: To evaluate the alterations in the peripapillary retinal thickness and its risk factors in dry-type high myopia (HM). Methods: One hundred and twenty eyes in 69 HM subjects were collected from March 2023 to July 2023 with the age, refractive diopter, axial length (AL), posterior scleral staphyloma, type of myopic maculopathy, and peripapillary retinal thickness. Divided into three groups according to the international photo-graphic classification system: Category 0 (C0) with no myopic retinal degenerative lesions, Category 1 (C1) with tessellated fundus, and Category 2 (C2) with diffuse chorioretinal atrophy. Peripapillary retinal thickness was assessed using swept-source optical coherence tomography (SS-OCT) B-scans. All data were analyzed with the SPSS software version 23.0 by one-way ANOVA test among three groups. Linear regression and pearson correlation analysis were used to determine the relationships among measurements. Results: The retinal thickness of the peripapillary was measured from the superior, nasal, inferior, and temporal directions around the optic disc. The superior, nasal, and inferior peripapillary retinal thickness in the C2 group decreased significantly in all three groups. The retinal thicknesses decreased significantly with the increase of AL in the superior, nasal, and inferior. The retinal thicknesses increased significantly with the increase of refractive diopter, except for the temporal sector. The retinal thickness decreased significantly with the increase of age in dry-type HM. There was no significant difference between peripapillary retinal thickness and the wide macular staphyloma. Conclusions: Individuals in the C2 group had a thinner peripapillary retinal thickness than other groups, except for the temporal sector. The retinal thicknesses of the peripapillary decreased significantly with the increase of AL and increased significantly with the increase of refractive diopter, except for the temporal sector. With the increase of age, the retinal thickness of the peripapillary decreased significantly. Ophthalmologists and HM patients should pay attention to changes in the thickness of the peripapillary retina and the growth of age.

Ecological restoration, green space morphology, and carbon emissions are intricately interconnected. Previous research utilizing case studies and econometric modeling has demonstrated that effective ecological restoration and well-structured green space configurations can significantly enhance carbon sequestration, reduce carbon emissions, and mitigate the adverse effects of climate change during urbanization. However, as urban land-use patterns become increasingly complex and development trajectories more diverse, the relationship between green space morphology and carbon dynamics (emissions and sequestration) reveals notable heterogeneity and non-linear characteristics. Understanding these complex, non-linear relationships and the underlying mechanisms is both theoretically and technically innovative, with profound implications for urban planning, policy formulation, climate change mitigation, and ecological conservation. In this study, we applied machine learning algorithms to model the non-linear relationships and threshold effects between green space evolution and carbon emissions/sequestration at different stages of ecological restoration in the Yangtze River Basin, China. Furthermore, we simulated the low-carbon performance of green spaces under various urban development scenarios. The key findings include: (1) Wetlands, particularly those composed of shallow water bodies and land–water interfaces such as marshes and mangroves, are critical determinants of the low-carbon performance of green spaces, with their effects on carbon emissions and sequestration exhibiting significant temporal dynamics throughout different stages of ecological restoration. (2) The fragmentation and shape complexity of green spaces substantially influence carbon efficiency. Preserving the connectivity and integrity of green spaces, particularly in large-scale forests and wetlands, while minimizing fragmentation and reducing shape complexity, can enhance carbon sequestration capacity. (3) Carbon performance varies markedly across different urban development trajectories. In cities prioritizing ecological restoration, future carbon emissions tend to stabilize, whereas in rapidly growing megacities, despite recent declines in carbon emissions, further optimization of green space configurations is required to effectively manage emissions and bolster sequestration. In summary, this study provides robust scientific evidence for ecological restoration and green space planning in the Yangtze River Basin, offering valuable insights for carbon management and ecological restoration in similar regions globally. These findings contribute to global environmental governance efforts and the ongoing fight against climate change.

Objective Polycystic ovary syndrome (PCOS) is a prevalent cause of menstrual irregularities and infertility in women, impacting quality of life. Despite advancements, current understanding of PCOS pathogenesis and treatment remains limited. This study uses machine learning-based data mining to identify acetylation-related genetic markers associated with PCOS, aiming to enhance diagnostic precision and therapeutic efficacy.Methods Advanced machine learning techniques were used to improve the precision of key gene identification and reveal their biological mechanisms. Validation on an independent dataset (GSE48301) confirmed their diagnostic value, assessed through ROC curves and nomograms for PCOS risk prediction. Molecular mechanisms of acetylation-related gene regulation in PCOS were further examined through clustering, immune-environmental, and gene network analyses.Results Our analysis identified 15 key acetylation-regulated genes differentially expressed in PCOS, including SGF29, NOL6, KLF15, and INO80D, which are relevant to PCOS pathogenesis. ROC curve analyses on training and validation datasets confirmed the model’s high diagnostic accuracy. Additionally, these genes were associated with immune cell infiltration, offering insights into the inflammatory aspect of PCOS.Conclusion The identified acetylation gene markers offer novel insights into the molecular mechanisms underlying PCOS and hold promise for enhancing the development of precise diagnostic and therapeutic strategies.

The water transfer project has alleviated the shortage of water resources, but frequent scheduling of water distribution hubs can harm the water transmission buildings. This article is based on the RNG k-ε turbulence model to construct a three-dimensional mathematical model of the water flow passing through the gate of the North-Line of the Huangchigou water distribution hub of the water diversion from the Han to the Wei River. Combined with the physical model experiment, the influence of the unsteady flow process of the North-line of the Huangchigou water distribution hub on the hydraulic response in its water distribution tank and tunnel is investigated. The research results indicate that, when the North-line gate closes faster, the earlier the overflow occurs in the side-channel spillway, increasing in abandoned water volume. In addition, excessively rapid gate adjustment can result in a sharp increase in pressure in front of the North-line gate. It will also increase the cavity area caused by the detachment of the bottom edge of the gate, forming a strong vortex behind the gate. From the perspective of safe operation of the gate, the closing time of the North-line gate should not be less than 100s. The research results can provide reference for the design, safe operation, and emergency control of water transmission and distribution hub projects.

ABSTRACT: In this study, we investigated the effects of dietary supplementation with Bacillus subtilis (QST713) on the performance and intestinal health of yellow feather broilers under Coccidia and Clostridium perfringens (CP) challenge or CP alone. One-day-old yellow-feathered broiler roosters (n = 600) were randomly assigned to 5 groups (6 replicates with 20 roosters per replicate): the Con blank group, the CIC.p group (d24 Coccidia+d28-30 of CP challenge), the CIC.p + BS group (CIC.p +100 mg/kg B. subtilis), the C.p group (d 28–34 of CP challenge), and the C.p +BS group (C.p +100 mg/kg B. subtilis). The experiment lasted 80 d. The birds were evaluated for parameters such as average daily gain (ADG), average daily feed intake (ADFI), feed efficiency (F/G), intestinal lesion score, villus histomorphometry, intestinal tight junctions, inflammatory factors, and cecal microorganisms. The results revealed that 1) C.p. increased the F/G of broilers from 22 to 42 d (P < 0.05), whereas CIC.p. significantly decreased the 42 d and 80 d body weights (BW) and 22–42 d and 1–80 d ADG (P < 0.05) and significantly increased the 22 to 42 d and 1 to 80 d F/G (P < 0.05). The number of intestinal lesions significantly increased at 35 d and 42 d (P < 0.05). CIC.p significantly decreased the jejunum and ileum villus height (VH) and the ileum villus height/crypt depth (P < 0.05) at 35 d. The challenge significantly upregulated the expression of Claudin-1 and IL-4 mRNAs in the jejunum at 35 d and significantly downregulated the expression of IL-10 mRNA in the ileum at 35 d (P < 0.05); the number of unique OTUs in the challenge group decreased significantly after challenge treatment, and the relative abundances of Romboutsia at 35 d and Cladomyces and Lactobacillus at 42 d decreased significantly (P < 0.05). 2) Compared with the challenge groups, the addition of BS decreased the F/G of broilers from 22 to 42 d. Compared with the CIC group, the addition of BS significantly increased the F/G of broilers from 22 to 42 d. Compared with that in the CIC.p group, the addition of BS significantly increased the VH in the jejunum and ileum at 35 d (P < 0.05). Compared with the challenge groups, the BS groups presented significantly lower mRNA expression levels of Claudin-1 (P < 0.05) in the jejunum at 35 d. The Shannon and Chao indices suggested that BS increased the alpha diversity of cecum microorganisms in broilers. Dietary supplementation with B. subtilis can alleviate the damage to intestinal morphology and intestinal barrier function, as well as the altered cecal flora structure in broilers caused by Coccidia and C. perfringens infections.

Background: Non-optimum temperatures are associated with a considerable mortality burden. However, there is a lack of evaluation of labour productivity losses related to premature deaths due to non-optimum temperatures. This study aimed to quantify the labour productivity burden associated with premature deaths related to non-optimum temperatures and explore the potential socio-economic vulnerabilities. Methods: Daily all-cause mortality data were collected from 1,066 locations in 7 countries (Australia, Brazil, Canada, Chile, New Zealand, South Korea, and Thailand). Productivity-Adjusted Life-Year (PALY) loss due to each premature death was calculated to measure the labour productivity loss, by multiplying the years of working life lost by the proportion of the equivalent full-time (EFT) workers. A two-stage times series design and the generalized linear regression model with a quasi-Poisson family were applied to assess the association between non-optimum temperatures and the PALY loss due to premature deaths. Results: We observed a U-shaped relationship between temperature and PALY lost due to premature mortality. We estimated that 2.51% (95% eCI: 2.05%, 2.92%) of PALY losses could be attributed to non-optimal temperatures, with cold-related deaths contributing 1.26% (95% eCI: 0.94%, 1.54%) and heat-related deaths contributing 1.25% (95% eCI: 0.96%, 1.51%). Cold temperature contributed to the most PALYs lost in those aged 45–54 and 55–64, while heat-related losses predominated among the 15–44 age group. We also observed that the fractions of PALY lost attributed to extreme heat were positively associated with the relative deprivation index, while negatively associated with GDP per capita. Conclusion: This multi-country study highlights that non-optimum temperatures led to a considerable labour productivity loss and socioeconomically disadvantaged communities experience greater losses.

The kidney plays a crucial role in maintaining the body’s microenvironment homeostasis. However, current treatment options and therapeutic agents for chronic kidney disease (CKD) are limited. Fortunately, the advent of kidney organoids has introduced a novel in vitro model for studying kidney diseases and drug screening. Despite significant efforts has been leveraged to mimic the spatial-temporal dynamics of fetal renal development in various types of kidney organoids, there is still a discrepancy in cell types and maturity compared to native kidney tissue. The extracellular matrix (ECM) plays a crucial role in regulating cellular signaling, which ultimately affects cell fate decision. As a result, ECM can refine the microenvironment of organoids, promoting their efficient differentiation and maturation. This review examines the existing techniques for culturing kidney organoids, evaluates the strengths and weaknesses of various types of kidney organoids, and assesses the advancements and limitations associated with the utilization of the ECM in kidney organoid culture. Additionally, it presents a discussion on constructing specific physiological and pathological microenvironments using decellularized extracellular matrix during certain developmental stages or disease occurrences, aiding the development of kidney organoids and disease models.

ABSTRACT: Hematological parameters refer to the assessment of changes in the number and distribution of blood cells, including leukocytes (LES), erythrocytes (ERS), and platelets (PLS), which are essential for the early diagnosis of hematological system disorders and other systemic diseases in livestock. In this context, the primary objectives of this study were to investigate the genomic background of 19 hematological parameters in Holstein cattle, focusing on LES, ERS, and PLS blood components. Genetic and phenotypic (co)variances of hematological parameters were calculated based on the average information restricted maximum likelihood method and 1,610 genotyped individuals and 5,499 hematological parameter records from 4,543 cows. Furthermore, we assessed the genetic relationship between these hematological parameters and other economically important traits in dairy cattle breeding programs. We also carried out genome-wide association studies and candidate gene analyses. Blood samples from 21 primiparous cows were used to identify candidate genes further through RNA sequencing (RNA-seq) analyses. Hematological parameters generally exhibited low-to-moderate heritabilities ranging from 0.01 to 0.29, with genetic correlations between them ranging from −0.88 ± 0.09 (between mononuclear cell ratio and lymphocyte cell ratio) to 0.99 ± 0.01 (between white blood cell count and granulocyte cell count). Furthermore, low-to-moderate approximate genetic correlations between hematological parameters with one longevity, 4 fertility, and 5 health traits were observed. One hundred ninety-nine significant SNP located primarily on the Bos taurus autosomes (BTA) BTA4, BTA6, and BTA8 were associated with 16 hematological parameters. Based on the RNA-seq analyses, 6,687 genes were significantly downregulated and 4,119 genes were upregulated when comparing 2 groups of cows with high and low phenotypic values. By integrating genome-wide association studies (GWAS), RNA-seq, and previously published results, the main candidate genes associated with hematological parameters in Holstein cattle were ACRBP, ADAMTS3, CANT1, CCM2L, CNN3, CPLANE1, GPAT3, GRIP2, PLAGL2, RTL6, SOX4, WDFY3, and ZNF614. Hematological parameters are heritable and moderately to highly genetically correlated among themselves. The large number of candidate genes identified based on GWAS and RNA-seq indicate the polygenic nature and complex genetic determinism of hematological parameters in Holstein cattle.

Abstract: Objective: This paper explores the relationship between alcohol consumption and psychological health outcome in an economically underdeveloped area of China. Methods: We conducted convenience sampling and recruited 439 participants at alcohol-related risk as identified by Alcohol Use Disorder Identification Test. Well-being and mental health were the primary outcomes. We employed multiple regression analysis to determine the correlation between alcohol consumption and health outcome. Results: Participants with higher scores for alcohol dependence were more likely to obtain higher scores for stress (0.11 [95% CI: 0.03, 0.19]), anxiety (0.15 [95% CI: 0.07, 0.23]) and depression (0.11 [95% CI: 0.03, 0.19]). Similarly, increasing scores for harmful alcohol use items were associated with higher scores for anxiety (0.08 [95% CI: 0.01,0.16]) and stress (0.08 [95% CI: 0.01,0.15]) and lower scores for positiveness (0.07 [95% CI: –0.14, –0.01]). Participants with stable incomes and the ethnic minority reported more favorable psychological outcomes or fewer negative emotions. Conversely, individuals who drank passively were more prone to experiencing lower positive and higher negative psychological effects. Conclusions: Higher scores on measures of alcohol dependence and harmful alcohol use indicate elevated psychological risks. Socioeconomic status, ethnicity, and drinking motivations modified the associations.

A method is proposed here for the automatic generation of piano fingerings based on a temporal difference reinforcement learning model. For the special scene generated by piano fingering, this method adopts the temporal difference reinforcement learning algorithm of Q-learning as the learning model, which is concise and clear, with high learning speed. A set of applicable music and visual mapping rules are proposed, and based on the analysis of existing music visualization cases, a music visualization design strategy suitable for piano learning is proposed. Then, an application is designed to assist users in piano learning. The visualization design, intelligent sparring, and evaluation visualization design, enable piano learners to understand the characteristics and emotional expression of music in multiple dimensions during the learning process, and can also intuitively understand their performance. In addition, you can also use the sparring mode to interact with the community to improve your performance and aesthetic level further. On the problems existing in online piano sparring learning at this stage and how to make it play an active role in the overall development of people, some suggestions and thinking are put forward, and it is believed that better sparring requires the joint efforts of society, platforms, teachers, and parents. From the current point of view, integrating online and offline should be the most suitable way for students to learn piano. Still, in the future, with the continuous development of network technology and the continuous progress of human thinking and ability, this model will be further improved.

Abstract Background Maintaining the structural and functional integrity of the blood–brain barrier (BBB) is vital for neuronal equilibrium and optimal brain function. Disruptions to BBB performance are implicated in the pathology of neurodegenerative diseases. Main body Early indicators of multiple neurodegenerative disorders in humans and animal models include impaired BBB stability, regional cerebral blood flow shortfalls, and vascular inflammation associated with BBB dysfunction. Understanding the cellular and molecular mechanisms of BBB dysfunction in brain disorders is crucial for elucidating the sustenance of neural computations under pathological conditions and for developing treatments for these diseases. This paper initially explores the cellular and molecular definition of the BBB, along with the signaling pathways regulating BBB stability, cerebral blood flow, and vascular inflammation. Subsequently, we review current insights into BBB dynamics in Alzheimer’s disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. The paper concludes by proposing a unified mechanism whereby BBB dysfunction contributes to neurodegenerative disorders, highlights potential BBB-focused therapeutic strategies and targets, and outlines lessons learned and future research directions. Conclusions BBB breakdown significantly impacts the development and progression of neurodegenerative diseases, and unraveling the cellular and molecular mechanisms underlying BBB dysfunction is vital to elucidate how neural computations are sustained under pathological conditions and to devise therapeutic approaches.

Abstract MuB is a non-specific DNA-binding protein and AAA+ ATPase that significantly influences the DNA transposition process of bacteriophage Mu, especially in target DNA selection for transposition. While studies have established the ATP-dependent formation of MuB filament as pivotal to this process, the high-resolution structure of a full-length MuB protomer and the underlying molecular mechanisms governing its oligomerization remain elusive. Here, we use cryo-EM to obtain a 3.4-Å resolution structure of the ATP(+)-DNA(+)-MuB helical filament, which encapsulates the DNA substrate within its axial channel. The structure categorizes MuB within the initiator clade of the AAA+ protein family and precisely locates the ATP and DNA binding sites. Further investigation into the oligomeric states of MuB show the existence of various forms of the filament. These findings lead to a mechanistic model where MuB forms opposite helical filaments along the DNA, exposing potential target sites on the bare DNA and then recruiting MuA, which stimulates MuB’s ATPase activity and disrupts the previously formed helical structure. When this happens, MuB generates larger ring structures and dissociates from the DNA.

Abstract Background Osteoporosis and atherosclerosis frequently afflict older adults, and recent insights suggest a deeper connection between these conditions that surpasses mere aging effects. The ratio of non-high-density to high-density lipoprotein cholesterol (NHHR) has emerged as a novel lipid marker for evaluating the risk of cardiovascular diseases. Nonetheless, investigations into the correlation of the NHHR with the risk of developing osteoporosis remain unexplored. Methods We collected NHHR and bone mineral density (BMD) data from 11,024 National Health and Nutrition Examination Survey (NHANES) participants between 2011 and 2018. Multivariate linear regression was employed to examine the correlation between BMD and NHHR. Smooth curves were employed to deal with the nonlinearity. To further account for the nonlinear link, we used a two-part linear regression model. The threshold effects were estimated using two components of a linear regression model. Subgroup and sensitivity analyses were carried out to ascertain the stability of the findings. Results We discovered a negative relationship between the NHHR and lumbar spine BMD in all three models. An L-shaped curvilinear association existed between the NHHR and lumbar spine BMD, with a key inflection point of 6.91. The fully adjusted model showed that the BMD of the lumbar spine fell by 0.03 g/cm2 in those who were in the fourth quartile as opposed to the lowest quartile. The sensitivity analysis using unweighted logistic analysis verified the stability of the results. In addition, BMD in the nondiabetic group was more significantly affected by the negative effect of the NHHR in the subgroup analysis. Conclusions According to this research, there appears to be a negative correlation between BMD and NHHR in US Adults. To clarify the precise physiological mechanisms by which the NHHR contributes to the onset of osteoporosis, more research is necessary.

Abstract Background A long-term follow-up of close contacts to monitor their infection status is essential to formulate a promising screening strategy. The study aimed to assess the dynamics of tuberculosis (TB) infection using Interferon-γ release assay (IGRA) and determine risk factors associated with TB infection. Methods Definite TB patients were interviewed and their household contacts were screened for TB infection by IGRA during 12-month longitudinal investigation. Results We included in our analyses 184 household contacts of 92 index TB patients. 87 individuals (47.3%) in contact group progressed to TB infection, of whom 86 developed into IGRA positive within 24 weeks. Close contacts with a higher age and comorbidities are easier to exhibit TB infection. Analysis showed that risk factors for becoming IGRA-positive individuals included residence, older age, comorbidities, BCG scar and high bacterial load. Contacts with BCG scar had a lower IGRA-positive rate. Conclusion IGRA conversion generally occurs within 24 weeks after exposure. The TB transmission happens since subclinical TB stage and the presence of BCG scar is an independent protective factor reducing risk of TB infection among close contacts. Repeated IGRA tests are sensible to conducted among close contacts at 24 weeks after exposure to identify the IGRA-positive individuals.

This study examined the potential correlation between the immoderate intake of sugar-sweetened beverages (SSBs) and the subsequent rate of diabetes remission (DR). 206 individuals who met the eligibility criteria between January 2019 and June 2022 were recruited. Inquiries were conducted to gather information on the participants’ beverage consumption before the onset. Subsequently, the participants were separated into the diabetes remission group (DR group) and nondiabetes remission group (NDR group) depending on whether they met the diagnostic criteria for diabetes remission. Baseline clinical elements within the two groups were juxtaposed, and factors influencing diabetes remission were identified through logistic regression analyses. The cutoff values of each critical factor were determined based on the receiver operating characteristic curve. One hundred and nine patients reported a history of SSB consumption, while the remaining 58 reported no such history. After 1 year, 40 patients achieved remission from diabetes. Compared with the NDR group, a higher SSBs ratio, body mass index (BMI), and blood creatinine (BCr) was observed in the DR group after adjusting for confounders, SSBs (odds ratio [OR] = 3.503; 95% confidence interval [CI] = 1.334–9.202; p = 0.011) and BCr (OR = 1.038; 95% CI = 1.003–1.079; p = 0.042) emerged as independent predictors of DR. The composite index of SSBs and BCr efficaciously predicted DR (area under the ROC curve [AUC] = 0.810, p < 0.001). SSBs and BCr were independent risk factors for DR. The amalgamation of these markers could more accurately predict DR.

Background Gallbladder cancer is featured by difficult early detection, poor treatment effectiveness and high mortality. An in-depth epidemiology research of gallbladder cancer can provide valuable data for the formulation of prevention and treatment strategies for gallbladder cancer. Objective To analyze the trend of disease burden of gallbladder cancer in China from 1990 to 2019, and to estimate its onset age, period, cohort effects and future trends. Methods Data of disease burden of gallbladder cancer, including the incidence, prevalence, mortality, disability adjusted life year (DALYs) rate and corresponding standardized rates in China from 1990 to 2019 were extracted from the 2019 Global Burden of Disease Research (GBD 2019) database from March to June 2023. The annual percentage change (APC) and average annual percentage change (AAPC) were calculated using Joinpoint to analyze the trend of disease burden of gallbladder cancer in China from 1990 to 2019. A Bayesian age-period-cohort analysis (BAPC) model was created to predict the incidence of gallbladder cancer in China from 2020 to 2030. Results From 1990 to 2019, the standardized incidence rate of gallbladder cancer in China significantly rose from 1.58/100 000 in 1990 to 2.01/100 000 in 2019, with the AAPC of 0.82% (95%CI=0.65%-1.00%, P

In order to make the active ingredients and flavor substances of fruit juice after sterilization treatment closer to the original freshly squeezed fruit juice, the compound juice was prepared with kiwifruit, pineapple and mango as raw materials in this paper. The effects of ultra-high pressure and heat treatment (85 ℃, 5 min) on the quality and shelf life of freshly squeezed compound juice were compared. The results showed that, as the volume ratio of the mixed juice was Vpineapple pulp:Vkiwi pulp:Vmango pulp=4:2:4, the pH, b* value and soluble solid content of the juice treated at 450 MPa, 25 ℃ and 15 min of ultra-high pressure had no significant difference (P>0.05) with the traditional heat treatment, but the loss of vitamin C content and polyphenol content decreased by 12.1% and 17.5%, respectively. By analyzing the main volatile components of the compound juice, it was found that the loss of flavor substances such as enes, esters, alcohols, ketones, and aldehydes in the UHP treatment juice was significantly less than that in the heat treatment juice (P

Abstract Honey authentication and traceability are crucial not only for economic purposes but also for ensuring safety. However, the widespread adoption of cutting-edge technologies in practical applications has been hampered by complex, time-consuming sample pre-treatment processes, the need for skilled personnel, and substantial associated expenses. This study aimed to develop a simple and cost-effective molecular technique to verify the entomological source of honey. By utilizing newly designed primers, we successfully amplified the mitochondrial 16S ribosomal RNA gene of honey bees from honey, confirming the high quality of the extracted DNA. Employing RFLP analysis with AseI endonuclease, species-specific restriction patterns were generated for honey derived from six closely related honey bees of the Apis genus. Remarkably, this method was proven equally effective in identifying heat-treated and aged honey by presenting the same RFLP profiles as raw honey. As far as we know, this is the initial research of the simultaneous differentiation of honey from closely related honey bee species using the restriction endonuclease AseI and mitochondrial 16S rRNA gene fragments. As a result, it holds tremendous potential as a standardized guideline for regulatory agencies to ascertain the insect origins of honey and achieve comprehensive traceability.

Abstract Background Floods are the most frequent weather-related disaster, causing significant health impacts worldwide. Limited studies have examined the long-term consequences of flooding exposure. Methods Flood data were retrieved from the Dartmouth Flood Observatory and linked with health data from 499,487 UK Biobank participants. To calculate the annual cumulative flooding exposure, we multiplied the duration and severity of each flood event and then summed these values for each year. We conducted a nested case-control analysis to evaluate the long-term effect of flooding exposure on all-cause and cause-specific mortality. Each case was matched with eight controls. Flooding exposure was modelled using a distributed lag non-linear model to capture its nonlinear and lagged effects. Results The risk of all-cause mortality increased by 6.7% (odds ratio (OR): 1.067, 95% confidence interval (CI): 1.063–1.071) for every unit increase in flood index after confounders had been controlled for. The mortality risk from neurological and mental diseases was negligible in the current year, but strongest in the lag years 3 and 4. By contrast, the risk of mortality from suicide was the strongest in the current year (OR: 1.018, 95% CI: 1.008–1.028), and attenuated to lag year 5. Participants with higher levels of education and household income had a higher estimated risk of death from most causes whereas the risk of suicide-related mortality was higher among participants who were obese, had lower household income, engaged in less physical activity, were non-moderate alcohol consumers, and those living in more deprived areas. Conclusions Long-term exposure to floods is associated with an increased risk of mortality. The health consequences of flooding exposure would vary across different periods after the event, with different profiles of vulnerable populations identified for different causes of death. These findings contribute to a better understanding of the long-term impacts of flooding exposure.

Abstract Background Hypothermia is a promising therapy for traumatic brain injury (TBI) in the clinic. However, the neuroprotective outcomes of hypothermia-treated TBI patients in clinical studies are inconsistent due to several severe side effects. Here, an injectable refrigerated hydrogel was designed to deliver 3-iodothyronamine (T1AM) to achieve a longer period of local hypothermia for TBI treatment. Hydrogel has four advantages: (1) It can be injected into injured sites after TBI, where it forms a hydrogel and avoids the side effects of whole-body cooling. (2) Hydrogels can biodegrade and be used for controlled drug release. (3) Released T1AM can induce hypothermia. (4) This hydrogel has increased medical value given its simple operation and ability to achieve timely treatment. Methods Pol/T hydrogels were prepared by a low-temperature mixing method and characterized. The effect of the Pol/T hydrogel on traumatic brain injury in mice was studied. The degradation of the hydrogel at the body level was observed with a small animal imager. Brain temperature and body temperature were measured by brain thermometer and body thermometer, respectively. The apoptosis of peripheral nerve cells was detected by immunohistochemical staining. The protective effect of the hydrogels on the blood–brain barrier (BBB) after TBI was evaluated by the Evans blue penetration test. The protective effect of hydrogel on brain edema after injury in mice was detected by Magnetic resonance (MR) in small animals. The enzyme linked immunosorbent assay (ELISA) method was used to measure the levels of inflammatory factors. The effects of behavioral tests on the learning ability and exercise ability of mice after injury were evaluated. Results This hydrogel was able to cool the brain to hypothermia for 12 h while maintaining body temperature within the normal range after TBI in mice. More importantly, hypothermia induced by this hydrogel leads to the maintenance of BBB integrity, the prevention of cell death, the reduction of the inflammatory response and brain edema, and the promotion of functional recovery after TBI in mice. This cooling method could be developed as a new approach for hypothermia treatment in TBI patients. Conclusion Our study showed that injectable and biodegradable frozen Pol/T hydrogels to induce local hypothermia in TBI mice can be used for the treatment of traumatic brain injury. Graphical Abstract

Abstract Narrative medicine has become a meaningful solution to promote medical students’ professional and personal growth. However, there is a lack of study on how students benefit from the narrative medicine approach when developing identities. This study aimed to establish and implement an integrated English reading and writing curriculum based on collaborative reflection and discussion using the narrative medicine approach, exploring how students presented and constructed physician identities by performing speech acts. First-year undergraduate students majoring in clinical medicine were recruited. Collaborative reflection and discussion were conducted in the integrated course involving 14 pieces of medical-related narrative works, along with essential elements that guided the students to engage in classroom activities. In the following analysis, the qualitative analysis software NVivo was used to identify the main speech acts and their frequency to analyze students’ perception and recognition of different physician identities. Our analysis presented 33 major speech acts and revealed their frequency and characteristics, which we summarize in five interrelated physician identities. The fine-grained analysis showed how these identities were influenced by the narrative medicine approach, which provides enlightenment for supporting students to develop their professional identities. Another unique contribution of this study was to present the teaching basis and essential elements in an integrated humanistic curriculum. The results helped clarify the relationship between speech acts and physician identity and suggested that collaborative reflection and discussion using the narrative medicine approach improved the humanistic component that was in short supply in medical education through its interdisciplinary advantages, thus promoting professional identity development that can lead to higher-quality medical and emotional care.