Search

Abstract Xanthomonas oryzae pv. oryzae (Xoo) causes bacterial blight in rice. Polyhydroxyalkanoates (PHAs) consitute a diverse group of biopolyesters synthesized by bacteria under nutrient-limited conditions. The phaC gene is important for PHA polymerization. We investigated the effects of phaC gene mutagensis in Xoo strain PXO99A. The phaC gene knock-out mutant exhibited reduced swarming ability relative to that of the wild-type. Under conditions where glucose was the sole sugar source, extracellular polysaccharide (EPS) production by ΔphaC declined by 44.8%. ΔphaC showed weak hypersensitive response (HR) induction in the leaves of non-host Nicotiana tabacum, concomitant with downregulation of hpa1 gene expression. When inoculated in rice leaves by the leaf-clipping method, ΔphaC displayed reduced virulence in terms of lesion length compared with the wild-type strain. The complemented strain showed no significant difference from the wild-type strain, suggesting that the deletion of phaC in Xoo induces significant alterations in various physiological and biological processes. These include bacterial swarming ability, EPS production, transcription of hrp genes, and glucose metabolism. These changes are intricately linked to the energy utilization and virulence of Xoo during plant infection. These findings revealed involvement of phaC in Xoo is in the maintaining carbon metabolism by functioning in the PHA metabolic pathway.

Abstract As a typical failure phenomenon in transformers, sulfur corrosion has garnered significant attention in the field of high‐voltage engineering. Grain boundary character distribution (GBCD) copper windings have been introduced to enhance sulfur corrosion resistance by slowing down intergranular corrosion. In this study, the sulfur corrosion behaviour and mechanisms of the GBCD copper windings under various temperatures were experimentally and theoretically studied. Results show that GBCD can enhance the corrosion resistance of copper in liquid environments. With the increase in temperatures, the insulating properties of oil and papers in traditional copper windings experience notable degradation, while GBCD copper windings show more stable insulating behaviours. In addition, modelling of grain boundary energy indicates that the grain boundary structure of GBCD copper windings has a lower average interface energy of 0.170 eV/Å2. Calculations of reaction thermodynamics show that GBCD copper windings possess a higher failure temperature (135.2°C) and inhibition degree (activation energy) of the sulfur corrosion (32,557.62 J/mol), revealing the stability and enhanced sulfur corrosion resistance at elevated temperatures.

ABSTRACT Antibiotic resistance poses a significant public health threat worldwide. The rise in antibiotic resistance and the sharp decline in effective antibiotics necessitate the development of innovative antibacterial agents. Based on the central symmetric structure of glycine–serine–glycine, combined with tryptophan and arginine, we designed a range of antimicrobial peptides (AMPs) that exhibited broad-spectrum antibacterial activity. Notably, AMP W5 demonstrated a rapid and effective sterilization against methicillin-resistant Staphylococcus aureus (MRSA), displaying both a minimum inhibitory concentration and a minimum bactericidal concentration of 8 µM. Mechanistic studies revealed that AMP W5 killed bacterial cells by disrupting the cytoplasmic membrane integrity, triggering leakage of cell contents. AMP W5 also exhibited excellent biocompatibility in both in vitro and in vivo safety evaluations. AMP W5 treatment significantly reduced skin bacterial load in our murine skin infection model. In conclusion, we designed a novel centrosymmetric AMP representing a promising medical alternative to conventional antibiotics for treating MRSA infections.IMPORTANCEIncreasing antibiotic resistance and the paucity of effective antibiotics necessitate innovative antibacterial agents. Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen causing bacterial infections with high incidence and mortality rates, showing increasing resistance to clinical drugs. Antimicrobial peptides (AMPs) exhibit significant potential as alternatives to traditional antibiotics. This study designed a novel series of AMPs, characterized by a glycine–serine–glycine-centered symmetrical structure, and our results indicated that AMP W5 exhibited a rapid and effective bactericidal effect against MRSA. AMP W5 also demonstrated excellent biocompatibility and a bactericidal mechanism that disrupted membrane integrity, leading to leakage of cellular contents. The notable reduction in skin bacterial load observed in mouse models reinforced the clinical applicability of AMP W5. This study provides a promising solution for addressing the increasing threat of antibiotic-resistant bacteria and heralds new prospects for clinical applications.

Abstract Hydrogel sensors are widely utilized in soft robotics and tissue engineering due to their excellent mechanical properties and biocompatibility. However, in high‐water environments, traditional hydrogels can experience significant swelling, leading to decreased mechanical and electrical performance, potentially losing shape, and sensing capabilities. This study addresses these challenges by leveraging the Hofmeister effect, coupled with directional freezing and salting‐out techniques, to develop a layered, high‐strength, tough, and antiswelling PVA/MXene hydrogel. In particular, the salting‐out process enhances the self‐entanglement of PVA, resulting in an S‐PM hydrogel with a tensile strength of up to 2.87 MPa. Furthermore, the S‐PM hydrogel retains its structure and strength after 7 d of swelling, with only a 6% change in resistance. Importantly, its sensing performance is improved postswelling, a capability rarely achievable in traditional hydrogels. Moreover, the S‐PM hydrogel demonstrates faster response times and more stable resistance change rates in underwater tests, making it crucial for long‐term continuous monitoring in challenging aquatic environments, ensuring sustained operation and monitoring.

BackgroundCardiac rupture (CR) after acute myocardial infarction (AMI) is a fatal mechanical complication. The early identification of factors related to CR in high-risk cases may reduce mortality. The purpose of our study was to discover relevant risk factors for CR after AMI and in-hospital mortality from CR.MethodsIn this study, we enrolled 1,699 AMI cases from October 2013 to May 2020. A total of 51 cases were diagnosed with CR. Clinical diagnostic information was recorded and analyzed retrospectively. We randomly matched these cases with AMI patients without CR in a 1:4 ratio. Univariate and multivariate logistic regression and stratifying analysis were used to identify risk factors for CR. Univariate and multivariate Cox regression hazard analysis and stratifying analysis were used to assess predictors of in-hospital mortality from CR.ResultsThe incidence of CR after AMI was 3.0% and in-hospital mortality was approximately 57%. Multivariate logistic regression analysis identified that white blood cell count, neutrophil percentage, anterior myocardial infarction, a Killip class of >II, and albumin level were independently associated with CR (p II, and neutrophil percentage were independent risk factors for male and female CR (p II were independent and significant predictors for CR. However, risk factors are different in male and female CR. The time from symptom to CR, the site of CR, and platelet counts were independent predictors for in-hospital mortality from CR. These may be helpful in the early and accurate identification of high-risk patients with CR and the assessment of prognosis. In addition, gender differences should be considered.

Presently, integrating multi-omics information into a prediction model has become a ameliorate strategy for genomic selection to improve genomic prediction accuracy. Here, we set the genomic and transcriptomic data as the training population data, using BSLMM, TWAS, and eQTL mapping to prescreen features according to | ^βb|>0, top 1% of phenotypic variation explained (PVE), expression-associated single nucleotide polymorphisms (eSNPs), and egenes (false discovery rate (FDR)

Exploring approaches to improve rural household well-being has always been an important task. This research investigates the effect of Internet use on rural household well-being measured by household consumption diversity, utilizing the 2016, 2018, and 2020 China Family Panel Studies survey data. To assess rural household consumption diversity, we employ the Simpson index and Shannon−Weaver index. To address the endogeneity of Internet use, we regress an instrumental variable-based two-stage least square (2SLS) method. The results show that Internet use substantially improves rural household consumption diversity. The disaggregated analysis suggests that low-income and small households in Central China benefit the most in consumption diversity improvement from using the Internet. Moreover, the mechanism analysis results show that household deposits and households’ beliefs about accessing commercial activities can positively mediate the relationship between Internet use and consumption diversity of rural household. Our findings provide new evidence for the literature on the role of Internet use in improving household consumption diversity in rural China.

BackgroundHeart failure is a common cause of adverse cardiovascular outcomes in patients with chronic kidney disease (CKD). Left atrial (LA) characteristics are thought to be involved in the development of heart failure. However, LA assessment is complex. Though a variety of parameters have been defined, there is no single parameter that best defines LA function. Pilot data indicate that left atrial volumetric/mechanical coupling index (LACI) may be useful, but data with CKD are lacking.AimThe objective of this study was to define LACI in a cohort of patients with CKD and to assess its value in evaluating LA function and predicting heart failure.MethodsA cohort of patients with CKD was enrolled at our hospital between 2021 and 2023. Follow-up was performed for heart failure. LACI is a volumetric to mechanical coupling index, calculated as the ratio of the LA volume index to the tissue-Doppler myocardial velocity at atrial contraction. Spearman’s rank correlation or Pearson’s correlation was used to calculate the correlation between LACI and echocardiographic/hemodynamic variables. Receiver operating characteristic curve (ROC) analysis was utilised to derive the area under the curve (AUC) for LACI, LVGLS, LASr, LASct and LASI for the detection of heart failure. Kaplan-Meier survival curves were employed to compare clinical outcomes based on LACI thresholds. A multivariable logistic regression analysis was employed to assess the relationship between risk factors and elevated LACI. Cox proportional hazards regression was used to identify risk factors for heart failure.ResultsLACI showed a positive correlation with NT-proBNP, CK-MB, LAVI, E/e’ and LASI (r = 0.504, 0.536, 0.856, 0.541 and 0.509, p 5.0 (log-rank test: P 5.0 was an independent predictor of heart failure [OR: 0.121, 95% CI (0.020–0.740), p = 0.022].ConclusionLACI may prove to be a valuable tool for assessing LA function in patients with CKD, and could be integrated into the routine assessment of LA for the purpose of prognostic assessment and clinical decision-making in patients with CKD.

Abstract Background Spermatogonial stem cells (SSCs) are the foundation cells for continual spermatogenesis and germline regeneration in mammals. SSC activities reside in the undifferentiated spermatogonial population, and currently, the molecular identities of SSCs and their committed progenitors remain unclear. Results We performed single-cell transcriptome analysis on isolated undifferentiated spermatogonia from mice to decipher the molecular signatures of SSC fate transitions. Through comprehensive analysis, we delineated the developmental trajectory and identified candidate transcription factors (TFs) involved in the fate transitions of SSCs and their progenitors in distinct states. Specifically, we characterized the Asingle spermatogonial subtype marked by the expression of Eomes. Eomes+ cells contained enriched transplantable SSCs, and more than 90% of the cells remained in the quiescent state. Conditional deletion of Eomes in the germline did not impact steady-state spermatogenesis but enhanced SSC regeneration. Forced expression of Eomes in spermatogenic cells disrupted spermatogenesis mainly by affecting the cell cycle progression of undifferentiated spermatogonia. After injury, Eomes+ cells re-enter the cell cycle and divide to expand the SSC pool. Eomes+ cells consisted of 7 different subsets of cells at single-cell resolution, and genes enriched in glycolysis/gluconeogenesis and the PI3/Akt signaling pathway participated in the SSC regeneration process. Conclusions In this study, we explored the molecular characteristics and critical regulators of subpopulations of undifferentiated spermatogonia. The findings of the present study described a quiescent SSC subpopulation, Eomes+ spermatogonia, and provided a dynamic transcriptional map of SSC fate determination.

Abstract Background There has been a significant surge in the global prevalence of diabetes mellitus (DM), which increases the susceptibility of individuals to ovarian cancer (OC). However, the relationship between DM and OC remains largely unexplored. The objective of this study is to provide preliminary insights into the shared molecular regulatory mechanisms and potential biomarkers between DM and OC. Methods Multiple datasets from the GEO database were utilized for bioinformatics analysis. Single cell datasets from the GEO database were analysed. Subsequently, immune cell infiltration analysis was performed on mRNA expression data. The intersection of these datasets yielded a set of common genes associated with both OC and DM. Using these overlapping genes and Cytoscape, a protein‒protein interaction (PPI) network was constructed, and 10 core targets were selected. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were then conducted on these core targets. Additionally, advanced bioinformatics analyses were conducted to construct a TF-mRNA-miRNA coregulatory network based on identified core targets. Furthermore, immunohistochemistry staining (IHC) and real-time quantitative PCR (RT-qPCR) were employed for the validation of the expression and biological functions of core proteins, including HSPAA1, HSPA8, SOD1, and transcription factors SREBF2 and GTAT2, in ovarian tumors. Results The immune cell infiltration analysis based on mRNA expression data for both DM and OC, as well as analysis using single-cell datasets, reveals significant differences in mononuclear cell levels. By intersecting the single-cell datasets, a total of 119 targets related to mononuclear cells in both OC and DM were identified. PPI network analysis further identified 10 hub genesincludingHSP90AA1, HSPA8, SNRPD2, UBA52, SOD1, RPL13A, RPSA, ITGAM, PPP1CC, and PSMA5, as potential targets of OC and DM. Enrichment analysis indicated that these genes are primarily associated with neutrophil degranulation, GDP-dissociation inhibitor activity, and the IL-17 signaling pathway, suggesting their involvement in the regulation of the tumor microenvironment. Furthermore, the TF-gene and miRNA-gene regulatory networks were validated using NetworkAnalyst. The identified TFs included SREBF2, GATA2, and SRF, while the miRNAs included miR-320a, miR-378a-3p, and miR-26a-5p. Simultaneously, IHC and RT-qPCR reveal differential expression of core targets in ovarian tumors after the onset of diabetes. RT-qPCR further revealed that SREBF2 and GATA2 may influence the expression of core proteins, including HSP90AA1, HSPA8, and SOD1. Conclusion This study revealed the shared gene interaction network between OC and DM and predicted the TFs and miRNAs associated with core genes in monocytes. Our research findings contribute to identifying potential biological mechanisms underlying the relationship between OC and DM.

Abstract Background Mutations in MPZL2, the characteristic genetic etiology of autosomal recessive deafness loci 111 (DFNB111), cause non-syndromic and moderate sensorineural hearing loss. Methods In this study, we analyzed the phenotype and genotype of eight pedigrees consisting of 10 hearing loss patients with bi-allelic pathogenic or likely pathogenic variants in MPZL2. These patients were identified from a 3272 Chinese patient cohort who underwent genetic testing. Results Apart from symmetrical and moderate sensorineural hearing loss, the MPZL2-related phenotype was characterized by progressive hearing loss with variation in the onset age (congenital defect to onset at the young adult stage). We determined that in the Chinese population, the genetic load of MPZL2 defects was 0.24% (8/3272) in patients diagnosed with hearing loss and 7.02% (8/114) in patients diagnosed with hereditary moderate sensorineural hearing loss caused by STRC, OTOA, OTOG, OTOGL, TECTA, MPZL2 and others. Three known MPZL2 variants (c.220C > T (p.Gln74*), c.68delC (p.Pro23Leufs*2), c.463delG (p.Ala155Leufs*10)) and a novel start loss variant (c.3G > T (p.Met1?)) were identified. MPZL2 c.220C > T was identified as the hotspot variant in the Chinese population and even in East Asia compared with c.72delA (p.Ile24Metfs*22) in European and West Asia through allele frequency. Conclusions We concluded that apart from moderate HL, progressive HL is another character of MPZL2-related HL. No specified variant was verified for the progression of HL, the penetrance and expressivity cannot be determined yet. A novel MPZL2 variant at the start codon was identified, enriching the variant spectrum of MPZL2. The hotspot variants of MPZL2 vary in different ethnicities. This study provides valuable data for the diagnosis, prognosis evaluation and genetic counseling of patients with moderate sensorineural hearing loss related to MPZL2.

A major impedance to neuronal regeneration after peripheral nerve injury (PNI) is the activation of various programmed cell death mechanisms in the dorsal root ganglion. Ferroptosis is a form of programmed cell death distinguished by imbalance in iron and thiol metabolism, leading to lethal lipid peroxidation. However, the molecular mechanisms of ferroptosis in the context of PNI and nerve regeneration remain unclear. Ferroportin (Fpn), the only known mammalian nonheme iron export protein, plays a pivotal part in inhibiting ferroptosis by maintaining intracellular iron homeostasis. Here, we explored in vitro and in vivo the involvement of Fpn in neuronal ferroptosis. We first delineated that reactive oxygen species at the injury site induces neuronal ferroptosis by increasing intracellular iron via accelerated UBA52-driven ubiquitination and degradation of Fpn, and stimulation of lipid peroxidation. Early administration of the potent arterial vasodilator, hydralazine (HYD), decreases the ubiquitination of Fpn after PNI by binding to UBA52, leading to suppression of neuronal cell death and significant acceleration of axon regeneration and motor function recovery. HYD targeting of ferroptosis is a promising strategy for clinical management of PNI.

Abstract Emerging evidence reveals associations between metabolic syndrome (MetS) and psychiatric disorders (PDs), although causality remains uncertain. Consequently, we conducted Mendelian randomization (MR) to systematically evaluate the causality between MetS and PDs. Linkage disequilibrium score regression estimated the heritability of PDs and their genetic correlations with MetS. In primary analyses, the main model employed inverse variance weighting method, with sensitivity analyses using various MR models to ensure robustness. Replication MR analyses, involving cohorts distinct from those in the primary analyses, were performed to validate the generalizability of the findings. Multivariable MR analyses were carried out to account for genetically predicted body mass index (BMI). As a result, genetic correlations of MetS with attention-deficit/hyperactivity disorder(ADHD), anorexia nervosa(ANO), major depressive disorder(MDD), and schizophrenia were identified. Causal effects of MetS on ADHD (OR: 1.59 [95% CI:1.45–1.74]), ANO (OR: 1.42 [95% CI:1.25–1.61]), MDD(OR: 1.23 [95% CI: 1.13–1.33]), and the effects of ADHD (OR: 1.03 [95% CI: 1.02–1.04]) and ANO (OR: 1.01 [95% CI: 1.01–1.02]) on MetS were observed in primary analyses. Results from sensitivity analyses and replication analyses were generally consistent with the primary analyses, confirming the robustness and generalizability of the findings. Associations between MetS and ADHD, as well as ANO persisted after adjusting for BMI, whereas the statistical significance of the association between MetS and MDD was no longer observable. These results contribute to a deeper understanding of the mechanisms underlying PDs, suggesting potential modifiable targets for public prevention and clinical intervention in specific PDs related to metabolic pathways.

Abstract Background Brentuximab vedotin (BV) was approved as a therapy for patients with CD30‐positive lymphoma in China in 2020 based on the results of multiple clinical trails. Few Chinese real‐world data of its use are yet available. Herein, we present the application situation of BV in patients with lymphoma among different hospitals in Henan province in China under real‐world conditions. Methods This was a multicenter and retrospective study in 104 patients with lymphoma who received BV for the first time between August 2020 and September 2022 across eight centers in Henan province. Data on the clinical use, effectiveness and adverse events (AEs) of BV were extracted from patient medical records. Short‐term effectiveness was assessed based on objective response rate (ORR), complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Progression‐free survival (PFS) and overall survival (OS) were calculated using Kaplan–Meier method. Safety was also evaluated in our study. Results 104 lymphoma patients were enrolled in our study, who had completed a median of two cycles (range,1–8) of BV‐based treatment. A total of 72.1% of patients were relapsed/refractory (R/R) lymphoma, and only 27.9% were previously untreated lymphoma who received BV in frontline treatment settings. Among them who received effectiveness evaluation, the ORR achieved 64.5% (CR 25.8%, PR 38.7%). After a median follow‐up of 11 months, the 6‐month PFS rate and OS rate achieved 77.2% and 90.1% respectively, and the 12‐month PFS rate and OS rate achieved 77.2% and 79.9% respectively. In general, BV‐based treatment was well‐tolerated, with 38.5% incidence of grade ≥3 AEs. The most commonly reported AEs were hematologic disorders, especially neutropenia, with the incidence reaching 50.0%. Conclusions BV‐based regimens could be a promising therapeutic option with remarkable effectiveness and moderate toxicity in treating Chinese lymphoma patients with CD30 expression.

To better understand the effects of agronomic practices on yield–nutrition relationships in wheat (Triticum aestivum L.) grains for Zn biofortification while improving yields simultaneously, effects of different soil fertilization and different drone-based foliar spraying treatments were investigated in calcareous soils. For soil fertilization, the incorporation of Zn or increasing the N/P ratio in compound fertilizers proved to be effective in enhancing grain Zn concentrations and yields. However, the overall effects of soil fertilization are limited, with a maximal yield increase of only 7.0% and a maximal increase of the grain Zn concentration from 19.4 to 27.0 mg/kg, which is far below the target biofortification value of 40–50 mg/kg. Unfortunately, there was a negative side effect, which decreased Fe and Mn concentrations and the Fe bioavailability. Notably, drone-based foliar Zn sprayings increased grain yields from the control 7.5 t/ha to 8.6 t/ha at ZnO treatment by 12.0% and 8.8 t/ha at ZnSO4·7H2O treatment by 17.3%. Meanwhile, grain Zn concentrations were increased from the control 33.5 mg/kg to 41.9 mg/kg at ZnO treatment by 25.1% and 43.6 mg/kg at ZnSO4·7H2O treatment by 30.1%. Treatments with ZnSO4·7H2O increased grain Zn concentrations and accumulation more so than ZnO, indicating the importance of chemical Zn forms in determining the effectiveness of foliar spraying. Moreover, foliar Zn sprayings simultaneously increased grain concentrations and accumulation of Fe, Mn and Cu, demonstrating multiple benefits. There were positive correlations between Zn and Fe, Mn or Cu, indicating synergistic interactions. Compared to micronutrients, concentrations of grain macronutrients (N, P, K, Ca and Mg) were less affected. Thus, a dual-benefit in both grain yields and micronutrient (particularly for Zn) nutrition could be effectively achieved through appropriate soil fertilization and foliar Zn spraying. These findings provide a better understanding of the yield–nutrition relationship among wheat grain yields, Zn and other nutrient elements for a better integrated manipulation to achieve a win–win situation in yield and nutrition.

Background: Radiotherapy has become a standard treatment for chest tumors, but a common complication of radiotherapy is radiation lung injury. Currently, there is still a lack of effective treatment for radiation lung injury. Methods: A mouse model of radioactive lung injury (RILI) was constructed and then treated with different cycles of hydrogen inhalation. Lung function tests were performed to detect changes in lung function.HE staining was used to detect pathological changes in lung tissue. Immunofluorescence staining was used to detect the polarization of macrophages in lung tissue. Immunohistochemistry was used to detect changes in cytokine expression in lung tissues. Western Blot was used to detect the expression of proteins related to the NF-κB signalling pathway. Results: Lung function test results showed that lung function decreased in the model group and improved in the treatment group.HE staining showed that inflammatory response was evident in the model group and decreased in the treatment group. Immunohistochemistry results showed that the expression of pro-inflammatory factors was significantly higher in the model group, and the expression of pro-inflammatory factors was significantly higher in the treatment group. The expression of pro-inflammatory factors in the treatment group was significantly lower than that in the model group, and the expression of anti-inflammatory factors in the treatment group was higher than that in the model group. Immunofluorescence showed that the expression of M1 subtype macrophages was up-regulated in the model group and down-regulated in the treatment group. The expression of M2 subtype macrophages was up-regulated in the treatment group relative to the model group. Western Blot showed that P–NF-κB p65/NF-κB p65 was significantly increased in the model group, and P–NF-κB p65/NF-κB p65 was decreased in the treatment group. Conclusion: Hydrogen therapy promotes macrophage polarization from M1 to M2 subtypes by inhibiting the NF-κB signalling pathway, thereby attenuating the inflammatory response to radiation lung injury.

Due to continuous plantation of poplar, its growth and biomass accumulation may be negatively affected by the accumulation of allelochemicals such as para-hydroxybenzoic acid (pHBA) in soil. As photosynthesis is the most fundamental process in plants, it can be negatively impacted by pHBA stress. Therefore, it is crucial to improve photosynthetic capacity under pHBA stress to facilitate poplar plant growth. The mitogen-activated protein kinase (MAPK) cascade pathway is widely involved in environmental stress responses in plants. However, the regulation mechanisms of photosynthesis-related pathways by MAPK pathway genes under pHBA stress are still unclear. In this study, through transcriptome analysis and weighted gene co-expression network analysis, we observed that PeMPK7 overexpression in poplar can regulate the expression of photosynthesis-related genes and transcription factor genes, namely, WRKY1, WRKY33, and ERF3, during the early stage of pHBA stress. In addition, PeMPK7 can improve photosynthesis in poplar under long-term pHBA stress. Moreover, yeast two-hybrid and pull-down assays confirmed the interaction between PeMPK7 and PeMKK7/10. Based on these results, a schematic diagram of the pathways involved in the regulation of photosynthesis by PeMPK7 was constructed. This study provided novel insights into the molecular mechanisms of regulation of pHBA stress via MAPK cascade pathway.

Mitochondrial transfer RNA mutation is one of the most important causes of hereditary hearing loss in humans. Mitochondrial transfer RNASer (UCN) gene is another hot spot for mutations associated with non-syndromic hearing loss, besides the 12S ribosomal RNA gene. In this study, we assessed the clinical phenotype and the molecular characteristics of two Chinese families with non-syndromic hearing loss. Mutational analysis revealed that 7445A > G and 7510T > C mutations in the mitochondrial transfer RNASer (UCN) gene were the molecular etiology of Family 1 and Family 2, respectively. However, the clinical and genetic characteristics of the two families carrying the above mutations in the transfer RNASer (UCN) gene exhibited a variable expression of hearing loss and an incomplete penetrance. Sequencing analysis of the complete mitochondrial genome showed the presence of transfer RNATrp 5568A > G and NADH-ubiquinone oxidoreductase chain 4 11696G > A mutations in Family 1. The mitochondrial haplotype analysis showed that the two families belonged to Asian D4 and M80′D haplotypes, respectively, and no pathogenic variations were found in the nuclear genes. To our knowledge, our study is the first to report 7445A > G and 7510T > C mutations in the mitochondrial transfer RNASer (UCN) gene, in multi-generation non-syndromic hearing loss pedigrees from China. Our study suggests that 5568A > G and 11696G > A mutations may enhance the penetrance of hearing loss in Chinese Family 1, while mitochondrial haplotypes and known nuclear genes may not be modifiers for the phenotypic expression of 7445A > G and 7510T > C mutations in these Chinese families.

Low expression levels of breast cancer metastasis suppressor 1 like (BRMS1L) have been associated with the growth of cancer cells. However, the mechanisms underlying the role of BRMS1L as an antitumour transcription factor in the progression of NSCLC have not been explored. Herein, we reveal that BRMS1L plays a key role as a tumour suppressor in inhibiting NSCLC proliferation and metastasis. Mechanistically, BRMS1L overexpression results in the downregulation of glutathione peroxidase 2 (GPX2) expression and consequently causes abnormal glutathione metabolism and increased levels of reactive oxygen species (ROS) in cells, inducing oxidative stress injury and apoptosis. Furthermore, overexpression of GPX2 enhances the growth advantage and oxidative stress repair conferred by knockdown of BRMS1L. Importantly, we show that low expression of BRMS1L in NSCLC cells causes relatively high levels of antioxidant accumulation to maintain cell redox balance and renders cancer cells more sensitive to treatment with piperlongumine as an ROS inducer both in vitro and in vivo. These findings offer new insights into the role of BRMS1L as a transcriptional repressor in NSCLC and suggest that the BRMS1L expression level may be a potential biomarker for predicting the therapeutic response to small molecule ROS inducers, providing new ideas for targeted therapy.

Abstract The phenomenon of transformer failure caused by oil‐sulphur corrosion of oil₋paper insulation system has always been concerned by scholars. Irgamet 39 is the most used metal passivator for inhibiting sulphur corrosion. However, Irgamet 39 causes abnormal dissolved gas in oil during the process of exerting anti‐corrosion effect. Herein, the gas production mechanism of Irgamet 39 and its long‐term corrosion resistance were investigated. Compared with other metal passivators, the Irgamet 39 produces more dissolved gases in oil, especially H2, CO and CO2. The main sources of free radicals in the gas production process are from the branched chains of the Irgamet 39 structure (−CH2N(C8H17)2 and −CH3). Furthermore, the ageing products of insulating paper and oil promote the cleavage of the chain in the Irgamet 39 molecule, which then causes Irgamet 39 to generate more dissolved gases. Irgamet 39 exhibits excellent long‐term corrosion inhibition properties,while it also leads to abnormal gases in the oil, which can affect the interpretation of the dissolved gas analysis data and thus interfere with the diagnosis. This work provides useful information for the practical application of Irgamet 39 and helps electrical workers make reasonable predictions for transformer problems.

Abstract The CRISPR-Cas13 ribonucleases have been widely applied for RNA knockdown and transcriptional modulation owing to their high programmability and specificity. However, the large size of Cas13 effectors and their non-specific RNA cleavage upon target activation limit the adeno-associated virus based delivery of Cas13 systems for therapeutic applications. Herein, we report detailed biochemical and structural characterizations of a compact Cas13 (Cas13bt3) suitable for adeno-associated virus delivery. Distinct from many other Cas13 systems, Cas13bt3 cleaves the target and other nonspecific RNA at internal “UC” sites and is activated in a target length-dependent manner. The cryo-electron microscope structure of Cas13bt3 in a fully active state illustrates the structural basis of Cas13bt3 activation. Guided by the structure, we obtain engineered Cas13bt3 variants with minimal off-target cleavage yet maintained target cleavage activities. In conclusion, our biochemical and structural data illustrate a distinct mechanism for Cas13bt3 activation and guide the engineering of Cas13bt3 applications.

Abstract DNA base editors use deaminases fused to a programmable DNA-binding protein for targeted nucleotide conversion. However, the most widely used TadA deaminases lack post-translational control in living cells. Here, we present a split adenine base editor (sABE) that utilizes chemically induced dimerization (CID) to control the catalytic activity of the deoxyadenosine deaminase TadA-8e. sABE shows high on-target editing activity comparable to the original ABE with TadA-8e (ABE8e) upon rapamycin induction while maintaining low background activity without induction. Importantly, sABE exhibits a narrower activity window on DNA and higher precision than ABE8e, with an improved single-to-double ratio of adenine editing and reduced genomic and transcriptomic off-target effects. sABE can achieve gene knockout through multiplex splice donor disruption in human cells. Furthermore, when delivered via dual adeno-associated virus vectors, sABE can efficiently convert a single A•T base pair to a G•C base pair on the PCSK9 gene in mouse liver, demonstrating in vivo CID-controlled DNA base editing. Thus, sABE enables precise control of base editing, which will have broad implications for basic research and in vivo therapeutic applications.

Carbon use efficiency (CUE) was identified as a pivotal parameter for elucidating the carbon cycle within ecosystems. It signified the efficiency with which light energy was transformed into organic matter by vegetation. In light of the challenges posed by global warming, it was deemed essential to gain a comprehensive understanding of the fluctuations and determinants of CUE. Despite the significance of this topic, the current research on factors influencing CUE remained incomplete, notably lacking in exploration of the impacts of ecological engineering on CUE. The objective of this study is to elucidate the influences of climate change and ecological engineering on CUE, quantifying their effects using residual analysis. Additionally, it aims to analyze the primary factors contributing to the fluctuations in CUE. Our findings indicated an average CUE of 0.8536 (±0.0026) with minor interannual variation. In the Three Rivers Source region, CUE is jointly influenced by ecological engineering (30.88%) and climate change (69.12%). Notably, climatic factors predominantly regulate CUE, accounting for approximately 90.20% of its regional variations, with over 44.70% of areas exhibiting contributions exceeding 80%. Moreover, the impact of evapotranspiration on CUE surpasses that of precipitation and temperature, while factors such as elevation and vegetation types also play significant roles. This study showed the quantification of climate change and ecological engineering effects on CUE, which would hold substantial implications for predicting and evaluating global carbon cycling.

Complex traits are widely considered to be the result of a compound regulation of genes, environmental factors, and genotype-by-environment interaction (G × E). The inclusion of G × E in genome-wide association analyses is essential to understand animal environmental adaptations and improve the efficiency of breeding decisions. Here, we systematically investigated the G × E of growth traits (including weaning weight, yearling weight, 18-month body weight, and 24-month body weight) with environmental factors (farm and temperature) using genome-wide genotype-by-environment interaction association studies (GWEIS) with a dataset of 1350 cattle. We validated the robust estimator’s effectiveness in GWEIS and detected 29 independent interacting SNPs with a significance threshold of 1.67 × 10−6, indicating that these SNPs, which do not show main effects in traditional genome-wide association studies (GWAS), may have non-additive effects across genotypes but are obliterated by environmental means. The gene-based analysis using MAGMA identified three genes that overlapped with the GEWIS results exhibiting G × E, namely SMAD2, PALMD, and MECOM. Further, the results of functional exploration in gene-set analysis revealed the bio-mechanisms of how cattle growth responds to environmental changes, such as mitotic or cytokinesis, fatty acid β-oxidation, neurotransmitter activity, gap junction, and keratan sulfate degradation. This study not only reveals novel genetic loci and underlying mechanisms influencing growth traits but also transforms our understanding of environmental adaptation in beef cattle, thereby paving the way for more targeted and efficient breeding strategies.

Abstract Mutations in Atp2b2, an outer hair cell gene, cause dominant hearing loss in humans. Using a mouse model Atp2b2 Obl/+, with a dominant hearing loss mutation (Oblivion), we show that liposome-mediated in vivo delivery of CRISPR-Cas9 ribonucleoprotein complexes leads to specific editing of the Obl allele. Large deletions encompassing the Obl locus and indels were identified as the result of editing. In vivo genome editing promotes outer hair cell survival and restores their function, leading to hearing recovery. We further show that in a double-dominant mutant mouse model, in which the Tmc1 Beethoven mutation and the Atp2b2 Oblivion mutation cause digenic genetic hearing loss, Cas9/sgRNA delivery targeting both mutations leads to partial hearing recovery. These findings suggest that liposome-RNP delivery can be used as a strategy to recover hearing with dominant mutations in OHC genes and with digenic mutations in the auditory hair cells, potentially expanding therapeutics of gene editing to treat hearing loss.

Abstract Background Ocular trauma is a leading cause of vision loss. Penetrating ocular injury is a major type of open globe injury(OGI), while its epidemiology and clinical characteristics are still uncertain. The aim of this study is to reveal the prevalence and prognostic factors of penetrating ocular injury in the Shandong province. Methods A retrospective study of penetrating ocular injury was performed at the Second Hospital of Shandong University, from January 2010 to December 2019. Demographic information, injury causes, ocular trauma types, and initial and final visual acuity(VA) were analyzed. To obtain more precise characteristics of penetrating injury, the eye global was divided into three zones and analyzed. Results Among 210 OGI, there are 83 penetrating injuries which account for 39.5% of all. In addition, the final VA of 59 penetrating injuries recovered to 0.1 or better, which possesses the highest frequency among OGI. In order to research the relationship between the wound location and the final VA, we took 74 cases of penetrating injuries without retina or optic nerve damage for analysis. Results show that 62 were male and 12 were female. The average age was 36.01 ± 14.15. The most frequent occupation is the worker followed by the peasant. Statistics show that there is an obvious deviation in the Ocular trauma score (OTS) predicting the final VA and the actual final VA in the 45–65 score group (p

The exploration of ways to reduce the downside risk of grain yield posed by meteorological disasters has become a primary task in China. This study employs a moment-based model to estimate the downside risks of maize, rice, and wheat yields. It further analyses the risk mitigation effects of implementing a high-standard farmland construction policy in China using a continuous difference-in-differences (DID) model and Chinese provincial data from 2005 to 2017. The results show that the downside risk of wheat yield but not of maize or rice yield increases when meteorological disasters are considered, implying that wheat is more vulnerable to the adverse effects of meteorological disasters than are maize and rice. China’s high-standard farmland construction policy can significantly mitigate the downside risk of wheat yield. The heterogeneity analysis suggests that provinces with higher education levels and lower population density benefit the most from the downside risk reduction due to the implementation of the high-standard farmland construction policy. To further mitigate the downside risk posed by meteorological disasters, China should accelerate the construction of high-standard farmland while simultaneously focusing on upgrading human capital and promoting urbanization in rural areas.

We previously conducted a systematic study on the metabolic process and products of hederasaponin B in rats. We hypothesized that the sugar chain structures play a key role in the metabolism of triterpenoid saponins. To verify this hypothesis, we conducted metabolic research on ciwujianoside B ascribed to the same sugar chains and a distinct aglycone and compared it with hederasaponin B. Specifically, we collected feces, urine, and plasma of rats after gavage with ciwujianoside B and identified 42 metabolites by UPLC-Fusion Lumos Orbitrap mass spectrometry. Finally, ciwujianoside B metabolism and hederasaponin B metabolism were compared, reaching the following conclusions: (i) more than 40 metabolites were identified in both, with the majority of metabolites identified in feces; (ii) the corresponding metabolic pathways in vivo were basically similar, including deglycosylation, acetylation, hydroxylation, glucuronidation, oxidation, and glycosylation; and (iii) deglycosylation was considered the main metabolic reaction, and its metabolites accounted for approximately 50% of all metabolites. Overall, this study provides a foundation for further research on the metabolism of triterpenoid saponins.

BackgroundWe previously found that the respiratory epithelial cells could eliminate the invaded group A streptococcus (GAS) through autophagy induced by binding a fibronectin (Fn) binding protein (FnBp) expressed on the surface of GAS to plasma protein Fn and its receptor integrin α5β1 of epithelial cells. Is autophagy initiated by FnBp+ bacteria via FnBp-Fn-Integrin α5β1 axis a common event in respiratory epithelial cells?MethodsWe chose Staphylococcus aureus (S. aureus/S. a) and Listeria monocytogenes (L. monocytogenes/L. m) as representatives of extracellular and intracellular FnBp+ bacteria, respectively. The FnBp of them was purified and the protein function was confirmed by western blot, viable bacteria count, confocal and pull-down. The key molecule downstream of the action axis was detected by IP, mass spectrometry and bio-informatics analysis.ResultsWe found that different FnBp from both S. aureus and L. monocytogenes could initiate autophagy through FnBp-Fn-integrin α5β1 axis and this could be considered a universal event, by which host tries to remove invading bacteria from epithelial cells. Importantly, we firstly reported that S100A8, as a key molecule downstream of integrin β1 chain, is highly expressed upon activation of integrin α5β1, which in turn up-regulates autophagy.ConclusionsVarious FnBp from FnBp+ bacteria have the ability to initiate autophagy via FnBp-Fn-Integrin α5β1 axis to promote the removal of invading bacteria from epithelial cells in the presence of fewer invaders. S100A8 is a key molecule downstream of Integrin α5β1 in this autophagy pathway.

Abstract Background A detailed understanding of genetic variants that affect beef merit helps maximize the efficiency of breeding for improved production merit in beef cattle. To prioritize the putative variants and genes, we ran a comprehensive genome-wide association studies (GWAS) analysis for 21 agronomic traits using imputed whole-genome variants in Simmental beef cattle. Then, we applied expression quantitative trait loci (eQTL) mapping between the genotype variants and transcriptome of three tissues (longissimus dorsi muscle, backfat, and liver) in 120 cattle. Results We identified 1,580 association signals for 21 beef agronomic traits using GWAS. We then illuminated 854,498 cis-eQTLs for 6,017 genes and 46,970 trans-eQTLs for 1,903 genes in three tissues and built a synergistic network by integrating transcriptomics with agronomic traits. These cis-eQTLs were preferentially close to the transcription start site and enriched in functional regulatory regions. We observed an average of 43.5% improvement in cis-eQTL discovery using multi-tissue eQTL mapping. Fine-mapping analysis revealed that 111, 192, and 194 variants were most likely to be causative to regulate gene expression in backfat, liver, and muscle, respectively. The transcriptome-wide association studies identified 722 genes significantly associated with 11 agronomic traits. Via the colocalization and Mendelian randomization analyses, we found that eQTLs of several genes were associated with the GWAS signals of agronomic traits in three tissues, which included genes, such as NADSYN1, NDUFS3, LTF and KIFC2 in liver, GRAMD1C, TMTC2 and ZNF613 in backfat, as well as TIGAR, NDUFS3 and L3HYPDH in muscle that could serve as the candidate genes for economic traits. Conclusions The extensive atlas of GWAS, eQTL, fine-mapping, and transcriptome-wide association studies aid in the suggestion of potentially functional variants and genes in cattle agronomic traits and will be an invaluable source for genomics and breeding in beef cattle.

Abstract Further deployment of rooftop solar photovoltaics (PV) hinges on the reduction of soft (non-hardware) costs—now larger and more resistant to reductions than hardware costs. The largest portion of these soft costs is the expenses solar companies incur to acquire new customers. In this study, we demonstrate the value of a shift from significance-based methodologies to prediction-oriented models to better identify PV adopters and reduce soft costs. We employ machine learning to predict PV adopters and non-adopters, and compare its prediction performance with logistic regression, the dominant significance-based method in technology adoption studies. Our results show that machine learning substantially enhances adoption prediction performance: The true positive rate of predicting adopters increased from 66 to 87%, and the true negative rate of predicting non-adopters increased from 75 to 88%. We attribute the enhanced performance to complex variable interactions and nonlinear effects incorporated by machine learning. With more accurate predictions, machine learning is able to reduce customer acquisition costs by 15% ($0.07/Watt) and identify new market opportunities for solar companies to expand and diversify their customer bases. Our research methods and findings provide broader implications for the adoption of similar clean energy technologies and related policy challenges such as market growth and energy inequality.

Copy number variation (CNV) serves as a significant source of genetic diversity in mammals and exerts substantial effects on various complex traits. Pingliang red cattle, an outstanding indigenous resource in China, possess remarkable breeding value attributed to their tender meat and superior marbling quality. However, the genetic mechanisms influencing carcass and meat quality traits in Pingliang red cattle are not well understood. We generated a comprehensive genome-wide CNV map for Pingliang red cattle using the GGP Bovine 100K SNP chip. A total of 755 copy number variable regions (CNVRs) spanning 81.03 Mb were identified, accounting for approximately 3.24% of the bovine autosomal genome. Among these, we discovered 270 potentially breed-specific CNVRs in Pingliang red cattle, including 143 gains, 73 losses, and 54 mixed events. Functional annotation analysis revealed significant associations between these specific CNVRs and important traits such as carcass and meat quality, reproduction, exterior traits, growth traits, and health traits. Additionally, our network and transcriptome analysis highlighted CACNA2D1, CYLD, UBXN2B, TG, NADK, and ITGA9 as promising candidate genes associated with carcass weight and intramuscular fat deposition. The current study presents a genome-wide CNV map in Pingliang red cattle, highlighting breed-specific CNVRs, and transcriptome findings provide valuable insights into the underlying genetic characteristics of Pingliang red cattle. These results offer potential avenues for enhancing meat quality through a targeted breeding program.

Integration of inverter-based distributed energy resources (DERs) is reshaping the landscape of distribution grids to fulfill the socioeconomic, environmental, and sustainability goals. Addressing the technological challenges of DER grid integration requires an adaptive communication layer for efficient DER management and control. This transition has given rise to a cyberphysical system (CPS) architecture within the distribution system, causing new vulnerabilities for cyberphysical attacks. To better address potential threats, this paper presents a comprehensive risk assessment framework for cyberphysical security in distribution grids with grid-edge DERs. The framework incorporates a detailed CPS model accounting for dynamic DER characteristics within the distribution grid. It identifies vulnerabilities in DER communication systems, models attack scenarios, and addresses communication latency crucial for inverter control timescales. Subsequently, the quantification of attack impacts employs an attack probability model including both the vulnerability and criticality of cyber components. The proposed risk assessment framework was validated through testing on the modified IEEE 13-node and 123-node test feeders.

Continuous spring cropping of Qingke (Hordeum viilgare L. var. nudum Hook. f.) results in a reduction in grain yield in the Xizang autonomous region. However, knowledge on the influence of continuous cropping on grain yield caused by reactive oxygen species (ROS)-induced stress remains scarce. A systematic comparison of the antioxidant defensive profile at seedling, tillering, jointing, flowering, and filling stages (T1 to T5) of Qingke was conducted based on a field experiment including 23-year continuous cropping (23y-CC) and control (the first year planted) treatments. The results reveal that the grain yield and superoxide anion (SOA) level under 23y-CC were significantly decreased (by 38.67% and 36.47%), when compared to the control. The hydrogen peroxide content under 23y-CC was 8.69% higher on average than under the control in the early growth stages. The higher ROS level under 23y-CC resulted in membrane lipid peroxidation (LPO) and accumulation of malondialdehyde (MDA) at later stages, with an average increment of 29.67% and 3.77 times higher than that in control plants. Qingke plants accumulated more hydrogen peroxide at early developmental stages due to the partial conversion of SOA by glutathione (GSH) and superoxide dismutase (SOD) and other production pathways, such as the glucose oxidase (GOD) and polyamine oxidase (PAO) pathways. The reduced regeneration ability due to the high oxidized glutathione (GSSG) to GSH ratio resulted in GSH deficiency while the reduction in L-galactono-1,4-lactone dehydrogenase (GalLDH) activity in the AsA biosynthesis pathway, higher enzymatic activities (including ascorbate peroxidase, APX; and ascorbate oxidase, AAO), and lower activities of monodehydroascorbate reductase (MDHAR) all led to a lower AsA content under continuous cropping. The lower antioxidant capacity due to lower contents of antioxidants such as flavonoids and tannins, detected through both physiological measurement and metabolomics analysis, further deteriorated the growth of Qingke through ROS stress under continuous cropping. Our results provide new insights into the manner in which ROS stress regulates grain yield in the context of continuous Qingke cropping.

Background/aimHuman epidermal growth factor receptor 2 (HER2)-positive breast cancer is associated with a higher risk of metastasis and poorer overall survival (OS) due to HER2 gene overexpression/amplification. Although anti-HER2 targeted therapy has shown survival benefits in HER2-positive advanced breast cancer (ABC) patients, long-term treatment often leads to drug resistance, complicating further treatment options. RC48, an antibody-drug conjugate (ADC), combines the benefits of antibody targeting with the cytotoxic effects of a small molecule drug.Case reportWe present a case involving a female patient with HER2-positive ABC who developed drug resistance and disease progression following multi-line anti-HER2 targeted therapy. In this instance, RC48 exhibited anti-tumor activity in an ABC patient resistant to HER2-targeted therapy. After eight treatment cycles with 120 mg of RC48, the tumor size decreased and stabilized.ConclusionThis case report underscores the potential clinical value of RC48 as a promising treatment alternative for patients resistant to HER2 targeted therapies.

Abstract Addressing the challenge of promoting directional axonal regeneration in a hostile astrocytic scar, which often impedes recovery following spinal cord injury (SCI), remains a daunting task. Cell transplantation is a promising strategy to facilitate nerve restoration in SCI. In this research, a pro‐regeneration system is developed, namely miR‐26a@SPIONs‐OECs, for olfactory ensheathing cells (OECs), a preferred choice for promoting nerve regeneration in SCI patients. These entities show high responsiveness to external magnetic fields (MF), leading to synergistic multimodal cues to enhance nerve regeneration. First, an MF stimulates miR‐26a@SPIONs‐OECs to release extracellular vesicles (EVs) rich in miR‐26a. This encourages axon growth by inhibiting PTEN and GSK‐3β signaling pathways in neurons. Second, miR‐26a@SPIONs‐OECs exhibit a tendency to migrate and orientate along the direction of the MF, thereby potentially facilitating neuronal reconnection through directional neurite elongation. Third, miR‐26a‐enriched EVs from miR‐26a@SPIONs‐OECs can interact with host astrocytes, thereby diminishing inhibitory cues for neurite growth. In a rat model of SCI, the miR‐26a@SPIONs‐OECs system led to significantly improved morphological and motor function recovery. In summary, the miR‐26a@SPIONS‐OECs pro‐regeneration system offers innovative insights into engineering exogenous cells with multiple additional cues, augmenting their efficacy for stimulating and guiding nerve regeneration within a hostile astrocytic scar in SCI.

BackgroundTumor microenvironment (TME) status is closely related to breast cancer (BC) prognosis and systemic therapeutic effects. However, to date studies have not considered the interactions of immune and stromal cells at the gene expression level in BC as a whole. Herein, we constructed a predictive model, for adjuvant decision-making, by mining TME molecular expression information related to BC patient prognosis and drug treatment sensitivity.MethodsClinical information and gene expression profiles were extracted from The Cancer Genome Atlas (TCGA), with patients divided into high- and low-score groups according to immune/stromal scores. TME-related prognostic genes were identified using Kaplan-Meier analysis, functional enrichment analysis, and protein-protein interaction (PPI) networks, and validated in the Gene Expression Omnibus (GEO) database. Least absolute shrinkage and selection operator (LASSO) Cox regression analysis was used to construct and verify a prognostic model based on TME-related genes. In addition, the patients’ response to chemotherapy and immunotherapy was assessed by survival outcome and immunohistochemistry (IPS). Immunohistochemistry (IHC) staining laid a solid foundation for exploring the value of novel therapeutic target genes.ResultsBy dividing patients into low- and high-risk groups, a significant distinction in overall survival was found (p < 0.05). The risk model was independent of multiple clinicopathological parameters and accurately predicted prognosis in BC patients (p < 0.05). The nomogram-integrated risk score had high prediction accuracy and applicability, when compared with simple clinicopathological features. As predicted by the risk model, regardless of the chemotherapy regimen, the survival advantage of the low-risk group was evident in those patients receiving chemotherapy (p < 0.05). However, in patients receiving anthracycline (A) therapy, outcomes were not significantly different when compared with those receiving no-A therapy (p = 0.24), suggesting these patients may omit from A-containing adjuvant chemotherapy. Our risk model also effectively predicted tumor mutation burden (TMB) and immunotherapy efficacy in BC patients (p < 0.05).ConclusionThe prognostic score model based on TME-related genes effectively predicted prognosis and chemotherapy effects in BC patients. The model provides a theoretical basis for novel driver-gene discover in BC and guides the decision-making for the adjuvant treatment of early breast cancer (eBC).

Mitogen-activated protein kinase (MAPK) plays a crucial role in plant stress response. Poplar is one of the most important afforestation and timber species and inevitably encounters allelopathy effects during continuous cropping. para-hydroxybenzoic acid (pHBA) is a primary soil allelochemical, which can restrict the growth and biomass of poplar. However, the involvement of MAPKs in the underlying physiological and molecular regulatory mechanisms in response to pHBA stress remains unclear. In this study, PeMPK17, a gene encoding a group D MAPK, was cloned from Populus × euramericana. PeMPK17 protein was localized in both nucleus and plasma membrane. Quantitative real-time polymerase chain reaction analysis demonstrated that PeMPK17 expression in poplar increased when treated with pHBA, PEG, and H2O2. Exogenous pHBA and H2O2 induced PeMPK17 expression mediated by reactive oxygen species (ROS). The transgenic poplar plants overexpressing PeMPK17 demonstrated attenuated phenotypic injury, higher relative water content in leaves, and lower ion leakage under pHBA stress. In transgenic poplar, the activity and expression of antioxidant enzymes including superoxide dismutase, peroxidase, and catalase increased, while the content of H2O2, O2·-, and malondialdehyde decreased. These results suggested that PeMPK17 protects cell membranes from oxidative damage by removing excess ROS. In addition, overexpression of PeMPK17 promoted osmoprotectant accumulation including soluble sugar and free proline, which may aid in the regulation of ROS balance under pHBA treatment. Furthermore, the interaction between PeMPK17 and PeMKK7 was confirmed. Collectively, these data identify the molecular mechanisms and signal pathways associated with PeMPK17 that regulate pHBA response in poplar.

Abstract Background Recent studies found associations between non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS), but the causal nature of this association is still uncertain. Methods We performed a bidirectional two-sample Mendelian randomization (MR) analysis to test for the causal association between NAFLD and PCOS using data from a large-scale biopsy-confirmed NAFLD genome-wide association study (GWAS) (1483 cases and 17,781 controls) and PCOS GWAS (10,074 cases and 103,164 controls) in European ancestries. Data from glycemic-related traits GWAS (in up to 200,622 individuals) and sex hormones GWAS (in 189,473 women) in the UK Biobank (UKB) were used in the MR mediation analysis to assess potential mediating roles of these molecules in the causal pathway between NAFLD and PCOS. Replication analysis was conducted using two independent datasets from NAFLD and PCOS GWASs in the UKB and a meta-analysis of data from FinnGen and the Estonian Biobank, respectively. A linkage disequilibrium score regression was conducted to assess genetic correlations between NAFLD, PCOS, glycemic-related traits, and sex hormones using full summary statistics. Results Individuals with higher genetic liability to NAFLD were more likely to develop PCOS (OR per one-unit log odds increase in NAFLD: 1.10, 95% CI: 1.02–1.18; P = 0.013). Indirect causal effects of NAFLD on PCOS via fasting insulin only (OR: 1.02, 95% CI: 1.01–1.03; P = 0.004) and further a suggestive indirect causal effect via fasting insulin in concert with androgen levels were revealed in MR mediation analyses. However, the conditional F statistics of NAFLD and fasting insulin were less than 10, suggesting likely weak instrument bias in the MVMR and MR mediation analyses. Conclusions Our study suggests that genetically predicted NAFLD was associated with a higher risk of developing PCOS but less evidence for vice versa. Fasting insulin and sex hormones might mediate the link between NAFLD and PCOS.

Abstract Genomic prediction (GP) based on haplotype alleles can capture quantitative trait loci (QTL) effects and increase predictive ability because the haplotypes are expected to be in linkage disequilibrium (LD) with QTL. In this study, we constructed haploblocks using LD‐based and the fixed number of single nucleotide polymorphisms (fixed‐SNP) methods with Illumina BovineHD chip in beef cattle. To evaluate the performance of different haplotype block partitioning methods, we constructed haploblocks based on LD thresholds (from r2 > 0.2 to r2 > 0.8) and the number of fixed‐SNPs (5, 10, 20). The performance of predictive methods for three carcass traits including liveweight (LW), dressing percentage (DP), and longissimus dorsi muscle weight (LDMW) was evaluated using three approaches (GBLUP and BayesB model based on the SNP, GHBLUP, and BayesBH models based on the haploblock, and GHBLUP+GBLUP and BayesBH+BayesB models based on the combined haploblock and the nonblocked SNPs, which were located between blocks). In this study, we found the accuracies of LD‐based and fixed‐SNP haplotype Bayesian methods outperformed the Bayesian models (up to 8.54 ± 7.44% and 5.74 ± 2.95%, respectively). GHBLUP showed a high improvement (up to 11.29 ± 9.87%) compared with GBLUP. The Bayesian models have higher accuracies than BLUP models in most scenarios. The average computing time of the BayesBH+BayesB model can reduce by 29.3% compared with the BayesB model. The prediction accuracies using the LD‐based haplotype method showed higher improvements than the fixed‐SNP haplotype method. In addition, to avoid the influence of rare haplotypes generated from haplotype construction, we compared the performance of GP by filtering four types of minor haplotype allele frequency (MHAF) (0.01, 0.025, 0.05, and 0.1) under different conditions (LD levels were set at r2 > 0.3, and the fixed number of SNPs was 5). We found the optimal MHAF threshold for LW was 0.01, and the optimal MHAF threshold for DP and LDMW was 0.025.

Abstract Pathogenic variants in MYO15A are known to cause autosomal recessive nonsyndromic hearing loss (ARNSHL), DFNB3. We have previously reported on one ARNSHL family including two affected siblings and identified MYO15A c.5964+3G > A and c.8375 T > C (p.Val2792Ala) as the possible deafness-causing variants. Eight year follow up identified one new affected individual in this family, who also showed congenital, severe to profound sensorineural hearing loss. By whole exome sequencing, we identified a new splice-site variant c.5531+1G > C (maternal allele), in a compound heterozygote with previously identified missense variant c.8375 T > C (p.Val2792Ala) (paternal allele) in MYO15A as the disease-causing variants. The new affected individual underwent unilateral cochlear implantation at the age of 1 year, and 5 year follow-up showed satisfactory speech and language outcomes. Our results further indicate that MYO15A-associated hearing loss is good candidates for cochlear implantation, which is in accordance with previous report. In light of our findings and review of the literatures, 58 splice-site variants in MYO15A are correlated with a severe deafness phenotype, composed of 46 canonical splice-site variants and 12 non-canonical splice-site variants.

Abstract Background Diet has long been hypothesized to play an important role in hyperuricemia, and weight gain is a factor that is strongly associated with the rise in serum urate. We aimed to clarify the mediating role of obesity in the relationship between diet and hyperuricemia and to determine whether a weight-loss diet is an effective way to prevent hyperuricemia. Methods This cross-sectional study analysed representative samples of United States (n = 20,081; NHANES 2007–2016) adults. Nutrient patterns were derived with two methods: principal component analysis (PCA) and reduced rank regression (RRR) with obesity. Logistic regression and multivariable linear regression were applied to analyse the association between nutrient patterns in obesity and hyperuricemia. Mediation analyses were used to determine whether four obesity indicators, including body mass index (BMI), waist circumference (WC), visceral adiposity index (VAI) and lipid accumulation product index (LAP), mediated the relationship between nutrient patterns and hyperuricemia. Results PCA revealed three nutrient patterns (including “Low energy diet”, “Lower vitamin A, C, K pattern” and “Vitamin B group”), and only Vitamin B group had a total effect on hyperuricemia. RRR revealed one main nutrient pattern associated with obesity, which was characterized by High fat and low vitamin levels and was significantly associated with hyperuricemia. Mediation analysis showed that obesity mostly or even completely mediated the relationship between nutrient patterns and hyperuricemia, especially traditional obesity indicators, which played a key intermediary effect. The proportions of indirect effects for BMI and WC were as high as 53.34 and 59.69, respectively. Conclusions Our findings suggest that the direct effect of diet on hyperuricemia is weak, and obesity plays a critical mediating role in the relationship between diet and hyperuricemia, which confirms that a weight-loss diet such as a “Low fat and high vitamin diet” may be useful in preventing hyperuricemia.

Abstract Background Essential trace elements (ETEs), such as copper (Cu), iron (Fe), manganese (Mn), molybdenum (Mo), selenium (Se), zinc (Zn), are very important elements for human health. Methods In this study, 89 drinking water samples and 85 highland barleys were collected from 48 villages in 11 townships, and the average daily dose (ADD) of ETEs were calculated, in addition, health effects of ETEs to rural residents in Luolong County, a typical Kashin-Beck disease (KBD) endemic area in Tibet, were assessed. Results The mean concentrations of Cu, Fe, Mn, Mo, Se, Zn in drinking water were 0.278 ± 0.264 μg·kg−1, 0.766 ± 0.312 μg·kg−1, 0.411 ± 0.526 μg·kg−1, 0.119 ± 0.223 μg·kg−1, 0.155 ± 0.180 μg·kg−1, and 0.804 ± 1.112 μg·kg−1, respectively; and mean concentrations of Cu, Fe, Mn, Mo, Se and Zn in highland barley were 3.550 ± 0.680 mg·kg−1, 81.17 ± 38.14 mg·kg−1, 14.03 ± 1.42 mg·kg−1, 0.350 ± 0.200 mg·kg−1, 0.0028 ± 0.0056 mg·kg−1, and 23.58 ± 3.10 mg·kg−1, respectively. The ADD of Cu in the study area was appropriate; the ADD of Fe and Mn in each township were higher than the maximum oral reference dose recommended by the National Health Commission of China, indicating that Fe and Mn had non-carcinogenic health risks; the ADD of Mo and Zn in 36.36% and 54.55% of the townships exceeded the maximum oral reference dose; and 72.73% of the townships had insufficient ADD of Se. The ADD of Mo, Cu and Se in different townships was significantly correlated with the prevalence of KBD. Conclusions Therefore, in order to prevent and control the prevalence of KBD and ensure the health of local residents, it is necessary to reduce the intake of high concentrations of Fe, Mn and Zn in diet, as well as increase the intake of Mo, Cu, especially Se. Graphical abstract

Abstract Background Genomic selection (GS) has revolutionized animal and plant breeding after the first implementation via early selection before measuring phenotypes. Besides genome, transcriptome and metabolome information are increasingly considered new sources for GS. Difficulties in building the model with multi-omics data for GS and the limit of specimen availability have both delayed the progress of investigating multi-omics. Results We utilized the Cosine kernel to map genomic and transcriptomic data as $${n}\times {n}$$ n × n symmetric matrix (G matrix and T matrix), combined with the best linear unbiased prediction (BLUP) for GS. Here, we defined five kernel-based prediction models: genomic BLUP (GBLUP), transcriptome-BLUP (TBLUP), multi-omics BLUP (MBLUP, $$\boldsymbol M=\mathrm{ratio}\times\boldsymbol G+(1-\mathrm{ratio})\times\boldsymbol T$$ M = ratio × G + ( 1 - ratio ) × T ), multi-omics single-step BLUP (mssBLUP), and weighted multi-omics single-step BLUP (wmssBLUP) to integrate transcribed individuals and genotyped resource population. The predictive accuracy evaluations in four traits of the Chinese Simmental beef cattle population showed that (1) MBLUP was far preferred to GBLUP (ratio = 1.0), (2) the prediction accuracy of wmssBLUP and mssBLUP had 4.18% and 3.37% average improvement over GBLUP, (3) We also found the accuracy of wmssBLUP increased with the growing proportion of transcribed cattle in the whole resource population. Conclusions We concluded that the inclusion of transcriptome data in GS had the potential to improve accuracy. Moreover, wmssBLUP is accepted to be a promising alternative for the present situation in which plenty of individuals are genotyped when fewer are transcribed.

The genetic bases of yak adaptations to extreme conditions remains elusive. This study compares yak and cattle at a genomic and transcriptomic level, revealing a new type of endothelial cell and candidate genes related with elastic fiber formation in yak lungs that might contribute to high altitude adaptation.