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Abstract The emergence of spatial multi-omics has helped address the limitations of single-cell sequencing, which often leads to the loss of spatial context among cell populations. Integrated analysis of the genome, transcriptome, proteome, metabolome, and epigenome has enhanced our understanding of cell biology and the molecular basis of human diseases. Moreover, this approach offers profound insights into the interactions between intracellular and intercellular molecular mechanisms involved in the development, physiology, and pathogenesis of human diseases. In this comprehensive review, we examine current advancements in multi-omics technologies, focusing on their evolution and refinement over the past decade, including improvements in throughput and resolution, modality integration, and accuracy. We also discuss the pivotal contributions of spatial multi-omics in revealing spatial heterogeneity, constructing detailed spatial atlases, deciphering spatial crosstalk in tumor immunology, and advancing translational research and cancer therapy through precise spatial mapping.

Determining the fertilization rate plays a pivotal role in agronomic practices as they directly impact yield targets, soil fertility, and environmental risks. In this study, we proposed a method that utilizes allowed ranges of partial nutrient balance and yield to estimate the threshold of nitrogen (N), phosphorus (P), and potassium (K) fertilizer applied to rice (Oryza sativa L.) fields in China. Based on a dataset of 6792 observations from rice fields, we determined the minimum and maximum rates of N, P and K suggested for single (mono-season rice), middle (summer-season rice rotated with winter-season upland crop), early and late (double-season rice cropping system) rice, ranging between 114−146 and 220−292 kg N ha−1 per season, 56−74 and 112−149 kg P2O5 ha−1 per season, and 170−230 and 329−347 kg K2O ha−1 per season, respectively. These values serve as the lower and upper fertilization thresholds, guiding yield goals and environmental protection. Furthermore, if rice straw is returned to fields, the demand for K fertilizer can theoretically decrease by 183 kg K2O ha−1, with corresponding decreases of 50 kg N ha−1 and 26 kg P2O5 ha−1, respectively. A recommended fertilization approach, excluding returned straw nutrients from the upper fertilization thresholds, suggested average application rates of 194 kg N ha−1, 105 kg P2O5 ha−1, and 157 kg K2O ha−1, which align well with the nutrient requirements of rice. Additionally, substituting organic N for chemical N is an effective approach to conserve chemical fertilizer N, potentially reducing chemical N usage by 20%−40%. Utilizing slow-release N is also a favorable option to enhance N use efficiency and optimize N balance. This study offers valuable insights into the development of fertilization restriction indicators, aiming to achieve a delicate balance between environmental impact and agricultural productivity through the adoption of balanced fertilization rates and utilization of organic residues.

Organic composts are significant sources of microplastic (MP) pollution in soils, and their input is much higher in greenhouse agriculture than open-field agriculture. However, how long-term compost application affects MPs pollution in greenhouse soil profiles remains unclear. This study examined MPs characteristics in chicken manure compost and earthworms, exploring the long-term impacts of compost application on MPs accumulation and vertical migration in 0–100 cm soil depth through a 15-year greenhouse experiment. Microplastics abundance was 3965 items kg−1in compost, 191–248 items kg−1in compost-amended soils, and 2.73–4.52 items individual−1in earthworms from compost-amended soils; the latter two increased significantly with compost application and were significantly higher than unamended soils. Soil MPs accumulation from long-term compost amendment contributed 45.4% of the total. The proportion of MPs

Introduction: Human papillomavirus (HPV) integration can induce gene expression dysregulation by destroying higher-order chromatin structure in cervical cancer. Objectives: We established a 13q22 site-specific HPV16 gene knock-in cell model to interrogate the changes in chromatin structure at the initial stages of host cell malignant transformation. Methods: We designed a CRISPR-Cas9 system with sgRNA targeting 13q22 site and constructed the HPV16 gene donor. Cells were cotransfected, screened, and fluorescence sorted. The whole genome sequencing (WGS) was used to confirm the precise HPV16 gene integration site. Western blot and qRT-PCR were used to measure gene expression. In vitro and in vivo analysis were performed to estimate the tumorigenic potential of the HPV16 knock-in cell model. Combined Hi-C, chromatin immunoprecipitation and RNA sequencing analyses revealed correlations between chromatin structure and gene expression. We performed a coimmunoprecipitation assay with anti-PIBF1 antibody to identify endogenous interacting proteins. In vivo analysis was used to determine the role of PIBF1 in the tumor growth of cervical cancer cells. Results: We successfully established a 13q22 site-specific HPV16 gene knock-in cell model. We found that HPV integration promoted cell proliferation, invasion and stratified growth in vitro, and monoclonal proliferation in vivo. HPV integration divided the affected topologically associated domain (TAD) into two smaller domains, and the progesterone-induced blocking factor 1 (PIBF1) gene near the integration site was upregulated, although PIBF1 was not enriched at the domain boundary by CUT-Tag signal analysis. Moreover, PIBF1 was found to interact with the cohesin complex off chromatin to reduce contact domain formation by disrupting the cohesin ring-shaped structure, causing dysregulation of tumorigenesis-related genes. Xenograft experiments determined the role of PIBF1 in the proliferation in cervical cancer cells. Conclusion: We highlight that PIBF1, a potential chromatin structure regulatory protein, is activated by HPV integration, which provides new insights into HPV integration-driven cervical carcinogenesis.

Abstract Background Assisted reproductive technologies (ART) have increased the incidence of multiple births, which can have a negative impact on maternal and offspring health. The study aimed to investigate the association between genetically predicted multiple birth and the risk of 42 common diseases of the nervous, psychiatric, cardiovascular, respiratory, digestive, and endocrine systems. Methods The study utilized two-sample Mendelian randomization (MR) analysis to explore the potential causal relationship between genetically predicted multiple birth and the genetically predicted risk of diseases. The study used the FinnGen and UK Biobank datasets for analysis. Results The study found no significant causal relationship between multiple birth and psychiatric disorders. However, the lower limits of the 95% confidence intervals for bipolar affective disorder and anxiety disorders were not robust, indicating a need for further investigation. The study found that multiple birth may be a strong risk factor for infantile cerebral palsy, and caution is necessary in both natural and ART multiple births. The study revealed a potential causal relationship between multiple birth and coronary heart disease, ischemic heart disease, and deep vein thrombosis, which may be related to abnormal intrauterine environments in multiple pregnancies. Surprisingly, multiple birth appears to have a protective effect against some respiratory diseases, such as chronic obstructive pulmonary disease and asthma. Conclusions The study highlights the need for caution regarding the risk of infantile cerebral palsy, cardiovascular diseases, and psychiatric disorders in multiple birth. Our study can lead to the development of preventive strategies and improved clinical management for affected infants.

Abstract Docosahexaenoic acid (DHA) supplementation is recommended for women during pregnancy because of its neurological, visual, and cognitive effects. Previous studies have suggested that DHA supplementation during pregnancy may prevent and treat certain pregnancy complications. However, there are contradictions in the current related studies, and the specific mechanism by which DHA acts remains unclear. This review summarizes the research on the relationship between DHA intake during pregnancy and preeclampsia, gestational diabetes mellitus, preterm birth, intrauterine growth restriction, and postpartum depression. Furthermore, we explore the impact of DHA intake during pregnancy on the prediction, prevention, and treatment of pregnancy complications as well as its impact on offspring neurodevelopment. Our results suggest that there is limited and controversial evidence for the protective effect of DHA intake on pregnancy complications, with the exception of preterm birth and gestational diabetes mellitus. However, additional DHA supplementation may improve long-term neurodevelopmental outcomes in the offspring of women with pregnancy complications.

Summary: Background: Cervical squamous cell carcinoma (CSCC) and adenocarcinoma (CAde) are two major pathological types of cervical cancer (CC), but their high-resolution heterogeneity of tumor and immune microenvironment remains elusive. Methods: Here, we performed single-nucleus RNA sequencing (snRNA-seq) from five CSCC and three CAde samples, and systematically outlined their specific transcriptome atlas. Findings: We found CD8+ T cells in CSCC were more cytotoxic but lower exhausted compared to those in CAde, and phagocytic MRC1+ macrophages were specifically enriched in CSCC. Interestingly, we discovered that pro-tumoral cancer-associated myofibroblasts (myoCAFs) and cancer-associated vascular-fibroblasts (vCAFs) were more abundant in CSCC, and further verified their pro-metastatic roles in vitro. Furthermore, we also identified some specific chemotherapy drugs for CSCC (Dasatinib and Doramapimod) and CAde (Pyrimethamine and Lapatinib) by revealing their heterogeneity in transcriptomic profiles of malignant epithelial cells, and further verified their specific sensitivity in cell lines and constructed CC-derived organoids. Cell–cell communication networks revealed that the pathways of NRG1-ERBB2, and FN1-ITAG3 were specific for CAde and CSCC, respectively, which may partly explain the specificities of identified chemotherapy drugs. Interpretation: Our study described the immune heterogeneity and specific cellular interactions between CSCC and CAde, which could provide insights for uncovering pathogenesis and designing personalized treatment. Fundings: National Key R&D Program of China (2021YFC2701201), National Natural Science Foundation of China (82072895, 82141106, 82103134, 81903114).

Cuproptosis is a copper-dependent model of cell death involved in tumor genesis and progression. Its roles in uterine corpus endometrial carcinoma (UCEC) remains elusive. Here, we aimed to explore the expression and prognostic values of cuprotosis-related genes (CRGs) in UCEC. Expression profiles and clinical data of UCEC were downloaded from The Cancer Genome Atlas (TCGA), and randomly divided into testing or training cohort (1:1 ratio). The CRG signature was identified by LASSO regression analysis. The differentially expressed genes and their functional enrichment analysis were performed by the “limma” R package and Metascape, respectively. The immunocytes infiltration was measured by TIMER, and “GSVA” R package. In total, seven differentially expressed prognostic genes of CRGs in UCEC were identified, and four genes (GLS, CDKN2A, PC, and SUCLG1) were selected to construct a predictive model in training cohort. UCEC patients from training and testing cohorts were further divided into high- or low-risk groups according to the median risk score. High-risk group favored poor prognosis compared to low-risk group. Functional enrichment analysis revealed this CRG signature were got involved in the process of cell-cell adhesion and immune activities (e.g., IL-1 signaling pathway, cellular response to cytokine stimulus). Further analyses revealed there were significant differences between high- and low-risk patients regarding immunocytes infiltration, chemokines, and chemokine receptors. Finally, the expression and biological functions of identified CRGs were confirmed by UCEC samples and experimental methods in vitro. In summary, the CRG signature was significantly correlated with patients' overall survival, which could provide insights into the diagnosis and prognosis prediction for UCEC.

Organic manure has been proposed to substitute part of the chemical fertilizers. However, past research was usually conducted in regimes with excessive nitrogen (N) fertilization, which was not conducive to the current national goal of green and sustainable development. Therefore, exploring the potential of organic fertilizer substitution for mineral N fertilizer under regimes with reduced N inputs is important to further utilize organic fertilizer resources and establish sustainable nutrient management recommendations in the winter wheat (Triticum aestivum L.) – summer maize (Zea mays L.) rotation system in North-central China. In this study, a 4-year field experiment was conducted to investigate the effects of different chicken manure substitution ratios on crop yield, N recovery efficiency (REN), soil N and soil organic matter contents, to clarify the optimal organic substitution ratio of N fertilizer under reduced N application (from 540 kg N ha−1 year−1 to 400 kg N ha−1 year−1). Six substitution ratios were assessed: 0%, 20%, 40%, 60%, 80% and 100% under 200 kg N ha−1 per crop season, respectively, plus a control with no N application from chemical fertilizer or chicken manure. Results showed that the highest yield was achieved under the 20% substitution ratio treatment, with 1.1% and 2.3% higher yield than chemical N alone in wheat season and maize seasons, respectively. At the chicken manure substitution ratios of 20% in wheat season and 20%-40% in maize season, the highest REN reached to 31.2% and 26.1%, respectively. Chicken manure application reduced soil residual inorganic N with increasing substitution ratio. All organic substitution treatments increased soil organic matter and total N content. Implementing 20% organic substitution in wheat season and 20%-40% in maize season under the reduced N application regime in the North-central China is therefore recommended in order to achieve high crop yields and REN, improve soil fertility and enhance livestock manure resource utilization.

Background: Kidney renal clear cell carcinoma (KIRC) is the most common pathological subtype of renal cell cancer. APOBEC3 activity has been identified in a variety of human cancers. Although its involvement in cancer has been studied widely, its influence on the tumor immune microenvironment remains poorly understood. Therefore, this study aimed to focus on the effect of APOBEC3 on tumor immune microenvironment of KIRC. Methods: In this study, we comprehensively analyzed the expression and prognostic significance of the APOBEC3 family in pan-cancer using multiple databases. The functions of key APOBEC3 family members were further investigated in KIRC, with APOBEC3G determined to be a candidate biomarker for unfavorable prognosis. We subsequently explored the correlation of APOBEC3G with the tumor immune environment in KIRC by analyzing the Cancer Genome Atlas (TCGA) dataset, then validated the prognostic significance and PD-L1 correlation of APOBEC3G by using tissue microarrays which included 233 primary tumor samples from patients with renal clear cell carcinoma. Results: The APOBEC3 family was overexpressed in KIRC and high APOBEC3 expression predicted poor prognosis. In addition, APOBEC3G was positively correlated with the expression of immunoinhibitors such as TIGIT, LAG3, CD96, PD-1, and CTLA4. In addition, APOBEC3G had a positive correlation with immunosuppressive cells, including regulatory T cell and myeloid-derived suppressor cell. Finally, based on 233 clinical samples, we validated that high expression of APOBEC3G contributed to a poor prognosis for KIRC patients and the positive relationship between APOBEC3G and PD-L1 expression. High APOBEC3G expression was also found to be more common in patients with sarcomatoid histology (P = 0.0026). Conclusions: Our study showed that APOBEC3G was a prognostic biomarker correlated with the immune response in KIRC. In addition, APOBE3G had a positive correlation with PD-L1 expression and sarcomatoid histology, perhaps suggesting the potential impact of APOBEC3G on immunotherapy.

Abstract The effective treatment of advanced cervical cancer remains challenging. Herein, single‐nucleus RNA sequencing (snRNA‐seq) and SpaTial enhanced resolution omics‐sequencing (Stereo‐seq) are used to investigate the immunological microenvironment of cervical squamous cell carcinoma (CSCC). The expression levels of most immune suppressive genes in the tumor and inflammation areas of CSCC are not significantly higher than those in the non‐cancer samples, except for LGALS9 and IDO1. Stronger signals of CD56+ NK cells and immature dendritic cells are found in the hypermetabolic tumor areas, whereas more eosinophils, immature B cells, and Treg cells are found in the hypometabolic tumor areas. Moreover, a cluster of pro‐tumorigenic cancer‐associated myofibroblasts (myCAFs) are identified. The myCAFs may support the growth and metastasis of tumors by inhibiting lymphocyte infiltration and remodeling of the tumor extracellular matrix. Furthermore, these myCAFs are associated with poorer survival probability in patients with CSCC, predict resistance to immunotherapy, and might be present in a small fraction (< 30%) of patients with advanced cancer. Immunohistochemistry and multiplex immunofluorescence staining are conducted to validate the spatial distribution and potential function of myCAFs. Collectively, these findings enhance the understanding of the immunological microenvironment of CSCC and shed light on the treatment of advanced CSCC.

Chaolong Wang and colleagues report a large genome-wide association study for COVID-19 severity in Chinese individuals. By meta-analysis with European data, they identify 3 loci associated with severe disease that suggest key roles for the adaptive immune system and the ABO blood group system in development of severe COVID-19.

COVID-19 is a critical public health threat, but molecular characterizations of patients’ immunity is still lacking. Here the authors collected blood from patients with various disease severity, and prefiltered to exclude selected comorbidity, to obtain genomic, transcriptomic, proteomic, metabolomic and lipidomic profiles to report a trans-omics landscape.

Abstract Purpose Critically ill COVID-19 patients have significantly increased risk of death. Although several circulating biomarkers are thought to be related to COVID-19 severity, few studies have focused on the characteristics of critically ill patients with different outcomes. The objective of this study was to perform a longitudinal investigation of the potential mechanisms affecting the prognosis of critically ill COVID-19 patients. Methods In addition to clinical data, 113 whole blood samples and 85 serum samples were collected from 33 severe and critical COVID-19 patients without selected comorbidities. Multi-omics analysis was then performed using longitudinal samples. Results Obvious transcriptional transitions were more frequent in critical survivors than in critical non-survivors, indicating that phase transition may be related to survival. Based on analysis of differentially expressed genes during transition, the erythrocyte differentiation pathway was significantly enriched. Furthermore, clinical data indicated that red blood cell counts showed greater fluctuation in survivors than in non-survivors. Moreover, declining red blood cell counts and hemoglobin levels were validated as prognostic markers of poor outcome in an independent cohort of 114 critical COVID-19 patients. Protein–metabolite–lipid network analysis indicated that tryptophan metabolism and melatonin may contribute to molecular transitions in critical COVID-19 patients with different outcomes. Conclusions This study systematically and comprehensively depicted the longitudinal hallmarks of critical COVID-19 patients and indicated that multi-omics transition may impact the prognosis. Take home message Frequent transcriptional phase transitions may contribute to outcome in critically ill COVID-19 patients. Furthermore, fluctuation in red blood cell and hemoglobin levels may relate to poor prognosis. The biological function of melatonin was suppressed in COVID-19 non-survivors, which may provide a potential theoretical basis for clinical administration.

As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to disperse globally with worrisome speed, identifying amino acid variations in the virus could help to understand the characteristics of it. Here, we studied 489 SARS-CoV-2 genomes obtained from 32 countries from the Nextstrain database and performed phylogenetic tree analysis by clade, country, and genotype of the surface spike glycoprotein (S protein) at site 614. We found that virus strains from mainland China were mostly distributed in Clade B and Clade undefined in the phylogenetic tree, with very few found in Clade A. In contrast, Clades A2 (one case) and A2a (112 cases) predominantly contained strains from European regions. Moreover, Clades A2 and A2a differed significantly from those of mainland China in age of infected population (P = 0.0071, mean age 40.24 to 46.66), although such differences did not exist between the US and mainland China. Further analysis demonstrated that the variation of the S protein at site 614 (QHD43416.1: p.614D>G) was a characteristic of stains in Clades A2 and A2a. Importantly, this variation was predicted to have neutral or benign effects on the function of the S protein. In addition, global quality estimates and 3D protein structures tended to be different between the two S proteins. In summary, we identified different genomic epidemiology among SARS-CoV-2 strains in different clades, especially in an amino acid variation of the S protein at 614, revealing potential viral genome divergence in SARS-CoV-2 strains.

Histone deacetylases (HDACs) have been linked to a variety of cancers, and HDAC inhibitors (HDACi) are a promising class of drugs that have demonstrated anti-cancer effects. However, we have little knowledge regarding the selection and application of HDAC inhibitors to the personalized treatment of ovarian cancer (OC). Here, we report a correlation between the high expression of HDACs and poor outcomes in OC patients, which reveals that HDACi are a class of agents that show great promise for the treatment of OC. Furthermore, we found that HDACi increased both the mRNA and protein levels of DHRS2, which has been shown to be closely linked to HDACi sensitivity when it is highly expressed, especially in ovarian cancer cells. Consistently, we found that suppression of DHRS2 reduced the sensitivity of OC cells to HDAC inhibitors via attenuation of the inhibitory effects of HDAC inhibitors on Mcl-1 in vitro. Our study demonstrated that DHRS2 expression was decreased in OC tissues and that high expression of DHRS2 was correlated with better outcomes in OC patients. In addition, DHRS2 expression was closely related to the effects of chemotherapy. Our study reveals the role of DHRS2 in cell apoptosis induced by HDAC inhibitors and explores the clinical attributes of DHRS2 in OC from a new perspective, suggesting that OC patients with high DHRS2 expression may benefit from treatment with HDAC inhibitors.

Microplastics pollution has been threatening the global environmental security, in which agricultural activities are considered as a main source of microplastics occurrence in soils. However, little is known about the occurrence characteristics of microplastics in agricultural soils with long-term plastic film mulching. Therefore, the abundance, distribution, and composition of microplastics were investigated by analyzing 225 soil samples collected from typical maize (Zea mays L.) planting zones with and without long-term (>20 years) plastic film mulching in northern China. Microplastics abundance in mulched soils (754 ± 477 items kg–1) was significantly higher than that in non-mulched soils (376 ± 149 items kg–1), which indicated that plastic film mulching contributed half of microplastics in soils. Moreover, microplastics abundance was significantly positively related to the length of time with film mulching applied. The percentage of microplastics

Human papillomavirus (HPV) integration in the human genome is suggested to be an important cause of cervical cancer. With the development of sequencing technologies, an increasing number of integration “hotspots” have been identified. However, this HPV integration information was derived from analysis of whole cervical cancer tissue, and we know very little about the integration in different cancer cell subgroups or individual cancer cells. This study optimized the preparation of probes and provided a dual-color fluorescence in situ hybridization (FISH) method to detect HPV integration sites in paraffin-embedded cervical cancer samples. We used both HPV probes and site-specific probes: 3p14 (FHIT), 8q24 (MYC), 13q22 (KLF5/KLF12), 3q28 (TP63), and 5p15 (TERT). We detected HPV signals in 75 of the 96 cases of cervical cancer; 62 cases showed punctate signals, and 13 cases showed diffuse punctate signals. We identified 3p14 as a high-frequency HPV integration site in 4 cervical cancer cases. HPV integration at 8p14 occurred in 2 cases of cervical cancer. In the same cervical cancer tissue of sample No.1321, two distinct subgroups of cells were observed based on the HPV probe but showed no difference in cell and nucleus morphology. Our study provides a new method to investigate the frequent HPV integration sites in cervical cancer and reports the heterogeneity within cervical cancer from the perspective of HPV integration.

Abstract Imbalanced fertilization has caused lower yield and nutrient use efficiency for radish (Raphanus sativus L.) production in China. Estimating nutrient requirements for radish is crucial in optimizing fertilization to resolve the problem. On-farm experiments in the radish-growing regions of China from 2000 to 2017 were collected to investigate the relationship between fleshy root yield and nutrient accumulation in radish plant using the Quantitative Evaluation of the Fertility of Tropical Soils (QUEFTS) model. The QUEFTS model predicted a linear increase in fleshy root yield if nutrients were taken up in balanced amounts until yield reached about 60%–70% of the potential yield. The balanced N, P, and K requirements in radish plant simulated by the QUEFTS model were 2.15, 0.45, and 2.58 kg to produce 1000 kg of fleshy root, and the corresponding internal efficiencies (IEs, kg fleshy root per kg nutrient in total plant dry matter) for N, P, and K were 465.1, 2222.2, and 387.1 kg kg−1. The simulated balanced N, P, and K removal by fleshy root to produce 1000 kg fleshy root were 1.34, 0.30, and 1.93 kg, respectively. Approximately 62%, 67%, and 75% of N, P, and K in radish plant were presented in the fleshy root and removed from the soil. Field validation experiments confirmed the consistency between the observed and simulated nutrient uptake values. The QUEFTS model was proven to be effective for estimating nutrient requirements of radish and will contribute to develop fertilizer recommendations for radish cultivated in China.

High-risk human papilloma virus (HR-HPV) infection is strongly associated with cervical cancer and current evidences link E7 to HPV-associated carcinogenesis. Here the authors propose a model in which the infection of epithelial cells with high risk HPV results in a burst of reactive oxygen species, translocation of LDHA to the nucleus and activation of a gene profile that supports the growth of cervical cancer.

ObjectivesThis study aimed to assess the effect of neoadjuvant chemotherapy (NACT) on the rate of lymph node metastasis (LNM) in FIGO stage IB1-IIB cervical cancer patients and compare the LNM between NACT plus surgery and surgery only.MethodsWe identified 34 eligible studies in PubMed, Web of Science, Cochrane Library, and EMBASE from inception to July 27, 2019. Data analyses were performed by Stata (version 13) and Revman (version 5.3).ResultsIn these 34 included studies, the pooled incidence of LNM was estimated as 23% (95% CI, 0.20-0.26; I2 = 79.6%, P

To confirm the relationship between sex and the progression of Coronavirus Disease-19 (COVID-19), and its potential mechanism, among severe patients. For this retrospective study, we included 168 consecutive severe patients with pathogen-confirmed COVID-19 who were hospitalized between January 16th and February 4th, 2020, at Tongji Hospital in Wuhan, China. Clinical characteristics, laboratory parameters, and outcomes were compared and analyzed between males and females. In the present study, we analyzed 168 severe patients with COVID-19, including 86 males and 82 females, and 48 patients (28.6%) were diagnosed as critically ill. Of 86 male patients, 12.8% (11/86) died and 75.6% (65/86) were discharged; of 82 female patients, 7.3% (6/82) died and 86.6% (71/82) were discharged. Eleven laboratory parameters showed significant differences between male and female patients, and six of them were higher during the whole clinical course in patients who died than in patients who were discharged. In adjusted logistic regression analysis, males with comorbidities presented a higher risk of being critically ill than males without comorbidities (OR = 3.824, 95% CI = 1.279-11.435). However, this association attenuated to null in female patients (OR = 2.992, 95% CI = 0.937-9.558). A similar sex-specific trend was observed in the relation between age and critically ill conditions. We highlighted sex-specific differences in clinical characteristics and prognosis. Male patients appeared to be more susceptible to age and comorbidities. Sex is an important biological variable that should be considered in the prevention and treatment of COVID-19.

Supplying adequate nitrogen (N) to meet crop demand is critical for enhancing agricultural sustainability. Not only fertilizer N, but also N from other available sources should be considered in N supply capacity. We conducted a 10-year farming experiment using a split-plot design with two different main fertilizer management approaches and three N application strategies as add-on sub-treatments. Based on the experiment, we estimated the total N supply (TNsupply) for the summer maize cropping system, through considering environmental, soil, crop residue, and fertilizer N sources. An appropriate TNsupply was established by correlating TNsupply with the relative yield (RY), N input and output, and N use efficiency (NUE). The results revealed a wide variation in TNsupply (from 88 to 755 kg ha−1). The RY, N input, and N output fitted well to TNsupply using linear-plateau, linear, and linear-plateau models, respectively. The lower limits of TNsupply for achieving the maximum RY and N output were 361 and 358 kg ha−1, respectively. The relationship between N input and N output was described as linear-plateau. We determined the slope of the linear curve (55.4%) as the lower limit of NUE, beyond which the upper limit of TNsupply was determined to be less than 497 kg ha−1. Thus, appropriate TNsupply values ranged from 325 to 497 kg ha−1 for summer maize production, which could ensure enough N supply for higher yields and avoid excessive N input for higher NUE and lower environmental N loss. Our findings highlight that TNsupply can be an alternative indicator for evaluating N management.

Increasing amounts of crop residues are being returned to croplands. Understanding nitrogen (N) availability in crop residues under various N fertilization regimes is important in optimizing N management. Pot experiments were conducted to investigate the contribution, fate and residual effects of urea and maize residue-N using a 15N isotope technique. Four N regimes were tested: three basal-topdressing ratios of N applied as urea (100-0, 75-25, 50-50) and one basal application of 75% N as urea and 25% N as manure (75U+25M). An average of 31.4% wheat N uptake was derived from urea, 9.2% from maize residue, and 59.5% from the soil in the first season. During the growing stages of wheat, maize residue contributed 0.3-4.8% and 3.1-13.2% to soil mineral and microbial biomass N, respectively, and those originated from urea was 1.0-4.2% and 4.6-16.8%, respectively. Regarding the fate of urea and residue-N after the first season, 35.9% and 16.9% of urea-15N and residue-15N were recovered by wheat, 28.1% and 46.9% remained in the soil, and 36.0% and 36.2% were lost. The contribution of urea to crop N uptake and N recovery efficiency increased, while that of residue-N decreased with increasing proportion of topdressing N. Substituting 25% mineral N with manure decreased the urea-15N loss without negative effects on crop dry matter and N uptake. Residual urea-15N and maize residue-15N from the previous season contributed 3.9% and 3.0% to summer maize N uptake. Additionally, 29.3% of residue-15N remained in the soil after the second season, while only 18.6% of urea-15N remained. Our study suggests that fertilizer and crop residue are actively involved in soil N transformation and plant N nutrition, emphasizing the capacities of organic residues to sustainably supply nutrients. Considering the utilization of both N fertilizer and maize residue, we may suggest a 75-25 split in N fertilizer application, but more appropriate options need to be further assessed under different cropping systems.

Shifts in soil bacterial diversity and community composition are suggested to be induced by elevated input of nitrogen (N) fertilization with implications for soil quality, and consequently production. In this study, we evaluated the impacts of recommended fertilization (RF) and conventional fertilization (CF) on soil chemical properties, crop yield, bacterial diversity, and community composition from two long-term experiments conducted in fluvo-aquic soil and black soil of China. Each site comprised of four treatments, i.e., RF N−, RF N+, CF N−, CF N+. No N fertilization was indicated by N− and N fertilization was indicated by N+. Across both sites, N fertilization significantly increased crop yield compared with no N fertilization and RF successfully enhanced crop yield over CF. Interestingly, the RF maintained bacterial diversity, while CF depressed bacterial diversity in the two soils. Microbial taxa performing important ecological roles such as order Rhodospirillales and Bacillales were significantly enhanced in the RF approach, while Rhizobiales declined under CF. Furthermore, the results of partial least square path modeling revealed that soil available phosphorus (AP) negatively affected bacterial diversity while it positively affected bacterial community structure in fluvo-aquic soils. In contrast, soil pH was positively linked with both bacterial diversity and community structure in black soil. Overall, our study demonstrated that RF is an environmentally friendly approach which not only maintained above ground plant productivity, but also preserved belowground microbial populations and important soil variables regulating bacterial communities varied in different soil types.

Linking potassium (K) balance to soil fertility creates a valuable indicator for sustainability assessment in agricultural land-use systems. It is crucial for the efficient use of K resources, food security and resource sustainability to realize soil K balance status in China. Therefore, temporal and spatial changes of K balance for farmland in China from 1980 to 2015 were analyzed at national and regional levels using statistical data and related parameters. At the national scale, K input increased from 6.78 Mt K2O in 1980 to 23.44 Mt K2O in 2015 with an average annual increment of 0.48 Mt K2O, and output changed from 8.10 Mt in 1980 to 21.31 Mt in 2015 with an average annual increment of 0.38 Mt K2O as well. On average, K balance was -24.17, -5.92, 21.31 and 19.50 kg K2O ha-1 in 1980s, 1990s, 2000s and 2010s, respectively. Moreover, the average balance of six regions was considerably different which were -21.37, 1.25, 13.70, -22.79, 99.22 and 7.18 kg K2O ha-1 from 1980 to 2015. The potassium use efficiency (KUE) decreased with time which were 127.09, 104.35, 87.69 and 89.69% in 1980s, 1990s, 2000s and 2010s, respectively, and the decline of slope could also reflect the variation tendency of KUE. Great variation of K balance across different regions demonstrated that fertilizer application and management practices need to be adjusted to local conditions.

Cervical cancer cells exhibit an increased requirement for ubiquitin-dependent protein degradation associated with an elevated metabolic turnover rate. Ubiquitin, which is a small, highly conserved protein expressed in all eukaryotic cells, can be covalently linked to certain target proteins to mark them for degradation by the ubiquitin-proteasome system. Previous studies highlight the essential role of Ubiquitin B (UbB) and UbB-dependent proteasomal protein degradation in histone deacetylase inhibitor (HDACi) -induced tumor selectivity. We hypothesized that UbB plays a critical role in the function of cervical cancer stem cells. We measured endogenous UbB levels in mammospheres in vitro by real-time PCR and Western blotting. The function of UbB in cancer stem-like cells was assessed after knockdown of UbB expression in prolonged Trichostatin A-selected HeLa cells (HeLa/TSA) by measuring in vitro cell proliferation, cell apoptosis, invasion, and chemotherapy resistance as well as by measuring in vivo growth in an orthotopic model of cervical cancer. We also assessed the cancer stem cell frequency, tumorsphere formation, and in vivo growth of human cervical cancer xenografts after UbB silencing. We found that HeLa/TSA were resistant to chemotherapy, highly expressed the UbB gene and the stem cell markers Sox2, Oct4 and Nanog. These cells also displayed induced differentiation abilities, including enhanced migration/invasion/malignancy capabilities in vitro and in vivo. Furthermore, an elevated expression of UbB was shown in the tumor samples of chemotherapy patients. Silencing of UbB inhibited tumorsphere formation, lowered the expression of stem cell markers and decreased cervical xenograft growth. Our results demonstrate that UbB was significantly increased in prolonged Trichostatin A-selected HeLa cells and it played a key role in the maintenance of cervical cancer stem-like cells.