Anomalous coarsening of coalescing nucleoli in human cells.

Coarsening is a ubiquitous phenomenon in droplet systems near thermodynamic equilibrium-as an increase in droplet size lowers the system's free energy-however, coarsening of droplets in nonequilibrium systems, such as the cell nucleus, is far from understood. Liquid condensates in the cell nucleus, like nucleoli, form by liquid-liquid phase separation and play a key role in the nuclear organization. In human cells, nucleolar droplets are nucleated at the beginning of the cell cycle and coarsen with time by coalescing with each other. Upon coarsening, human nucleoli exhibit an anomalous volume distribution P(V)∼V-1, which cannot be explained by any existing theory. In this work, we investigate physical mechanisms behind the anomalous coarsening of human nucleoli. Using spinning disk confocal microscopy, we simultaneously record dynamic behavior of nucleoli and their surrounding chromatin before their coalescence in live human cells. We find that nucleolar anomalous coarsening persists during the entire cell cycle. We measure chromatin flows and density between and around nucleoli, as well as relative motion of two nucleoli before they coalesce. We find that, before nucleolar coalescence, chromatin concentration decreases in the space between nucleoli and the nucleoli move faster toward each other, resembling an effective depletion attraction between the coalescing nucleoli. Indeed, our computational simulations of nucleolar dynamics show that short-ranged attraction is sufficient to explain the observed anomalous volume distribution of human nucleoli. Overall, our results reveal a potential physical mechanism contributing to coarsening of human nucleoli. Such knowledge expands our picture of the physical behavior of liquid condensates inside the cell nucleus and our understanding of the dynamic nuclear organization.

ZmELF6-ZmPRR37 module regulates maize flowering and salt response.

The control of flowering time in maize is crucial for reproductive success and yield, and it can be influenced by environmental stresses. Using the approaches of Ac/Ds transposon and transposable element amplicon sequencing techniques, we identified a Ds insertion mutant in the ZmPRR37 gene. The Ds insertion showed a significant correlation with days to anthesis. Further research indicated that ZmPRR37-CR knockout mutants exhibited early flowering, whereas ZmPRR37-overexpression lines displayed delayed flowering compared to WT under long-day (LD) conditions. We demonstrated that ZmPRR37 repressed the expression of ZmNF-YC2 and ZmNF-YA3 to delay flowering. Association analysis revealed a significant correlation between flowering time and a SNP2071-C/T located upstream of ZmPRR37. The SNP2071-C/T impacted the binding capacity of ZmELF6 to the promoter of ZmPRR37. ZmELF6 also acted as a flowering suppressor in maize under LD conditions. Notably, our study unveiled that ZmPRR37 can enhance salt stress tolerance in maize by directly regulating the expression of ABA-responsive gene ZmDhn1. ZmDhn1 negatively regulated maize salt stress resistance. In summary, our findings proposed a novel pathway for regulating photoperiodic flowering and responding to salt stress based on ZmPRR37 in maize, providing novel insights into the integration of abiotic stress signals into floral pathways.

ZmABF4-ZmVIL2/ZmFIP37 module enhances drought tolerance in maize seedlings.

Drought, as a primary environmental factor, imposes significant constraints on developmental processes and productivity of plants. PHDs were identified as stress-responsive genes in a wide range of eukaryotes. However, the regulatory mechanisms governing PHD genes in maize under abiotic stress conditions are still largely unknown and require further investigation. Here, we identified a mutant, zmvil2, in the EMS mutant library with a C to T mutation in the exon of the Zm00001d053875 (VIN3-like protein 2, ZmVIL2), resulting in premature termination of protein coding. ZmVIL2 belongs to PHD protein family. Compared to WT, zmvil2 mutant exhibited increased sensitivity to drought stress. Consistently, overexpression of ZmVIL2 enhances drought resistance in maize. Y2H, BiFC, and Co-IP experiments revealed that ZmVIL2 directly interacts with ZmFIP37 (FKBP12-interacting protein of 37). zmfip37 knockout mutants also exhibit decreased drought tolerance. Interestingly, we demonstrated that ZmABF4 directly binds to the ZmVIL2 promoter to enhance its activity in yeast one hybrid (Y1H), electrophoretic mobility shift assay (EMSA) and dual luciferase reporter assays. Therefore, we uncovered a novel model ZmABF4-ZmVIL2/ZmFIP37 that promotes drought tolerance in maize. Overall, these findings have enriched the knowledge of the functions of PHD genes in maize and provides genetic resources for breeding stress-tolerant maize varieties.

Ubiquitin-dependent Argonauteprotein MEL1 degradation is essential for rice sporogenesis and phasiRNA target regulation.

MEIOSIS ARRESTED AT LEPTOTENE1 (MEL1), a rice (Oryza sativa) Argonaute (AGO) protein, has been reported to function specifically at premeiotic and meiotic stages of germ cell development and is associated with a novel class of germ cell-specific small noncoding RNAs called phased small RNAs (phasiRNAs). MEL1 accumulation is temporally and spatially regulated and is eliminated after meiosis. However, the metabolism and turnover (i.e. the homeostasis) of MEL1 during germ cell development remains unknown. Here, we show that MEL1 is ubiquitinated and subsequently degraded via the proteasome pathway in vivo during late sporogenesis. Abnormal accumulation of MEL1 after meiosis leads to a semi-sterile phenotype. We identified a monocot-specific E3 ligase, XBOS36, a CULLIN RING-box protein, that is responsible for the degradation of MEL1. Ubiquitination at four K residues at the N terminus of MEL1 by XBOS36 induces its degradation. Importantly, inhibition of MEL1 degradation either by XBOS36 knockdown or by MEL1 overexpression prevents the formation of pollen at the microspore stage. Further mechanistic analysis showed that disrupting MEL1 homeostasis in germ cells leads to off-target cleavage of phasiRNA target genes. Our findings thus provide insight into the communication between a monocot-specific E3 ligase and an AGO protein during plant reproductive development.

IPF-related new macrophage subpopulations and diagnostic biomarker identification - combine machine learning with single-cell analysis.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease of unknown etiology that lacks a specific treatment. In IPF, macrophages play a key regulatory role as a major component of the lung immune system, especially during inflammation and fibrosis. However, our understanding of the cellular heterogeneity and molecular characterization of macrophages in IPF, as well as their relevance in the clinical setting, is relatively limited. In this study, we analyzed in-depth single-cell transcriptome sequencing (scRNA-seq) data from lung tissues of IPF patients, identified macrophage subpopulations in IPF, and probed their molecular characteristics and biological functions. hdWGCNA identified co-expressed gene modules of a subpopulation of IPF-associated macrophages (IPF-MΦ), and probed the IPF-MΦ by a machine-learning approach. hdWGCNA identified a subpopulation of IPF-associated macrophage subpopulations and probed the IPF-MΦ signature gene (IRMG) for its prognostic value, and a prediction model was developed on this basis. In addition, IPF-MΦ was obtained after recluster analysis of macrophages in IPF lung tissues. Coexpressed gene modules of IPF-MΦ were identified by hdWGCNA. Then, a machine learning approach was utilized to reveal the characteristic genes of IPF-MΦ, and a prediction model was built on this basis. In addition, we discovered a type of macrophage unique to IPF lung tissue named ATP5-MΦ. Its characteristic gene encodes a subunit of the mitochondrial ATP synthase complex, which is closely related to oxidative phosphorylation and proton transmembrane transport, suggesting that ATP5-MΦ may have higher ATP synthesis capacity in IPF lung tissue. This study provides new insights into the pathogenesis of IPF and provides a basis for evaluating disease prognosis and predictive medicine in IPF patients.

Prediction of Transcription Factor Binding Sites on Cell-Free DNA Based on Deep Learning.

Transcription factors (TFs) are important regulatory elements for vital cellular activities, and the identification of transcription factor binding sites (TFBS) can help to explore gene regulatory mechanisms. Research studies have proved that cfDNA (cell-free DNA) shows relatively higher coverage at TFBS due to the protection by TF from degradation by nucleases and short fragments of cfDNA are enriched in TFBS. However, there are still great difficulties in the noninvasive identification of TFBSs from experimental techniques. In this study, we propose a deep learning-based approach that can noninvasively predict TFBSs of cfDNA by learning sequence information from known TFBSs through convolutional neural networks. Under the addition of long short-term memory, our model achieved an area under the curve of 84%. Based on this model to predict cfDNA, we found consistent motifs in cfDNA fragments and lower coverage occurred upstream and downstream of these cfDNA fragments, which is consistent with a previous study. We also found that the binding sites of the same TF differ in different cell lines. TF-specific target genes were detected from cfDNA and were enriched in cancer-related pathways. In summary, our method of locating TFBSs from plasma has the potential to reflect the intrinsic regulatory mechanism from a noninvasive perspective and provide technical guidance for dynamic monitoring of disease in clinical practice.

Evaluation of AlphaFold2 Structures for Hit Identification across Multiple Scenarios.

The introduction of AlphaFold2 (AF2) has sparked significant enthusiasm and generated extensive discussion within the scientific community, particularly among drug discovery researchers. Although previous studies have addressed the performance of AF2 structures in virtual screening (VS), a more comprehensive investigation is still necessary considering the paramount importance of structural accuracy in drug design. In this study, we evaluate the performance of AF2 structures in VS across three common drug discovery scenarios: targets with holo, apo, and AF2 structures; targets with only apo and AF2 structures; and targets exclusively with AF2 structures. We utilized both the traditional physics-based Glide and the deep-learning-based scoring function RTMscore to rank the compounds in the DUD-E, DEKOIS 2.0, and DECOY data sets. The results demonstrate that, overall, the performance of VS on AF2 structures is comparable to that on apo structures but notably inferior to that on holo structures across diverse scenarios. Moreover, when a target has solely AF2 structure, selecting the holo structure of the target from different subtypes within the same protein family produces comparable results with the AF2 structure for VS on the data set of the AF2 structures, and significantly better results than the AF2 structures on its own data set. This indicates that utilizing AF2 structures for docking-based VS may not yield most satisfactory outcomes, even when solely AF2 structures are available. Moreover, we rule out the possibility that the variations in VS performance between the binding pockets of AF2 and holo structures arise from the differences in their biological assembly composition.

Spatial accessibility and inequality analysis of rabies-exposed patients to rabies post-exposure prophylaxis clinics in Guangzhou City, China.

BACKGROUND: The incidence of rabies exposure is high and increasing in China, leading to an urgent demand of rabies post-exposure prophylaxis (PEP) clinics for the injured. However, the spatial accessibility and inequality of rabies-exposed patients to rabies PEP clinics is less known in China. METHODS: Based on rabies exposure data, PEP clinic data, and resident travel origin-destination (OD) matrix data in Guangzhou City, China, we first described the incidence of rabies exposure in Guangzhou from 2020 to 2022. Then, the Gaussian two-step floating catchment area method (2SFCA) was used to analyze the spatial accessibility of rabies-exposed patients to rabies PEP clinics in Guangzhou, and the Gini coefficient and Moran's I statistics were utilized to evaluate the inequality and clustering of accessibility scores. RESULTS: From 2020 to 2022, a total of 524,160 cases of rabies exposure were reported in Guangzhou, and the incidence showed a significant increasing trend, with an average annual incidence of 932.0/100,000. Spatial accessibility analysis revealed that the overall spatial accessibility scores for three scenarios (threshold of driving duration [d0] = 30 min, 45 min, and 60 min) were 0.30 (95% CI: 0.07, 0.87), 0.28 (95% CI: 0.11, 0.53) and 0.28 (95% CI: 0.14, 0.44), respectively. Conghua, Huangpu, Zengcheng and Nansha districts had the higher accessibility scores, while Haizhu, Liwan, and Yuexiu districts exhibited lower spatial accessibility scores. The Gini coefficient and Moran's I statistics showed that there were certain inequality and clustering in the accessibility to rabies PEP clinics in Guangzhou. CONCLUSIONS: This study clarifies the heterogeneity of spatial accessibility to rabies PEP clinics, and provide valuable insights for resource allocation to achieve the WHO target of zero human dog-mediated rabies deaths by 2030.

Integrated analysis of whole genome and transcriptome sequencing uncovers genetic differences between Zi goose and Xianghai flying goose.

Zi goose is a famous indigenous breed originating from northeast China with high annual egg production. Xianghai flying goose is a composite breed and is bred by crosses of the wild swan goose and the Zi goose. Our previous study revealed significant differences in muscle fiber characteristics between the two populations. Here, we aimed to reveal the underlying genetic basis of the above phenotype differences through whole-genome and transcriptome analysis. A total of 20 blood samples (10 Zi geese and 10 Xianghai flying geese) were used for whole genome sequencing, and eight breast muscle tissue samples (four Zi geese and four Xianghai flying geese) were used for RNA sequencing. Using the FST and XP-EHH analysis, some highly differentiated genome regions annotated with egg production (RORB, WNT4, BMPR1B) and breast muscle development (WNT7B) between the two populations were detected. RNA-sequencing analysis revealed differentially expressed genes related to muscle development (IGF1, PAX7). Moreover, several genes were detected by both genome and transcriptome analysis, and some of them were reported to be associated with muscle growth (SLIT2, PREX1) and intramuscular fat (COL6A1). These findings will help researchers better understand the genetic basis related to egg production and muscle development in geese.

Associations of 24-hour movement behaviors with emotional and behavioral problems among Chinese adolescents.

PURPOSE: The role of adherence to the recommendations for 24-hour movement behaviors (24-HMB), including physical activity (PA), screen time (ST), and sleep duration (SLP), in relation to emotional and behavioral problems in Chinese adolescents remains uncertain. This study aimed to investigate these associations and explore potential sex differences. METHODS: This school-based cross-sectional study included 15,071 Chinese adolescents with a mean age of 14.53 (SD: 1.65) years. Data on emotional and behavioral problems and 24-HMB (including PA, ST, and SLP) were collected. Analysis was performed using general linear mixed models, with additional sex-stratified analyses conducted. RESULTS: The number of 24-HMB recommendations met was negatively associated with total difficulties (ß estimate=-0.96, 95% CI: -1.07 to -0.85) and positively related to prosocial behavior (ß estimate = 0.41, 95% CI: 0.37 to 0.46) among adolescents. Compared with none of the recommendations met, meeting all recommendations (total difficulties: ß estimate=-2.98, 95% CI: -3.41 to -2.55; prosocial behaviors: ß estimate = 1.05, 95%CI: 0.87 to 1.24) demonstrated the strongest association with both difficulties and prosocial behaviors, followed by meeting recommendations for PA + ST (total difficulties: ß estimate=-2.15, 95% CI: -2.41 to -1.90; prosocial behaviors: ß estimate = 0.98, 95% CI: 0.87 to 1.09). These associations were consistently significant in both boys and girls. CONCLUSION: Adherence to more 24-HMB recommendations, particularly meeting all recommendations or combined PA + ST recommendations, could improve emotional and behavioral well-being among adolescent girls and boys. The significance of balanced movement behaviors for promoting adolescent mental health merits increased attention.

The relationship between circulating metabolites and prostate hyperplasia: a Mendelian randomization study.

BACKGROUND: Circulating metabolites (CM) play a pivotal role in our overall health, yet the current evidence concerning the involvement of diverse CM in benign prostatic hyperplasia (BPH) remains limited. Mendelian randomization (MR) offers a promising avenue to explore the potential impact of CM on BPH. METHODS: In a forward MR analysis, a cohort of 249 circulating metabolites was employed as exposures to investigate their potential associations with BPH risk. Conversely, in a reverse MR analysis, BPH was employed as an exposure to assess its effects on CM. RESULTS: The forward MR analysis discerned a linkage between six metabolites and BPH, with careful consideration to excluding heterogeneity and pleiotropy. Subsequently, the reverse MR analysis unveiled that nine metabolic compounds, mainly comprising phospholipids and triglycerides, potentially exhibit elevated levels in BPH patients. CONCLUSION: Bidirectional MR analysis furnishes genetic insight into the interplay between CM and BPH. The prominence of lipids and triglycerides emerges as significant factors intricately linked to BPH risk.

Knowledge status of skin tear prevention and its demographic and occupational influencing factors: A National cross-sectional survey among nurses.

AIM: A skin tear (ST) is a common skin injury that is often misdiagnosed or overlooked. This study examined the current state of nurses' ST knowledge and its influencing factors. DESIGN: A national cross-sectional survey combined with a quantitative analysis was used to provide evidence of poor ST knowledge among nurses and its influencing factors. METHODS: An electronic questionnaire survey was conducted among 1293 nurses from 32 hospitals in 18 provinces across China, including a General Information Questionnaire, ST Knowledge Assessment Instrument (OASES) and a Self-directed Learning Competence Scale for Nurses (SLCS-N). RESULTS: The mean OASES score was 9.51 ± 3.15, with a score rate of 47.55%. Pearson's correlation analysis showed positive correlations, ranging from none to strong, between every dimension in the OASES and from strong to extremely strong between every dimension in the SLCS-N. Multivariate analysis revealed multiple independent factors influencing ST knowledge, such as hospital tier, specialized nurses in wound/ostomy/incontinence care, participation in training for wound/ostomy/incontinence management, willingness to undergo ST training, self-assessed grade in ST care and the degree of emphasis of managers. CONCLUSION: ST knowledge status was generally poor among nurses nationwide. Managers should establish a comprehensive and specialized curriculum-based system, develop evidence-based standardized nursing processes, and provide tailored training programs to address nurses' unique characteristics and individualized needs, thereby enhancing their proficiency in ST-related knowledge and skills. IMPACT: This study is the first to identify a poor level of ST knowledge among nurses nationwide, particularly in the four dimensions of risk assessment: prevention, treatment, classification, and observation. Based on the findings regarding demographic factors and ST experiences, an integrated management system and educational program should be implemented to improve nurses' awareness and knowledge in this field. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contributions.

Electrochemical C-N Bond Formation within Boron Imidazolate Cages Featuring Single Copper Sites.

Electrocatalysis expands the ability to generate industrially relevant chemicals locally and on-demand with intermittent renewable energy, thereby improving grid resiliency and reducing supply logistics. Herein, we report the feasibility of using molecular copper boron-imidazolate cages, BIF-29(Cu), to enable coupling between the electroreduction reaction of CO2 (CO2RR) with NO3- reduction (NO3RR) to produce urea with high selectivity of 68.5% and activity of 424 µA cm-2. Remarkably, BIF-29(Cu) is among the most selective systems for this multistep C-N coupling to-date, despite possessing isolated single-metal sites. The mechanism for C-N bond formation was probed with a combination of electrochemical analysis, in situ spectroscopy, and atomic-scale simulations. We found that NO3RR and CO2RR occur in tandem at separate copper sites with the most favorable C-N coupling pathway following the condensation between *CO and NH2OH to produce urea. This work highlights the utility of supramolecular metal-organic cages with atomically discrete active sites to enable highly efficient coupling reactions.

Clinical characteristics and immune profiles of patients with immune-mediated alopecia associated with COVID-19 vaccinations.

BACKGROUND: The clinical characteristics and pathomechanism for immune-mediated alopecia following COVID-19 vaccinations are not clearly characterized. OBJECTIVE: We investigated the causality and immune mechanism of COVID-19 vaccines-related alopecia areata (AA). STUDY DESIGN: 27 new-onset of AA patients after COVID-19 vaccinations and 106 vaccines-tolerant individuals were enrolled from multiple medical centers for analysis. RESULTS: The antinuclear antibody, total IgE, granulysin, and PARC/CCL18 as well as peripheral eosinophil count were significantly elevated in the patients with COVID-19 vaccines-related AA compared with those in the tolerant individuals (P = 2.03 × 10-5-0.039). In vitro lymphocyte activation test revealed that granulysin, granzyme B, and IFN-γ released from the T cells of COVID-19 vaccines-related AA patients could be significantly increased by COVID-19 vaccine excipients (polyethylene glycol 2000 and polysorbate 80) or spike protein (P = 0.002-0.04). CONCLUSIONS: Spike protein and excipients of COVID-19 vaccines could trigger T cell-mediated cytotoxicity, which contributes to the pathogenesis of immune-mediated alopecia associated with COVID-19 vaccines.

Adverse childhood and adulthood experiences and risk of new-onset cardiovascular disease with consideration of social support: a prospective cohort study.

BACKGROUND: The relationship between adverse childhood experiences (ACEs) and adverse adulthood experiences (AAEs) and their association with incident cardiovascular disease (CVD) have not been extensively studied. Considering social support, we evaluated the complex relations of ACEs and AAEs with incident CVD. METHODS: This prospective cohort study used data from the 2014 life course survey and the 2015 and 2018 surveys of the China Health and Retirement Longitudinal Study, a national survey of Chinese adults aged ≥ 45 years from 28 provinces across China. The study population included 5836 individuals (mean [SD] age, 59.59 [8.22] years, 49.7% were males). Information on ACEs, AAEs, young adulthood social support, health behavior factors, health status factors, and demographics was measured. Cox regression models, the difference method to estimate the mediation proportion, and the additive and multiplicative interactions were performed. Subgroup and sensitivity analyses were also conducted. RESULTS: During follow-up, 789 incident cases of CVD occurred. The fully adjusted model, including demographics, health behaviors, health status factors (e.g., depressive symptoms), and social support as control variables, demonstrated that the overall number of ACEs (Hazard ratio [HR]: 1.11, 95% CI: 1.08 to 1.14) and AAEs (HR: 1.19, 95% CI: 1.16 to 1.22) were associated with an increased risk of incident CVD. A dose-response relationship existed between the number of ACEs or AAEs and incident CVD risk. The overall AAEs were found to mediate 17.7% (95% CI: 8.2 to 34.2%) of the association between ACEs and incident CVD. Moreover, a significant additive interaction between ACEs and AAEs was detected (RERI [95% CI]: 0.32 [0.09 to 0.56]). Compared with adults without exposure to both ACE and AAE, those with exposure to both at least one ACE and one AAE indicator had the highest risk of incident CVD (HR: 1.96, 95% CI: 1.72 to 2.23). CONCLUSIONS: Exposure to ACEs or AAEs was independently associated with an increased risk of incident CVD among Chinese middle-aged and older adults in a dose-response manner, and the overall AAEs partially mediated the association between ACEs and incident CVD. Preventive measures aimed at addressing either ACEs or AAEs alone may not significantly reduce the risk of CVD later in life. The necessity of a comprehensive life-course health strategy targeting the prevention of adversity merits increased attention.

Characteristics of immune response profile in patients with immediate allergic and autoimmune urticarial reactions induced by SARS-CoV-2 vaccines.

Severe allergic reactions following SARS-COV-2 vaccination are generally rare, but the reactions are increasingly reported. Some patients may develop prolonged urticarial reactions following SARS-COV-2 vaccination. Herein, we investigated the risk factors and immune mechanisms for patients with SARS-COV-2 vaccines-induced immediate allergy and chronic urticaria (CU). We prospectively recruited and analyzed 129 patients with SARS-COV-2 vaccine-induced immediate allergic and urticarial reactions as well as 115 SARS-COV-2 vaccines-tolerant individuals from multiple medical centers during 2021-2022. The clinical manifestations included acute urticaria, anaphylaxis, and delayed to chronic urticaria developed after SARS-COV-2 vaccinations. The serum levels of histamine, IL-2, IL-4, IL-6, IL-8, IL-17 A, TARC, and PARC were significantly elevated in allergic patients comparing to tolerant subjects (P-values = 4.5 × 10-5-0.039). Ex vivo basophil revealed that basophils from allergic patients could be significantly activated by SARS-COV-2 vaccine excipients (polyethylene glycol 2000 and polysorbate 80) or spike protein (P-values from 3.5 × 10-4 to 0.043). Further BAT study stimulated by patients' autoserum showed positive in 81.3% of patients with CU induced by SARS-COV-2 vaccination (P = 4.2 × 10-13), and the reactions could be attenuated by anti-IgE antibody. Autoantibodies screening also identified the significantly increased of IgE-anti-IL-24, IgG-anti-FcεRI, IgG-anti-thyroid peroxidase (TPO), and IgG-anti-thyroid-related proteins in SARS-COV-2 vaccines-induced CU patients comparing to SARS-COV-2 vaccines-tolerant controls (P-values = 4.6 × 10-10-0.048). Some patients with SARS-COV-2 vaccines-induced recalcitrant CU patients could be successfully treated with anti-IgE therapy. In conclusion, our results revealed that multiple vaccine components, inflammatory cytokines, and autoreactive IgG/IgE antibodies contribute to SARS-COV-2 vaccine-induced immediate allergic and autoimmune urticarial reactions.

Deep Generation Model Guided by the Docking Score for Active Molecular Design.

A deep generation model, as a novel drug design and discovery tool, shows obvious advantages in generating compounds with novel backbones and has been applied successfully in the field of drug discovery. However, it is still a challenge to generate molecules with expected properties, especially high activity. Here, to obtain compounds both with novelty and high activity to a target, we proposed a conditional molecular generation model COMG by considering the docking score and 3D pharmacophore matching during molecular generation. The proposed model was based on the conditional variational autoencoder architecture constrained by the pharmacophore matching score. During Bayesian optimization, the docking score was applied to enhance the target relevance of generated compounds. Furthermore, to overcome the problem of high structural similarity caused by Bayesian optimization, the idea of the scaffold memory unit was also introduced. The evaluation results of COMG show that our model not only can improve the structural diversity of generated molecules but also can effectively improve the proportion of target-related drug-active molecules. The obtained results indicate that our proposed model COMG is a useful drug design tool.

OsmiR528 regulates rice-pollen intine formation by targeting an uclacyanin to influence flavonoid metabolism.

The intine, the inner layer of the pollen wall, is essential for the normal development and germination of pollen. However, the composition and developmental regulation of the intine in rice (Oryza sativa) remain largely unknown. Here, we identify a microRNA, OsmiR528, which regulates the formation of the pollen intine and thus male fertility in rice. The mir528 knockout mutant aborted pollen development at the late binucleate pollen stage, significantly decreasing the seed-setting rate. We further demonstrated that OsmiR528 affects pollen development by directly targeting the uclacyanin gene OsUCL23 (encoding a member of the plant-specific blue copper protein family of phytocyanins) and regulating intine deposition. OsUCL23 overexpression phenocopied the mir528 mutant. The OsUCL23 protein localized in the prevacuolar compartments (PVCs) and multivesicular bodies (MVBs). We further revealed that OsUCL23 interacts with a member of the proton-dependent oligopeptide transport (POT) family of transporters to regulate various metabolic components, especially flavonoids. We propose a model in which OsmiR528 regulates pollen intine formation by directly targeting OsUCL23 and in which OsUCL23 interacts with the POT protein on the PVCs and MVBs to regulate the production of metabolites during pollen development. The study thus reveals the functions of OsmiR528 and an uclacyanin during pollen development.

Construction and application of a nursing human resource allocation model based on the case mix index.

BACKGROUND: The case mix index (CMI) may reflect the severity of disease and the difficulty of care objectively, and is expected to be an ideal indicator for assessing the nursing workload. The purpose of this study was to explore the quantitative relationship between daily nursing worktime (DNW) and CMI to provide a method for the rational allocation of nursing human resources. METHODS: Two hundred and seventy-one inpatients and 36 nurses of the department of hepatobiliary surgery were prospectively included consecutively from August to September 2022. The DNW of each patient were accurately measured, and the CMI data of each patient were extracted. Among 10 curve estimations, the optimal quantitative model was selected for constructing the nursing human resource allocation model. Finally, the applicability of the allocation model was preliminarily assessed by analyzing the relationship between the relative gap in nursing human resources and patient satisfaction, as well as the incidence of adverse events in 17 clinical departments. RESULTS: The median (P25, P75) CMI of the 271 inpatients was 2.62 (0.92, 4.07), which varied by disease type (F = 3028.456, P < 0.001), but not by patient gender (F = 0.481, P = 0.488), age (F = 2.922, P = 0.089), or level of care (F = 0.096, P = 0.757). The median (P25, P75) direct and indirect DNW were 76.07 (57.98, 98.85) min and 43.42 (39.42, 46.72) min, respectively. Among the 10 bivariate models, the quadratic model established the optimal quantitative relationship between CMI and DNW; DNW = 92.3 + 4.8*CMI + 2.4*CMI2 (R2 = 0.627, F = 225.1, p < 0.001). The relative gap between theoretical and actual nurse staffing in the 17 clinical departments were linearly associated with both patient satisfaction (r = 0.653, P = 0.006) and incidence of adverse events (r = - 0.567, P = 0.021). However, after adjusting for other factors, it was partially correlated only with patient satisfaction (rpartial = 0.636, P = 0.026). CONCLUSION: The DNW derived from CMI can be used to allocate nursing human resources in a rational and convenient way, improving patient satisfaction while ensuring quality and safety.

[Research on performance optimization method of human-machine physical interaction system considering exoskeleton wearing comfort].

In order to improve the wearing comfort and bearing effectiveness of the exoskeleton, based on the prototype and working mechanism analysis of a relaxation wearable system for knee exoskeleton robot, the static optimization synthesis and its method are studied. Firstly, based on the construction of the virtual prototype model of the system, a comprehensive wearable comfort evaluation index considering the factors such as stress, deformation and the proportion of stress nodes was constructed. Secondly, based on the static simulation and evaluation index of system virtual prototype, multi-objective genetic optimization and local optimization synthesis of armor layer topology were carried out. Finally, the model reconstruction simulation data confirmed that the system had good wearing comfort. Our study provides a theoretical basis for the bearing performance and prototype construction of the subsequent wearable system.