Long-term expandable mouse and human-induced nephron progenitor cells enable kidney organoid maturation and modeling of plasticity and disease.

Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional units of the kidney. Here, manipulation of p38 and YAP activity allowed for long-term clonal expansion of primary mouse and human NPCs and induced NPCs (iNPCs) from human pluripotent stem cells (hPSCs). Molecular analyses demonstrated that cultured iNPCs closely resemble primary human NPCs. iNPCs generated nephron organoids with minimal off-target cell types and enhanced maturation of podocytes relative to published human kidney organoid protocols. Surprisingly, the NPC culture medium uncovered plasticity in human podocyte programs, enabling podocyte reprogramming to an NPC-like state. Scalability and ease of genome editing facilitated genome-wide CRISPR screening in NPC culture, uncovering genes associated with kidney development and disease. Further, NPC-directed modeling of autosomal-dominant polycystic kidney disease (ADPKD) identified a small-molecule inhibitor of cystogenesis. These findings highlight a broad application for the reported iNPC platform in the study of kidney development, disease, plasticity, and regeneration.

Predicting ICU Interventions: A Transparent Decision Support Model Based on Multivariate Time Series Graph Convolutional Neural Network.

In this study, we present a novel approach for predicting interventions for patients in the intensive care unit using a multivariate time series graph convolutional neural network. Our method addresses two critical challenges: the need for timely and accurate decisions based on changing physiological signals, drug administration information, and static characteristics; and the need for interpretability in the decision-making process. Drawing on real-world ICU records from the MIMIC-III dataset, we demonstrate that our approach significantly improves upon existing machine learning and deep learning methods for predicting two targeted interventions, mechanical ventilation and vasopressors. Our model achieved an accuracy improvement from 81.6% to 91.9% and a F1 score improvement from 0.524 to 0.606 for predicting mechanical ventilation interventions. For predicting vasopressor interventions, our model achieved an accuracy improvement from 76.3% to 82.7% and a F1 score improvement from 0.509 to 0.619. We also assessed the interpretability by performing an adjacency matrix importance analysis, which revealed that our model uses clinically meaningful and appropriate features for prediction. This critical aspect can help clinicians gain insights into the underlying mechanisms of interventions, allowing them to make more informed and precise clinical decisions. Overall, our study represents a significant step forward in the development of decision support systems for ICU patient care, providing a powerful tool for improving clinical outcomes and enhancing patient safety.

Impacts of Perioperative Comprehensive Nursing Intervention on Postoperative Urinary Incontinence and Quality of Life of Patients Undergoing Laparoscopic Radical Prostatectomy.

To evaluate the impact of perioperative comprehensive nursing intervention on postoperative urinary incontinence, various aspects of patient well-being were assessed. The comprehensive group, that received the nursing intervention, demonstrated significant improvements in self-care skills, health knowledge level, self-care responsibility, and self-concept compared to the standard group. The findings indicate that perioperative comprehensive nursing intervention has a remarkable effect on patients undergoing laparoscopic radical prostatectomy. This nursing intervention not only effectively improves postoperative urinary incontinence and alleviates negative emotions, such as anxiety and depression. Therefore, the implementation of this nursing intervention model is highly recommended for clinical practice and wider application.

The association between prenatal exposure to bisphenol A and offspring obesity: A systematic review.

In recent years, the global prevalence of childhood overweight and obesity has surged. Bisphenol A (BPA), prevalent in the manufacture of polycarbonate plastics and epoxy resins, is associated with this escalating obesity pattern. Both early life stages and pregnancy emerge as pivotal windows of vulnerability. This review systematically evaluates human studies to clarify the nexus between prenatal BPA exposure and offspring obesity. Our extensive literature search covered databases like PubMed, Web of Science, Cochrane Library, Embase, and Scopus, encompassing articles from their inception until July 2023. We utilized the Newcastle-Ottawa Scale (NOS) to evaluate the methodological rigor of the included studies, the Oxford Center for Evidence-Based Medicine Levels of Evidence Working Group (OCEBM) table to determine the level of the evidence, and the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) guidelines to evaluate the certainty of the evidence with statistical significance. We centered on primary studies investigating the link between urinary BPA levels during pregnancy and offspring obesity. Our analysis included thirteen studies, with participant counts ranging from 173 to 1124 mother-child dyads. Among them, eight studies conclusively linked prenatal BPA exposure to increased obesity in offspring. Evaluation metrics for the effect of prenatal BPA on offspring obesity comprised BMI z-score, waist circumference, overweight/obesity classification, aggregate skinfold thickness, body fat percentage, and more. Present findings indicate that prenatal BPA exposure amplifies offspring obesity risk, with potential effect variations by age and gender. Therefore, further research is needed to explore the causal link between prenatal BPA exposure and obesity at different developmental stages and genders, and to elucidate the underlying mechanisms.

The Association of Human Milk Proportion with the Clinical Outcomes of Necrotizing Enterocolitis in Preterm Infants: A Retrospective Study.

Human milk (HM) has been associated with a lower risk of necrotizing enterocolitis (NEC). However, the association of precise HM proportion with the outcome of NEC remains unclear. A total of 77 cases and 154 matched controls were included in this study. The samples were divided into three groups based on the HM proportion of the total enteral intake before NEC onset: ≥70% (HHM), <70% (LHM), and 0% (NHM). The study cohort did not show a significant association between different HM proportions and NEC risk. The adjusted odds ratio (OR) for the highest versus the lowest intake was 0.599. In the prognosis of NEC, different HM proportions significantly affected weight gain, the timing of NEC onset, diagnosis time, hospitalization cost, and the severity of NEC (p < 0.05). Our findings support the beneficial effects of HM on reducing NEC in preterm infants, particularly when a greater proportion of HM of the total enteral intake is included in their feeding. Additionally, the study indicates that preterm infants fed with lower proportions of HM of the total enteral feeding are more prone to experiencing severe cases of NEC.

The Association of Different Proportions of Human Milk of the Total Enteral Intake on Health Outcomes in Preterm Infants: A Systematic Review.

Background: Human milk (HM) is a proven optimal food for preterm infants. However, there is uncertainty regarding the effects of different proportions of HM of the total enteral intake on health outcomes in preterm infants. Therefore, we conducted a systematic review of studies examining the effects of different proportions of HM of the total enteral intake on health outcomes in preterm infants. Methods: We conducted a literature search in the Web of Science, PubMed, and Scopus databases. The methodological quality of the included articles and the certainty of evidence were assessed according to the Newcastle-Ottawa Scale and the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool, respectively. Results: Twelve studies were included in the review. Among the clinical findings, the effect of different proportions of HM of the total enteral feeding on health outcomes in preterm infants was divided into six primary outcomes: physical growth, length of stay, morbidity of any disease, all-cause mortality, feeding-related outcomes, and other health outcomes. The studies presented a high risk of bias for most of the domains. The certainty of the evidence was considered low or very low. Conclusions: The findings reiterated that greater proportions of HM positively affect the health outcomes of preterm infants. Overall, when the HM accounts for at least 20% of the total enteral intake, it has an effect on health outcomes in preterm infants. If the proportion of HM reaches 50%, the incidence and severity of necrotizing enterocolitis, as well as the time to reach enteral feeds, will be reduced. Increasing the proportion of HM in enteral feeding should be considered a priority in the feeding strategy for preterm infants in clinical practice.

Direct androgen receptor control of sexually dimorphic gene expression in the mammalian kidney.

Mammalian organs exhibit distinct physiology, disease susceptibility, and injury responses between the sexes. In the mouse kidney, sexually dimorphic gene activity maps predominantly to proximal tubule (PT) segments. Bulk RNA sequencing (RNA-seq) data demonstrated that sex differences were established from 4 and 8 weeks after birth under gonadal control. Hormone injection studies and genetic removal of androgen and estrogen receptors demonstrated androgen receptor (AR)-mediated regulation of gene activity in PT cells as the regulatory mechanism. Interestingly, caloric restriction feminizes the male kidney. Single-nuclear multiomic analysis identified putative cis-regulatory regions and cooperating factors mediating PT responses to AR activity in the mouse kidney. In the human kidney, a limited set of genes showed conserved sex-linked regulation, whereas analysis of the mouse liver underscored organ-specific differences in the regulation of sexually dimorphic gene expression. These findings raise interesting questions on the evolution, physiological significance, disease, and metabolic linkage of sexually dimorphic gene activity.

Prenatal exposure to bisphenol A and neonatal health outcomes: A systematic review.

Bisphenol A (BPA) is an endocrine-disrupting chemical substance responsible for the composition of polycarbonate plastics and epoxy resins. Early life and pregnancy are important windows of susceptibility. This review aimed to conduct a systematic assessment of human studies to comprehensively describe the association between prenatal BPA exposure and neonatal health outcomes. Literature was searched in Cochrane Library, Embase, PubMed, Scopus, and Web of Science published before November 2022, and were selected according to clear inclusion and exclusion criteria. The Newcastle-Ottawa scale (NOS) and Grades of Recommendation, Assessment, Development, and Evaluation guidelines (GRADE) were followed to grade the methodological quality of studies and the certainty of the evidence respectively. As a result, a total of 22259 participants from 45 trials were included. And the potential associations of prenatal exposure to BPA and neonatal health outcomes were mainly shown in four aspects: gestational age/preterm birth, physical health at birth, the incidence of systemic abnormalities or diseases, and other health outcomes. Although the certainty of the evidence was low to very low, the methodological quality of the included studies was high. Prenatal BPA exposure tended to have negative effects on most of the health outcomes in neonates but showed inconsistent results on physical health at birth. This systematic review is the first to comprehensively synthesize the existing evidence on the association between prenatal BPA exposure and neonatal health outcomes. In the future, further studies are still needed to verify these effects and elucidate the underlying mechanisms.

Modeling kidney development, disease, and plasticity with clonal expandable nephron progenitor cells and nephron organoids.

Nephron progenitor cells (NPCs) self-renew and differentiate into nephrons, the functional units of the kidney. Here we report manipulation of p38 and YAP activity creates a synthetic niche that allows the long-term clonal expansion of primary mouse and human NPCs, and induced NPCs (iNPCs) from human pluripotent stem cells. Cultured iNPCs resemble closely primary human NPCs, generating nephron organoids with abundant distal convoluted tubule cells, which are not observed in published kidney organoids. The synthetic niche reprograms differentiated nephron cells into NPC state, recapitulating the plasticity of developing nephron in vivo. Scalability and ease of genome-editing in the cultured NPCs allow for genome-wide CRISPR screening, identifying novel genes associated with kidney development and disease. A rapid, efficient, and scalable organoid model for polycystic kidney disease was derived directly from genome-edited NPCs, and validated in drug screen. These technological platforms have broad applications to kidney development, disease, plasticity, and regeneration.

Comparative single-cell analyses identify shared and divergent features of human and mouse kidney development.

Mammalian kidneys maintain fluid homeostasis through the cellular activity of nephrons and the conjoined collecting system. Each epithelial network originates from distinct progenitor cell populations that reciprocally interact during development. To extend our understanding of human and mouse kidney development, we profiled chromatin organization (ATAC-seq) and gene expression (RNA-seq) in developing human and mouse kidneys. Data were analyzed at a species level and then integrated into a common, cross-species multimodal data set. Comparative analysis of cell types and developmental trajectories identified conserved and divergent features of chromatin organization and linked gene activity, revealing species- and cell-type specific regulatory programs. Identification of human-specific enhancer regions linked through GWAS studies to kidney disease highlights the potential of developmental modeling to provide clinical insight.

Optimizing drip fertigation at different periods to improve yield, volatile compounds and cup quality of Arabica coffee.

How to improve and regulate coffee bean yield and quality through split fertilization in the whole life cycle of coffee is still unclear and deserves further study. A field experiment of 5-year-old Arabica coffee trees was conducted for 2 consecutive years from 2020 to 2022. The fertilizer (750 kg ha-1 year-1, N-P2O5-K2O:20%-20%-20%) was split in three times at early flowering (FL), the berry expansion (BE), and the berry ripening (BR). Taking equal fertilization throughout the growth cycle (FL250BE250BR250) as the control check, variable fertilizations including FL150BE250BR350, FL150BE350BR250, FL250BE150BR350, FL250BE350BR150, FL350BE150BR250, and FL350BE250BR150. Leaf net photosynthetic rate (A net), stomatal conductance (g s), transpiration rate (T r), leaf water use efficiency (LWUE), carboxylation efficiency (CE), partial factor productivity of fertilizer (PFP), bean yield, crop water use efficiency (WUE), bean nutrients, volatile compounds and cup quality, and the correlation of nutrients with volatile compounds and cup quality was evaluated. FL350BE250BR150 had the maximum A net and g s, followed by FL250BE350BR150. The highest dry bean yield and WUE were obtained from FL250BE350BR150, which increased by 8.86% and 8.47% compared with FL250BE250BR250 in two-year average. The ash, total sugar, fat, protein, caffeine and chlorogenic acid in FL250BE350BR150 were 6.47%, 9.48%, 3.60%, 14.02%, 4.85% and 15.42% higher than FL250BE250BR250. Cluster analysis indicated FL150BE350BR250, FL250BE350BR150, FL350BE150BR250 and FL350BE250BR150 under medium roasted degree increased pyrazines, esters, ketones and furans, FL150BE350BR250 and FL250BE350BR150 under dark roasted degree increased ketones and furans. The aroma, flavor, acidity and overall score of medium roasted coffee were higher than dark roasted coffee, while the body score of dark roasted coffee was higher than medium roasted coffee. The nutrient contents were correlated with the volatile compounds and cup quality. TOPSIS indicated that FL250BE350BR150 was the optimal fertilization mode in the xerothermic regions. The obtained optimum fertilization mode can provide a scientific basis for coffee fertilization optimization and management.

Direct androgen receptor regulation of sexually dimorphic gene expression in the mammalian kidney.

Mammalian organs exhibit distinct physiology, disease susceptibility and injury responses between the sexes. In the mouse kidney, sexually dimorphic gene activity maps predominantly to proximal tubule (PT) segments. Bulk RNA-seq data demonstrated sex differences were established from 4 and 8 weeks after birth under gonadal control. Hormone injection studies and genetic removal of androgen and estrogen receptors demonstrated androgen receptor (AR) mediated regulation of gene activity in PT cells as the regulatory mechanism. Interestingly, caloric restriction feminizes the male kidney. Single-nuclear multiomic analysis identified putative cis-regulatory regions and cooperating factors mediating PT responses to AR activity in the mouse kidney. In the human kidney, a limited set of genes showed conserved sex-linked regulation while analysis of the mouse liver underscored organ-specific differences in the regulation of sexually dimorphic gene expression. These findings raise interesting questions on the evolution, physiological significance, and disease and metabolic linkage, of sexually dimorphic gene activity.

Lineage Tracing and Single-Nucleus Multiomics Reveal Novel Features of Adaptive and Maladaptive Repair after Acute Kidney Injury.

SIGNIFICANCE STATEMENT: Understanding the mechanisms underlying adaptive and maladaptive renal repair after AKI and their long-term consequences is critical to kidney health. The authors used lineage tracing of cycling cells and single-nucleus multiomics (profiling transcriptome and chromatin accessibility) after AKI. They demonstrated that AKI triggers a cell-cycle response in most epithelial and nonepithelial kidney cell types. They also showed that maladaptive proinflammatory proximal tubule cells (PTCs) persist until 6 months post-AKI, although they decreased in abundance over time, in part, through cell death. Single-nucleus multiomics of lineage-traced cells revealed regulatory features of adaptive and maladaptive repair. These included activation of cell state-specific transcription factors and cis-regulatory elements, and effects in PTCs even after adaptive repair, weeks after the injury event. BACKGROUND: AKI triggers a proliferative response as part of an intrinsic cellular repair program, which can lead to adaptive renal repair, restoring kidney structure and function, or maladaptive repair with the persistence of injured proximal tubule cells (PTCs) and an altered kidney structure. However, the cellular and molecular understanding of these repair programs is limited. METHODS: To examine chromatin and transcriptional responses in the same cell upon ischemia-reperfusion injury (IRI), we combined genetic fate mapping of cycling ( Ki67+ ) cells labeled early after IRI with single-nucleus multiomics-profiling transcriptome and chromatin accessibility in the same nucleus-and generated a dataset of 83,315 nuclei. RESULTS: AKI triggered a broad cell cycle response preceded by cell type-specific and global transcriptional changes in the nephron, the collecting and vascular systems, and stromal and immune cell types. We observed a heterogeneous population of maladaptive PTCs throughout proximal tubule segments 6 months post-AKI, with a marked loss of maladaptive cells from 4 weeks to 6 months. Gene expression and chromatin accessibility profiling in the same nuclei highlighted differences between adaptive and maladaptive PTCs in the activity of cis-regulatory elements and transcription factors, accompanied by corresponding changes in target gene expression. Adaptive repair was associated with reduced expression of genes encoding transmembrane transport proteins essential to kidney function. CONCLUSIONS: Analysis of genome organization and gene activity with single-cell resolution using lineage tracing and single-nucleus multiomics offers new insight into the regulation of renal injury repair. Weeks to months after mild-to-moderate IRI, maladaptive PTCs persist with an aberrant epigenetic landscape, and PTCs exhibit an altered transcriptional profile even following adaptive repair.

Jerk-Level Zhang Neurodynamics Equivalency of Bound Constraints, Equation Constraints, and Objective Indices for Cyclic Motion of Robot-Arm Systems.

Equivalency is a powerful approach that can transform an original problem into another problem that is relatively more ready to be resolved. In recent years, Zhang neurodynamics equivalency (ZNE), in the form of neurodynamics or recurrent neural networks (RNNs), has been investigated, abstracted, and proposed as a process that can equivalently solve equations at different levels. After long-term research, we have noticed that the ZNE can not only work with equations, but also inequations. Thus, the ZNE of inequation type is proposed, proved, and applied in this study. The ZNE of inequation type can transform different-level bound constraints into unified-level bound constraints. Applications of the jerk-level ZNE of bound constraints, equation constraints, and objective indices ultimately build up effective time-varying quadratic-programming schemes for cyclic motion planning and control (CMPC) of single and dual robot-arm systems. In addition, as an effective time-varying quadratic-programming solver, a projection neural network (PNN) is introduced. Experimental results with single and dual robot-arm systems substantiate the correctness and efficacy of ZNE and especially the ZNE of inequation type. Comparisons with conventional methods also exhibit the superiorities of ZNE.

A genetic model for in vivo proximity labelling of the mammalian secretome.

Organ functions are highly specialized and interdependent. Secreted factors regulate organ development and mediate homeostasis through serum trafficking and inter-organ communication. Enzyme-catalysed proximity labelling enables the identification of proteins within a specific cellular compartment. Here, we report a BirA*G3 mouse strain that enables CRE-dependent promiscuous biotinylation of proteins trafficking through the endoplasmic reticulum. When broadly activated throughout the mouse, widespread labelling of proteins was observed within the secretory pathway. Streptavidin affinity purification and peptide mapping by quantitative mass spectrometry (MS) proteomics revealed organ-specific secretory profiles and serum trafficking. As expected, secretory proteomes were highly enriched for signal peptide-containing proteins, highlighting both conventional and non-conventional secretory processes, and ectodomain shedding. Lower-abundance proteins with hormone-like properties were recovered and validated using orthogonal approaches. Hepatocyte-specific activation of BirA*G3 highlighted liver-specific biotinylated secretome profiles. The BirA*G3 mouse model demonstrates enhanced labelling efficiency and tissue specificity over viral transduction approaches and will facilitate a deeper understanding of secretory protein interplay in development, and in healthy and diseased adult states.

A set of sampling, preparation, and staining techniques for studying meiosis in cucumber.

The development of genetic and genomic resources for biological studies in cucumber has experienced an unprecedented boom in recent years. To investigate the function of putative meiotic genes and germplasm in breeding programs, an accurate cytogenetic characterization is required. Cytological methods and reference to investigate meiosis in cucumber are limited at present. Here we provide a set of cytological techniques that have been adapted for the study of meiosis in cucumber. The meiotic stages can be identified with high precision using hierarchical criteria from developing buds, undisturbed meiocytes, and freshly stained chromosomes. A meiotic cytological atlas of all stages is presented as a reference for identifying particular stages and for comparison of meiosis between normal and mutant plants. We performed a comparative analysis of the distribution of cytoplasmic organelles between cucumber and Arabidopsis, and we described a highly nonsynchronous condensation of chromosome parts during diplotene. A simplified fluorescence in situ hybridization (FISH) protocol, using robustly spread chromosomes, were developed. In addition, we designed a single oligonucleotide probe for 5S rDNA to use in karyotyping and monitoring of homologous chromosome pairing, which will make FISH analysis of 5S rDNA easier and more economical.

Discrete-Time Advanced Zeroing Neurodynamic Algorithm Applied to Future Equality-Constrained Nonlinear Optimization With Various Noises.

This research first proposes the general expression of Zhang et al. discretization (ZeaD) formulas to provide an effective general framework for finding various ZeaD formulas by the idea of high-order derivative simultaneous elimination. Then, to solve the problem of future equality-constrained nonlinear optimization (ECNO) with various noises, a specific ZeaD formula originating from the general ZeaD formula is further studied for the discretization of a noise-perturbed continuous-time advanced zeroing neurodynamic model. Subsequently, the resulting noise-perturbed discrete-time advanced zeroing neurodynamic (NP-DTAZN) algorithm is proposed for the real-time solution to the future ECNO problem with various noises suppressed simultaneously. Moreover, theoretical and numerical results are presented to show the convergence and precision of the proposed NP-DTAZN algorithm in the perturbation of various noises. Finally, comparative numerical and physical experiments based on a Kinova JACO2 robot manipulator are conducted to further substantiate the efficacy, superiority, and practicability of the proposed NP-DTAZN algorithm for solving the future ECNO problem with various noises.

The Current Status of Breastfeeding Knowledge and Its Influencing Factors in Nursing Undergraduates: A Cross-Sectional Study in China.

The aim of this study was to explore the breastfeeding knowledge of nursing undergraduates and the influencing factors. Human milk (HM) is one of the most effective nutritional supplies to improve early development and physical health, but the current status of breastfeeding in China is still not optimal. The breastfeeding knowledge of perinatal women influences their feeding beliefs and behavior. Nursing undergraduates, as core professionals who will care for perinatal women and provide feeding guidance in the future, can significantly affect feeding behavior of mothers and their babies, so their knowledge of breastfeeding may have a potential impact on breastfeeding in China. However, studies on breastfeeding knowledge among nursing undergraduates in China are limited. A convenience sampling method was conducted in four medical universities in China, and eligible nursing undergraduates were selected. An online survey was collected from 5 July 2022 to 5 August 2022. Categorical data were reported as number and percentage, while continuous data were reported as mean ± SD. Multivariate linear regression was used to evaluate the association between influencing factors and breastfeeding knowledge. The overall mean score of the 460 returned questionnaires was 43.991 out of 100. The pass rate of the questionnaire was only 23.04%. Nursing undergraduates had a relatively better grasp of the benefits of breastfeeding and related advice (correct rates: 67.83%). Birthplace, only child or not, the course in obstetrics and gynecological nursing, the course in pediatrics nursing, and placements in maternity or neonatology units were relevant factors for breastfeeding knowledge (p < 0.05). Nursing undergraduates showed unsatisfactory breastfeeding knowledge. It is urgent to raise the knowledge level of breastfeeding among nursing undergraduates. Medical colleges should optimally structure a curriculum of breastfeeding knowledge. Furthermore, it is also necessary to improve the public's understanding of breastfeeding and the whole society's attention to breastfeeding in China.

Spatial transcriptional mapping of the human nephrogenic program.

Congenital abnormalities of the kidney and urinary tract are among the most common birth defects, affecting 3% of newborns. The human kidney forms around a million nephrons from a pool of nephron progenitors over a 30-week period of development. To establish a framework for human nephrogenesis, we spatially resolved a stereotypical process by which equipotent nephron progenitors generate a nephron anlage, then applied data-driven approaches to construct three-dimensional protein maps on anatomical models of the nephrogenic program. Single-cell RNA sequencing identified progenitor states, which were spatially mapped to the nephron anatomy, enabling the generation of functional gene networks predicting interactions within and between nephron cell types. Network mining identified known developmental disease genes and predicted targets of interest. The spatially resolved nephrogenic program made available through the Human Nephrogenesis Atlas (https://sckidney.flatironinstitute.org/) will facilitate an understanding of kidney development and disease and enhance efforts to generate new kidney structures.