Scalable Layered Heterogeneous Hydrogel Fibers with Strain-Induced Crystallization for Tough, Resilient, and Highly Conductive Soft Bioelectronics.

The advancement of soft bioelectronics hinges critically on the electromechanical properties of hydrogels. Despite ongoing research into diverse material and structural strategies to enhance these properties, producing hydrogels that are simultaneously tough, resilient, and highly conductive for long-term, dynamic physiological monitoring remains a formidable challenge. Here, a strategy utilizing scalable layered heterogeneous hydrogel fibers (LHHFs) is introduced that enables synergistic electromechanical modulation of hydrogels. High toughness (1.4 MJ m-3) and resilience (over 92% recovery from 200% strain) of LHHFs are achieved through a damage-free toughening mechanism that involves dense long-chain entanglements and reversible strain-induced crystallization of sodium polyacrylate. The unique symmetrical layered structure of LHHFs, featuring distinct electrical and mechanical functional layers, facilitates the mixing of multi-walled carbon nanotubes to significantly enhance electrical conductivity (192.7 S m-1) without compromising toughness and resilience. Furthermore, high-performance LHHF capacitive iontronic strain/pressure sensors and epidermal electrodes are developed, capable of accurately and stably capturing biomechanical and bioelectrical signals from the human body under long-term, dynamic conditions. The LHHF offers a promising route for developing hydrogels with uniquely integrated electromechanical attributes, advancing practical wearable healthcare applications.

Soluble sugar, organic acid and phenolic composition and flavor evaluation of plum fruits.

Plums (Prunus salicina and Prunus domestica) are prevalent in southwestern China, and have attracted interest owing to their delectable taste and exceptional nutritional properties. Therefore, this study aimed to investigate the nutritional and flavor properties of plum to improve its nutritional utilization. Specifically, we determined the soluble sugars, organic acids, and phenolic components in 86 accessions using high-performance liquid chromatography. Notably, glucose, fructose, malic, and quinic acids were the predominant sweetness and acidity in plums, with sucrose contributing more to the sweetness of the flesh than the peel. Moreover, The peel contains 5.5 fold more phenolics than flesh, epicatechin, gallic acid, and proanthocyanidins C1 and B2 were the primary sources of astringency. Correlation and principal component analyses showed eight core factors for plum flavor rating, and a specific rating criterion was established. Conclusively, these findings provide information on the integrated flavor evaluation criteria and for enhancing optimal breeding of plums.

A multi-omic analysis reveals that Gamabufotalin exerts anti-hepatocellular carcinoma effects by regulating amino acid metabolism through targeting STAMBPL1.

BACKGROUND: Hepatocellular carcinoma (HCC), a prevalent type of liver cancer, is characterized by an unfavorable prognosis and a high mortality rate. Identifying novel treatments to prevent HCC recurrence and metastasis remains crucial for improving patient survival. Gamabufotalin (CS-6), a primary bufadienolide derived from the traditional Chinese medicine Chansu, has demonstrated significant anti-tumor activity. However, the effects and underlying mechanisms of CS-6 on HCC cells are not yet fully understood. PURPOSE: This study sought to elucidate the anti-HCC effects and potential mechanisms of CS-6. In vitro experiments were conducted using the HCC cell lines MHCC97H and Huh-7, employing CCK-8 assays, colony formation assays, wound healing assays, transwell invasion and migration assays, and flow cytometry to assess apoptosis and cell cycle dynamics. A multi-omics approach, including metabolomics and RNA sequencing analysis, was utilized to identify CS-6's molecular targets and mechanisms in HCC therapy. Additionally, in vivo assessments were performed using xenografts in nude mice. RESULTS: CS-6 significantly inhibited HCC cell proliferation, migration, and invasion. Multi-omics analysis suggested that CS-6's anti-HCC effects may involve the modulation of metabolic pathways, potentially through the downregulation of STAMBPL1, resulting in reduced mTOR signaling, increased apoptosis, and suppression of malignant HCC behavior. In vivo studies further confirmed that CS-6 significantly suppressed tumor growth and enhanced apoptosis and autophagy within tumors. CONCLUSION: These results underscore the therapeutic potential of CS-6 in HCC treatment. The study offers novel insights into the mechanism of CS-6, suggesting that its therapeutic efficacy may be uniquely mediated by targeting STAMBPL1. This distinct mechanism sets CS-6 apart from existing HCC treatments and positions it as a promising candidate for further clinical investigation.

Rice Varieties Intercropping Induced Soil Metabolic and Microbial Recruiting to Enhance the Rice Blast (Magnaporthe Oryzae) Resistance.

[Background] Intercropping is considered an effective approach to defending rice disease. [Objectives/Methods] This study aimed to explore the resistance mechanism of rice intraspecific intercropping by investigating soil metabolites and their regulation on the rhizosphere soil microbial community using metabolomic and microbiome analyses. [Results] The results showed that the panicle blast disease occurrence of the resistant variety Shanyou63 (SY63) and the susceptible variety Huangkenuo (HKN) were both decreased in the intercropping compared to monoculture. Notably, HKN in the intercropping system exhibited significantly decreased disease incidence and increased disease resistance-related enzyme protease activity. KEGG annotation from soil metabolomics analysis revealed that phenylalanine metabolic pathway, phenylalanine, tyrosine, and tryptophan biosynthesis pathway, and fructose and mannose metabolic pathway were the key pathways related to rice disease resistance. Soil microbiome analysis indicated that the bacterial genera Nocardioides, Marmoricola, Luedemannella, and Desulfomonile were significantly enriched in HKN after intercropping, while SY63 experienced a substantial accumulation of Ruminiclostridium and Cellulomonas. Omics-based correlation analysis highlighted that the community assembly of Cellulomonas and Desulfomonile significantly affected the content of the metabolites D-sorbitol, D-mannitol, quinic acid, which further proved that quinic acid had a significantly inhibitory effect on the mycelium growth of Magnaporthe oryzae, and these three metabolites had a significant blast control effect. The optimal rice blast-control efficiency on HKN was 51.72%, and Lijiangxintuanheigu (LTH) was 64.57%. [Conclusions] These findings provide a theoretical basis for rice varieties intercropping and sustainable rice production, emphasizing the novelty of the study in elucidating the underlying mechanisms of intercropping-mediated disease resistance.

Polystyrene microplastics alleviate the developmental toxicity of silver nanoparticles in embryo-larval zebrafish (Danio rerio) at the transcriptomic level.

Since silver nanoparticles (AgNPs) and polystyrene microplastics (PS-MP) share common environmental niches, their interactions can modulate their hazard impacts. Herein, we assessed the developmental toxicity of 1 mg/L PS-MP, 0.5 mg/L AgNPs and the mixtures of AgNPs and PS-MP on embryo-larval zebrafish. We found that AgNPs co-exposure with PS-MP remarkably decreased mortality rates, malformation rates, heart rates and yolk sac area, while it increased hatching rates and eye size compared to the AgNPs group. These phenomena revealed that the cell cycle, oxidative stress, apoptosis, lipid metabolism, ferroptosis and p53 signalling pathway were obviously affected by single AgNPs exposure at 96 hpf (hours post fertilization). Interestingly, all these effects were effectively ameliorated by co-exposure with PS-MP. The combination of transcriptomic and metabolomic analyses showed that the imbalance of DEGs (differentially expressed genes) and DEMs (differentially expressed metabolites) (PI, phosphatidylinositol and TAG-FA, triacylglycerol-fatty acid) disturbed both the cell cycle and lipid metabolism following single AgNPs exposure and co-exposure with PS-MP. These findings suggest that PS-MP attenuates the developmental toxicity of AgNPs on embryo-larval zebrafish. Overall, this study provides important insight into understanding the transcriptional responses and mechanisms of AgNPs alone or in combination with PS-MPs on embryo-larval zebrafish, providing a reference for ecological risk assessment of combined exposure to PS-MP and metal nanoparticles.

Aged bone marrow macrophages drive systemic aging and age-related dysfunction via extracellular vesicle-mediated induction of paracrine senescence.

The accumulation and systemic propagation of senescent cells contributes to physiological aging and age-related pathology. However, which cell types are most susceptible to the aged milieu and could be responsible for the propagation of senescence has remained unclear. Here we found that physiologically aged bone marrow monocytes/macrophages (BMMs) propagate senescence to multiple tissues, through extracellular vesicles (EVs), and drive age-associated dysfunction in mice. We identified peroxisome proliferator-activated receptor α (PPARα) as a target of microRNAs within aged BMM-EVs that regulates downstream effects on senescence and age-related dysfunction. Demonstrating therapeutic potential, we report that treatment with the PPARα agonist fenofibrate effectively restores tissue homeostasis in aged mice. Suggesting conservation to humans, in a cohort study of 7,986 participants, we found that fenofibrate use is associated with a reduced risk of age-related chronic disease and higher life expectancy. Together, our findings establish that BMMs can propagate senescence to distant tissues and cause age-related dysfunction, and they provide supportive evidence for fenofibrate to extend healthy lifespan.

Long-term safety and influence on growth in patients receiving sirolimus: a pooled analysis.

BACKGROUND: Sirolimus is increasingly utilized in treating diseases associated with mTOR pathway overactivation. Despite its potential, the lack of evidence regarding its long-term safety across all age groups, particularly in pediatric patients, has limited its further application. This study aims to assess the long-term safety of sirolimus, with a specific focus on its impact on growth patterns in pediatric patients. METHODS: This pooled analysis inlcudes two prospective cohort studies spanning 10 years, including 1,738 participants (aged 5 days to 69 years) diagnosed with tuberous sclerosis and/or lymphangioleiomyomatosis. All participants were mTOR inhibitor-naive and received 1 mg/m²/day of sirolimus, with dose adjustments during a two-week titration period to maintain trough blood concentrations between 5 and 10 ng/ml (maximum dose 2 mg). Indicators of physical growth, hematopoietic, liver, renal function, and blood lipid levels were all primary outcomes and were analyzed. The adverse events and related management were also recorded. RESULTS: Sirolimus administration did not lead to deviations from normal growth ranges, but higher doses exhibited a positive association with Z-scores exceeding 2 SD in height, weight, and BMI. Transient elevations in red blood cell and white blood cell counts, along with hyperlipidemia, were primarily observed within the first year of treatment. Other measured parameters remained largely unchanged, displaying only weak correlations with drug use. Stomatitis is the most common adverse event (920/1738, 52.9%). In adult females, menstrual disorders were observed in 48.5% (112/217). CONCLUSIONS: Sirolimus's long-term administration is not associated with adverse effects on children's physical growth pattern, nor significant alterations in hematopoietic, liver, renal function, or lipid levels. A potential dose-dependent influence on growth merits further exploration. TRIAL REGISTRATION: Pediatric patients: Chinese clinical trial registry, No. ChiCTR-OOB-15,006,535. Adult patients: ClinicalTrials, No. NCT03193892.

Icariin targets p53 to protect against ceramide-induced neuronal senescence: Implication in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a leading cause of dementia. The aging brain is particularly vulnerable to various stressors, including increased levels of ceramide. However, the role of ceramide in neuronal cell senescence and AD progression and whether icariin, a natural flavonoid glucoside, could reverse neuronal senescence remain inadequately understood. AIM: In this study, we explore the role of ceramide in neuronal senescence and AD, and whether icariin can counteract these effects. METHODS: We pretreated HT-22 cells with icariin and then induced senescence with ceramide. Various assays were employed to assess cell senescence, such as reactive oxygen species (ROS) production, cell cycle progression, ß-galactosidase staining, and expression of senescence-associated proteins. In vivo studies utilized APP/PS1 mice and C57BL/6J mice injected with ceramide to evaluate behavioral changes, histopathological alterations, and senescence-associated protein expression. Transcriptomics, molecular docking, molecular dynamics simulations, and cellular thermal shift assays were employed to verify the interaction between icariin and P53. The specificity of icariin targeting of P53 was further confirmed through rescue experiments utilizing the P53 activator Navtemadlin. RESULTS: Our data demonstrated that ceramide could induce neuronal senescence and AD-related pathologies, which were reversed by icariin. Moreover, molecular studies revealed that icariin directly targeted P53, and its neuroprotective effects were attenuated by P53 activation, providing evidence for the role of P53 in icariin-mediated neuroprotection. CONCLUSION: Icariin demonstrates a protective effect against ceramide-induced neuronal senescence by inhibiting the P53 pathway. This identifies a novel mechanism of action for icariin, offering a novel therapeutic approach for AD and other age-related neurodegenerative diseases.

The proto-oncogene tyrosine kinase c-SRC facilitates glioblastoma progression by remodeling fatty acid synthesis.

Increased fatty acid synthesis benefits glioblastoma malignancy. However, the coordinated regulation of cytosolic acetyl-CoA production, the exclusive substrate for fatty acid synthesis, remains unclear. Here, we show that proto-oncogene tyrosine kinase c-SRC is activated in glioblastoma and remodels cytosolic acetyl-CoA production for fatty acid synthesis. Firstly, acetate is an important substrate for fatty acid synthesis in glioblastoma. c-SRC phosphorylates acetyl-CoA synthetase ACSS2 at Tyr530 and Tyr562 to stimulate the conversion of acetate to acetyl-CoA in cytosol. Secondly, c-SRC inhibits citrate-derived acetyl-CoA synthesis by phosphorylating ATP-citrate lyase ACLY at Tyr682. ACLY phosphorylation shunts citrate to IDH1-catalyzed NADPH production to provide reducing equivalent for fatty acid synthesis. The c-SRC-unresponsive double-mutation of ACSS2 and ACLY significantly reduces fatty acid synthesis and hampers glioblastoma progression. In conclusion, this remodeling fulfills the dual needs of glioblastoma cells for both acetyl-CoA and NADPH in fatty acid synthesis and provides evidence for glioma treatment by c-SRC inhibition.

Simultaneous detection of multiple microRNAs based on fluorescence resonance energy transfer under a single excitation wavelength.

MicroRNAs (miRNAs) play a key role in physiological processes, and their dysregulation is closely related to various human diseases. Simultaneous detection of multiple miRNAs is pivotal to cancer diagnosis at an early stage. However, most multicomponent analyses generally involve multiple excitation wavelengths, which are complicated and often challenging to simultaneously acquire multiple detection signals. In this study, a convenient and sensitive sensor was developed to simultaneously detection of multiple miRNAs under a single excitation wavelength through the fluorescence resonance energy transfer between the carbon dots (CDs)/quantum dots (QDs) and graphene oxide (GO). A hybridization chain reaction (HCR) was triggered by miRNA-141 and miRNA-21, resulting in the high sensitivity with a limit of detection (LOD) of 50 pM (3σ/k) for miRNA-141 and 60 pM (3σ/k) for miRNA-21. This simultaneous assay also showed excellent specificity discrimination against the mismatch. Furthermore, our proposed method successfully detected miRNA-21 and miRNA-141 in human serum samples at a same time, indicating its diagnostic potential in a clinical setting.

Eg5 UFMylation promotes spindle organization during mitosis.

UFMylation is a highly conserved ubiquitin-like post-translational modification that catalyzes the covalent linkage of UFM1 to its target proteins. This modification plays a critical role in the maintenance of endoplasmic reticulum proteostasis, DNA damage response, autophagy, and transcriptional regulation. Mutations in UFM1, as well as in its specific E1 enzyme UBA5 and E2 enzyme UFC1, have been genetically linked to microcephaly. Our previous research unveiled the important role of UFMylation in regulating mitosis. However, the underlying mechanisms have remained unclear due to the limited identification of substrates. In this study, we identified Eg5, a motor protein crucial for mitotic spindle assembly and maintenance, as a novel substrate for UFMylation and identified Lys564 as the crucial UFMylation site. UFMylation did not alter its transcriptional level, phosphorylation level, or protein stability, but affected the mono-ubiquitination of Eg5. During mitosis, Eg5 and UFM1 co-localize at the centrosome and spindle apparatus, and defective UFMylation leads to diminished spindle localization of Eg5. Notably, the UFMylation-defective Eg5 mutant (K564R) exhibited shorter spindles, metaphase arrest, spindle checkpoint activation, and a failure of cell division in HeLa cells. Overall, Eg5 UFMylation is essential for proper spindle organization, mitotic progression, and cell proliferation.

Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer.

Emotional distress (ED), commonly characterized by symptoms of depression and/or anxiety, is prevalent in patients with cancer. Preclinical studies suggest that ED can impair antitumor immune responses, but few clinical studies have explored its relationship with response to immune checkpoint inhibitors (ICIs). Here we report results from cohort 1 of the prospective observational STRESS-LUNG study, which investigated the association between ED and clinical efficacy of first-line treatment of ICIs in patients with advanced non-small-cell lung cancer. ED was assessed by Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale. The study included 227 patients with 111 (48.9%) exhibiting ED who presented depression (Patient Health Questionnaire-9 score ≥5) and/or anxiety (Generalized Anxiety Disorder 7-item score ≥5) symptoms at baseline. On the primary endpoint analysis, patients with baseline ED exhibited a significantly shorter median progression-free survival compared with those without ED (7.9 months versus 15.5 months, hazard ratio 1.73, 95% confidence interval 1.23 to 2.43, P = 0.002). On the secondary endpoint analysis, ED was associated with lower objective response rate (46.8% versus 62.1%, odds ratio 0.54, P = 0.022), reduced 2-year overall survival rate of 46.5% versus 64.9% (hazard ratio for death 1.82, 95% confidence interval 1.12 to 2.97, P = 0.016) and detriments in quality of life. The exploratory analysis indicated that the ED group showed elevated blood cortisol levels, which was associated with adverse survival outcomes. This study suggests that there is an association between ED and worse clinical outcomes in patients with advanced non-small-cell lung cancer treated with ICIs, highlighting the potential significance of addressing ED in cancer management. ClinicalTrials.gov registration: NCT05477979 .

Validation of the Chinese version of the coping strategies for victims of cyberbullying scale.

BACKGROUND: Although abundant evidence has confirmed cyberbullying as a global online risk, little is known about the coping strategies employed by victims and those who experiencing bullying. A validated scale for coping with cyberbullying could inform evidence-based social services and enable comparative studies of this phenomenon among victims from different backgrounds. This study aims to validate the Coping Strategies for Victims of Cyberbullying (CSVC) scale among Chinese adolescents and to compare its effectiveness between victims and bully-victims (individuals with dual roles). METHODS: A 25-item CSVC scale was translated and adapted for cultural relevance in the Chinese context. A sample of 1,716 adolescents, aged 13-18 years, from two middle schools and one high school in China, was recruited. Both exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were conducted. RESULTS: The EFA revealed that the Chinese version of the CSVC scale had satisfactory validity. The CFA demonstrated a good fit for the eight-factor model in assessing different coping strategies for cyberbullying. Differences in the selection of coping strategies were observed between the general adolescent population and sexual and gender minorities. CONCLUSIONS: Future intervention studies may use this validated scale to educate adolescents, both those affected by cyberbullying and those who are not, to learn a broader range of coping strategies and to choose more effective ones.

An ARF gene mutation creates flint kernel architecture in dent maize.

Dent and flint kernel architectures are important characteristics that affect the physical properties of maize kernels and their grain end uses. The genes controlling these traits are unknown, so it is difficult to combine the advantageous kernel traits of both. We found mutation of ARFTF17 in a dent genetic background reduces IAA content in the seed pericarp, creating a flint-like kernel phenotype. ARFTF17 is highly expressed in the pericarp and encodes a protein that interacts with and inhibits MYB40, a transcription factor with the dual functions of repressing PIN1 expression and transactivating genes for flavonoid biosynthesis. Enhanced flavonoid biosynthesis could reduce the metabolic flux responsible for auxin biosynthesis. The decreased IAA content of the dent pericarp appears to reduce cell division and expansion, creating a shorter, denser kernel. Introgression of the ARFTF17 mutation into dent inbreds and hybrids improved their kernel texture, integrity, and desiccation, without affecting yield.

Structuring and Shaping of Mechanically Robust and Functional Hydrogels toward Wearable and Implantable Applications.

Hydrogels possess unique features such as softness, wetness, responsiveness, and biocompatibility, making them highly suitable for biointegrated applications that have close interactions with living organisms. However, conventional man-made hydrogels are usually soft and brittle, making them inferior to the mechanically robust biological hydrogels. To ensure reliable and durable operation of biointegrated wearable and implantable devices, mechanical matching and shape adaptivity of hydrogels to tissues and organs are essential. Recent advances in polymer science and processing technologies have enabled mechanical engineering and shaping of hydrogels for various biointegrated applications. In this review, polymer network structuring strategies at micro/nanoscales for toughening hydrogels are summarized, and representative mechanical functionalities that exist in biological materials but are not easily achieved in synthetic hydrogels are further discussed. Three categories of processing technologies, namely, 3D printing, spinning, and coating for fabrication of tough hydrogel constructs with complex shapes are reviewed, and the corresponding hydrogel toughening strategies are also highlighted. These developments enable adaptive fabrication of mechanically robust and functional hydrogel devices, and promote application of hydrogels in the fields of biomedical engineering, bioelectronics, and soft robotics.

Selective Random Walk for Transfer Learning in Heterogeneous Label Spaces.

Transfer learning has been widely used in different scenarios, especially in those lacking enough labeled data. However, most of the existing transfer learning methods are based on the assumption that the source and target domains should share the label space entirely or partially, which greatly limits their application scopes. In this article, a Selective Random Walk (SRW) method for transfer learning in heterogeneous label spaces is proposed to make full use of unlabeled auxiliary data, which acts as a bridge for knowledge transfer from the source domain to the target domain. The proposed SRW method can explicitly identify transfer sequences between source and target instances via auxiliary instances based on random walk techniques. Since not all of the transfer sequences generated by random walk are credible for the target task, the SRW method can learn to weight transfer sequences adaptively. Based on the weights of the transfer sequences, the SRW method leverages knowledge by forcing adjacent data points in the transfer sequence to be similar and making the target data point in the sequence represented by other data points in the same sequence. Experiments show that the SRW method outperforms state-of-the-art models in plenty of transfer learning tasks with heterogeneous label spaces constructed within and across several benchmark datasets.

GGC expansions in NOTCH2NLC contribute to Parkinson disease and dopaminergic neuron degeneration.

BACKGROUND AND PURPOSE: The role of GGC repeat expansions within NOTCH2NLC in Parkinson's disease (PD) and the substantia nigra (SN) dopaminergic neuron remains unclear. Here, we profile the NOTCH2NLC GGC repeat expansions in a large cohort of patients with PD. We also investigate the role of GGC repeat expansions within NOTCH2NLC in the dopaminergic neurodegeneration of SN. METHODS: A total of 2,522 patients diagnosed with PD and 1,085 health controls were analyzed for the repeat expansions of NOTCH2NLC by repeat-primed PCR and GC-rich PCR assay. Furthermore, the effects of GGC repeat expansions in NOTCH2NLC on dopaminergic neurons were investigated by using recombinant adeno-associated virus (AAV)-mediated overexpression of NOTCH2NLC with 98 GGC repeats in the SN of mice by stereotactic injection. RESULTS: Four PD pedigrees (4/333, 1.2%) and three sporadic PD patients (3/2189, 0.14%) were identified with pathogenic GGC repeat expansions (larger than 60 GGC repeats) in the NOTCH2NLC gene, while eight PD patients and one healthy control were identified with intermediate GGC repeat expansions ranging from 41 to 60 repeats. No significant difference was observed in the distribution of intermediate NOTCH2NLC GGC repeat expansions between PD cases and controls (Fisher's exact test p-value = 0.29). Skin biopsy showed P62-positive intranuclear NOTCH2NLC-polyGlycine (polyG) inclusions in the skin nerve fibers of patient. Expanded GGC repeats in NOTCH2NLC produced widespread intranuclear and perinuclear polyG inclusions, which led to a severe loss of dopaminergic neurons in the SN. Consistently, polyG inclusions were presented in the SN of EIIa-NOTCH2NLC-(GGC)98 transgenic mice and also led to dopaminergic neuron loss in the SN. CONCLUSIONS: Overall, our findings provide strong evidence that GGC repeat expansions within NOTCH2NLC contribute to the pathogenesis of PD and cause degeneration of nigral dopaminergic neurons.

Effects of a Rapid Response Team on Patient Outcomes: A Systematic Review.

BACKGROUND: Despite the widespread adoption of the rapid response team (RRT) by many hospitals, questions remain regarding their effectiveness in improving several aspects of patient outcomes, such as hospital mortality, cardiopulmonary arrests, unplanned intensive care unit (ICU) admissions, and length of stay (LOS). OBJECTIVES: To conduct a systematic review to understand the rapid response team's (RRT) effect on patient outcomes. METHODS: A systematic search was conducted using PubMed, Cochrane, Embase, CINAHL, Web of Science, and two trial registers. The studies published up to May 6, 2022, from the inception date of the databases were included. Two researchers filtered the title, abstract and full text. The Version 2 of the Cochrane Risk of Bias tool and Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool were used separately for randomized and non-randomized controlled trials for quality appraisal. RESULTS: Sixty-one eligible studies were identified, four randomized controlled trials(RCTs), four non-randomized controlled trials, six interrupted time-series(ITS) design , and 47 pretest-posttest studies. A total of 52 studies reported hospital mortality, 51 studies reported cardiopulmonary arrests, 18 studies reported unplanned ICU admissions and ten studies reported LOS. CONCLUSION: This systematic review found the variation in context and the type of RRT interventions restricts direct comparisons. The evidence for improving several aspects of patient outcomes was inconsistent, with most studies demonstrating that RRT positively impacts patient outcomes.

Maize DDK1 encoding an Importin-4 ß protein is essential for seed development and grain filling by mediating nuclear exporting of eIF1A.

Nuclear-cytoplasmic trafficking is crucial for protein synthesis in eukaryotic cells due to the spatial separation of transcription and translation by the nuclear envelope. However, the mechanism underlying this process remains largely unknown in plants. In this study, we isolated a maize (Zea mays) mutant designated developmentally delayed kernel 1 (ddk1), which exhibits delayed seed development and slower filling. Ddk1 encodes a plant-specific protein known as Importin-4 ß, and its mutation results in reduced 80S monosomes and suppressed protein synthesis. Through our investigations, we found that DDK1 interacts with eIF1A proteins in vivo. However, in vitro experiments revealed that this interaction exhibits low affinity in the absence of RanGTP. Additionally, while the eIF1A protein primarily localizes to the cytoplasm in the wild-type, it remains significantly retained within the nuclei of ddk1 mutants. These observations suggest that DDK1 functions as an exportin and collaborates with RanGTP to facilitate the nuclear export of eIF1A, consequently regulating endosperm development at the translational level. Importantly, both DDK1 and eIF1A are conserved among various plant species, implying the preservation of this regulatory module across diverse plants.

A homozygous variant in INTS11 links mitosis and neurogenesis defects to a severe neurodevelopmental disorder.

The INTS11 endonuclease is crucial in modulating gene expression and has only recently been linked to human neurodevelopmental disorders (NDDs). However, how INTS11 participates in human development and disease remains unclear. Here, we identify a homozygous INTS11 variant in two siblings with a severe NDD. The variant impairs INTS11 catalytic activity, supported by its substrate's accumulation, and causes G2/M arrest in patient cells with length-dependent dysregulation of genes involved in mitosis and neural development, including the NDD gene CDKL5. The mutant knockin (KI) in induced pluripotent stem cells (iPSCs) disturbs their mitotic spindle organization and thus leads to slow proliferation and increased apoptosis, possibly through the decreased neurally functional CDKL5-induced extracellular signal-regulated kinase (ERK) pathway inhibition. The generation of neural progenitor cells (NPCs) from the mutant iPSCs is also delayed, with long transcript loss concerning neurogenesis. Our work reveals a mechanism underlying INTS11 dysfunction-caused human NDD and provides an iPSC model for this disease.