A plant immune protein enables broad antitumor response by rescuing microRNA deficiency.

Cancer cells are featured with uncontrollable activation of cell cycle, and microRNA deficiency drives tumorigenesis. The RNA-dependent RNA polymerase (RDR) is essential for small-RNA-mediated immune response in plants but is absent in vertebrates. Here, we show that ectopic expression of plant RDR1 can generally inhibit cancer cell proliferation. In many human primary tumors, abnormal microRNA isoforms with 1-nt-shorter 3' ends are widely accumulated. RDR1 with nucleotidyltransferase activity can recognize and modify the problematic AGO2-free microRNA duplexes with mononucleotides to restore their 2 nt overhang structure, which eventually rescues AGO2-loading efficiency and elevates global miRNA expression to inhibit cancer cell-cycle specifically. The broad antitumor effects of RDR1, which can be delivered by an adeno-associated virus, are visualized in multiple xenograft tumor models in vivo. Altogether, we reveal the widespread accumulation of aberrant microRNA isoforms in tumors and develop a plant RDR1-mediated antitumor stratagem by editing and repairing defective microRNAs.

Global miRNA dosage control of embryonic germ layer specification.

MicroRNAs (miRNAs) have essential functions during embryonic development, and their dysregulation causes cancer1,2. Altered global miRNA abundance is found in different tissues and tumours, which implies that precise control of miRNA dosage is important1,3,4, but the underlying mechanism(s) of this control remain unknown. The protein complex Microprocessor, which comprises one DROSHA and two DGCR8 proteins, is essential for miRNA biogenesis5-7. Here we identify a developmentally regulated miRNA dosage control mechanism that involves alternative transcription initiation (ATI) of DGCR8. ATI occurs downstream of a stem-loop in DGCR8 mRNA to bypass an autoregulatory feedback loop during mouse embryonic stem (mES) cell differentiation. Deletion of the stem-loop causes imbalanced DGCR8:DROSHA protein stoichiometry that drives irreversible Microprocessor aggregation, reduced primary miRNA processing, decreased mature miRNA abundance, and widespread de-repression of lipid metabolic mRNA targets. Although global miRNA dosage control is not essential for mES cells to exit from pluripotency, its dysregulation alters lipid metabolic pathways and interferes with embryonic development by disrupting germ layer specification in vitro and in vivo. This miRNA dosage control mechanism is conserved in humans. Our results identify a promoter switch that balances Microprocessor autoregulation and aggregation to precisely control global miRNA dosage and govern stem cell fate decisions during early embryonic development.

Diabetes mellitus and Alzheimer's disease: Vacuolar adenosine triphosphatase as a potential link.

Globally, the incidence of diabetes mellitus (DM) and Alzheimer's disease (AD) is increasing year by year, causing a huge economic and social burden, and their pathogenesis and aetiology have been proven to have a certain correlation. In recent years, more and more studies have shown that vacuolar adenosine triphosphatases (v-ATPases) in eukaryotes, which are biomolecules regulating lysosomal acidification and glycolipid metabolism, play a key role in DM and AD. This article describes the role of v-ATPase in DM and AD, including its role in glycolysis, insulin secretion and insulin resistance (IR), as well as its relationship with lysosomal acidification, autophagy and ß-amyloid (Aß). In DM, v-ATPase is involved in the regulation of glucose metabolism and IR. v-ATPase is closely related to glycolysis. On the one hand, v-ATPase affects the rate of glycolysis by affecting the secretion of insulin and changing the activities of key glycolytic enzymes hexokinase (HK) and phosphofructokinase 1 (PFK-1). On the other hand, glucose is the main regulator of this enzyme, and the assembly and activity of v-ATPase depend on glucose, and glucose depletion will lead to its decomposition and inactivation. In addition, v-ATPase can also regulate free fatty acids, thereby improving IR. In AD, v-ATPase can not only improve the abnormal brain energy metabolism by affecting lysosomal acidification and autophagy but also change the deposition of Aß by affecting the production and degradation of Aß. Therefore, v-ATPase may be the bridge between DM and AD.

Calcium homeostasis restoration in pyramidal neurons through micrometer-scale wireless electrical stimulation in spinal cord injured mice.

Spinal Cord Injury (SCI) is a significant neurological disorder that can result in severe motor and cognitive impairments. Neuronal regeneration and functional recovery are critical aspects of SCI treatment, with calcium signaling being a crucial indicator of neuronal excitability. In this study, we utilized a murine model to investigate the effects of targeted wireless electrical stimulation (ES) on neuronal activity following SCI. After establishing a complete SCI model in normal mice, flexible electrodes were implanted, and targeted wireless ES was administered to the injury site. We employed fiber-optic photometric in vivo calcium imaging to monitor calcium signals in pyramidal neurons within the CA3 region of the hippocampus and the M1 region of the primary motor cortex. The experimental results demonstrated a significant reduction in calcium signals in CA3 and M1 pyramidal neurons following SCI (reduced by 76 % and 59 %, in peak respectively). However, the application of targeted wireless ES led to a marked increase in calcium signals in these neurons (increased by 118 % and 69 %, in peak respectively), indicating a recovery of calcium activity. These observations suggest that wireless ES has a positive modulatory effect on the excitability of pyramidal neurons post-SCI. Understanding these mechanisms is crucial for developing therapeutic strategies aimed at enhancing neuronal recovery and functional restoration following spinal cord injuries.

Maternal dietary patterns during pregnancy and birth weight: a prospective cohort study.

BACKGROUND: Existing data on maternal dietary patterns and birth weight remains limited and inconsistent, especially in non-Western populations. We aimed to examine the relationship between maternal dietary patterns and birth weight among a cohort of Chinese. METHODS: In this study, 4,184 mother-child pairs were included from the Iodine Status in Pregnancy and Offspring Health Cohort. Maternal diet during pregnancy was evaluated using a self-administered food frequency questionnaire with 69 food items. Principal component analysis was used to identify dietary patterns. Information on birth weight and gestational age was obtained through medical records. Adverse outcomes of birth weight were defined according to standard clinical cutoffs, including low birth weight, macrosomia, small for gestational age, and large for gestational age. RESULTS: Three maternal dietary patterns were identified: plant-based, animal-based, and processed food and beverage dietary patterns, which explained 23.7% variance in the diet. In the multivariate-adjusted model, women with higher adherence to the plant-based dietary patten had a significantly higher risk of macrosomia (middle tertile vs. low tertile: odds ratio (OR) 1.45, 95% CI 1.00-2.10; high tertile vs. low tertile: OR 1.55, 95% CI 1.03-2.34; P-trend = 0.039). For individual food groups, potato intake showed positive association with macrosomia (high tertile vs. low tertile: OR 1.72, 95% CI 1.20-2.47; P-trend = 0.002). Excluding potatoes from the plant-based dietary pattern attenuated its association with macrosomia risk. No significant associations was observed for the animal-based or processed food and beverage dietary pattern with birth weight outcomes. CONCLUSIONS: Adherence to a plant-based diet high in carbohydrate intake was associated with higher macrosomia risk among Chinese women. Future studies are required to replicate these findings and explore the potential mechanisms involved.

The impact of lactating Hu sheep's dietary protein levels on lactation performance, progeny growth and rumen development.

This study aimed to investigate whether lactating Hu sheep's dietary protein levels could generate dynamic effects on the performance of their offspring. Twelve ewes with similar parity were fed iso-energy diets which contained different protein levels (P1: 9.82%, P2: 10.99%) (n = 6), and the corresponding offspring were divided into SP1 and SP2 (n = 12). At 60 days, half of the lambs were harvested for further study: the carcass weight (p = 0.043) and dressing percentage (p = 0.004) in the SP2 group were significantly higher than SP1. The acetic acid (p = 0.007), propionic acid (p = 0.003), butyric acid (p < 0.001) and volatile fatty acids (p < 0.001) in rumen fluid of SP2 were significantly lower than SP1. The expression of MCT2 (p = 0.024), ACSS1 (p = 0.039) and NHE3 (p = 0.006) in the rumen of SP2 was lower than SP1, while the HMGCS1 (p = 0.026), HMGCR (p = 0.024) and Na+/K+-ATPase (p = 0.020) was higher than SP1. The three dominant phyla in the rumen are Bacteroidetes, Proteobacteria and Firmicutes. The membrane transport, amino acid metabolism and carbohydrate metabolism of SP1 were relatively enhanced, the replication and repair function of SP2 was relatively enhanced. To sum up, the increase of dietary protein level significantly increased the carcass weight and dressing percentage of offspring and had significant effects on rumen volatile fatty acids, acetic acid activation and cholesterol synthesis related genes. HIGHLIGHTSIn the early feeding period, the difference in ADG of lambs was mainly caused by the sucking effect.The increase in dietary protein level of ewes significantly increased the carcass weight and dressing percentage of offspring.The dietary protein level of ewes significantly affected the volatile fatty acids (VFAs) and genes related to acetic acid activation and cholesterol synthesis in the rumen of their offspring.The membrane transport, amino acid metabolism and carbohydrate metabolism of the offspring of ewes fed with a low protein diet were relatively enhanced.The replication and repair function of the offspring of ewes fed with a high protein diet was relatively strengthened.

Heterogeneous effects of China's low-carbon city pilots policy.

Global south countries, including China, have faced a challenging dilemma of reducing carbon emissions while maintaining rapid economic growth. The low-carbon city pilots (LCCPs) policy in China is a demonstration of how state power intervenes and commands national low-carbon development through voluntary policy tools. Our study, based on panel data of 331 cities from 2005 to 2019, evaluates the policy effect of all three batches of LCCPs and presents an analysis of time-varying effects through batch decomposition and synthetic difference-in-difference models. The study found that implementing low-carbon policies can significantly reduce total carbon emissions and carbon emissions per capita. However, the reduction in carbon emissions per unit of GDP is insignificant, and the policy effect varies according to the batches and their characteristics. The reduction effects in the first and second batches, as well as the insignificance or even increasing effects of the third batch, may be due to carbon leakage between different batches of LCCPs. Overall, this research provides novel and quantitative evidence on low-carbon development in China, making theoretical and empirical contributions to the field, and expanding econometric assessment methods to evaluate the effectiveness of environmental and climate change policies.

Port resilience in the post-COVID-19 era.

With the COVID-19 pandemic evitably becoming the "New Normality" and will continue to impact human society much longer than anticipated, it is essential to explore effective measures that global ports can take to adapt to unexpected challenges in the post-COVID-19 era. This paper builds a port resilience index system based on the entropy weight method from a multistakeholder's view. We utilize the port resilience index system for 22 major Chinese ports during 2020-2021. We further investigate the direct impact of port resilience on port governance performance. Our results indicate that resiliently-governed ports can guarantee higher port throughput while sustaining lower congestion when facing challenges from the global pandemic.

Terahertz magneto-optical response of bismuth-gadolinium-substituted rare-earth garnet film.

We report the magneto-optical Faraday response of bismuth-gadolinium-substituted rare-earth iron garnet at terahertz frequencies ranging from 100 GHz to 1.2 THz. The maximum transmittance of ±45° component is about 60% near the frequency point of 0.63 THz. When the external magnetic field change from -100 mT to +100 mT, the Faraday rotation angle is between -6° and +7.5°. The overall change of ellipticity is relatively small. The maximum value of the Verdet constant is about 260 °/mm/T at 0.1 THz and then gradually decreases to 80 °/mm/T at 1.2 THz. Within the considered frequency range, the thick film exhibits magnetically tunable, non-reciprocal characters and a strong magneto-optical effect within a small external magnetic field at room temperature, which will be widely used for the terahertz isolators, circulators, nonreciprocal phase shifters, and magneto-optical modulators.

Terahertz magneto-optical effect of wafer-scale La: yttrium iron garnet single-crystal film with low loss and high permittivity.

The wafer-scale La:YIG single crystal thick films were fabricated on a three-inch gadolinium gallium garnet (GGG) substrate by liquid phase epitaxy method. The terahertz (THz) optical and magneto-optical properties of La:YIG film were demonstrated by THz time domain spectroscopy (THz-TDS). The results show that a high refractive index of approximately 4.09 and a low absorption coefficient of 10-50 cm-1 from 0.1 to 1.6 THz for this La:YIG film. Moreover, the THz Faraday rotation effect of La:YIG film was measured by the orthogonal polarization detection method in THz-TDS system, which can be actively manipulated by a weak longitudinal magnetic field of up to 0.155 T. With 5 samples stacked together, the Faraday rotation angle varies linearly from -15° to 15°, and the Verdet constant of La:YIG is about 100 °/mm/T within the saturation magnetization. This magneto-optical single crystal thick film with large area shows low loss, high permittivity and strong magneto-optical effect in the THz regime, which will be widely used in magneto-optical polarization conversion, nonreciprocal phase shifter and isolator for THz waves.

Genomic Analyses Reveal Potential Independent Adaptation to High Altitude in Tibetan Chickens.

Much like other indigenous domesticated animals, Tibetan chickens living at high altitudes (2,200-4,100 m) show specific physiological adaptations to the extreme environmental conditions of the Tibetan Plateau, but the genetic bases of these adaptations are not well characterized. Here, we assembled a de novo genome of a Tibetan chicken and resequenced whole genomes of 32 additional chickens, including Tibetan chickens, village chickens, game fowl, and Red Junglefowl, and found that the Tibetan chickens could broadly be placed into two groups. Further analyses revealed that several candidate genes in the calcium-signaling pathway are possibly involved in adaptation to the hypoxia experienced by these chickens, as these genes appear to have experienced directional selection in the two Tibetan chicken populations, suggesting a potential genetic mechanism underlying high altitude adaptation in Tibetan chickens. The candidate selected genes identified in this study, and their variants, may be useful targets for clarifying our understanding of the domestication of chickens in Tibet, and might be useful in current breeding efforts to develop improved breeds for the highlands.

Bilayer metallic nanofilms as broadband antireflection coatings in terahertz optical systems.

We present the potential of ultrathin bilayer metallic nanofilms for use as broadband antireflection coatings in the terahertz frequency range. The metallic layers are modeled using a wave-impedance matching approach. The experimental and theoretical results are in good agreement. Further, a novel method using our broadband antireflection coatings is proposed to eliminate unwanted reflections that interfere with the important reflection from the sample in terahertz reflection measurement. The proposed method significantly improves the calculation of the optical properties of liquid and biological samples.

High-speed and broadband terahertz wave modulators based on large-area graphene field-effect transistors.

We present a broadband terahertz wave modulator with improved modulation depth and switch speed by cautiously selecting the gate dielectric materials in a large-area graphene-based field-effect transistor (GFET). An ultrathin Al2O3 film (∼60 nm) is deposited by an atomic-layer-deposition technique as a high-k gate dielectric layer, which reduces the Coulomb impurity scattering and cavity effect, and thus greatly improves the modulation performance. Our modulator has achieved a modulation depth of 22% and modulation speed of 170 kHz in a frequency range from 0.4 to 1.5 THz, which is a large improvement in comparison to its predecessor of SiO2-based GFET.

miRNA dosage control in development and human disease.

In mammals, miRNAs recognize target mRNAs via base pairing, which leads to a complex 'multiple-to-multiple' regulatory network. Previous studies have focused on the regulatory mechanisms and functions of individual miRNAs, but alterations of many individual miRNAs do not strongly disturb the miRNA regulatory network. Recent studies revealed the important roles of global miRNA dosage control events in physiological processes and pathogenesis, suggesting that miRNAs can be considered as a 'cellular buffer' that controls cell fate. Here, we review the current state of research on how global miRNA dosage is tightly controlled to regulate development, tumorigenesis, neurophysiology, and immunity. We propose that methods of controlling global miRNA dosage may serve as effective therapeutic tools to cure human diseases.

Potential biomarkers: The hypomethylation of cg18949415 and cg22193385 sites in colon adenocarcinoma.

Overall cancer hypomethylation had been identified in the past, but it is not clear exactly which hypomethylation site is the more important for the occurrence of cancer. To identify key hypomethylation sites, we studied the effect of hypomethylation in twelve regions on gene expression in colon adenocarcinoma (COAD). The key DNA methylation sites of cg18949415, cg22193385 and important genes of C6orf223, KRT7 were found by constructing a prognostic model, survival analysis and random combination prediction a series of in-depth systematic calculations and analyses, and the results were validated by GEO database, immune microenvironment, drug and functional enrichment analysis. Based on the expression values of C6orf223, KRT7 genes and the DNA methylation values of cg18949415, cg22193385 sites, the least diversity increment algorithm were used to predict COAD and normal sample. The 100 % reliability and 97.12 % correctness of predicting tumor samples were obtained in jackknife test. Moreover, we found that C6orf223 gene, cg18949415 site play a more important role than KRT7 gene, cg22193385 site in COAD. In addition, we investigate the impact of key methylation sites on three-dimensional chromatin structure. Our results will be help for experimental studies and may be an epigenetic biomarker for COAD.

Coregulatory effects of multiple histone modifications in key ferroptosis-related genes for lung adenocarcinoma.

Aim: The present study was designed to investigate the coregulatory effects of multiple histone modifications (HMs) on gene expression in lung adenocarcinoma (LUAD). Materials & methods: Ten histones for LUAD were analyzed using ChIP-seq and RNA-seq data. An innovative computational method is proposed to quantify the coregulatory effects of multiple HMs on gene expression to identify strong coregulatory genes and regions. This method was applied to explore the coregulatory mechanisms of key ferroptosis-related genes in LUAD. Results: Nine strong coregulatory regions were identified for six ferroptosis-related genes with diverse coregulatory patterns (CA9, PGD, CDKN2A, PML, OTUB1 and NFE2L2). Conclusion: This quantitative method could be used to identify important HM coregulatory genes and regions that may be epigenetic regulatory targets in cancers.

Plant-based and planetary-health diets, environmental burden, and risk of mortality: a prospective cohort study of middle-aged and older adults in China.

BACKGROUND: Plant-based diets (PBDs) and planetary-health diets (PHDs) are recommended for their potential health and environmental benefits, but population-based evidence in diverse cultures is scarce. METHODS: We included 9364 adults aged 45 years and older (52·3% female, 47·7% male) from the open cohort of the China Health and Nutrition Survey. Dietary intake was assessed using 3-day 24 h dietary recalls combined with weighing methods from 1997 to 2011, and mortality was documented from 1997 to 2015. We calculated the overall PBD index (PDI), healthful PBD index (hPDI), and unhealthful PBD index (uPDI; ranges 18-90), and the PHD score (range 0-140). We also estimated the related greenhouse gas emissions, land appropriation, and total water footprint and examined their associations with mortality. FINDINGS: PBD indices were inversely related to greenhouse gas emissions, land appropriation, and total water footprint, whereas higher PHD score was related to higher environmental burdens (p<0·0001). During follow-up (mean 9·2 years), 792 (8·5%) death cases were documented. PDI (HR 1·08 [95% CI 0·88-1·32]) and hPDI (0·98 [0·80-1·21]) were not significantly associated with mortality, whereas higher uPDI was related to a higher mortality risk (1·55 [1·26-1·91]). In contrast, higher PHD score was associated with lower mortality risk (0·79 [0·63-0·99]). INTERPRETATION: The PBDs showed environmental benefits, but are not necessarily associated with lower mortality risk. The PHD, developed mainly in western populations, was related to lower mortality risk but higher environmental burdens in the Chinese population. FUNDING: Fundamental Research Funds for the Central Universities, Zhejiang University Global Partnership Fund, and National Natural Science Foundation of China.

The effect of PM2.5 exposure on the mortality of patients with hepatocellular carcinoma in Tianjin, China.

Several studies have shown the effects of PM2.5 exposure on respiratory and cardiovascular systems. However, there is no cohort study evidence of adverse effects of PM2.5 exposure on survival in patients with hepatocellular carcinoma (HCC) in China. This study is aimed at evaluating this association. This cohort study included 1440 HCC patients treated at the Third Central Clinical College of Tianjin Medical University from September 2013 to December 2018. We collected patient information, including demographic data, medical history, lifestyle characteristics, and disease characteristics. Based on PM2.5 concentrations measured at monitoring stations, the inverse distance weighted (IDW) method was used to assess the individuals' exposure during their survival period. Survival status was analysed by the Kaplan-Meier method. Restricted cubic splines and Cox proportional hazards models were used to estimate the relationship between PM2.5 and mortality, and potential confounders were adjusted for. The mortality rate of HCC patients exposed to PM2.5 ≥ 58.56 µg/m3 was significantly higher than that of HCC patients living in environments with PM2.5 < 58.56 µg/m3 (79.0% vs 50.7%, P < 0.001). The restricted cubic spline model showed a linear relationship between the PM2.5 concentration and mortality risk (P overall-association < 0.0001 and P nonlinear-association = 0.3568). Cox regression analysis showed that after adjusting for confounding factors, for every 10-µg/m3 increase in atmospheric PM2.5, the risk of death for HCC patients increased by 44% [hazard ratio (HR) = 1.44, 95% confidence interval (CI) 1.34, 1.56; P < 0.001]. Compared with patients exposed to PM2.5 <58.56 µg/m3, those exposed to PM2.5 ≥ 58.56 µg/m3 had a 1.55-fold increased risk of death. Stratified analysis results showed that the effects of PM2.5 on HCC mortality were more significant in patients aged ≥60 years or patients living in central urban areas. We found that exposure to elevated PM2.5 after HCC diagnosis may affect survival, with a higher concentration corresponding to a greater effect.

Highly efficient metal-free borocarbonitride catalysts for electrochemical reduction of N2 to NH3.

The electrocatalytic nitrogen reduction reaction (NRR) for ammonia (NH3) under ambient conditions is emerging as a potentially sustainable alternative to the traditional, energy-intensive Haber-Bosch process for ammonia production. Currently, metal-based electrocatalysts constitute the majority of reported NRR catalysts. However, they often suffer from the shortcomings of competitive reactions of nitrogen adsorption/activation and hydrogen generation. Therefore, there is an urgent need to develop more environmentally friendly, low energy consumption, and non-polluting high-performance metal-free electrocatalysts. In this study, borocarbonitride (BCN) materials derived from boron imidazolate framework (BIF-20) were used to boost efficient electrochemical nitrogen conversion to ammonia under ambient conditions. The BCN catalyst demonstrated excellent performance in 0.1 M KOH, with an ammonia yield of 21.62 µg h-1 mgcat-1 and a Faradaic efficiency of 9.88% at -0.3 V (Reversible Hydrogen Electrode, RHE). This performance is superior to most metal-free catalysts and even some metal catalysts for NRR. The 15N2/14N2 isotope labeling experiments and density functional theory (DFT) calculations showed that N2 can be adsorbed and converted to NH3 on the surface of BCN, and that the energy barrier can be significantly reduced by structural design for BCN. This work highlights the important role played by the presence of Lewis acid-base pairs in metal-free catalysts for enhancing electrochemical NRR performance.