Search

Abstract Background Spinal cord motor neurons (MNs) from human iPS cells (iPSCs) have wide applications in disease modeling and therapeutic development for amyotrophic lateral sclerosis (ALS) and other MN-associated neurodegenerative diseases. We need highly efficient MN differentiation strategies for generating iPSC-derived disease models that closely recapitulate the genetic and phenotypic complexity of ALS. An important application of these models is to understand molecular mechanisms of action of FDA-approved ALS drugs that only show modest clinical efficacy. Novel mechanistic insights will help us design optimal therapeutic strategies together with predictive biomarkers to achieve better efficacy. Methods We induce efficient MN differentiation from iPSCs in 4 days using synthetic mRNAs coding two transcription factors (Ngn2 and Olig2) with phosphosite modification. These MNs after extensive characterization were applied in electrophysiological and neurotoxicity assays as well as transcriptomic analysis, to study the neuroprotective effect and molecular mechanisms of edaravone, an FDA-approved drug for ALS, for improving its clinical efficacy. Results We generate highly pure and functional mRNA-induced MNs (miMNs) from control and ALS iPSCs, as well as embryonic stem cells. Edaravone alleviates H2O2-induced neurotoxicity and electrophysiological dysfunction in miMNs, demonstrating its neuroprotective effect that was also found in the glutamate-induced miMN neurotoxicity model. Guided by the transcriptomic analysis, we show a previously unrecognized effect of edaravone to induce the GDNF receptor RET and the GDNF/RET neurotrophic signaling in vitro and in vivo, suggesting a clinically translatable strategy to activate this key neuroprotective signaling. Notably, edaravone can replace required neurotrophic factors (BDNF and GDNF) to support long-term miMN survival and maturation, further supporting the neurotrophic function of edaravone-activated signaling. Furthermore, we show that edaravone and GDNF combined treatment more effectively protects miMNs from H2O2-induced neurotoxicity than single treatment, suggesting a potential combination strategy for ALS treatment. Conclusions This study provides methodology to facilitate iPSC differentiation and disease modeling. Our discoveries will facilitate the development of optimal edaravone-based therapies for ALS and potentially other neurodegenerative diseases. Graphical abstract

Super Typhoon Doksuri is a significant meteorological challenge for China this year due to its strong intensity and wide influence range, as well as significant and prolonged hazards. In this work, we studied Doksuri's main characteristics and assessed its forecast accuracy meticulously based on official forecasts, global models and regional models with lead times varying from 1 to 5 days. The results indicate that Typhoon Doksuri underwent rapid intensification and made landfall at 09:55 BJT on July 28 with a powerful intensity of 50 m s−1 confirmed by the real-time operational warnings issued by China Meteorological Administration (CMA). The typhoon also caused significant wind and rainfall impacts, with precipitation at several stations reaching historical extremes, ranking eighth in terms of total rainfall impact during the event. The evaluation of forecast accuracy for Doksuri suggests that Shanghai Multi-model Ensemble Method (SSTC) and Fengwu Model are the most effective for short-term track forecasts. Meanwhile, the forecasts from the European Centre for Medium-Range Weather Forecasts (ECMWF) and United Kingdom Meteorological Office (UKMO) are optimal for long-term predictions. It is worth noting that objective forecasts systematically underestimate the typhoon maximum intensity. The objective forecast is terribly poor when there is a sudden change in intensity. CMA-National Digital Forecast System (CMA-NDFS) provides a better reference value for typhoon accumulated rainfall forecasts, and regional models perform well in forecasting extreme rainfall. The analyses above assist forecasters in pinpointing challenges within typhoon predictions and gaining a comprehensive insight into the performance of each model. This improves the effective application of model products.

Abstract Transcription-blocking lesions (TBLs) stall elongating RNA polymerase II (Pol II), which then initiates transcription-coupled repair (TCR) to remove TBLs and allow transcription recovery. In the absence of TCR, eviction of lesion-stalled Pol II is required for alternative pathways to address the damage, but the mechanism is unclear. Using Protein-Associated DNA Damage Sequencing (PADD-seq), this study reveals that the p97-proteasome pathway can evict lesion-stalled Pol II independently of repair. Both TCR and repair-independent eviction require CSA and ubiquitination. However, p97 is dispensable for TCR and Pol II eviction in TCR-proficient cells, highlighting repair’s prioritization over repair-independent eviction. Moreover, ubiquitination of RPB1-K1268 is important for both pathways, with USP7’s deubiquitinase activity promoting TCR without abolishing repair-independent Pol II release. In summary, this study elucidates the fate of lesion-stalled Pol II, and may shed light on the molecular basis of genetic diseases caused by the defects of TCR genes.

High-k gate dielectrics have attracted a great deal of attention in the investigation of transistors due to their unique properties such as superior gate controllability. However, their integration into graphene field-effect transistors (GFETs) remains problematic and the physical mechanisms governing the performance of these devices are still not fully understood. In this study, the effects of post-annealing on GFETs utilizing the high-k HfLaO ternary oxide as the gate dielectric were comprehensively investigated. The HfLaO film was deposited on top of graphene by magnetron sputtering, and the device performance with various post-annealing temperatures was conducted. It was found that post-annealing temperature can effectively increase the dielectric constant through balancing the oxygen-vacancy defects and moisture absorption. Both the surface morphology of HfLaO and performance of GFETs were investigated, and the fabricated GFETs exhibit notable electrical performance enhancements. Specifically, GFETs with a 200 °C post-annealed HfLaO gate dielectric demonstrate the optimal device performance, featuring a minimal Dirac point voltage (VDirac) of 1.1 V and a minimal hysteresis (ΔVDirac) of 0.5 V. The extracted hole and electron mobilities are 4012 and 1366 cm2/V · s, respectively, nearly one order of magnitude higher than that of GFETs with as-deposited HfLaO. This work outperforms other existing GFETs utilizing high-k gate dielectric and chemical vapor deposition grown graphene in terms of both carrier mobility and on–off ratio. It is also noted that the excessive post-annealing temperature can negatively impact the GFET performance through introducing oxygen vacancies, increasing the surface roughness, lowering the breakdown voltage, and inducing recrystallization.

Uneven regional development has long been a focal issue for both academia and policymakers, with numerous studies over the past decades actively engaging in discussions on measuring regional development disparities. Generally, most existing studies measure the Human Development Index (HDI) using relatively simple indicators, with a focus on national and provincial scales. As a crucial component of regional development, counties can directly reflect the regional characteristics of socio-economic progress. This study employs a multi-dimensional approach to develop an improved Human Development Index (improved HDI) system, using machine learning techniques to establish the relationship between nighttime light (NTL) data and the improved HDI. Subsequently, NTL data are utilized to infer the spatial distribution characteristics of the improved HDI across China’s county-level regions. The improved HDI for county-level areas in the Ningxia Hui Autonomous Region was validated using a machine learning model, resulting in a Pearson correlation coefficient of 0.93. The adjusted R-squared value for the linear fit was 0.86, and the residuals were relatively balanced, ensuring the accuracy of the simulations. This study reveals that 1439 county-level units, representing 50% of all county-level units in China, have development levels at or above the medium level. At the provincial and national levels, the improved HDI shows significant clustering, characterized by a multi-center pattern with declining diffusion. The spatial distribution of the improved Human Development Index remains closely associated with the natural geographic background and socio-economic development levels of the county regions. Lower HDI values are predominantly found in the inland areas of central and western China, often in ecologically sensitive areas, inter-provincial border zones, and mountainous regions of mainland China, sometimes forming contiguous distribution patterns. This underscores the need for the government and society to focus more on these specific geographic development areas, promoting continuous improvements in health, education, and living standards to achieve coordinated regional development.

Abstract A novel recursive cascaded full‐resolution residual network (RCFRR‐Net) for abdominal four‐dimensional computed tomography (4D‐CT) image registration was proposed. The entire network was end‐to‐end and trained in the unsupervised approach, which meant that the deformation vector field, which presented the ground truth, was not needed during training. The network was designed by cascading three full‐resolution residual subnetworks with different architectures. The training loss consisted of the image similarity loss and the deformation vector field regularization loss, which were calculated based on the final warped image and the fixed image, allowing all cascades to be trained jointly and perform the progressive registration cooperatively. Extensive network testing was conducted using diverse datasets, including an internal 4D‐CT dataset, a public DIRLAB 4D‐CT dataset, and a 4D cone‐beam CT (4D‐CBCT) dataset. Compared with the iteration‐based demon method and two deep learning‐based methods (VoxelMorph and recursive cascaded network), the RCFRR‐Net achieved consistent and significant gains, which demonstrated that the proposed method had superior performance and generalization capability in medical image registration. The proposed RCFRR‐Net was a promising tool for various clinical applications.

By considering the uncertainties in the initial field, model physical processes, and lateral boundary conditions, the Shanghai Weather And Risk Model System-Ensemble Prediction System (SWARMS-EN) is constructed. According to the prediction results of typhoon Muifa (2022), the daily track error of SWARMS-EN within 5 days is 70.6 km, 142.2 km, 129.1 km, 174.5 km, and 203.5 km, respectively. When compared with the Typhoon Ensemble Data Assimilation and Prediction System (TEDAPS) and the Global Ensemble Forecast System (GEFS) of the National Centers for Environmental Prediction (NCEP) in homogeneous conditions, SWARMS-EN performs better than TEDAPS within 72 h and better than GEFS beyond 72 h in track forecasting. This indicates an improvement in forecasting accuracy. The ensemble spread within two days is less than the root mean square error (RMSE), according to an analysis of the relationship between ensemble RMSE and spread, which shows that SWARMS-EN has no apparent systematic bias overall. The system has improved the ensemble RMSE and spread, indicating that it can better represent the uncertainty of the forecast and produce more reliable forecasts. Additionally, SWARMS-EN provides the landfall forecast five days in advance. The ensemble-based analysis suggests that the large-scale circulation is the primary factor contributing to the forecast differences among members, and the strong steering flow provides an indication of the landfalling forecast. The analysis of the ensemble characteristics of the initial field indicates that the initial perturbation between the wind field and the temperature field in the dynamically unstable region (such as near a tropical cyclone) exhibits flow dependence, and the small perturbation shows continuity throughout the entire troposphere. The distribution of ensemble spread and disturbance energy exhibited a reasonable growth stage as the forecast lead time increased. Disturbance internal energy dominated the lower troposphere, while the upper troposphere was mainly characterized by disturbance kinetic energy. Disturbance kinetic energy played a leading role in the evolution process. This conclusion further confirms the importance of paying attention to the initial small perturbations near TC in order to optimize the initial perturbation.

China's economy has achieved remarkable success, while it has also paid a high environmental cost. Environmental pollution not only causes great economic losses, but also severely restricts the development of society. Both theory and practice demonstrate that financial development plays a significant role in environmental governance, but the internal mechanism of its impacts has remained to be explored. It is vital to investigate the influence mechanism of financial development on the environmental quality in order to accomplish sustainable economic development through finance and enhance environmental quality concurrently. This paper, using mediating model, spatial Durbin and spatial error model, constructs a theoretical framework financial development on environmental quality from two dimensions, i.e., Financial Interrelations Ratio (FIR) and Financial Efficiency (FE), based on panel data of 234 cities in China from 2010 to 2019. And the results are as follows: (1) the improvement of Financial Interrelations Ratio (FIR) and Financial Efficiency (FE) had not yet reached the level of environmental pollution improvement; (2) in terms of mechanism, the rise of the level of financial development promoted economic growth, but inhibited the optimization of industrial structure, which increased industrial pollution emissions and deteriorates environmental quality; (3) urban environment had significant spatial dependence; (4) the impact of financial development on environmental quality in eastern region has been transformed into an improvement effect, while it still shows a deteriorating effect in central and western regions. Some policy recommendations related to the use of financial development to improve environmental quality are proposed at last, which will help to promote ecological protection and high quality synergistic economic development in China.

Maintaining proper mechanical strength and tissue volume is important for bone growth at the site of a bone defect. In this study, potassium magnesium phosphate hexahydrate (KMgPO4·6H2O, MPC) was applied to gelma-methacrylate hydrogel (GelMA) to prepare GelMA/MPC composites (GMPCs). Among these, 5 GMPC showed the best performance in vivo and in vitro. These combinations significantly enhanced the mechanical strength of GelMA and regulated the degradation and absorption rate of MPC. Considerably better mechanical properties were noted in 5 GMPC compared with other concentrations. Better bioactivity and osteogenic ability were also found in 5 GMPC. Magnesium ions (Mg2+) are bioactive and proven to promote bone tissue regeneration, in which the enhancement efficiency is closely related to Mg2+ concentrations. These findings indicated that GMPCs that can release Mg2+ are effective in the treatment of bone defects and hold promise for future in vivo applications.

Bone defect repair poses significant challenges in orthopedics, thereby increasing the demand for bone substitutes. Magnesium phosphate cements (MPCs) are widely used for bone defect repair because of their excellent mechanical properties and biodegradability. However, high crystallinity and uncontrolled magnesium ion (Mg2+) release limit the surface bioactivity of MPCs in bone regeneration. Here, we fabricate chondroitin sulfate (CS) as a surface coating via the lyophilization method, namely CMPC. We find that the CS coating is uniformly distributed and improves the mechanical properties of MPC through anionic electrostatic adsorption, while mediating degradation-related controlled ion release of Mg2+. Using a combination of in vitro and in vivo analyses, we show that the CS coating maintained cytocompatibility while increasing the cell adhesion area of MC3T3-E1s. Furthermore, we display accelerated osteogenesis and angiogenesis of CMPC, which are related to appropriate ion concentration of Mg2+. Our findings reveal that the preparation of a lyophilized CS coating is an effective method to promote surface bioactivity and mediate Mg2+ concentration dependent osteogenesis and angiogenesis, which have great potential in bone regeneration.

Triple negative breast cancer is distinguished by its high malignancy, aggressive invasion, rapid progression, easy recurrence, and distant metastases. Additionally, it has a poor prognosis, a high mortality, and is unresponsive to conventional endocrine and targeted therapy, making it a challenging problem for breast cancer treatment and a hotspot for scientific research. Recent research has revealed that certain miRNA can directly or indirectly affect the occurrence, progress and recurrence of TNBC. Their expression levels have a significant impact on TNBC diagnosis, treatment and prognosis. Some miRNAs can serve as biomarkers for TNBC diagnosis and prognosis. This article summarizes the progress of miRNA research in TNBC, discusses their roles in the occurrence, invasion, metastasis, prognosis, and chemotherapy of TNBC, and proposes a treatment strategy for TNBC by interfering with miRNA expression levels.

Summary: Cellular circadian clocks direct a daily transcriptional program that supports homeostasis and resilience. Emerging evidence has demonstrated age-associated changes in circadian functions. To define age-dependent changes at the systems level, we profile the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in three age groups. We find age-dependent and tissue-specific clock output changes. Aging reduces the number of rhythmically expressed genes (REGs), indicative of weakened circadian control. REGs are enriched for the hallmarks of aging, adding another dimension to our understanding of aging. Analyzing differential gene expression within a tissue at four different times of day identifies distinct clusters of differentially expressed genes (DEGs). Increased variability of gene expression across the day is a common feature of aged tissues. This analysis extends the landscape for understanding aging and highlights the impact of aging on circadian clock function and temporal changes in gene expression.

To explore the effect of corn peptide on enhancing exercise performance and preventing overtraining-induced myocardial injury, 40 male mice were divided into normal control, swimming training control, swimming training with low, medium, and high-dose corn peptide groups for 8-week interventions. After interventions, exhaustive swimming time and blood lactate were determined to evaluate exercise performance. Creatine kinase (CK) and CK-MB levels were determined by ELISA. The proteins associated with autophagy and apoptosis in myocardial tissue were evaluated by Western blot. Results indicated that corn peptide could effectively prolong exhaustive swimming time, and accelerate blood lactate elimination, suggesting its enhancing exercise performance and alleviating exercise fatigue. Meanwhile, it could also reduce serum CK and CK-MB levels, up-regulate Atg7 and Beclin1, increase LC3-II/LC3-I ratio, and down-regulate p62 and Bax. Therefore, corn peptide cooperated with regular swimming training can enhance exercise performance and execute overtraining-induced myocardial protection through activating autophagy and inhibiting apoptosis.

Circadian rhythms are maintained by a cell-autonomous, transcriptional–translational feedback loop known as the molecular clock. While previous research suggests a role of the molecular clock in regulating skeletal muscle structure and function, no mechanisms have connected the molecular clock to sarcomere filaments. Utilizing inducible, skeletal muscle specific, Bmal1 knockout (iMSBmal1-/-) mice, we showed that knocking out skeletal muscle clock function alters titin isoform expression using RNAseq, liquid chromatography–mass spectrometry, and sodium dodecyl sulfate-vertical agarose gel electrophoresis. This alteration in titin’s spring length resulted in sarcomere length heterogeneity. We demonstrate the direct link between altered titin splicing and sarcomere length in vitro using U7 snRNPs that truncate the region of titin altered in iMSBmal1-/- muscle. We identified a mechanism whereby the skeletal muscle clock regulates titin isoform expression through transcriptional regulation of Rbm20, a potent splicing regulator of titin. Lastly, we used an environmental model of circadian rhythm disruption and identified significant downregulation of Rbm20 expression. Our findings demonstrate the importance of the skeletal muscle circadian clock in maintaining titin isoform through regulation of RBM20 expression. Because circadian rhythm disruption is a feature of many chronic diseases, our results highlight a novel pathway that could be targeted to maintain skeletal muscle structure and function in a range of pathologies.

It is generally considered that protein supplementation and resistance exercise significantly increase muscle mass and muscle growth. As the hydrolysis products of proteins, peptides may play the crucial role on muscle growth. In this study, male rats were orally administrated 0.4 g/kg body weight of pea peptide combined with 8 weeks of moderate intensity resistance exercise training. After treatment, the body gains, upper limb grip, muscle thickness, and wet weight of biceps brachii were tested, and the cross-sectional area of biceps brachii muscle fiber and the types of muscle fibers were determined by HE staining, immunofluorescence staining, and lactate dehydrogenase activity, respectively. Western blot analysis was used to investigate the level of growth-signaling pathway-related proteins. The results showed that pea peptide supplementation combined with resistance exercise training significantly increased body weight, upper limb grip, muscle thickness, wet weight of biceps brachii, and cross-sectional area of muscle fiber. Meanwhile, pea peptide supplementation obviously elevated the ratio of fast-twitch fiber (type II) and the expression of muscle growth-signaling pathway-related proteins. In addition, the PP2 oligopeptide in pea peptide with the amino acid sequence of LDLPVL induced a more significant promotion on C2C12 cell growth than other oligopeptides.

The consumption of bamboo leaf flavonoids (BLFs) as novel dietary antioxidants has increased owing to their beneficial biological and pharmacological functions. This study assessed the in vivo effects of BLFs on antioxidant capacity, as well as caecal microbiota, serum metabolome, and health status. The Gallus gallus domesticus model and the oral administration approach were used with four treatment groups (basal diet, basal diet with 20 mg bacitracin/kg, basal diet with 50 mg BLF/kg, and basal diet with 250 mg BLF/kg). Ultra-high-performance liquid chromatography triple-quadrupole mass spectrometry analysis indicated that vitexin, fumaric acid, orientin, isoorientin, and p-coumaric acid were the predominant BLF components. From days 1 to 21, BLF increased the average daily gain and decreased the feed:gain of broilers. Moreover, BLF enhanced the serum antioxidant capacity and immune responses. Further, 16S rRNA sequencing showed that BLF modulated the caecal microbial community structure, which was dominated by Betaproteobacteriales, Erysipelatoclostridium, Parasutterella, Lewinella, Lactobacillus, and Candidatus Stoquefichus in BLF broilers. Among the 22 identified serum metabolites in BLF broilers, sphinganine, indole-3-acetaldehyde retinol, choline, 4-methylthio-2-oxobutanoic acid, and L-phenylalanine were recognised as biomarkers. In summary, BLFs appeared to modulate the caecal microbiome, alter the serum metabolome, and indirectly improve antioxidant capacity and health status.

The track forecasts of tropical cyclones (TC) in the western North Pacific (WNP) basin during 2021 typhoon season with five global models and four regional models are evaluated here. The results show that the average direct position errors (DPEs) of the global and regional models are approximately 80, 150, 200, 300, and 400 km at 24 h, 48 h, 72 h, 96 h, and 120 h lead-times, respectively. The European Centre for Medium-Range Weather Forecasts Integrated Forecasting System (ECMWF-IFS) achieved the best track forecast performance at each lead among the five global models. Among the four regional models, The China Meteorological Administration Tropical Regional Atmosphere Model for the South China Sea (CMA-TRAMS) attained the smallest DPEs within a 72 h lead, while The Hurricane Weather Research and Forecasting (HWRF) achieved the best track forecast performance at 96 h and 120 h leads. Most of the models produced an obvious westward systematic bias on track forecast from a 24 h to a 120 h lead. Further correlation and cluster analyses indicate that initial TC intensity and size and environmental steering flow can be regarded as good predictors for TC DPEs. TCs with a stronger initial intensity, a bigger initial size, and a larger environmental steering flow in general attain a smaller DPE, and the improvements may go up to 36% at short lead-time.

BackgroundNeoadjuvant chemoradiotherapy (nCRT) before total mesorectal excision (TME) and followed systemic chemotherapy is widely accepted as the standard therapy for locally advanced rectal cancer (LARC). This meta-analysis was to evaluate the current evidence regarding nCRT in combination with induction or consolidation chemotherapy for rectal cancer in terms of oncological outcomes.MethodsA systematic search of medical databases (PubMed, EMBASE and Cochrane Library) was conducted up to the end of July 1, 2021. This meta-analysis was performed to evaluate the efficacy of TNT in terms of pathological complete remission (pCR), nCRT or surgical complications, R0 resection, local recurrence, distant metastasis, disease-free survival (DFS) and overall survival (OS) in LARC.ResultsEight nRCTs and 7 RCTs, including 3579 patients were included in the meta-analysis. The rate of pCR was significantly higher in the TNT group than in the nCRT group, (OR 1.85, 95% CI 1.39-2.46, p < 0.0001), DFS (HR 0.80, 95% CI 0.69-0.92, p = 0.001), OS (HR 0.75, 95% CI 0.62-0.89, p = 0.002), nCRT complications (OR 1.05, 95% CI 0.77-1.44, p = 0.75), surgical complications (OR 1.02, 95% CI 0.83-1.26, p = 0.83), local recurrence (OR 1.82, 95% CI 0.95-3.49, p = 0.07), distant metastasis (OR 0.77, 95% CI 0.58-1.03, p = 0.08) did not differ significantly between the TNT and nCRT groups.ConclusionTNT appears to have advantages over standard therapy for LARC in terms of pCR, R0 resection, DFS, and OS, with comparable nCRT and postoperative complications, and no increase in local recurrence and distant metastasis.