Beinaglutide for weight management in Chinese individuals with overweight or obesity: A phase 3 randomized controlled clinical study.

AIM: To investigate the efficacy and safety of beinaglutide as an adjunct to lifestyle intervention among non-diabetic Chinese individuals with overweight or obesity. METHODS: This multicentre, randomized, double-blind, placebo-controlled trial (ChiCTR1900023428) included 427 Chinese adults with a body mass index of 28 kg/m2 or higher (obesity) or 24-27.9 kg/m2 (overweight) with weight-related complications. Patients were randomized in a 2:1 ratio to receive 0.2 mg of beinaglutide (subcutaneous) thrice daily or placebo for 16 weeks. Co-primary endpoints were body weight change and the proportion of patients with a weight reduction of 5% or more. RESULTS: Mean body weight change from baseline to week 16 was -6.0% and -2.4% in the beinaglutide (n = 282) and placebo (n = 138) groups, respectively; the mixed model repeated measures difference was -3.6% (95% confidence interval: -4.6% to -2.6%; P < .0001). At week 16, more beinaglutide-treated patients achieved a weight reduction of 5% or more (58.2% vs. 25.4% [placebo], odds ratio: 4.4; P < .0001) and of 10% or more (21.3% vs. 5.1% [placebo], odds ratio: 5.5; P < .0001). Beinaglutide also resulted in greater waist circumference reduction (difference: -1.81 cm; P < .01). The weight regain rate 12 weeks after beinaglutide treatment was 0.78%. Nausea (transient and mild-to-moderate) was the most common adverse event in the beinaglutide group (49.3% vs. 7.1% [placebo]). More patients receiving beinaglutide discontinued treatment because of adverse events (5.9% vs. 0.7% [placebo]). Pancreatitis or an increased resting heart rate was not observed in the beinaglutide group. CONCLUSION: Beinaglutide combined with lifestyle intervention resulted in significant and clinically meaningful weight reduction with good tolerance in non-diabetic Chinese individuals with overweight or obesity.

Efficacy of noiiglutide injection on body weight in obese Chinese adults without diabetes: A multicentre, randomized, double-blind, placebo-controlled, phase 2 trial.

AIM: To evaluate the effect of noiiglutide as an adjunct to lifestyle intervention on the reduction in body weight and tolerability in obese Chinese adults without diabetes. MATERIALS AND METHODS: In this 24-week, randomized, double-blind, placebo-controlled phase 2 trial, 254 obese adults with a body mass index of 28.0-40.0 kg/m2 and without diabetes were enrolled. Participants were initially randomized in a 1:1:1 ratio to one of three dose levels: 0.12, 0.24, or 0.36 mg of the study treatment. Within each dose level, participants were further randomized in a 3:1 ratio to receive either subcutaneous injection of noiiglutide or a matching placebo. The primary endpoint was the change in body weight from baseline to week 24. RESULTS: Across all noiiglutide dosage levels, least squares mean reductions in body weight from baseline to week 24 ranged from 8.03 to 8.50 kg, compared with 3.65 kg in the placebo group (all p-values <.0001). In the noiiglutide groups (0.12, 0.24, 0.36 mg/day), a significantly higher proportion of participants achieved a weight loss ≥5% (68.8%, 60.0%, 73.0%) and ≥10% (37.5%, 36.9%, 39.7%), compared with the pooled placebo group (≥5%: 29.0%; ≥10%: 8.1%). Gastrointestinal adverse events, such as nausea, diarrhoea and vomiting, were more common in all noiiglutide groups (15.4%-30.2%, 18.8%-22.2%, 15.6%-18.5%) than in the pooled placebo group (8.1%, 6.5%, 0%). CONCLUSIONS: In obese Chinese adults without diabetes, once-daily subcutaneous noiiglutide significantly reduced body week at week 24 compared with placebo, and had a manageable safety profile, primarily involving gastrointestinal disorders.

Catechol compounds as dual-targeting agents for fish protection against Ichthyophthirius multifiliis infections.

Aquaculture is one of the fastest growing sectors in global food production, recognized as a significant contributor to poverty alleviation, food security, and income generation. However, the frequent occurrence of diseases caused by pathogen infections result in reduced yields and economic losses, posing a substantial constraint to the sustainable development of aquaculture. Here, our study identified that four catechol compounds, quercetin, luteolin, caffeic acid, and chlorogenic acid, exhibited potent antiparasitic effects against Ichthyophthirius multifiliis in both, in vitro and in vivo. The parasite is recognized as one of the most pathogenic to fish worldwide. Using a combination of in silico methods, the dipeptidyl peptidase (DPP) was identified as a critical target for catechol compounds. The two hydroxyl radicals of the catechol group were essential for its binding to and interacting with the DPP protein. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses indicated that catechol compounds disrupt pathways associated with the metabolism and growth of I. multifiliis, thereby exerting antiparasitic effects. Furthermore, these compounds attenuated the expression of proinflammatory cytokines in vivo in fish and promoted macrophage polarization toward M2 phenotype by inhibiting the STAT1 signaling pathway. The dual activity of catechol compounds, acting as both direct antiparasitic and anti-inflammatory agents in fish, offers a promising therapeutic approach for combating I. multifiliis infections in aquaculture.

Data Science Applications in Circular Economy: Trends, Status, and Future.

The circular economy (CE) aims to decouple the growth of the economy from the consumption of finite resources through strategies, such as eliminating waste, circulating materials in use, and regenerating natural systems. Due to the rapid development of data science (DS), promising progress has been made in the transition toward CE in the past decade. DS offers various methods to achieve accurate predictions, accelerate product sustainable design, prolong asset life, optimize the infrastructure needed to circulate materials, and provide evidence-based insights. Despite the exciting scientific advances in this field, there still lacks a comprehensive review on this topic to summarize past achievements, synthesize knowledge gained, and navigate future research directions. In this paper, we try to summarize how DS accelerated the transition to CE. We conducted a critical review of where and how DS has helped the CE transition with a focus on four areas including (1) characterizing socioeconomic metabolism, (2) reducing unnecessary waste generation by enhancing material efficiency and optimizing product design, (3) extending product lifetime through repair, and (4) facilitating waste reuse and recycling. We also introduced the limitations and challenges in the current applications and discussed opportunities to provide a clear roadmap for future research in this field.

Evaluating Losses from Water Scarcity and Benefits of Water Conservation Measures to Intercity Supply Chains in China.

The severe water scarcity in China poses significant economic risks to its agriculture, energy, and manufacturing sectors, which can have a cascading effect through the supply chains. Current research has assessed water scarcity losses for global countries and Chinese provinces by using the water scarcity risk (WSR) method. However, this method involves subjective functions and parameter settings, and it fails to capture the adaptive behaviors of economies to water scarcity, compromising the reliability of quantified water scarcity loss. There is a pressing need for a new method to assess losses related to water scarcity. Here, we develop an agent-based complex network model to estimate the inter-regional and intersectoral impacts of water scarcity on both cities and basins. Subsequently, we evaluate the supply chain-wide economic benefits of four different water conservation measures as stipulated by the 14th Five-Year Plan for the Construction of a Water-Saving Society. These measures include increasing the utilization rate of recycled water in water-scarce cities, reducing the national water consumption per industrial value-added, and implementing agricultural and residential water conservation measures. Results show that direct losses constitute only 9% of the total losses from water scarcity. Approximately 37% of the losses can be attributed to interregional impacts. Among the water-scarce cities, Qingdao, Lanzhou, Jinan, and Zhengzhou pose a significant threat to China's supply chains. Agricultural water conservation yields the highest amount of water savings and economic benefits, while residential water conservation provides the highest economic benefit per unit of water saved. The results provide insights into managing water scarcity, promoting cross-regional cooperation, and mitigating economic impacts.

Correlation Between Impaired Sensitivity to Thyroid Hormones and Serum Uric Acid in Female Patients With Obesity and After Laparoscopic Sleeve Gastrectomy.

OBJECTIVE: An alterable risk factor for hyperuricemia is obesity. Additionally, obese people may have a moderate form of acquired resistance to thyroid hormones. Thyrotropin, thyroid hormones, and obesity all interact subtly. However, the connection between thyroid hormone sensitivity and hyperuricemia in obese patients both before and after laparoscopic sleeve gastrectomy (LSG) has not yet been clarified. The objective of our study was to investigate the connection between impaired thyroid hormone sensitivity and elevated uric acid (UA) levels before and after LSG. METHODS: In total, 1054 euthyroid patients with obesity (481 males, 573 females), 248 (143 female patients) of whom underwent subsequent LSG, were enrolled in this retrospective study. Anthropometric measurements and thyroid hormone and UA levels were taken before and 3 months after LSG. RESULTS: Female patients with obesity with impaired sensitivity to thyroid hormones had higher UA levels (P for trend <.01). The odds ratio of the fourth vs first quartile of thyroid feedback quantile index, thyrotropin index, and thyrotropin-thyroxine resistance index were 4.285 (confidence interval: 1.360-13.507), 3.700 (confidence interval: 1.276-10.729), and 2.839 (confidence interval: 1.014-7.948), respectively, with robust relationships with female hyperuricemia (all P < .05). However, there was only a positive correlation between the decline in UA levels and thyroid feedback quantile index, thyrotropin, and thyrotropin-thyroxine resistance index in female patients following LSG. CONCLUSION: Female hyperuricemia is correlated with higher thyroid hormone resistance index scores. Resistance to thyroid hormones was greatly improved by LSG. The decrease in UA levels after surgery is correlated with the improvement of thyroid hormone resistance after LSG.

Efficacy and safety of orlistat in male patients with overweight/obesity and hyperuricemia: results of a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Obesity is associated with elevated serum uric acid (SUA) levels and frequent gout flares. Losing weight can reduce the SUA level and gout flares. The effect of orlistat on SUA levels and gout flares in patients with overweight/obesity and hyperuricemia (HUA) has not been extensively studied. This study investigated the effects of orlistat on SUA levels and gout flares compared to placebo in overweight and obese patients with HUA. METHODS: A total of 72 Chinese patients with overweight/obesity and HUA were randomly divided into a placebo group (35, 48.6%) and an orlistat group (37, 51.4%); the trial lasted 12 weeks. The primary endpoints were the relative changes in body weight, the SUA level, and gout flares in the per-protocol population. RESULTS: Orlistat reduced the proportion of patients with gout flares (log-rank P = 0.023, hazard ratio = 0.31, 95% confidence interval 0.11-0.85). There was no significant difference in SUA level between the two groups. The average weight loss of the orlistat group was 2.85 kg, and the average weight loss of the placebo group was 0.76 kg. The weight loss in the orlistat group was significantly greater than that in the control group (P < 0.05). CONCLUSIONS: This study is the first to demonstrate that orlistat has no significant effect on SUA levels in patients with overweight/obesity and HUA. The utility of orlistat as an adjunct therapy to prevent gout flares during weight loss in patients with HUA was emphasized. TRIAL REGISTRATION: Clinicaltrials.gov NCT05496075.

Posterior capsular radial sign: a novel method to confirm anterior vitreous cortex resection in phacovitrectomy.

BACKGROUND: The main purpose of this paper is to introduce a method that can accurately locate the posterior capsule of the lens to facilitate a relatively complete resection of the anterior vitreous body. METHODS: A total of 51 patients in the experimental group and control group were enrolled in this study. Phacoemulsification combined with vitrectomy was performed in all cases. After the cataract procedure was completed in the control group, the surgeon performed a conventional anterior vitrectomy with the operative eye. In the experimental group, anterior vitrectomy was performed according to the threadiness corrugation of the posterior capsule of the lens. During the operation, with the help of triamcinolone, two surgeons confirmed the resection of the anterior vitreous cortex; the best corrected visual acuity and intraocular pressure of all patients were recorded at 1 week, 1 month and 3 months after surgery. RESULTS: Fifty patients underwent phacoemulsification combined with vitrectomy, except one patient in the experimental group who was lost to follow-up. After surgery, no significant complications were observed in all patients except two patients in the control group with temporary increases in intraocular pressure. There was no significant difference in preoperative visual acuity between the two groups (t = 0.83, P = 0.25). Both groups had varying degrees of improvement in best corrected visual acuity at 1 week, 1 month and 3 months after surgery. Moreover, there was no significant difference in BCVA between the two groups at the three follow-up time points (t=-1.15, -1.65, -1.09, P = 0.53, 0.21, 0.23). After surgery, no significant complications were observed in all patients except two patients in the control group with temporary increases in intraocular pressure. Incomplete resection of the anterior vitreous cortex was observed in 2 patients in each group, but there was no significant difference (χ2 = 7.81, P > 0.05). CONCLUSION: In the process of cataract surgery combined with vitrectomy, thready corrugation appears in the posterior capsule of the lens and is an important sign of its localization. Anterior vitrectomy can be accomplished safely and effectively with the help of thread-like corrugation, and the surgical effect is almost the same as that of traditional surgery. Especially suitable for beginners in vitreous surgery.

Unveiling complementarities between national sustainable development strategies through network analysis.

The 2030 agenda of the United Nations provides a framework of 17 Sustainable Development Goals (SDGs) and 232 indicators for its members to fulfill. The overall achievement critically depends on how nations understand the interactions between these SDGs and set priorities for development pathways. This study provides a comprehensive network analysis of global SDG complementarities, measured by the co-occurrences of SDG pairs' comparative advantages in the same region by adopting the 'product space' concept from economics. We construct the 'SDG space' at goal and indicator levels with the most recently available data and then validate its robustness by comparing it to the commonly used correlation network and confirm its predictive power using historical data. Network analysis reveals a strongly connected socioeconomic-related core and an environmental-related periphery, with 'bridge' indicators connecting different clusters. The goal-level space identifies the 'bridge' goals as SDG 17 (Partnerships for the Goals), SDG 8 (Decent Work and Economic Growth), and SDG 15 (Life on Hand) in the environmental-related cluster, while identifying SDG 7 (Affordable and Clean Energy), SDG 6 (Clean water and Sanitation), and SDG 16 (Justice and Strong Institutions) in the socioeconomic cluster. The indicator-level space provides details to explain how they act as 'bridges' in the network. In particular, 16-9: Free Press Index is the 'bridge' indicator with the highest betweenness centrality value and acts as the bottleneck indicator in China for its overall sustainable development. Improving it can enhance connected indicators' performance, leading to positive cascading effects on different aspects of sustainability.

Non-alcoholic fatty liver disease and gut microbial dysbiosis- underlying mechanisms and gut microbiota mediated treatment strategies.

Non-alcoholic fatty liver disease (NAFLD) is by far the most prevalent form of liver disease worldwide. It's also the leading cause of liver-related hospitalizations and deaths. Furthermore, there is a link between obesity and NAFLD risk. A projected 25% of the world's population grieves from NAFLD, making it the most common chronic liver disorder. Several factors, such as obesity, oxidative stress, and insulin resistance, typically accompany NAFLD. Weight loss, lipid-lowering agents, thiazolidinediones, and metformin help prominently control NAFLD. Interestingly, pre-clinical studies demonstrate gut microbiota's potential causal role in NAFLD. Increased intestinal permeability and unhindered transport of microbial metabolites into the liver are the major disruptions due to gut microbiome dysbiosis, contributing to the development of NAFLD by dysregulating the gut-liver axis. Hence, altering the pathogenic bacterial population using probiotics, prebiotics, synbiotics, and fecal microbiota transplantation (FMT) could benefit patients with NAFLD. Therefore, it is crucial to acknowledge the importance of microbiota-mediated therapeutic approaches for NAFLD and comprehend the underlying mechanisms that establish a connection between NAFLD and gut microbiota. This review provides a comprehensive overview of the affiliation between dysbiosis of gut microbiota and the progress of NAFLD, as well as the potential benefits of prebiotic, probiotic, synbiotic supplementation, and FMT in obese individuals with NAFLD.

Genetic advancements in obesity management and CRISPR-Cas9-based gene editing system.

Human genome research has reached new heights in the recent decade thanks to a major advance in genome editing. Genome editing enables scientists to understand better the functions of a single gene and its impact on a wide range of diseases. In brief, genome editing is a technique for introducing alterations into specific DNA sequences, such as insertions, deletions, or base substitutions. Several methods are adopted to perform genome editing and clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated nuclease 9 (Cas9) systems. Unfortunately, despite substantial progress in understanding the molecular pathways behind obesity, anti-obesity medications are now ineffective. If you are obese, a 10% weight decrease would be preferable to healthy body weight for most people. CRISPR-Cas9, on the other hand, has been shown to reduce body weight by an astonishing 20%. Hence, this updated review elaborates on the molecular basis of obesity, risk factors, types of gene therapy, possible mechanisms, and advantages of the CRISPR-Cas9 system over other methods.

Telecoupling China's City-Level Water Withdrawal with Distant Consumption.

Trade causes the geospatial separation of production and consumption, which drives telecoupling between resource utilization and distant consumption. While benefiting the economy, trade can also exacerbate resource use inequality among regions. Here, we propose telecoupled water withdrawal (TWW) to examine the impact of distant consumption on local water resources, defined as local water withdrawal driven remotely by consumption in other regions. We characterize the TWW in China in 2015 at the city level (350 cities) using a nested multiregional input-output model. We find that approximately 20% of TWW is linked to foreign consumption, more than a quarter of which is driven by the United States. Moreover, cities with high TWW are concentrated on the Southeast coast and in Northwest China. Cities in Xinjiang province (Northwest China) account for 12% of the national TWW but only 0.7% of China's GDP. Our findings shed light on the telecoupling of pressure on local water resources in China cities and distant consumption at the global scale, calling for joint efforts by the contributors and beneficiaries of TWW to ensure the synergistic sustainability of water resources and trade.

Scaling of Energy, Water, and Waste Flows in China's Prefecture-Level and Provincial Cities.

Cities have been envisioned as biological organisms as the integral part of nature's energy and material flows. Recent advances in urban scaling research have uncovered systematic changes in socioeconomic rates and infrastructural networks as urban population increases, providing predictive contents for the comparison between cities and organisms. However, it is still unclear how and why larger and smaller cities may differ in their per capita environmental impacts. Here, we study scaling patterns of urban energy, water, and waste flows as well as other relevant measures in Chinese cities. We divide cities into different groups using an algorithm that automatically assigns cities to clusters with distinct scaling patterns. Despite superlinear scaling of urban GDP, as predicted by urban scaling theories, resource consumption, such as the supply of electricity and water, and waste generation, such as wastewater and domestic waste, do not show significant deviations from linear scaling. The lengths of resource pipelines scale linearly in most cases, as opposed to sub-linearity predicted by theory. Furthermore, we show two competing forces underlying the overall observed effects of scale: a higher population density tends to decrease per capita resource consumption and infrastructure provisions, while intensified socioeconomic activities have the opposite effect.

Sliding Window-Based Machine Learning for Environmental Inspection Resource Allocation.

Environmental regulation is pivotal in mitigating environmental risks and promoting sustainable development, yet regulators frequently encounter resource constraints when inspecting enterprises. To address this limitation, we employed four sliding window-based machine learning techniques to enhance effective environmental inspections. Utilizing feature-engineered time-series data of characteristic and compliance records from 16,777 chemical enterprises in Jiangsu between 2010 and 2021, the four models were used to establish the predictive models that link enterprise characteristics to the likelihood of inspection failure. The results indicated that the models were comparable with the widely utilized deep learning sequence model, the Long Short-Term Memory model, achieving areas under the ROC (receiver operating characteristic) curves exceeding 0.83. Past violation significantly influences future violations, with a more recent violation history exerting stronger impacts. Besides, using predicted failure rates, we proposed seven resource allocation scenarios, considering different regulation intensities to target high-risk enterprises. Notably, the provincial-level risk-based method yielded a significant inspection failure rate increase (detecting violation), surpassing 8-fold the baseline. Overall, our study offers regulators an optimized inspection resource allocation method, thereby enhancing the regulatory effectiveness. Moreover, this study demonstrates the potential of window-based machine learning techniques in environmental regulation and highlights the importance of data-driven decision-making for promoting sustainable development.

Allocating China's CO2 Emissions Based on Economic Welfare Gains from Environmental Externalities.

To achieve carbon neutrality (i.e., net zero carbon emissions) by 2060, China must make significant changes in its socioeconomic systems, including appropriately allocating emissions responsibility. Traditional methods of delineating responsibilities (such as production-based and consumption-based accounting) can lead to double counting when applied simultaneously and therefore difficulty in determining responsibilities of different agents. An alternative approach based on economic welfare gains from environmental externalities has been refined, ensuring that the responsibilities of consumers and producers add up to the total emissions. The application of this approach to 48 countries and 31 Chinese provinces reveals that regions with less elastic supply and demand, such as Hebei in China and Russia, have higher responsibilities. Furthermore, larger externalities associated with unitary product value shift the burden of obligations from producers to consumers. Regions with high levels of wealth and carbon-intensive imports, such as Zhejiang and Guangdong in China, as well as the United States, typically have higher consumer-based accounting (CBA) emissions than production-based accounting (PBA) emissions and, as a result, redistributed responsibilities between PBA and CBA emissions. The new distribution results vary significantly from PBA or CBA emissions, indicating opportunities for more comprehensive and accessible policy goals.

Large-scale surface water-groundwater origins and connectivity in the Ordos Basin, China: Insight from hydrogen and oxygen isotopes.

The sustainability of water resources is a major challenge for the Ordos Basin and Loess Plateau of China. The basis of effective water management is an understanding of the water cycle process. This study investigated the surface water-groundwater origins and connectivity using stable isotopes (δD and δ18O) of surface water and groundwater in 11 river basins in the Ordos Basin. It was found that the surface water-groundwater origins and hydraulic connection were characterized by regional differences, mainly induced by climatic characteristics, hydrogeological conditions and human activities. Specifically, the impact of thick loess deposits caused surface water and groundwater to take long time to produce a hydraulic connection. In contrast, areas with thin loess deposits and frequent human activities showed a good connectivity between surface water and groundwater. As for water origins, summer precipitation was a common source of surface water and groundwater in the study area, and groundwater discharge was another source of surface water. However, surface water and groundwater were subjected to different degrees of evaporation during receiving precipitation recharge. Notably, thick loess deposits had an impact on groundwater evaporation because both the recharge of precipitation to groundwater and the discharge of groundwater to surface water took a long time. In addition, it was found that frequent human activities (mining, irrigation and urban construction) could weaken the impact of evaporation. This large-scale analysis provided new insights into the origins and connectivity of surface water and groundwater in areas with thick unsaturated zones for water resources management.

The "Gravity" for global virtual water flows: From quantity and quality perspectives.

The virtual water trade (VWT) has been proposed as a means of balancing national water budgets while also saving water globally. Since humans require both sufficient quantity and quality of water, the drivers of VWT flows should be thoroughly examined, including its three components. Multiregional input-output (MRIO) and gravity methods are used to investigate the influence of multiple factors on the green, blue, and grey water trading flows among 177 countries in 2014. Several factors were found to be strongly correlated with the grey water trade, offering valuable insight into water resource management, especially about water pollution. The findings verify the driving effects of socio-economic status and agricultural activities on virtual water trade. The study shows that the influence of water resources endowment on the virtual water trade flow is relatively small compared to economic structure in determining virtual water trade flows. The paper contributes to the research on the interaction between virtual water trade and various factors, which can assist decision-makers in optimizing economic structure by integrating water quantity and quality factors and realize sustainable management of water resources.

Do tourism clusters contribute to low-carbon destinations? The spillover effect of tourism agglomerations on urban residential CO2 emissions.

A burgeoning literature has investigated the relationship between tourism and regional CO2 emissions. However, the results are equivocal. Some scholars find that tourism induces more emissions, while others find that tourism benefits emission mitigation. Previous research suffers three deficiencies: (1) the CO2 emissions induced by tourism beyond the tourism sectors are neglected; (2) the role of tourism agglomerations in sustainable destination development is underrated; (3) the tripartite mechanism of tourism agglomerations, household income, and urban direct residential CO2 emissions (DRCEs) remains to be determined. Based on the theories of complex adaptive system and an empirical study of 30 provinces in China, we examine the relationship between the tripartite roles via multiple spatial econometric models. The results disclose that tourism agglomerations have dual effects on urban DRCEs and an inverted U-shaped effect on household income. The growth of tourism agglomerations has generally promoted urban DRCEs in many provinces of mainland China during the last fourteen years because its indirect effect (positive) outweighs the direct effect (negative). However, tourism agglomerations are feasible for low-carbon destinations once the emission-income decoupling happens. This study contributes to low-carbon destination management by presenting a more holistic image of the social-economic-environmental impacts of tourism agglomerations.

STAT3 regulates SRGN and promotes metastasis of nasopharyngeal carcinoma through the FoxO1-miR-148a-5p-CREB1 axis.

Nasopharyngeal carcinoma (NPC), which is marked by a distinct distribution, is a common subtype of epithelial carcinoma arising from the nasopharyngeal mucosal lining. SRGN acts as an important and poor prognostic factor of NPC through multiple different mechanisms. However, the biological role and mechanism of SRGN in NPC remain unknown. Expression levels of miR-148a-5p, CREB1, FoxO1, and SRGN in NPC tissues and cell lines were tested by qRT-PCR or/and Western blot. The impacts of miR-148a-5p, CREB1, FoxO1, and SRGN on NPC cell viability, proliferation, migration, and invasion were estimated in vitro by CCK-8, colony formation, wound healing and Transwell experiments, and in vivo by a xenograft tumor model. JASPAR analysis was used to predict the binding activity of Foxo1 (CREB1) with the miR-148a-5p (SRGN) promoter, and the interaction was validated by EMSA and ChIP assays. The miR-148a-5p-CREB1 interaction was validated by a dual-luciferase reporter and RIP assays. CREB1 and SRGN were increased while miR-148a-5p was decreased in NPC. Silencing of SRGN and CREB1, as well as miR-148a-5p overexpression, repressed NPC tumor progression in vitro and in vivo. CREB1 promoted SRGN expression in NPC by targeting the promoter area of SRGN. Silencing of FoxO1 facilitated NPC tumor progression, while silencing of STAT3 repressed NPC tumor progression. FoxO1 bound to and regulated miR-148a-5p in NPC, and miR-148a-5p targeted CREB1. Additionally, FoxO1 knockdown abolished the downregulation of CREB1 and SRGN induced by STAT3 silencing. Our results suggest that STAT3 regulates SRGN and promotes the growth and metastasis of NPC through the FoxO1-miR-148a-5p-CREB1 axis.

Data imbalance in CRISPR off-target prediction.

For genome-wide CRISPR off-target cleavage sites (OTS) prediction, an important issue is data imbalance-the number of true OTS recognized by whole-genome off-target detection techniques is much smaller than that of all possible nucleotide mismatch loci, making the training of machine learning model very challenging. Therefore, computational models proposed for OTS prediction and scoring should be carefully designed and properly evaluated in order to avoid bias. In our study, two tools are taken as examples to further emphasize the data imbalance issue in CRISPR off-target prediction to achieve better sensitivity and specificity for optimized CRISPR gene editing. We would like to indicate that (1) the benchmark of CRISPR off-target prediction should be properly evaluated and not overestimated by considering data imbalance issue; (2) incorporation of efficient computational techniques (including ensemble learning and data synthesis techniques) can help to address the data imbalance issue and improve the performance of CRISPR off-target prediction. Taking together, we call for more efforts to address the data imbalance issue in CRISPR off-target prediction to facilitate clinical utility of CRISPR-based gene editing techniques.