Construction of heterogeneous MOF-on-MOF for highly efficient gaseous iodine sequestration under static conditions.

Considering the unexpected nuclear power waste emission and potential nuclear leakage, the exploration of robust materials for the effective capture and storage of radioactive iodine is of great importance but still remains a challenge. In this work, we report the rational synthesis of functionalized NH2-UiO-66-on-ZIF-67 architecture to enhance the static adsorption and retention of volatile iodine. Such MOF-on-MOF heterostructures was fabricated through seeding ZIF-67 core on the surface of NH2-UiO-66 satellite via a facile polyvinylpyrrolidone (PVP) regulated internal extended growth strategies. NH2-UiO-66-on-ZIF-67 exhibited unique core-satellite structure, which significantly promotes the binding interactions with iodine through synergizing of the N-rich imidazole moieties and surface functionalized amino groups within the porosity channels. As a result, the as fabricated NH2-UiO-66-on-ZIF-67 achieves enhanced mass diffusion and high capture capacity of 3600 mg/g for iodine vapor under static sorption conditions. Moreover, water vapor in humid conditions (relative humidity of 18 %) has almost no effect on the static iodine adsorption performance of the material. This study sheds light on a reliable MOF-on-MOF hybrid strategy for effective radioiodine treatment to ensure the safety nuclear waste management.

5-aminosalicylic acid alleviates colitis and protects intestinal barrier function by modulating gut microbiota in mice.

5-aminosalicylic acid (5-ASA) is widely used in the treatment of ulcerative colitis (UC), but its anti-inflammatory mechanism is complex and has not been fully understood. DSS model was used to test the effect of 5-ASA. Tight junction and Ki-67 were detected by western blot, immunofluorescence, and immunohistochemistry or qPCR. 16S rRNA gene sequencing of gut microbiota and subsequent bioinformatics and statistical analysis were performed to identify the specific bacteria which were associated with the treatment effect of 5-ASA. GC-MS was performed to test short-chain fatty acids (SCFAs). Antibiotic-treated mice were used to demonstrate the key role of endogenous gut microbiota. Here, we found that 5-ASA alleviated dextran sulfate sodium (DSS)-induced colitis in mice. Moreover, 5-ASA significantly repaired the intestinal barrier. At the molecular level, 5-ASA markedly raised the expression of tight junction proteins including JAM-A and occludin and cell proliferation marker Ki-67 in mice. In addition, bacterial 16S rRNA gene sequencing and bioinformatics analysis showed that 5-ASA significantly modulated the DSS-induced gut bacterial dysbiosis. In detail, it stimulated the growth of protective bacteria belonging to Faecalibaculum and Dubosiella, which were negatively correlated with colitis parameters, and blocked the expansion of pro-inflammatory bacteria such as Escherichia-Shigella and Oscillibacter, which were positively correlated with colitis in mice. Meanwhile, 5-ASA increased the cecal acetate level. Most notably, 5-ASA was no longer able to treat colitis and reverse gut barrier dysfunction in antibiotic-treated mice that lacked endogenous gut microbiota. Our data suggested that the anti-inflammatory activity of 5-ASA required the inherent intestinal flora, and the gut microbiota was a potential and effective target for the treatment of ulcerative colitis.

Gut microbiota-derived acetate promotes long-term recovery through angiogenesis guided by lymphatic ingrowth in older adults with stroke.

Introduction: Ischemic stroke is a leading cause of morbidity and mortality in older adults. Therefore, in this study, we sought to understand the interplay between the microbiota, gut, and brain in the context of stroke in older adults. Objective: To determine whether gut microbiota from younger individuals promotes recovery through angiogenesis in both elderly stroke patients and aged stroke mice, we explored the changes in gut microbiota and the correlation between short-chain fatty acids (SCFAs) and angiogenesis in the aged stroke population. Then, we altered the gut microbiome in aged mice by transplanting microbiota from younger donors before inducing experimental stroke to explore the mechanism by which gut microbiota-derived SCFAs promote angiogenesis. Methods: Part I: We conducted a single-center, double-blind trial to compare gut microbiota diversity and SCFA levels in fecal samples from older stroke patients with those from younger stroke patients. Additionally, we measured levels of vascular endothelial growth factor (VEGF) and VEGFC levels in plasma to assess their correlation with SCFA levels. Part II: We performed fecal microbiota transplantation (FMT) 3 days before inducing ischemic stroke in aged male mice (16-18) via distal middle cerebral artery occlusion (dMCAO). The FMT was conducted using gut microbiomes from either young donors (2-3 months) or aged donors (16-18 months). Results: In older stroke patients, gut microbiota diversity was significantly reduced compared to that in younger stroke patients. Furthermore, levels of acetate, a bacterially derived SCFA, were lower and positively correlated with angiogenesis markers (VEGF and VEGF-C). In aged stroke mice, transplantation of young microbiota improved stroke outcomes by promoting angiogenesis, which was facilitated by lymphatic ingrowth into the cortex. This protective effect was linked to gut microbiota-derived acetate, which enhanced lymphangiogenesis by replenishing acetyl coenzyme A. Conclusions: (a) Gut microbiota-derived acetate promotes angiogenesis post-stroke and (b) lymphatic ingrowth into the cerebral cortex was observed in post-dMCAO mice. These findings suggest that selectively promoting SCFA-producing bacteria, particularly acetate-producers, could be a promising therapeutic strategy to reduce functional impairments in older stroke subjects.

Dosage constraint of the ribosome-associated molecular chaperone drives the evolution and fates of its duplicates in bacteria.

Gene duplication events happen prevalently during evolution, and the mechanisms governing the loss or retention of duplicated genes are mostly elusive. Our genome scanning analysis revealed that trigger factor (TF), the one and only bacterial ribosome-associated molecular chaperone, is singly copied in virtually every bacterium except for a very few that possess two or more copies. However, even in these exceptions, only one complete TF copy exists, while other homologs lack the N-terminal domain that contains the conserved ribosome binding site (RBS) motif. Consistently, we demonstrated that the overproduction of the N-terminal complete TF proteins is detrimental to the cell, which can be rescued by removing the N-terminal domain. Our findings also indicated that TF overproduction leads to a decrease in protein productivity and profile changes in proteome due to its characteristic ribosome binding and holdase activities. Additionally, these N-terminal deficient TF homologs in bacteria with multiple TF homologs partition the function of TF via subfunctionalization. Our results revealed that TF is subjected to a dosage constraint that originates from its own intrinsic functions, which may drive the evolution and fates of duplicated TFs in bacteria. IMPORTANCE: Gene duplication events presumably occur in tig, which encodes the ribosome-associated molecular chaperone trigger factor (TF). However, TF is singly copied in virtually every bacterium, and these exceptions with multiple TF homologs always retain only one complete copy while other homologs lack the N-terminal domain. Here, we reveal the manner and mechanism underlying the evolution and fates of TF duplicates in bacteria. We discovered that the mutation-to-loss or retention-to-sub/neofunctionalization of TF duplicates is associated with the dosage constraint of N-terminal complete TF. The dosage constraint of TF is attributed to its characteristic ribosome binding and substrate-holding activities, causing a decrease in protein productivity and profile changes in cellular proteome.

Space-Confined Amplification for In Situ Imaging of Single Nucleic Acid and Single Pathogen on Biological Samples.

Direct in situ imaging of nucleic acids on biological samples is advantageous for rapid analysis without DNA extraction. However, traditional nucleic acid amplification in aqueous solutions tends to lose spatial information because of the high mobility of molecules. Similar to a cellular matrix, hydrogels with biomimetic 3D nanoconfined spaces can limit the free diffusion of nucleic acids, thereby allowing for ultrafast in situ enzymatic reactions. In this study, hydrogel-based in situ space-confined interfacial amplification (iSCIA) is developed for direct imaging of single nucleic acid and single pathogen on biological samples without formaldehyde fixation. With a polyethylene glycol hydrogel coating, nucleic acids on the sample are nanoconfined with restricted movement, while in situ amplification can be successfully performed. As a result, the nucleic acids are lighted-up on the large-scale surface in 20 min, with a detection limit as low as 1 copy/10 cm2. Multiplex imaging with a deep learning model is also established to automatically analyze multiple targets. Furthermore, the iSCIA imaging of pathogens on plant leaves and food is successfully used to monitor plant health and food safety. The proposed technique, a rapid and flexible system for in situ imaging, has great potential for food, environmental, and clinical applications.

Upregulated DNMT3a coupling with inhibiting p62-dependent autophagy contributes to NNK tumorigenicity in human bronchial epithelial cells.

NNK, formally known as 4-(methyl nitrosamine)-1-(3-pyridyl)-1-butanoe, is a potent chemical carcinogen prevalent in cigarette smoke and is a key contributor to the development of human lung adenocarcinomas. On the other hand, autophagy plays a complex role in cancer development, acting as a "double-edged sword" whose impact varies depending on the cancer type and stage. Despite this, the relationship between autophagy and NNK-induced lung carcinogenesis remains largely unexplored. Our current study uncovers a marked reduction in p62 protein expression in both lung adenocarcinomas and lung tissues of mice exposed to cigarette smoke. Interestingly, this reduction appears to be contingent upon the activity of extrahepatic cytochrome P450 (CYP450), revealing that NNK metabolic activation by CYP450 enzyme escalates its potential to induce p62 downregulation. Further mechanistic investigations reveal that NNK suppresses autophagy by accelerating the degradation of p62 mRNA, thereby promoting the malignant transformation of human bronchial epithelial cells. This degradation process is facilitated by the hypermethylation of the Human antigen R (HuR) promoter, resulting in the transcriptional repression of HuR - a key regulator responsible for stabilizing p62 mRNA through direct binding. This hypermethylation is triggered by the activation of ribosomal protein S6, which is influenced by NNK exposure and subsequently amplifies the translation of DNA methyltransferase 3 alpha (DNMT3a). These findings provide crucial insights into the nature of p62 in both the development and potential treatment of tobacco-related lung cancer.

Alteration of ascending colon mucosal microbiota in patients after cholecystectomy.

BACKGROUND: Cholecystectomy is a successful treatment option for gallstones, although the incidence of colorectal cancer (CRC) has notably increased in post-cholecystectomy (PC) patients. However, it remains uncertain whether the altered mucosal microbiota in the ascending colon is related. AIM: To investigate the potential correlation between gut microbiota and the surgical procedure of cholecystectomy. METHODS: In total, 30 PC patients and 28 healthy controls underwent colonoscopies to collect mucosal biopsy samples. PC patients were divided based on their clinical features. Then, 16S-rRNA gene sequencing was used to analyze the amplicon, alpha diversity, beta diversity, and composition of the bacterial communities. Additionally, the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) database, sourced from the Kyoto Encyclopedia of Genes and Genomes, was used to predict the functional capabilities of the bacteria. RESULTS: PC patients were comparable with healthy controls. However, PC patients older than 60 years had a distinct composition compared to those under 60 years old. Bacteroidetes richness was considerably higher at the phylum level in PC patients. Bacteroides, Parabacteroides, and Bilophila were more abundant in the PC group than in the control group. Furthermore, PC patients exhibited greater enrichment in metabolic pathways, specifically those related to lipopolysaccharide biosynthesis and vancomycin group antibiotic production, than controls. CONCLUSION: This study indicated that the mucosal microbiota in PC patients was altered, perhaps offering new perspectives on the treatment possibilities for CRC and diarrhea following cholecystectomy.

Glutathione-responsive biodegradable nanohybrid for cancer photoacoustic imaging and gas-assisted photothermal therapy.

Photothermal therapy (PTT), particularly in the near-infrared-II (NIR-II) range, has attracted widespread attention over the past years. However, the accompanied inflammatory responses can result in undesirable side effects and contribute to treatment ineffectiveness. Herein, we introduced a novel biodegradable nanoplatform (CuS/HMON-PEG) capable of PTT and hydrogen sulfide (H2S) generation, aimed at modulating inflammation for improved cancer treatment outcomes. The embedded ultrasmall copper sulphide (CuS) nanodots (1-2 nm) possessed favorable photoacoustic imaging (PAI) and NIR-II photothermal capabilities, rendering CuS/HMON-PEG an ideal phototheranostic agent. Upon internalization by 4T1 cancer cells, the hollow mesoporous organosilica nanoparticle (HMON) component could react with the overproduced glutathione (GSH) to produce H2S. In addition to the anticipated photothermal tumor ablation and H2S-induced mitochondrial dysfunction, the anti-inflammatory regulation was also been demonstrated by the downregulation of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1beta (IL-1ß). More importantly, the modulation of inflammation also promoted wound healing mediated by PTT. This work not only presents a H2S-based nanomodulator to boost NIR-II PTT but also provides insights into the construction of novel organic/inorganic hybrid nanosystems.

Experimental study on soil deformation caused by overexploitation of groundwater.

Due to the overexploitation of deep groundwater, the largest cone of depression in the world has formed in the North China Plain. This led to severe geological hazards, including land subsidence and ground fissures, and also caused economic losses. The prevention and treatment of subsidence needs to rely on the accurate prediction of subsidence amount. According to the one-dimensional consolidation theory and effective stress principle, combined with stratum structure, groundwater flow, stress distribution, and so forth, the high-pressure consolidation test results of 569.6 m deep borehole soil samples are adopted; with a specific focus on stress and deformation parameters under exploitation of groundwater condition, the soil-water coupling prediction model of groundwater level lowering depth and land subsidence has been established. Verification with measured subsidence data near the study sites demonstrated that the predicted curve is consistent with the measured one and the differences between them are acceptable. The model can be applied in different areas after making adjustment based on different regional stratigraphic structures. Its key advantage lies in the ability to provide land subsidence prediction for areas lacking monitoring data, making it highly valuable for widespread application. PRACTITIONER POINTS: There is a compressible stratum structure; it is the internal factors of land subsidence. The groundwater level decline causes the soil body stress to change. It is land subsidence of the external factors. Based on the one-dimensional consolidation theory and by combining stratigraphic structures, groundwater flow, and stress distribution, a ground settlement prediction model was established.

Electroporation Delivery of Cas9 sgRNA Ribonucleoprotein-Mediated Genome Editing in Sheep IVF Zygotes.

The utilization of electroporation for delivering CRISPR/Cas9 system components has enabled efficient gene editing in mammalian zygotes, facilitating the development of genome-edited animals. In this study, our research focused on targeting the ACTG1 and MSTN genes in sheep, revealing a threshold phenomenon in electroporation with a voltage tolerance in sheep in vitro fertilization (IVF) zygotes. Various poring voltages near 40 V and pulse durations were examined for electroporating sheep zygotes. The study concluded that stronger electric fields required shorter pulse durations to achieve the optimal conditions for high gene mutation rates and reasonable blastocyst development. This investigation also assessed the quality of Cas9/sgRNA ribonucleoprotein complexes (Cas9 RNPs) and their influence on genome editing efficiency in sheep early embryos. It was highlighted that pre-complexation of Cas9 proteins with single-guide RNA (sgRNA) before electroporation was essential for achieving a high mutation rate. The use of suitable electroporation parameters for sheep IVF zygotes led to significantly high mutation rates and heterozygote ratios. By delivering Cas9 RNPs and single-stranded oligodeoxynucleotides (ssODNs) to zygotes through electroporation, targeting the MSTN (Myostatin) gene, a knock-in efficiency of 26% was achieved. The successful generation of MSTN-modified lambs was demonstrated by delivering Cas9 RNPs into IVF zygotes via electroporation.

Genetic Analysis of a Fetus with 14q11.2 Microdeletion in Ultrasound Abnormalities.

BACKGROUND: This study aimed to explore the genetic basis of a fetus with ultrasound indicating a thickening of the nuchal translucency (NT) and a choroid plexus cyst. METHODS: Fetal amniotic fluid and peripheral blood were collected for a G-banding karyotype analysis and single nucleotide polymorphism array (SNP-array) detection. RESULTS: The chromosome karyotypes of the fetus and its parents were normal. SNP-array showed the fetus had carried 277 kb microdeletion at 14q11.2, which was a new mutation. After the induced abortion, the fetus was diagnosed with macrocephaly. CONCLUSIONS: A prenatal diagnosis of a fetus with 14q11.2 microdeletion-induced intrauterine growth retardation was confirmed, which has provided guidance for the subsequent pregnancy.

The genetic basis of leaf hair development in upland cotton (Gossypium hirsutum).

Trichomes, which originate from the epidermal cell of aerial organs, provide plants with defense and secretion functions. Although numerous genes have been implicated in trichome development, the molecular mechanisms underlying trichome cell formation in plants remain incompletely understood. Here, we using genome-wide association study (GWAS) across 1037 diverse accessions in upland cotton (Gossypium hirsutum) to identify three loci associated with leaf pubescence (hair) amount, located on chromosome A06 (LPA1), A08 (LPA2) and A11 (LPA3), respectively. GhHD1, a previously characterized candidate gene, was identified on LPA1 and encodes an HD-Zip transcription factor. For LPA2 and LPA3, we identified two candidate genes, GhGIR1 and GhGIR2, both encoding proteins with WD40 and RING domains that act as inhibitors of leaf hair formation. Expression analysis revealed that GhHD1 was predominantly expressed in hairy accessions, whereas GhGIR1 and GhGIR2 were expressed in hairless accessions. Silencing GhHD1 or overexpressing GhGIR1 in hairy accessions induced in a hairless phenotype, whereas silencing GhGIR2 in hairless accessions resulted in a hairy phenotype. We also demonstrated that GhHD1 interact with both GhGIR1 and GhGIR2, and GhGIR1 can interact with GhGIR2. Further investigation indicated that GhHD1 functions as a transcriptional activator, binding to the promoters of the GhGIR1 and GhGIR2 to active their expression, whereas GhGIR1 and GhGIR2 can suppress the transcriptional activation of GhHD1. Our findings shed light on the intricate regulatory network involving GhHD1, GhGIR1 and GhGIR2 in the initiation and development of plant epidermal hairs in cotton.

Adaptive Ant Colony Optimization Algorithm Based on Real-Time Logistics Features for Instant Delivery.

Ant colony optimization (ACO) algorithm is widely used in the instant delivery order scheduling because of its distributed computing capability. However, the order delivery efficiency decreases when different logistics statuses are faced. In order to improve the performance of ACO, an adaptive ACO algorithm based on real-time logistics features (AACO-RTLFs) is proposed. First, features are extracted from the event dimension, spatial dimension, and time dimension of the instant delivery to describe the real-time logistics status. Five key factors are further selected from the above three features to assist in problem modeling and ACO designing. Second, an adaptive instant delivery model is built considering the customer's acceptable delivery time. The acceptable time is calculated by emergency order mark and weather conditions in the event dimension feature. Third, an adaptive ACO algorithm is proposed to obtain the instant delivery order schedules. The parameters of the probability equation in ACO are adjusted according to the extracted key factors. Finally, the Gurobi solver in Python is used to perform numerical experiments on the classical datasets to verify the effectiveness of the instant delivery model. The proposed AACO-RTLF algorithm shows its advantages in instant delivery order scheduling when compared to the other state-of-the-art algorithms.

High performance filtering and high-sensitivity concentration retrieval of methane in photoacoustic spectroscopy utilizing deep learning residual networks.

A novel method is introduced to improve the detection performance of photoacoustic spectroscopy for trace gas detection. For effectively suppressing various types of noise, this method integrates photoacoustic spectroscopy with residual networks model which encompasses a total of 40 weighted layers. Firstly, this approach was employed to accurately retrieve methane concentrations at various levels. Secondly, the analysis of the signal-to-noise ratio (SNR) of multiple sets of photoacoustic spectroscopy signals revealed significant enhancement. The SNR was improved from 21 to 805, 52-962, 98-944, 188-933, 310-941, and 587-936 across the different concentrations, respectively, as a result of the application of the residual networks. Finally, further exploration for the measurement precision and stability of photoacoustic spectroscopy system utilizing residual networks was carried out. The measurement precision of 0.0626 ppm was obtained and the minimum detectable limit was found to be 1.47 ppb. Compared to traditional photoacoustic spectroscopy method, an approximately 46-fold improvement in detection limit and 69-fold enhancement in measurement precision were achieved, respectively. This method not only advances the measurement precision and stability of trace gas detection but also highlights the potential of deep learning algorithms in spectroscopy detection.

Virus-Induced galactinol-sucrose galactosyltransferase 2 Silencing Delays Tomato Fruit Ripening.

Tomato fruit ripening is an elaborate genetic trait correlating with significant changes at physiological and biochemical levels. Sugar metabolism plays an important role in this highly orchestrated process and ultimately determines the quality and nutritional value of fruit. However, the mode of molecular regulation is not well understood. Galactinoal-sucrose galactosyltransferase (GSGT), a key enzyme in the biosynthesis of raffinose family oligosaccharides (RFOs), can transfer the galactose unit from 1-α-D-galactosyl-myo-inositol to sucrose and yield raffinose, or catalyze the reverse reaction. In the present study, the expression of SlGSGT2 was decreased by Potato Virus X (PVX)-mediated gene silencing, which led to an unripe phenotype in tomato fruit. The physiological and biochemical changes induced by SlGSGT2 silencing suggested that the process of fruit ripening was delayed as well. SlGSGT2 silencing also led to significant changes in gene expression levels associated with ethylene production, pigment accumulation, and ripening-associated transcription factors (TFs). In addition, the interaction between SlGSGT2 and SlSPL-CNR indicated a possible regulatory mechanism via ripening-related TFs. These findings would contribute to illustrating the biological functions of GSGT2 in tomato fruit ripening and quality forming.

Placental growth factor alleviates hyperglycemia-induced trophoblast pyroptosis by regulating mitophagy.

INTRODUCTION: Hyperglycemia is closely related to trophoblast dysfunction during pregnancy and results in suppressed invasion, migration, and pro-inflammatory cell death of trophoblasts. Hyperglycemia is a dependent risk factor for gestational hypertension accompanied by decreased placental growth factor (PLGF), which is important for maternal and fetal development. However, there is currently a lack of evidence to support whether PLGF can alleviate trophoblast cell dysfunction caused by high blood sugar. Here, we aim to clarify the effect of hyperglycemia on trophoblast dysfunction and determine how PLGF affects this process. METHODS: The changes in placental tissue histomorphology from gestational diabetes mellitus (GDM) patients were compared with those of normal placentas. HTR8/SVneo cells were cultured in different amounts of glucose to examine cellular pyroptosis, migration, and invasion as well as PLGF levels. Furthermore, the levels of pyroptosis-related proteins (NLRP3, pro-caspase1, caspase1, IL-1ß, and Gasdermin D [GSDMD]) as well as autophagy-related proteins (LC3-II, Beclin1, and p62) were examined by Western blotting. The GFP-mRFP-LC3-II system and transmission electron microscopy were used to detect mitophagy levels, and small interfering RNAs targeting BCL2 Interacting Protein 3 (siBNIP3) and PTEN-induced kinase 1 (siPINK1) were used to determine the role of mitophagy in pyroptotic death of HTR-8/SVneo cells. RESULTS: Our results show that hyperglycemia upregulates NLRP3, pro-caspase1, caspase1, IL-1ß at the protein level in GDM patients. High glucose (HG, 25 mM) inhibits viability, invasion, and migration of trophoblast cells while suppressing superoxide dismutase levels and promoting malondialdehyde production, thus leading to a senescence associated beta-gal-positive cell burst. PLGF levels in nucleus and the cytosol are also inhibited by HG, whereas PLGF treatment inhibited pyroptosis-related protein levels of NLRP3, pro-caspase1, caspase1, IL-1ß, and GSDMD, Gasdermin D N-terminal domain (GSDMD-N). HG-induced mitochondrial dysfunction and BNIP3 and PINK1/Parkin expression. Knocking down BINP3 and PINK1 abolished the protective role of PLGF by preventing mitophagy. CONCLUSION: PLGF inhibited hyperglycemia, while PLGF reversed hyperglycemic injury by promoting mitophagy via the BNIP3/PINK1/Parkin pathway. Altogether, these results suggest that PLGF may protect against trophoblast dysfunction in diabetes.

Post-marketing surveillance framework of cell and gene therapy products in the European Union, the United States, Japan, South Korea and China: a comparative study.

BACKGROUND: Cell and gene therapy products (CGTPs) often receive accelerated approvals, lacking comprehensive long-term safety and efficacy data, which can raise significant safety concerns. This research aims to study the post-marketing surveillance (PMS) of CGTPs in the European Union (EU), the United States (US), Japan, South Korea, and China, to offer insights for the development of a secure and standardized post-marketing regulatory framework for CGTPs. METHODS: Related regulations and the implementation effect of PMS for approved CGTPs were studied searching PubMed, CNKI, and the official websites of the European Medicines Agency, the US Food and Drug Administration, Japan's Pharmaceuticals and Medical Device Agency, South Korea's Ministry of Food and Drug Safety, and the National Medical Products Administration of China. RESULTS: Compared to those in China, the guidelines of PMS for CGTPs in the EU, the US, Japan, and South Korea was more comprehensive. Notably, the EU had dedicated regulations and supporting guidelines of PMS. Of the 26 CGTPs approved in the EU, 88% were under additional monitoring, 38% received conditional marketing authorization, and 12% were authorized under exceptional circumstances, with 77% designated as orphan drugs. The US had released 34 guidelines specifically for CGTPs which, forming the foundation of post-marketing risk management. Among the 27 CGTPs approved in the US, 22% were required to perform risk evaluation and mitigation strategies, 37% added black box warnings in the package inserts, 63% mandated to post-marketing requirements, and 15% subject to post-marketing commitments. In Japan, stringent supervision measures encompassing all-case surveillance (79%) and re-examination (53%) were applied to the 19 approved CGTPs, with 21% approved through conditional and time-limited approval. The PMS for CGTPs in South Korea, mainly included PSUR, re-examination, and re-evaluation. China had introduced several relevant regulations, which consisted of general statements and lacked detailed guidance. CONCLUSIONS: This study demonstrates that the regulatory policies of PMS for CGTPs in the EU, the US, Japan, and South Korea were comprehensive. The implementation of PMS for CGTPs in the EU, the US, and Japan was well developed. This knowledge holds valuable insights for China's future learning and development in this field.

Study on the response mechanisms and evolution prediction of groundwater microbial-toxicological indicators.

This study aims to investigate the response mechanisms of groundwater microbial-toxicological indicators, specifically total bacteria count (TBC) and total coliform count (TCC), to water quality indicators and environmental conditions. Using data from a water source in the western plateau of China, a predictive model focusing on TBC and TCC was developed. An orthogonal experimental design was employed to manipulate environmental conditions such as temperature, pH, and porosity, facilitating laboratory experiments. These experiments measured pH, chemical oxygen demand (COD), oxidation-reduction potential (ORP), TBC, and TCC at varying depths and environmental conditions. Principal component analysis elucidated the mechanisms by which water quality indicators and environmental conditions affect groundwater microbial-toxicological indicators. A prediction model for these indicators in plateau regions was established based on a backpropagation neural network (BP-NN), using TBC and TCC as target variables and the newly extracted principal components as influencing factors. The results demonstrate that environmental conditions and water quality indicators primarily influence the evolution of groundwater microbial-toxicological indicators by altering the ionic charge quantities, redox conditions, and temperature of the groundwater. The predictive model for groundwater microbial-toxicological indicators shows trends consistent with experimental outcomes, with an average relative error of less than 15%, meeting engineering requirements. PRACTITIONER POINTS: The values of total bacteria count (TBC) and total coliform count (TCC) under different conditions were obtained by column experiments. The influence mechanism of environmental conditions and groundwater indicators on TBC and TCC was elaborated by principal component analysis. TBC and TCC prediction models were established through the investigation of water sources in a plateau area and laboratory experiments.