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Objective To explore the approach to establish a temporal lobe epilepsy model via intraperitoneal pilocarpine injection in C57BL/6J mice, and to summarize behavioral indicators predicting successful modeling during the acute phase of epileptic seizures after pilocarpine administration, aiming to offer a practical mice model for future epilepsy research.MethodsThirty C57BL/6J substrain mice (primary subjects) and forty C57BL/6N substrain mice (control subjects) were selected to establish a temporal lobe epilepsy model by inducing seizures through a single intraperitoneal injection of pilocarpine. The mice from the two substrains were each divided into 3 groups, and were injected intraperitoneally with 300 mg/kg, 330 mg/kg, or 360 mg/kg of pilocarpine, respectively. Motor seizure behaviors were observed and compared between the two substrains of C57BL/6 mice post pilocarpine injection, and the spontaneous recurrent seizures (SRS) were continuously monitored from the 7th day after injection. On the 28th day post-injection, the mice were euthanized and the histopathological changes in their hippocampi were examined. ResultsAfter pilocarpine administration, C57BL/6N mice displayed characteristic motor seizures followed by the onset of status epilepticus (SE). Conversely, C57BL/6J mice showed fewer instances of typical motor seizure behavior and the subsequent SE. Instead, they more often exhibited systemic tremors lasting several seconds to tens of seconds following limb twitching. This behavior is classified as “severe seizure (SS)” in current study. Following intraperitoneal injection of 330 mg/kg and 360 mg/kg pilocarpine, C57BL/6J mice displaying SS during the acute phase of seizure might exhibit SRS after a latency period. The percentage of spontaneous seizures observed in C57BL/6J mice post-modeling (70%) was comparable to that seen in C57BL/6N mice (75%) which developed SRS subsequent to SE. C57BL/6J mice displayed characteristic pathological alterations associated with temporal lobe epilepsy in the hippocampi after 28 d following pilocarpine injection, including increased mossy fiber sprouting and neuronal death. ConclusionsWhen inducing an epilepsy model via intraperitoneal pilocarpine injection in C57BL/6J mice, the behavioral criteria to predict the successful establishment of the model could be either the occurrence of SE or the manifestation of SS.

Abstract The stacking order and twist angle provide abundant opportunities for engineering band structures of two-dimensional materials, including the formation of moiré bands, flat bands, and topologically nontrivial bands. The inversion symmetry breaking in rhombohedral-stacked transitional metal dichalcogenides endows them with an interfacial ferroelectricity associated with an out-of-plane electric polarization. By utilizing twist angle as a knob to construct rhombohedral-stacked transitional metal dichalcogenides, antiferroelectric domain networks with alternating out-of-plane polarization can be generated. Here, we demonstrate that such spatially periodic ferroelectric polarizations in parallel-stacked twisted WSe2 can imprint their moiré potential onto a remote bilayer graphene. This remote moiré potential gives rise to pronounced satellite resistance peaks besides the charge-neutrality point in graphene, which are tunable by the twist angle of WSe2. Our observations of ferroelectric hysteresis at finite displacement fields suggest the moiré is delivered by a long-range electrostatic potential. The constructed superlattices by moiré ferroelectricity represent a highly flexible approach, as they involve the separation of the moiré construction layer from the electronic transport layer. This remote moiré is identified as a weak potential and can coexist with conventional moiré. Our results offer a comprehensive strategy for engineering band structures and properties of two-dimensional materials by utilizing moiré ferroelectricity.

Abstract Background Trichinella spiralis (T. spiralis) is a parasitic helminth that causes a globally prevalent neglected zoonotic disease, and worms at different developmental stages (muscle larvae, adult worms, newborn larvae) induce immune attack at different infection sites, causing serious harm to host health. Several innate immune cells release extracellular traps (ETs) to entrap and kill most pathogens that invade the body. In response, some unicellular pathogens have evolved a strategy to escape capture by ETs through the secretion of nucleases, but few related studies have investigated multicellular helminths. Results In the present study, we observed that ETs from neutrophils capture adult worms of T. spiralis, while ETs from macrophages trap muscle larvae and newborn larvae, and ETs had a killing effect on parasites in vitro. To defend against this immune attack, T. spiralis secretes plancitoxin-1, a DNase II-like protein, to degrade ETs and escape capture, which is essential for the survival of T. spiralis in the host. Conclusions In summary, these findings demonstrate that T. spiralis escapes ET-mediated capture by secreting deoxyribonuclease as a potential conserved immune evasion mechanism, and plancitoxin-1 could be used as a potential vaccine candidate.

Abstract In zebrafish, brain lymphatic endothelial cells (BLECs) are essential for meningeal angiogenesis and cerebrovascular regeneration. Although epidermal growth factor-like domain 7 (Egfl7) has been reported to act as a pro-angiogenic factor, its roles in lymphangiogenesis remain unclear. Here, we show that Egfl7 is expressed in both blood and lymphatic endothelial cells. We generate an egfl7 cq180 mutant with a 13-bp-deletion in exon 3 leading to reduced expression of Egfl7. The egfl7 cq180 mutant zebrafish exhibit defective formation of BLEC bilateral loop-like structures, although trunk and facial lymphatic development remains unaffected. Moreover, while the egfl7 cq180 mutant displays normal BLEC lineage specification, the migration and proliferation of these cells are impaired. Additionally, we identify integrin αvβ3 as the receptor for Egfl7. αvβ3 is expressed in the CVP and sprouting BLECs, and blocking this integrin inhibits the formation of BLEC bilateral loop-like structures. Thus, this study identifies a role for Egfl7 in BLEC development that is mediated through the integrin αvβ3.

Abstract Conventional macrolide-lincosamide-streptogramin B-ketolide (MLSBK) antibiotics are unable to counter the growing challenge of antibiotic resistance that is conferred by the constitutive methylation of rRNA base A2058 or its G2058 mutation, while the presence of unmodified A2058 is crucial for high selectivity of traditional MLSBK in targeting pathogens over human cells. The absence of effective modes of action reinforces the prevailing belief that constitutively antibiotic-resistant Staphylococcus aureus remains impervious to existing macrolides including telithromycin. Here, we report the design and synthesis of a novel series of macrolides, featuring the strategic fusion of ketolide and quinolone moieties. Our effort led to the discovery of two potent compounds, MCX-219 and MCX-190, demonstrating enhanced antibacterial efficacy against a broad spectrum of formidable pathogens, including A2058-methylated Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and notably, the clinical Mycoplasma pneumoniae isolates harboring A2058G mutations which are implicated in the recent pneumonia outbreak in China. Mechanistic studies reveal that the modified quinolone moiety of MCX-190 establishes a distinctive secondary binding site within the nascent peptide exit tunnel. Structure-activity relationship analysis underscores the importance of this secondary binding, maintained by a sandwich-like π–π stacking interaction and a water–magnesium bridge, for effective engagement with A2058-methylated ribosomes rather than topoisomerases targeted by quinolone antibiotics. Our findings not only highlight MCX-219 and MCX-190 as promising candidates for next-generation MLSBK antibiotics to combat antibiotic resistance, but also pave the way for the future rational design of the class of MLSBK antibiotics, offering a strategic framework to overcome the challenges posed by escalating antibiotic resistance.

Abstract The estuarine plastisphere, a novel ecological habitat in the Anthropocene, has garnered global concerns. Recent geochemical evidence has pointed out its potential role in influencing nitrogen biogeochemistry. However, the biogeochemical significance of the plastisphere and its mechanisms regulating nitrogen cycling remain elusive. Using 15N- and 13C-labelling coupled with metagenomics and metatranscriptomics, here we unveil that the plastisphere likely acts as an underappreciated nitrifying niche in estuarine ecosystems, exhibiting a 0.9 ~ 12-fold higher activity of bacteria-mediated nitrification compared to surrounding seawater and other biofilms (stone, wood and glass biofilms). The shift of active nitrifiers from O2-sensitive nitrifiers in the seawater to nitrifiers with versatile metabolisms in the plastisphere, combined with the potential interspecific cooperation of nitrifying substrate exchange observed among the plastisphere nitrifiers, collectively results in the unique nitrifying niche. Our findings highlight the plastisphere as an emerging nitrifying niche in estuarine environment, and deepen the mechanistic understanding of its contribution to marine biogeochemistry.

In the era of knowledge economy, social development has higher requirements for artistic talents’ quality. The teaching mode of music and dance in colleges and universities needs to be changed urgently. This study introduced deep learning theory and designed a SPOC teaching mode for music and dance in universities to improve the quality of music and dance teaching. Firstly, the K-means clustering algorithm was used to extract the features of online learning behavior. Radial basis function neural network was used to predict students’ performance to improve teachers’ mastery of students’ online learning behavior. Subsequently, the teaching quality evaluation system was constructed using hierarchical analysis. Finally, the effectiveness of the teaching model was tested. The results showed that under this teaching model, students’ overall literacy score reached a maximum of 11.5, and their average score in music and dance reached a maximum of 94, an increase of 11 points compared to the SPOC teaching mode. This indicates that the teaching mode gives full play to the advantages of SPOC teaching, enhances students’ enthusiasm and initiative in learning, and improves their professionalism and comprehensive quality.

The protective effect and underlying mechanism of melatonin (MT) treatment against Rhizopus stolonifer in postharvest peach fruit (Prunus persica (L.) Batsch cv ‘Xiahui 8’) were studied. Freshly harvested peaches were inoculated with R. stolonifer following pretreatment with different concentrations of MT (0, 0.05, 0.10, 0.50 and 1.00 mmol/L) and then stored at 20 ℃ for up to 60 h. Disease development was measured to determine the most effective MT concentration. Subsequently, the effects of MT treatment on quality parameters, total phenol and lignin contents, disease resistance-related enzyme activity and gene expression in peaches during postharvest storage, and the in vitro growth of R. stolonifer were investigated. The results showed that 0.50 mmol/L MT treatment could most significantly reduce the occurrence of Rhizopus rot and maintain postharvest fruit quality. Furthermore, compared with either of them alone, R. stolonifer inoculation after MT treatment exhibited stronger disease resistance response, resulting in a marked increase in the activities of chitinase (CHI), β-1,3-glucanase (GLU), phenylalanine ammonia lyase (PAL), cinnamate 4-hydroxylase (C4H), 4-coumarate-CoA ligase (4CL), peroxidase (POD) and polyphenol oxidase (PPO), the contents of total phenols and lignin, and the expression levels of defense-related genes such as those encoding CHI (PpCHI), GLU (PpGLU), PAL (PpPAL) and POD (PpPOD). Moreover, MT treatment had no significant inhibitory effect on the growth of R. stolonifer in vitro. Taken together, these results indicate that MT can initiate defense responses to pathogenic infection indirectly by priming defense, thereby reducing the occurrence of peach postharvest diseases.

Icebergs are big chunks of ice floating on the ocean surface, and melting of icebergs contributes for the major part of freshwater flux into ocean. Dynamic monitoring of the icebergs in Antarctica and accurate estimation of their volume are important for predicting the trend of freshwater budget of the Southern Ocean. The iceberg freeboard is a key parameter for measuring the thickness and volume of an iceberg and is defined as the difference between the elevation of iceberg surface and sea level. So far, freeboards of icebergs have been successfully extracted using InSAR DEM, and the laser and radar altimeter. However, uncertainties exist in these results mainly caused by missed detection of small icebergs due to the spatially sparse and temporally incomplete data coverage. In addition to the above techniques, optical images can also be used to extract the iceberg freeboard based on its geometric relationship with shadow length, which can effectively compensate for the above shortcomings. Although the feasibility has been preliminarily presented, the precision and extensive application of shadow-height method deserves further research, such as estimating the basal melting of icebergs. In this work, we tested an optical image-based freeboard extraction method over icebergs in Prydz Bay, Antarctica. A normalized shadow pixel index (NSPI) is designed to identify iceberg shadows with different shapes in HY-1C/D CZI and Sentinel-2 MSI optical images. The iceberg freeboard can be determined with an acceptable precision (2 m) in optical images compared with laser altimeter (i.e. ICESat-2) measurements. Moreover, basal melting of icebergs has been assessed according to the variation of freeboard using repeated optical observations. The results indicate that icebergs in the study area were with a mean freeboard of about 56 m in early December 2022, and experienced a decrease in freeboard of 1.9 m within two months, in correspondence with the Antarctic seasonal trend. The methodological framework, therefore, turns out to be a reliable complementary approach to studying the iceberg freeboard in polar regions.

Abstract Background Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by CGG repeat expansion of FMR1 gene. Both FXTAS and neuronal intranuclear inclusion disease (NIID) belong to polyglycine diseases and present similar clinical, radiological, and pathological features, making it difficult to distinguish these diseases. Reversible encephalitis-like attacks are often observed in NIID. It is unclear whether they are presented in FXTAS and can be used for differential diagnosis of NIID and FXTAS. Case presentation A 63-year-old Chinese male with late-onset gait disturbance, cognitive decline, and reversible attacks of fever, consciousness impairment, dizziness, vomiting, and urinary incontinence underwent neurological assessment and examinations, including laboratory tests, electroencephalogram test, imaging, skin biopsy, and genetic test. Brain MRI showed T2 hyperintensities in middle cerebellar peduncle and cerebrum, in addition to cerebellar atrophy and DWI hyperintensities along the corticomedullary junction. Lesions in the brainstem were observed. Skin biopsy showed p62-positive intranuclear inclusions. The possibilities of hypoglycemia, lactic acidosis, epileptic seizures, and cerebrovascular attacks were excluded. Genetic analysis revealed CGG repeat expansion in FMR1 gene, and the number of repeats was 111. The patient was finally diagnosed as FXTAS. He received supportive treatment as well as symptomatic treatment during hospitalization. His encephalitic symptoms were completely relieved within one week. Conclusions This is a detailed report of a case of FXTAS with reversible encephalitis-like episodes. This report provides new information for the possible and rare features of FXTAS, highlighting that encephalitis-like episodes are common in polyglycine diseases and unable to be used for differential diagnosis.

The emergence of myelinating oligodendrocytes represents a pivotal developmental milestone in vertebrates, given their capacity to ensheath axons and facilitate the swift conduction of action potentials. It is widely accepted that cortical oligodendrocyte progenitor cells (OPCs) arise from medial ganglionic eminence (MGE), lateral/caudal ganglionic eminence (LGE/CGE), and cortical radial glial cells (RGCs). Here, we used two different fate mapping strategies to challenge the established notion that the LGE generates cortical OPCs. Furthermore, we used a Cre/loxP-dependent exclusion strategy to reveal that the LGE/CGE does not give rise to cortical OPCs. Additionally, we showed that specifically eliminating MGE-derived OPCs leads to a significant reduction of cortical OPCs. Together, our findings indicate that the LGE does not generate cortical OPCs, contrary to previous beliefs. These findings provide a new view of the developmental origins of cortical OPCs and a valuable foundation for future research on both normal development and oligodendrocyte-related disease.

The recent years have witnessed the rapid advancement of clustered regularly interspaced short palindromic repeats/associated protein 9 (CRISPR/Cas9)-mediated gene editing in cancer therapy. The success of cancer gene therapy relies heavily on the development of safe and effective delivery vectors. We focus on organic nanocarriers because of their flexible customizability, which permits them to accomplish excellent delivery efficiency and performance. In this review, the pharmacokinetic behavior of CRISPR/Cas9 nanocarriers serves as a guide to outline the strategies for improving the bioavailability of nanocarriers through physical, chemical, and biological means. Furthermore, the potential of organic nanocarriers for simultaneous delivery of therapeutic agents and gene editing tools is highlighted. Finally, we discuss future directions for the development of cancer therapeutic nanosystems, paving the way for the construction of effective CRISPR/Cas9 delivery systems.

The ubiquity of refractory organic matter in aquatic environments necessitates innovative removal strategies. Sulfate radical-based advanced oxidation has emerged as an attractive solution, offering high selectivity, enduring efficacy, and anti-interference ability. Among many technologies, sulfite activation, leveraging its cost-effectiveness and lower toxicity compared to conventional persulfates, stands out. Yet, the activation process often relies on transition metals, suffering from low atom utilization. Here we introduce a series of single-atom catalysts (SACs) employing transition metals on g-C3N4 substrates, effectively activating sulfite for acetaminophen degradation. We highlight the superior performance of Fe/CN, which demonstrates a degradation rate constant significantly surpassing those of Ni/CN and Cu/CN. Our investigation into the electronic and spin polarization characteristics of these catalysts reveals their critical role in catalytic efficiency, with oxysulfur radical-mediated reactions predominating. Notably, under visible light, the catalytic activity is enhanced, attributed to an increased generation of oxysulfur radicals and a strengthened electron donation-back donation dynamic. The proximity of Fe/CN's d-band center to the Fermi level, alongside its high spin polarization, is shown to improve sulfite adsorption and reduce the HOMO-LUMO gap, thereby accelerating photo-assisted sulfite activation. This work advances the understanding of SACs in environmental applications and lays the groundwork for future water treatment technologies.

Abstract Flat-band systems with strongly correlated electrons can exhibit a variety of phenomena, such as correlated insulating and topological states, unconventional superconductivity, and ferromagnetism. Rhombohedral multilayer graphene has recently emerged as a promising platform for investigating exotic quantum states due to its hosting of topologically protected surface flat bands at low energy, which have a layer-dependent energy dispersion. However, the complex relationship between the surface flat bands and the highly dispersive high-energy bands makes it difficult to study correlated surface states. In this study, we introduce moiré superlattices as a method to isolate the surface flat bands of rhombohedral multilayer graphene. The observed pronounced screening effects in the moiré potential-modulated rhombohedral multilayer graphene indicate that the two surface states are electronically decoupled. The flat bands that are isolated promote correlated surface states in areas that are distant from the charge neutrality points. Notably, we observe tunable layer-polarized ferromagnetism, which is evidenced by a hysteretic anomalous Hall effect. This is achieved by polarizing the surface states with finite displacement fields.

Abstract Trichinella spiralis (T. spiralis) is a zoonotic parasitic nematode with a unique life cycle, as all developmental stages are contained within a single host. Excretory-secretory (ES) proteins are the main targets of the interactions between T. spiralis and the host at different stages of development and are essential for parasite survival. However, the ES protein profiles of T. spiralis at different developmental stages have not been characterized. The proteomes of ES proteins from different developmental stages, namely, muscle larvae (ML), intestinal infective larvae (IIL), preadult (PA) 6 h, PA 30 h, adult (Ad) 3 days post-infection (dpi) and Ad 6 dpi, were characterized via label-free mass spectrometry analysis in combination with bioinformatics. A total of 1217 proteins were identified from 9341 unique peptides in all developmental stages, 590 of which were quantified and differentially expressed. GO classification and KEGG pathway analysis revealed that these proteins were important for the growth of the larvae and involved in energy metabolism. Moreover, the heat shock cognate 71 kDa protein was the centre of protein interactions at different developmental stages. The results of this study provide comprehensive proteomic data on ES proteins and reveal that these ES proteins were differentially expressed at different developmental stages. Differential proteins are associated with parasite survival and the host immune response and may be potential early diagnostic antigen or antiparasitic vaccine candidates.

Passive wireless surface acoustic wave (SAW) sensors are very useful for on-site monitoring of the working status of machines in complex environments, such as high-temperature rotating objects. For rotating parts, it is difficult to realize real-time and continuous monitoring because of the unstable sensing signal caused by the continuous change of the relative position of the rotating part to the sensor and shielding of the signal. In our SAW sensing system, we propose a loop antenna integrated with the rotating part to obtain a stable sensing signal owing to its omnidirectional radiation pattern. Methodologies for determining the antenna dimension, system operating frequency, and procedures for designing a SAW sensor tag are discussed in this paper. By fully utilizing the influence of metal rotor on antenna performance, the antenna needs no impedance matching elements while it provides sufficient gain, which equips the antenna with nearly zero temperature drift at a wide temperature-sensing range. Experimental verification results show that this sensing system can greatly improve the stability of the sensing signal significantly and can achieve a temperature sensing accuracy of ~1 °C at different rotational speeds, demonstrated by the feasibility of the loop antenna for monitoring the working status of rotating metal parts.

Passiflora edulis, also known as passion fruit, is celebrated for its rich nutritional content, distinctive flavour, and significant medicinal benefits. At present, viral diseases pose a major challenge to the passion fruit industry, affecting both the production and quality of the fruit. These diseases impede the sustainable and healthy growth of the passion fruit sector. In recent years, with the expansion of P. edulis cultivation areas, virus mutations, and advances in virus detection technology, an increasing number of virus species infecting P. edulis have been discovered. To date, more than 40 different virus species have been identified; however, there are different strains within the same virus. This poses a challenge for the control and prevention of P. edulis virus disease. Therefore, this review discusses the different types of viruses and their characteristics, modes of transmission, and effects on the growth of the passion fruit plant, as well as the mechanisms of virus generation and preventive measures, with the hope that these discussions will provide a comprehensive understanding of and countermeasures for viruses in passion fruit.

Abstract Aims To establish a comprehensive understanding of the roles of midwives and the challenges they encounter in the prevention, diagnosis and management of postpartum haemorrhage (PPH) following normal vaginal delivery. Design We conducted a scoping review following the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis for Scoping Reviews (PRISMA‐ScR) recommendations. Methods We considered studies related to the roles of midwives and the challenges they encounter in the prevention, diagnosis and management of PPH during vaginal delivery. We excluded guidelines, consensuses, abstracts of meetings and non‐English language studies. Databases, including the Cochrane Library, PubMed, Web of Science, Ovid, Medline, Embase, JBI EBP and BIOSIS Previews, were searched on January 1, 2023, with no time limitations. Results We included 28 publications. Midwives play important roles in the prevention, diagnosis and management of postpartum haemorrhage during vaginal delivery. In the prevention of PPH, midwives' roles include identifying and managing high‐risk factors, managing labour and implementing skin‐to‐skin contact. In the diagnosis of PPH, midwives' roles include early recognition and blood loss estimation. In the management of PPH, midwives are involved in mobilizing other professional team members, emergency management, investigating causes, enhancing uterine contractions, the repair of perineal tears, arranging transfers and preparation for surgical intervention. However, midwives face substantial challenges, including insufficient knowledge and skills, poor teamwork skills, insufficient resources and the need to deal with their negative emotions. Midwives must improve their knowledge, skills and teamwork abilities. Health care system managers and the government should give full support to midwives. Future research should focus on developing clinical practice guidelines for midwives for preventing, diagnosing and managing postpartum haemorrhage.

Stenotrophomonas strains, which are often described as plant growth promoting (PGP) bacteria, are ubiquitous in many environments. A total of 213 genomes of strains of Stenotrophomonas were analyzed using comparative genomics to better understand the ecological roles of these bacteria in the environment. The pan-genome of the 213 strains of Stenotrophomonas consists of 27,186 gene families, including 710 core gene families, 11,039 unique genes and 15,437 accessory genes. Nearly all strains of Stenotrophomonas harbor the genes for GH3-family cellulose degradation and GH2- and GH31-family hemicellulose hydrolase, as well as intact glycolysis and tricarboxylic acid cycle pathways. These abilities suggest that the strains of this genus can easily obtain carbon and energy from the environment. The Stenotrophomonas strains can respond to oxidative stress by synthesizing catalase, superoxide dismutase, methionine sulfoxide reductase, and disulfide isomerase, as well as managing their osmotic balance by accumulating potassium and synthesizing compatible solutes, such as betaine, trehalose, glutamate, and proline. Each Stenotrophomonas strain also contains many genes for resistance to antibiotics and heavy metals. These genes that mediate stress tolerance increase the ability of Stenotrophomonas strains to survive in extreme environments. In addition, many functional genes related to attachment and plant colonization, growth promotion and biocontrol were identified. In detail, the genes associated with flagellar assembly, motility, chemotaxis and biofilm formation enable the strains of Stenotrophomonas to effectively colonize host plants. The presence of genes for phosphate-solubilization and siderophore production and the polyamine, indole-3-acetic acid, and cytokinin biosynthetic pathways confer the ability to promote plant growth. These strains can produce antimicrobial compounds, chitinases, lipases and proteases. Each Stenotrophomonas genome contained 1–9 prophages and 17–60 genomic islands, and the genes related to antibiotic and heavy metal resistance and the biosynthesis of polyamines, indole-3-acetic acid, and cytokinin may be acquired by horizontal gene transfer. This study demonstrates that strains of Stenotrophomonas are highly adaptable for different environments and have strong potential for use as plant growth-promoting bacteria.

Summary: Background: Hospitals in China are classified into tiers (1, 2 or 3), with the largest (tier 3) having more equipment and specialist staff. Differential health insurance cost-sharing by hospital tier (lower deductibles and higher reimbursement rates in lower tiers) was introduced to reduce overcrowding in higher tier hospitals, promote use of lower tier hospitals, and limit escalating healthcare costs. However, little is known about the effects of differential cost-sharing in health insurance schemes on choice of hospital tiers. Methods: In a 9-year follow-up of a prospective study of 0.5 M adults from 10 areas in China, we examined the associations between differential health insurance cost-sharing and choice of hospital tiers for patients with a first hospitalisation for stroke or ischaemic heart disease (IHD) in 2009–2017. Analyses were performed separately in urban areas (stroke: n = 20,302; IHD: n = 19,283) and rural areas (stroke: n = 21,130; IHD: n = 17,890), using conditional logit models and adjusting for individual socioeconomic and health characteristics. Findings: About 64–68% of stroke and IHD cases in urban areas and 27–29% in rural areas chose tier 3 hospitals. In urban areas, higher reimbursement rates in each tier and lower tier 3 deductibles were associated with a greater likelihood of choosing their respective hospital tiers. In rural areas, the effects of cost-sharing were modest, suggesting a greater contribution of other factors. Higher socioeconomic status and greater disease severity were associated with a greater likelihood of seeking care in higher tier hospitals in urban and rural areas. Interpretation: Patient choice of hospital tiers for treatment of stroke and IHD in China was influenced by differential cost-sharing in urban areas, but not in rural areas. Further strategies are required to incentivise appropriate health seeking behaviour and promote more efficient hospital use. Funding: Wellcome Trust, Medical Research Council, British Heart Foundation, Cancer Research UK, Kadoorie Charitable Foundation, China Ministry of Science and Technology, and National Natural Science Foundation of China.

Chitosan (CTS) as an environment-friendly biological macromolecule was applied to investigate its effect in improving the property of zirconium-based Cr(III) conversion coating on Zn-55Al-1.6Si coated steel sheet (Zn55Al). High-resolution transmission electron microscope gave the key evidence that CTS can effectively wrap the main film-forming substances and participate in the construction of Zr@CTS-TCC. A comparative analysis of electrochemical measurements showed that the addition of 0.2 g·L–1 CTS can improve the corrosion resistance of Zr@CTS-TCC and decrease the surface density of micro defects. Surface spectroscopy characterization provided a theoretical explanation for the role of CTS as an electron supplier in reduction of Cr(VI). Results demonstrate the potential of CTS as an environmentally friendly and effective cross-linking additive, which provides an alternative approach in developing next generation of trivalent chromium or chromium-free passivator for nonferrous alloy and their coatings.

Background: Timely diagnosis and treatment of silent cerebrovascular disease (SCD) are critical for future cerebrovascular disease prevention, whereas asymptomatic specificity of SCD can lead to a lack of reasonable healthcare utilization. In China, access barriers to care for SCD patients is rarely studied. This study aimed to estimate the access barriers to care for SCD patients in rural China and explored associated factors. Methods: We constructed a demand-side questionnaire using the six-dimensional model of access barriers to care, and collected survey data in Guizhou province, China. Data from SCD patients were collected including demographics, health status, and self-perceived access barriers to care. Linear regression was used to estimate the association between access barriers to care and self-reported health status. Results: A total of 162 SCD patients were included in the analysis. The questionnaire’s measures are adoptable with reliability (Cronbach’s α = 0.86) and validity (KMO = 0.774, Bartlett’s test p-value

To investigate the effect of ultrasonic cleaning treatment on the quality of pork, the water-holding capacity, nutrients, shear force, and flavor compounds of raw pork washed by ultrasonicfor 0–­30 minutes were measured, and the data obtained were evaluated by principal component analysis (PCA). The results showed that the total volatile basic nitrogen (TVB-N) and thiobarbituric acid reactive substance (TBARS) values of pork treated by ultrasonic for 30 minutes were the lowest, (8.45 mg/100 g and 0.36 mg/kg, respectively), and the shear force significantly decreased to 33.92 N. The pork treated by ultrasonic for 20 minutes had the lowest pressing loss (17.99%). Ultrasonic cleaning could cause slight loss of trace metal elements, but did not affect the nutritional composition, cooking loss, or pH of pork. Compared with the control group, the relative contents of aldehydes and alcohols in the ultrasonic treated pork significantly decreased, the types and relative contents of hydrocarbon acid ketone esters significantly increased, and the overall flavor was improved. Linear discriminant analysis (LDA) of electronic nose data showed that there was a correlation between the flavor improvement and the duration of ultrasonic cleaning treatment. PCA results showed that the quality of pork was significantly different before and after ultrasonic cleaning. In summary, appropriate ultrasonic cleaning improved the water-holding capacity and tenderness of pork, and significantly improved its storage quality and flavor, but had little impact on its nutrients.

Abstract Upon encountering exogenous pathogens, polymorphonucleocytes (PMNs) engage in various processes to destroy them, including releasing neutrophil extracellular traps (NETs) that trap pathogens and induce phagocytosis and cytokine production. Parasites have unique strategies with which to evade the host's immune response. However, the strategy employed by Trichinella spiralis in response to the reaction of PMNs has yet to be elucidated. This study explored the effect of excretory/secretory products (ESP) on three major functions: NETs, phagocytosis, and cytokine production. Specifically, PMNs were pre-treated with the ESP of 3-day-old adults and then stimulated with phorbol 12-myristate 13-acetate (PMA). We found that in PMNs pretreated with ESP, PMA-induced NET generation was suppressed by ESP. ROS production is a hallmark of PMA-induced NETosis. The LDH assay results showed that ESP inhibits NETs by suppressing ROS rather than promoting PMN death. Furthermore, ESP enhanced Escherichia coli engulfment by PMNs, improving overall phagocytic function. Finally, cytokine analysis revealed an increase in pro-inflammatory cytokine IL-1β, and other cytokines (IL-10, TNF-α), while IL-4 displayed a significant reduction. In conclusion, this study has unraveled T. spiralis' evasion and regulation mechanisms against innate immune cells, providing insights into parasite strategies to manipulate host immunity, potentially informing new treatments for NET-related autoimmune diseases. Graphical Abstract

Abstract Increasing evidences demonstrate that chlorogenic acid (CGA), a polyphenol with multiple effects such as anti-inflammatory and anti-oxidation, protects against myocardial ischemia–reperfusion injury (MIRI) in vitro and in vivo. But its detailed cardiac protection mechanism is still unclear. The MIRI mice model was established by ligating the left anterior descending branch (LAD) of the left coronary artery in C57BL/6 mice. Sixty C57BL/6 mice were randomly divided into four groups. CGA group and CGA + I/R group (each group n = 15) were gavaged with 30 mg/kg/day CGA for 4 weeks. Sham group and I/R group mice (each group n = 15) were administered equal volumes of saline. In vitro MIRI model was constructed by hypoxia and reoxygenation of HL-1 cardiomyocytes. The results showed that CGA pretreatment reduced myocardial infarction size and cTnT contents in serum, simultaneously reduced the levels of Lnc Neat1 expression and attenuated NLRP3 inflammasome-mediated pyroptosis in myocardial tissue. Consistent with in vivo results, the pretreatment of 0.2 μM and 2 μM CGA for 12 h in HL-1 cardiomyocytes depressed hypoxia/reoxygenation-induced Lnc Neat1 expression, NLRP3 inflammasome activation and pyroptosis. Lnc Neat1 shRNA transfection mediated by lentivirus in HL-1 cardiomyocytes significantly reduced activation of NLRP3 inflammasome and pyroptosis. Our findings suggest that CGA protects against MIRI by depressing Lnc Neat1 expression and NLRP3 inflammasome-mediated pyrotosis. Inhibiting the levels of Lnc Neat1 expression may be a therapeutic strategy for MIRI.

The release of greenhouse gases (GHGs) is a major contributor to global warming, endangering both human and nonhuman well-being, environmental integrity, economic development, and the planet’s long-term survival. This study delves into the interplay between crop production, livestock production, fertilizer utilization, and agricultural land usage on CO2 emissions in four Asian economies: China, India, Pakistan, and Bangladesh. Employing panel data analysis techniques, the research uncovers the significant impacts of various agricultural activities on environmental degradation. The findings derived from the panel autoregressive distributed lag (PARDL) estimation reveal that crop production in these emerging economies contributes to CO2 emissions, as evidenced by the positive coefficients and statistically significant results. Similarly, livestock production and agricultural land used for crop production exhibit a substantial impact on CO2 emissions, further highlighting their role in environmental degradation. While fertilizer usage also displays a positive coefficient, its impact on CO2 emissions is not statistically significant. The results of our study highlight the critical importance of addressing the environmental impacts of agricultural practices, particularly in emerging economies. Crop and livestock production, along with the expansion of agricultural land, significantly contribute to CO2 emissions, which underscores the urgent need for sustainable agricultural practices. These findings suggest that policymakers should prioritize the development and implementation of strategies that mitigate the environmental impacts of agriculture. This could include promoting sustainable land management practices, investing in technology that reduces emissions from crop and livestock production, and encouraging the adoption of eco-friendly fertilizers.

Abstract Background Circulating tumor cells (CTCs), an indispensable liquid biopsy classifier, can provide extra information for the diagnosis and prognosis of hepatocellular carcinoma (HCC). Methods We systematically analyzed the peripheral blood of preoperative HCC patients (n = 270) for CTC number, Ki67 index reflecting the proliferative CTC percentage (PCP), and CTC clusters correlated with the characteristics of malignant HCC tumors. Results Driver gene mutations were found with high levels of consistency between CTCs and primary tumors (n = 73). CTC number and PCP were associated with tumor size, microvascular invasion (MVI), presence or absence of multiple tumors, and thrombosis significantly. CTC number and PCP robustly separated patients with and without relapse, with a sensitivity of 88.89%/81.48% and a specificity of 72.73%/94.81% in the training set (n = 104) and corresponding values of 80.00%/86.67% and 78.38%/89.19% in the validation set (n = 52), showing a better performance than that associated with the alpha‐fetoprotein (AFP) level. CTC number, PCP, CTC clusters, and MVI were independent significant risk factors for HCC recurrence (P = 0.0375, P

Summary: Trichinella spiralis infection is associated with the formation of cysts within host skeletal muscle cells, thereby enabling immune evasion and subsequent growth and development; however, the pathogenic factors involved in this process and their mechanisms remain elusive. Here, we found that Ts-RNF secreted by T. spiralis is required for its growth and development in host cells. Further study revealed that Ts-RNF functions as an E3 ubiquitin ligase that targets the UBA domain of SQSTM1/p62 by forming K63-type ubiquitin chains. This modification interferes with autophagic flux, leading to impaired mitochondrial clearance and abnormal myotube differentiation and fusion. Our results established that T. spiralis increases its escape by interfering with host autophagy via the secretion of an E3 ubiquitin ligase.

ObjectiveThis study aimed to evaluate perioperative antibiotic use for induced abortion and its association with lower genital tract infections (LGTI) two weeks post-surgery in China.MethodsWe conducted a prospective cohort study of women seeking induced abortion. We interviewed participants on the day of surgery and two weeks after, and evaluated preoperative tests, gynecological exams, perioperative antibiotic usage, postoperative vaginal microbiota, and LGTI diagnosis. Multivariate logistic regression was used to assess the association between the perioperative antibiotic use and LGTI risk.ResultsWe recruited 8,190 women undergoing induced abortion at 27 participating hospitals. Of these, 95% had gynecological exams, but over 80% lacked tests for vaginal microbiota, chlamydia, and gonorrhea. Approximately 20% of those examined had increased vaginal discharge and abnormal vaginal cleanliness. The positive rates for gram-positive rods, fungi, and trichomonas were 38.6, 2.4, and 0.3%, respectively. More than three-quarters (78.5%) of participants received antibiotics, mainly second-gen cephalosporins (36.8%) and nitroimidazoles (12.3%). LGTI rates two weeks post-surgery were 2.7% for antibiotic recipients and 3.1% for non-recipients, with no statistically significant difference (p > 0.05). Logistic regression showed no association between perioperative antibiotic use and LGTI risk (OR = 1.01, 95% CI 0.59–1.74). However, this risk increased with abnormal preoperative discharge tests (OR = 1.39, 95% CI 1.04–1.86).ConclusionMost Chinese women undergoing induced abortion used perioperative antibiotics, but this did not significantly reduce LGTI risk. Instead, this risk was related to abnormal preoperative discharge tests. Standardization of perioperative antibiotic use for induced abortion is recommended, and prophylactic treatment in Chinese abortion services warrants further investigation.

In recent years, the domestic live pig price has risen and fallen rapidly and fluctuated frequently, which has greatly impacted the live pig industry. The level of price volatility in the pig market has served as a significant indication of the progress of the agricultural sector. Identifying the dominant factors affecting the fluctuation of pig prices has become more important. Based on the monthly data of the pig industry from February 2009 to December 2022, this paper constructs an index system of influencing factors of pig price from four aspects: uncertain impact, supply factors, demand factors, and macro-environment factors. By using the transfer model of the Markov regime (MS-VAR), we obtained the probability plot of zone transition for pig price volatility, the impulse response effect diagram of factors affecting pig price, and the cumulated impulse response effect diagram of factors affecting pig price, and analyze the reasons for the ups and downs of pig price according to the above results. The findings indicate prominent features of zone transition in the price fluctuation of China's pig market. From 2017 to 2022, the domestic pig price frequently switches between rising and falling zones, and the "falling pig price stage" and "rising pig price stage" in the non-stationary state last for a relatively short and discontinuous period. There is little probability that the price of live pigs will directly change from rising to falling, and there will be a smooth buffer stage in the price rise and fall process. Among the factors that affect the fluctuation of live pig prices, the dominant factor of frequent and large fluctuation of pig prices is the pig epidemic situation in external factors. Among the internal influencing factors, the changes in farming costs have the greatest significant influence on the fluctuation of pig prices. These results provide a decision-making reference for legislators to carry out epidemic risk prevention and control better, stabilize the market pig price, and provide empirical evidence for market participants to accurately avoid price risks through multiple channels and ways and ensure stable profitability.

Diseases related to cartilage abnormalities pose a serious threat to human health. Normal cartilage contains only one type of cell, chondrocytes. This study aims to investigate the impact of inositol polyphosphate-5-phosphatase E (INPP5E) on chondrocytes and its underlying mechanisms. Following transfection of small interfering RNA INPP5E into chondrocytes, real-time quantitative PCR (RT-PCR) and western blot (WB) assays were conducted to detect the expression of intraflagellar transport 88 (IFT88), Bcl-2-interacting protein 1 (Beclin1), microtubule-associated protein 1 light chain 3 alpha (MAP1LC3A), microtubule-associated protein 1 light chain 3 beta (MAP1LC3B), phosphoinositide 3-kinase (PI3K), protein kinase B (Akt), mammalian target of rapamycin (mTOR), collagen type II alpha 1 chain (COL2A1), and cyclin D1 (CCND1). Furthermore, immunofluorescence was used to detect the expression of acetylated α-tubulin and microtubule-associated protein 1 light chain 3 (LC3) II. RT-PCR, WB, and the dual luciferase assay demonstrated the regulation between SNHG12, hsa-miR-181a-5p, hsa-miR-138-5p, and INPP5E. Functional recovery experiments were used to observe the regulation of these factors on IFT88, Beclin1, LC3 I, LC3 II, p-PI3K, p-Akt, p-mTOR, collagen II, and cyclin D1 in chondrocytes. The results showed that silencing INPP5E inhibited the mRNA and protein expressions of the investigated factors in chondrocytes. SNHG12 promoted INPP5E expression by inhibiting hsa-miR-181a-5p or hsa-miR-138-5p, which resulted in regulation of the expression of various factors via the hsa-miR-181a-5p/hsa-miR-138-5p-INPP5E axis in chondrocytes. These findings provide a theoretical basis for the treatment of patients with cartilage-related abnormalities.

Background: Jujuboside B (JuB) is the main bioactive saponin component of Chinese anti-insomnia herbal medicine Ziziphi Spinosae Semen, which has been reported to possess varied pharmacological functions. Even though it has been traditionally used to treat inflammation- and toxicity-related diseases, the effects of JuB on acetaminophen (APAP) overdose-induced hepatotoxicity have not been determined yet. Methods: C57BL/6 J mice were pre-treated with JuB (20 or 40 mg/kg) for seven days before APAP (400 mg/kg) injection. After 24 h of APAP treatment, serum, and liver tissues were collected to evaluate the therapeutic effects. To investigate whether the Nrf2-STING signaling pathway is involved in the protective effects of JuB against APAP-induced hepatotoxicity, the mice received the DMXAA (the specific STING agonist) or ML385 (the specific Nrf2 inhibitor) during the administration of JuB, and Hematoxylin-eosin staining, Real-time PCR, immunohistochemical, and western blot were performed. Results: JuB pretreatment reversed APAP-induced CYP2E1 accumulations and alleviated APAP-induced acute liver injury. Furthermore, JuB treatment significantly inhibited oxidative stress and the pro-inflammatory cytokines, as well as alleviated hepatocyte apoptosis induced by APAP. Besides, our result also demonstrated that JuB treatment upregulated the levels of total Nrf2, facilitated its nuclear translocation, upregulated the expression of HO-1 and NQO-1, and inhibited the APAP-induced STING pathway activation. Finally, we verified that the beneficial effects of JuB were weakened by DMXAA and ML385. Conclusion: Our study suggested that JuB could ameliorate APAP-induced hepatic damage and verified a previously unrecognized mechanism by which JuB prevented APAP-induced hepatotoxicity through adjusting the Nrf2-STING pathway.

Abstract Whole exome sequencing (WES) can also detect some intronic variants, which may affect splicing and gene expression, but how to use these intronic variants, and the characteristics about them has not been reported. This study aims to reveal the characteristics of intronic variant in WES data, to further improve the clinical diagnostic value of WES. A total of 269 WES data was analyzed, 688,778 raw variants were called, among these 367,469 intronic variants were in intronic regions flanking exons which was upstream/downstream region of the exon (default is 200 bps). Contrary to expectation, the number of intronic variants with quality control (QC) passed was the lowest at the +2 and −2 positions but not at the +1 and −1 positions. The plausible explanation was that the former had the worst effect on trans-splicing, whereas the latter did not completely abolish splicing. And surprisingly, the number of intronic variants that passed QC was the highest at the +9 and −9 positions, indicating a potential splicing site boundary. The proportion of variants which could not pass QC filtering (false variants) in the intronic regions flanking exons generally accord with “S”-shaped curve. At +5 and −5 positions, the number of variants predicted damaging by software was most. This was also the position at which many pathogenic variants had been reported in recent years. Our study revealed the characteristics of intronic variant in WES data for the first time, we found the +9 and −9 positions might be a potentially splicing sites boundary and +5 and −5 positions were potentially important sites affecting splicing or gene expression, the +2 and −2 positions seem more important splicing site than +1 and −1 positions, and we found variants in intronic regions flanking exons over ± 50 bps may be unreliable. This result can help researchers find more useful variants and demonstrate that WES data is valuable for intronic variants analysis.

Abstract Background Fish-borne zoonotic clonorchiasis, caused by Clonorchis sinensis, is an emerging public health problem in several countries with more than 15 million people infected globally. However, a lack of accurate point-of-care (POC) diagnostic tests in resource-limited areas is still a critical barrier to effective treatment and control of clonorchiasis. The development of the recombinase polymerase amplification(RPA) assay, a POC diagnostic test based on the amplification of pathogen DNA, has provided a new, simple and inexpensive tool for disease detection with high sensitivity and specificity. Methods A novel RPA method was developed based on specific primers and probes, and combined with the dipstick, to allow for the rapid and intuitive detection of C. sinensis through the amplification of the mitochondrial cytochrome c oxidase subunit 1 (COX1) gene. The lower limit of detection for the combined RPA/lateral flow dipstick (RPA-LFD) assay was evaluated using dilutions of the target DNA sequence. Cross-reactivity was evaluated using genomic DNA from 10 additional control parasites. Forty human clinical stool samples were tested to verify its performance. Results The evaluated primers designed from the C. sinensis COX1 region can be used to detect adult worms, metacercariae, and eggs at 39 °C within 20 min, and the results can be visually observed using the LFD. The detection limit of pathogen genomic DNA was as low as 10 fg, and the number of metacercaria(e) in fish and egg(s) in faeces were both as low as one. This improved the sensitivity of low-infection detection tremendously. The test is species-specific, and no other related control parasites were detected. In human stool samples with eggs per gram (EPG) > 50, the RPA-LFD assay was performed consistent with conventional Kato-Katz (KK) and PCR methods. Conclusion The established RPA-LFD assay provides a powerful tool for the diagnosis and epidemiological survey of C. sinensis from human and animal samples, and has important implications for the effective control of clonorchiasis. Graphical Abstract

To verify the accuracy of AIWS, we weighed 106 pen growing-finishing pigs’ weights using both the manual and AIWS methods, respectively. Accuracy was evaluated based on the values of MAE, MAPE, and RMSE. In the growth experiment, manual weighing was conducted every two weeks and AIWS predicted weight data was recorded daily, followed by fitting the growth curves. The results showed that MAE, MAPE, and RMSE values for 60 to 120 kg pigs were 3.48 kg, 3.71%, and 4.43 kg, respectively. The correlation coefficient r between the AIWS and manual method was 0.9410, and R2 was 0.8854. The two were extremely significant correlations (p < 0.001). In growth curve fitting, the AIWS method has lower AIC and BIC values than the manual method. The Logistic model by AIWS was the best-fit model. The age and body weight at the inflection point of the best-fit model were 164.46 d and 93.45 kg, respectively. The maximum growth rate was 831.66 g/d. In summary, AIWS can accurately predict pigs’ body weights in actual production and has a better fitting effect on the growth curves of growing-finishing pigs. This study suggested that it was feasible for AIWS to replace manual weighing to measure the weight of 50 to 120 kg live pigs in large-scale farming.

Penicillium species are ubiquitous in the environment and are of substantial importance, especially in industrial and medical aspects. During our investigation of the biodiversity of Penicillium, three new species were discovered in soil samples collected from East and Northeast China. They were determined as new to science based on morphological comparisons and phylogenetic analyses, and were found to belong to the subgenus Penicillium section Robsamsonia and subgenus Aspergilloides sections Aspergilloides and Citrina. Descriptions and illustrations of these species are provided, and their geographic distributions are also discussed.

In response to the numerous challenges faced by traditional human pose recognition methods in practical applications, such as dense targets, severe edge occlusion, limited application scenarios, complex backgrounds, and poor recognition accuracy when targets are occluded, this paper proposes a YOLO-Pose algorithm for human pose estimation. The specific improvements are divided into four parts. Firstly, in the Backbone section of the YOLO-Pose model, lightweight GhostNet modules are introduced to reduce the model’s parameter count and computational requirements, making it suitable for deployment on unmanned aerial vehicles (UAVs). Secondly, the ACmix attention mechanism is integrated into the Neck section to improve detection speed during object judgment and localization. Furthermore, in the Head section, key points are optimized using coordinate attention mechanisms, significantly enhancing key point localization accuracy. Lastly, the paper improves the loss function and confidence function to enhance the model’s robustness. Experimental results demonstrate that the improved model achieves a 95.58% improvement in mAP50 and a 69.54% improvement in mAP50-95 compared to the original model, with a reduction of 14.6 M parameters. The model achieves a detection speed of 19.9 ms per image, optimized by 30% and 39.5% compared to the original model. Comparisons with other algorithms such as Faster R-CNN, SSD, YOLOv4, and YOLOv7 demonstrate varying degrees of performance improvement.

BackgroundIn 2016, the Chinese government introduced an integration reform of the health insurance system with the aim to enhance equity in healthcare coverage and reduce disparities between urban and rural sectors. The gradual introduction of the policy integrating urban and rural medical insurance in pilot cities provides an opportunity to evaluate the policy impact. This study attempts to assess the policy impact of urban–rural health insurance integration on the chronic poverty of rural residents and to analyze the mechanisms.MethodBased on the four waves of data from the China Health and Retirement Longitudinal Study (CHARLS) conducted in 2011, 2013, 2015, and 2018, we employed a staggered difference-in-differences (staggered DID) model to assess the impact of integrating urban–rural health insurance on poverty vulnerability among rural inhabitants and a mediation model to analyze the mechanism channel of the policy impact.Results(1) Baseline regression analysis revealed that the urban–rural health insurance integration significantly reduced the poverty vulnerability of rural residents by 6.32% (p

The effects of air pollution and meteorology on asthma is less studied in North China Plain. In the last decade, air quality in this region is markedly mitigated. This study compared the short-term effects of air pollutants on daily asthma outpatient visits (AOV) within different sex and age groups from 2014 to 2016 and 2017–2019 in Tianjin, with the application of distributed lag nonlinear model. Moreover, relative humidity (RH) and temperature as well as the synergistic impact with air pollutants were assessed. Air pollutants-associated risk with linear (different reference values were used) and non-linear assumptions were compared. In 2014–2016, PM10 and PM2.5 exhibited a larger impact on AOV, with the corresponding cumulative excess risks (ER) for every 10 μg/m3 increase at 1.04 % (95%CI:0.67–1.40 %, similarly hereafter) and 0.79 % (0.35–1.23 %), as well as increased to 43 % (26–63 %) and 20 % (10–31 %) at severe pollution. In 2017–2019, NO2 and MDA8 O3 exhibited a larger impact on AOV, with a cumulative ER for every 10 μg/m3 increase at 1.0 (0.63–1.4 %) and 0.36 % (0.15–0.57 %), with corresponding values of 7.9 % (4.8–11 %) and 5.6 % (2.3–9.0 %), at severe pollution. SO2 associated risk was only significant from 2014 to 2016. Cold effect, including extremely low temperature exposure and sharp temperature drop could generate a pronounced increase in AOV at 9.6 % (3.8–16 %) and 24 % (9.1–41 %), respectively. Moderate low temperature combined with air pollutants can enhance AOV during winter. Higher temperature in spring and autumn could trigger asthma by increasing pollen levels. Low RH resulted in AOV increase by 4.6 % (2.4–6.9), while higher RH generated AOV increase by 3.4 % (1.6–5.3). Females, children, and older adults tended to have a higher risk for air pollution, non-optimum temperature, and RH. As air pollution-associated risks on AOV tends to be weaker due to air quality improvement in recent years, the impact of extreme meteorological condition amidst climate change on asthma visits warrants further attention.

Aging is associated with gradual changes in liver structure, altered metabolites and other physiological/pathological functions in hepatic cells. However, its characterized phenotypes based on altered metabolites and the underlying biological mechanism are unclear. Advancements in high-throughput omics technology provide new opportunities to understand the pathological process of aging. Here, in our present study, both metabolomics and phosphoproteomics were applied to identify the altered metabolites and phosphorylated proteins in liver of young (the WTY group) and naturally aged (the WTA group) mice, to find novel biomarkers and pathways, and uncover the biological mechanism. Analysis showed that the body weights, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased in the WTA group. The grips decreased with age, while the triglyceride (TG) and cholesterol (TC) did not change significantly. The increase of fibrosis, accumulation of inflammatory cells, hepatocytes degeneration, the deposition of lipid droplets and glycogen, the damaged mitochondria, and deduction of endoplasmic reticulum were observed in the aging liver under optical and electron microscopes. In addition, a network of metabolites and phosphorylated proteomes of the aging liver was established. Metabolomics detected 970 metabolites in the positive ion mode and 778 metabolites in the negative ion mode. A total of 150 pathways were pooled. Phosphoproteomics identified 2618 proteins which contained 16621 phosphosites. A total of 164 pathways were detected. 65 common pathways were detected in two omics. Phosphorylated protein heat shock protein HSP 90-alpha (HSP90A) and v-raf murine viral oncogene homolog B1(BRAF), related to cancer pathway, were significantly upregulated in aged mice liver. Western blot verified that protein expression of MEK and ERK, downstream of BRAF pathway were elevated in the liver of aging mice. However, the protein expression of BRAF was not a significant difference. Overall, these findings revealed a close link between aging and cancer and contributed to our understanding of the multi-omics changes in natural aging.

Abstract Metformin, a biguanide drug, is the most commonly used first-line medication for type 2 diabetes mellites due to its outstanding glucose-lowering ability. After oral administration of 1 g, metformin peaked plasma concentration of approximately 20–30 μM in 3 h, and then it mainly accumulated in the gastrointestinal tract, liver and kidney. Substantial studies have indicated that metformin exerts its beneficial or deleterious effect by multiple mechanisms, apart from AMPK-dependent mechanism, also including several AMPK-independent mechanisms, such as restoring of redox balance, affecting mitochondrial function, modulating gut microbiome and regulating several other signals, such as FBP1, PP2A, FGF21, SIRT1 and mTOR. On the basis of these multiple mechanisms, researchers tried to repurpose this old drug and further explored the possible indications and adverse effects of metformin. Through investigating with clinical studies, researchers concluded that in addition to decreasing cardiovascular events and anti-obesity, metformin is also beneficial for neurodegenerative disease, polycystic ovary syndrome, aging, cancer and COVID-19, however, it also induces some adverse effects, such as gastrointestinal complaints, lactic acidosis, vitamin B12 deficiency, neurodegenerative disease and offspring impairment. Of note, the dose of metformin used in most studies is much higher than its clinically relevant dose, which may cast doubt on the actual effects of metformin on these disease in the clinic. This review summarizes these research developments on the mechanism of action and clinical evidence of metformin and discusses its therapeutic potential and clinical safety.

Anxiety is thought to be evolutionarily rooted in predator defense. Yan et al. show that GABAergic neurons in the anterior hypothalamic nucleus (AHN), a node in the predator defense network, play an essential role in anxiety-like behaviors.

Abstract Background More information about the impacts of comprehensive pharmaceutical care program (CPCP) on the identification and resolution of drug-related problems (DRPs) is needed. This study aimed at researching the characteristics of DRPs in osteoporosis patients and evaluating the effect of CPCP in identifying and addressing DRPs. Methods We performed a prospective interventional study in a teaching hospital. CPCP was established and conducted to identify and resolve DRPs by a multidisciplinary team (MDT) based on the Pharmaceutical Care Network Europe (PCNE) classification V9.0. Six pharmacists and one doctor worked directly in the study. All data was obtained from electronic medical records, direct observation and visits. The statistical analyses were performed using the SPSS Statistics software version 26.0. Results Two hundred nineteen patients with osteoporosis were included in the final analysis. A total of 343 DRPs were identified, with an average of 1.57 DRPs per patient. The most common DRPs identified were “treatment safety P2” (66.8%; 229/343), followed by “other P3” (21.0%; 72/343) and “treatment effectiveness, P1” (12.2%; 42/343). The primary causes of DRPs were “dose selection C3” (35.9%; 211/588), followed by “drug use process C6” (28.9%; 170/588) and “drug selection C1” (12.6%; 74/588). Seven hundred eleven interventions were proposed to address the 343 DRPs, with an average of 2.1 interventions per DRP. The acceptance rate reached 95.9, and 91.0% of these accepted interventions were fully implemented. As a result, only 30 DRPs were unsolved before discharge. Additionally, the number of drugs was found to be associated with the number of DRPs significantly (p = 0.023). Conclusion DRPs frequently occurred in hospitalized osteoporosis patients. CPCP could be an effect option to solve and reduce DRPs for osteoporosis patients and should be implemented widely to increase patient safety.