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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.

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.

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.

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.

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

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.

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.

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 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

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.

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.

Graphitic carbon nitride is considered as an ideal semiconductor material for photocatalytic hydrogen evolution due to its suitable energy band structure, durability and environmental friendliness. To further improve the catalytic performance of g-C3N4, nickel phosphide-loaded one-dimensional tubular carbon nitride (Ni2P/TCN) was prepared by thermal polymerization and photo deposition. The beneficial effect of the one-dimensional tubular structure on hydrogen generation was mainly attributed to its larger specific surface area (increased light absorption) as well as the linear movement of the carriers, which reduced their diffusion distance to the surface and facilitated the separation of photogenerated carriers. The loading of Ni2P co-catalyst improved the visible light utilization efficiency and enabled the migration of photogenerated electrons towards Ni2P, which ultimately reacted with the enhanced adsorbed H+ on the Ni2P surface to facilitate the photocatalytic hydrogen evolution process. This study provides new clues for the further development of efficient, environmentally friendly and low-cost g-C3N4 catalysts.

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

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.

We previously discovered WS-6 as a new antidepressant in correlation to its function of stimulating neurogenesis. Herein, several different scaffolds (stilbene, 1,3-diphenyl 1-propene, 1,3-diphenyl 2-propene, 1,2-diphenyl acrylo-1-nitrile, 1,2-diphenyl acrylo-2-nitrile, 1,3-diphenyl trimethylamine), further varied through substitutions of twelve amide substituents plus the addition of a methylene unit and an inverted amide, were examined to elucidate the SARs for promoting adult rat neurogenesis. Most of the compounds could stimulate proliferation of progenitors, but just a few chemicals possessing a specific structural profile, exemplified by diphenyl acrylonitrile 29b, 32a, and 32b, showed better activity than the clinical drug NSI-189 in promoting newborn cells differentiation into mature neurons. The most potent diphenyl acrylonitrile 32b had an excellent brain AUC to plasma AUC ratio (B/P = 1.6), suggesting its potential for further development as a new lead.

The physiochemical properties of graphene oxide may be affected by sunlight irradiation. However, the underlying mechanisms that alter the properties and subsequent intergenerational effects are not sufficiently investigate. Epigenetics is an early sensitive marker for the intergenerational effects of nanomaterial exposure due to the epigenetic memory. In this study, we investigate changes in the physicochemical properties and the intergenerational effects of maternal exposure to simulated sunlight-irradiated polyethyleneimine-functionalized graphene oxide (SL-PEI-GO). Results show that the physicochemical properties of polyethyleneimine-functionalized graphene oxide (PEI-GO) can be altered significantly by the oxidation of carbon atoms with unpaired electrons present in the defects and on the edges of PEI-GO by sunlight. First, the positive charges, sharp edges, defects and disordered structures of SL-PEI-GO make it translocate from maternal zebrafish to offspring, thus catalyzing the production of reactive oxygen species and damaging mitochondria directly. In addition, changes in DNA methylation reduce the expression of protocadherin1a, protocadherin19 and cadherin4, thus destroying cell membrane integrity, cell adhesion and Ca2+ binding. The alteration of DNA methylation induced by maternal exposure activates the Ca2+-CaMKK-brsk2a pathway, which catalyzes the phosphorylation of Tau and eventually results in the appearance of neurodegeneration-like symptoms, including the loss of neurons and neurobehavioral disorders. This study demonstrates that maternal exposure to SL-PEI-GO induces clear neurodegeneration-like symptoms in offspring through both the intergenerational translocation of nanomaterials and differential DNA methylation. These findings may provide new insights into the health risks of nanomaterials altered by nature conditions.

BackgroundHematopoietic stem cell transplantation (HSCT) is an important treatment for T-cell lymphoblastic lymphoma/leukemia (T-LBL). To compare the efficacy and influencing factors of autologous hematopoietic stem cell transplantation (auto-HSCT) with those of allogeneic hematopoietic stem cell transplantation (allo-HSCT) from different donors for the treatment of T-cell lymphoblastic lymphoma/leukemia (T-LBL) and provide a basis for selection of appropriate transplant methods and donors.MethodsTo provide evidence of appropriate transplant methods for these patients, we retrospectively summarized the clinical characteristics of 75 T-LBL patients receiving HSCT at Henan Cancer Hospital between March 2012 and October 2021. Overall survival (OS), progression-free survival (PFS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and related factors affecting efficacy were analyzed.ResultsThe 3-year CIR (39.9% vs 31.1%, P=0.745), 3-year PFS (60.1% vs 49.6%, P=0.434), and 3-year OS (62.8% vs 53.0%, P=0.450) were not significantly different between the auto-HSCT and allo-HSCT groups. However, the 3-year NRM was significantly higher in the allo-HSCT group (0% vs 27.2%, P=0.033). Multivariate analysis showed that the first complete remission (CR1) after HSCT was an independent influencing factor of higher OS (HR=2.498, P=0.029) and PFS (HR=2.576, P=0.016). The absence of mediastinal invasion in patients receiving HSCT was an independent influencing factor of better PFS (HR=2.977, P=0.029) and lower CIR (HR=4.040, P=0.027). With respect to the impact of donor source, the NRM in the unrelated donor (URD) and haploid donor (HPD) groups was significantly higher than that in the auto-HSCT group (P=0.021 and P=0.003, respectively), while there was no significant difference between matched sibling donors (MSD) and auto-HSCT. Compared with the MSD-HSCT group, the auto-HSCT group showed an increasing trend in 3-year CIR (39.9 ± 11.1% vs 32.6 ± 11.2%, P=0.697) and a lower trend in 3-year OS (62.8 ± 11.4% vs 64.4 ± 12.2%, P=0.929).ConclusionsHSCT is an effective consolidation treatment option for patients with T-LBL without mediastinal invasion and with CR1 before transplantation. For CR1 patients, auto-HSCT and MSD-HSCT are effective modalities for improving survival. In non-CR1 patients without an MSD, matched unrelated donors and haploidentical donor transplantations are the best treatment options to reduce relapse and improve prognosis.

Abnormal Copper (Cu) accumulation shared a close association with hepatocellular carcinoma (HCC), but the regulatory role of Copper-binding proteins in HCC remains largely unknown. The aim of study was to identify the potential regulatory role of Cu-binding proteins, including copper homeostasis maintainer and the downstream effectors of Cu, in the progression of HCC. We conducted a comprehensive bioinformatic analysis of Cu-binding proteins in HCC using data from TCGA and ICGC database. Univariate cox regression analysis was conducted, and four prognostic Cu-binding proteins was identified to be differentially expressed between the normal liver tissues and HCC tissues. In addition, the Cu-binding proteins-based predictive signature (CuPscore) model was generated using the least absolute shrinkage and selection operator (LASSO) cox regression model. Here, we identified the crucial prognostic value of CuPscore in HCC. The pathological stage and CuPscore were independent risk factors for the prognosis of HCC patients. Pathological stage and CuPscore-based nomogram model exhibited great performance in predicting the prognosis of HCC patients. We also observed that the CuPscore shared a close association with several immunomodulatory molecules and the proportion of several tumor infiltrating immune cells, suggesting a potential value of CuPscore in predicting the response to immunotherapy in HCC. Our results demonstrated the prognostic value of Cu-binding proteins and its correlation with immune microenvironment in HCC, providing a therapeutic basis for the precision medicine strategy through targeting Cu-binding proteins in HCC.

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.

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.

Abstract Background RNA N 6-methyladenosine (m6A) is involved in mammalian spermatogenesis. In both germ cells and Leydig cells, ALKBH5 regulates spermatogenesis and androgen synthesis in an m6A-dependent manner. However, it is unclear whether ALKBH5 plays a role in testicular Sertoli cells, which constitute the blood–testis barrier (BTB) through cell junctions between adjacent Sertoli cells. Methods ALKBH5 expression in the testes of humans and mice was detected by immunohistochemical staining and immunofluorescence staining. BTB integrity was evaluated by BTB assay. m6A-seq was performed to screen for BTB-related molecules regulated by ALKBH5. m6A immunoprecipitation–quantitative real-time polymerase chain reaction (qPCR), RNA immunoprecipitation–qPCR, western blot, coimmunoprecipitation, and polysome fractionation–qPCR analyses were performed to explore the mechanisms of ALKBH5 in BTB. Transmission electron microscopy was applied to observe the BTB ultrastructure. Results ALKBH5 in Sertoli cells is related to the integrity of the BTB. Subsequently, the m6A level on Cdh2 mRNA, encoding a structural protein N-cadherin in the BTB, was found to be regulated by ALKBH5. IGF2BP1/2/3 complexes and YTHDF1 promoted Cdh2 mRNA translation. In addition, we found that basal endoplasmic specialization, in which N-cadherin is a main structural protein, was severely disordered in the testes of Alkbh5-knockout mice. Conclusions Our study revealed that ALKBH5 regulates BTB integrity via basal endoplasmic specialization by affecting Cdh2 mRNA translation.

Proper interface and band alignment always play essential roles in the separation of photoexcited charge of photocatalysts. In this work, we prepared a homodispersed S-scheme carbon nitride homojunction with local electron structure difference by a facile pre-doping and two-step calcination approach. Boron doping into heptazine created extra acceptor impurity, and phosphorus doping into heptazine created extra donor impurity, which eventually modulated the electronic structure of carbon nitride. As heptazines with different element doping were integrated into carbon nitride by recalcination, B–CN and P–CN formed a homodispersed homojunction and thus produced a rich interface. Meanwhile, caused by Fermi energy levels equilibrium, the band bending constructed an S-scheme homojunction, which stimulated photogenerated electrons to transfer from CB of B–CN to VB of P–CN. The homodispersed S-scheme homojunction structure led to efficient suppression of recombination of photoinduced charge and retained stronger redox charge. Consequently, the photocatalytic performance was dramatically boosted to 2620 μmol g−1 from 60 μmol g−1 of pure CN in 4-h hydrogen evolution from water. This novel method for electron structure engineering helped to provide a new strategy for designing homojunction photocatalysts with excellent photocatalytic performance.

Abstract Background In 2015, the International League Against Epilepsy proposed a new conceptual definition of status epilepticus (SE) with two operational dimensions (t1 and t2) to guide emergency treatment. The purpose of this study was to compare clinical characteristics and prognoses of patients at these two different time points. Methods We conducted a prospective observational cohort study of consecutive adults diagnosed with SE. In case of convulsive SE, t1 is 5 min and t2 is 30 min, whereas in case of focal SE with impaired consciousness, t1 is 10 min, t2 is 60 min. Data on clinical characteristics, including age, gender, history of prior seizures, neuroimaging, semiology, duration, and etiology of SE, were collected. The primary outcome was mortality, with seizure recurrence as a secondary measure, and functional status as tertiary outcome of enrolled patients at 3 months after SE onset. Results We screened one hundred patients with SE, with a median age of 66 years and 61% were male. Fifty-six (56.0%) patients reached t1 of SE, while 44 (44.0%) reached t2 of SE. Convulsive SE (52.0%, n = 52) was more common than focal SE with impaired consciousness (48.0%, n = 48). Status epilepticus secondary to an acute symptomatic process was the most common (50%, n = 50). Patients meeting t2 of SE demonstrated a remarkably increased risk of mortality (unadjusted analysis-RR 3.606, 95%CI 1.552–8.376, p = 0.003; adjusted analysis-RR 2.924, 95%CI 1.221–7.003, p = 0.016) and unfavorable functional status (unadjusted analysis-RR 1.803, 95%CI 1.280–2.539, p = 0.001; adjusted analysis-RR 1.664, 95%CI 1.184–2.340, p = 0.003) at 3 months compared to those who only reached t1 of SE. Patients reaching t2 of SE were more likely to experience seizure recurrence, however, there was no significant difference between the two cohorts. Conclusions Our study provides strong support for the new definition of SE. Patients meeting t2 of SE tend to have a remarkably increased risk of mortality and unfavorable functional outcomes compared to those who only reached t1 of SE. Furthermore, patients were likely to experience seizure recurrence after undergoing an episode of SE. Physicians must be educated about prompt recognition and appropriate management of SE.

Abstract The prognosis of most thyroid cancer patients is excellent, but for those with advanced or metastatic thyroid cancer, effective treatments are still lacking. Chimeric antigen receptor (CAR) T-cell therapy has gained remarkable achievements in hematologic malignancy but shown limited efficacy in solid tumors. In this report, we showed a relapsed and refractory thyroid cancer patient treated with TSHR + CD19 CAR-T, a combination of two 2nd generation CAR-T molecules targeting both TSHR and CD19. This patient finally achieved partial remission at 3 months and was tolerate well to the regimen. Our study suggested that the CAR-T therapy could be a feasible way in treating relapsed and refractory thyroid cancer.

Abstract Evidence about the interaction between circadian rhythms (CR) and epilepsy has been expanded with the application of advanced detection technology. An adequate understanding of how circadian system and epilepsy interact with each other could contribute to more accurate seizure prediction as well as rapid development of potential treatment timed to specific phases of CR. In this review, we present the reciprocal relationship between CR and epileptic activities from aspects of sleep effect, genetic modulation and brain biochemistry. It has been found that sleep-wake patterns, circadian timing systems and multidien rhythms have essential roles in seizure activities and interictal epileptiform discharge (IED). For instance, specific distribution patterns of seizures and IED have been reported, i.e., lighter non-rapid eye movement (NREM) sleep stage (stage 2) induces seizures while deeper NREM sleep stage (stage 3) activates IEDs. Furthermore, the epilepsy type, seizure type and seizure onset zone can significantly affect the rhythms of seizure occurrence. Apart from the common seizure types, several specific epilepsy syndromes also have a close correlation with sleep-wakefulness patterns. Sleep influences the epilepsy rhythm, and conversely, epilepsy alters the sleep rhythm through multiple pathways. Clock genes accompanied by two feedback loops of regulation have an important role in cortical excitability and seizure occurrence, which may be involved in the mTORopathy. The suprachiasmatic nuclei (SCN) has a rhythm of melatonin and cortisol secretion under the circadian pattern, and then these hormones can feed back into a central oscillator to affect the SCN-dependent rhythms, leading to variable but prominent influence on epilepsy. Furthermore, we discuss the precise predictive algorithms and chronotherapy strategies based on different temporal patterns of seizure occurrence for patients with epilepsy, which may offer a valuable indication for non-invasive closed-loop treatment system. Optimization of the time and dose of antiseizure medications, and resynchronization of disturbed CR (by hormone therapy, light exposure, ketogenic diet, novel small molecules) would be beneficial for epileptic patients in the future. Before formal clinical practice, future large-scale studies are urgently needed to assist prediction and treatment of circadian seizure activities and address unsolved restrictions.

Abstract Background Apoptosis signal-regulating kinase 1 (ASK1) not only causes neuronal programmed cell death via the mitochondrial pathway but also is an essential component of the signalling cascade during microglial activation. We hypothesize that ASK1 selective deletion modulates inflammatory responses in microglia/macrophages(Mi/Mϕ) and attenuates seizure severity and long-term cognitive impairments in an epileptic mouse model. Methods Mi/Mϕ-specific ASK1 conditional knockout (ASK1 cKO) mice were obtained for experiments by mating ASK1flox/flox mice with CX3CR1creER mice with tamoxifen induction. Epileptic seizures were induced by intrahippocampal injection of kainic acid (KA). ASK1 expression and distribution were detected by western blotting and immunofluorescence staining. Seizures were monitored for 24 h per day with video recordings. Cognition, social and stress related activities were assessed with the Y maze test and the three-chamber social novelty preference test. The heterogeneous Mi/Mϕ status and inflammatory profiles were assessed with immunofluorescence staining and real-time polymerase chain reaction (q-PCR). Immunofluorescence staining was used to detect the proportion of Mi/Mϕ in contact with apoptotic neurons, as well as neuronal damage. Results ASK1 was highly expressed in Mi/Mϕ during the acute phase of epilepsy. Conditional knockout of ASK1 in Mi/Mϕ markedly reduced the frequency of seizures in the acute phase and the frequency of spontaneous recurrent seizures (SRSs) in the chronic phase. In addition, ASK1 conditional knockout mice displayed long-term neurobehavioral improvements during the Y maze test and the three-chamber social novelty preference test. ASK1 selective knockout mitigated neuroinflammation, as evidenced by lower levels of Iba1+/CD16+ proinflammatory Mi/Mϕ. Conditional knockout of ASK1 increased Mi/Mϕ proportion in contact with apoptotic neurons. Neuronal loss was partially restored by ASK1 selective knockout. Conclusion Conditional knockout of ASK1 in Mi/Mϕ reduced seizure severity, neurobehavioral impairments, and histological damage, at least via inhibiting proinflammatory microglia/macrophages responses. ASK1 in microglia/macrophages is a potential therapeutic target for inflammatory responses in epilepsy.

Trichinella spiralis (T. spiralis) adult-specific deoxyribonuclease II-7 (TsDNase II-7), a member of the DNase II-like nuclease family with no DNase II activity, was identified in the excretory-secretory (ES) products of adult worms (AWs). However, its biological functions are still unclear. Our previous study revealed that TsDNase II-7 is located around the infection site in the intestinal tissue, speculating that it was involved in the T. spiralis invasion of host intestinal epithelial cells (IECs). This study aimed to use RNA interference to verify our speculation that TsDNase II-7 in 3-day old adult T. spiralis (Ad3) plays a role in intestinal invasion. TsDNase II-7-specific small interfering RNAs (siRNAs) were delivered into muscle larvae (MLs) to knockdown TsDNase II-7 expression by electroporation. Twenty-four hours later, the MLs transfected with 2 μM siRNA-841 exhibited decreased in TsDNase II-7 transcription and expression as compared to the control MLs. The knockdown of TsDNase II-7 expression did not affect ML viability, and the low expression of TsDNase II-7 still maintained in Ad3 recovered from TsDNase II-7-RNAi-ML infected mice, resulting in a weakened ability of Ad3 to invade intestinal epithelial cells (IECs). These results indicated that knockdown of TsDNase II-7 gene expression via RNA interference (RNAi) suppressed adult worm invasion and confirmed that TsDNase II-7 plays a crucial role during the intestinal phase of T. spiralis infections, which provided new candidate for vaccine development of T. spiralis.

IntroductionInborn errors of immunity (IEI) are a heterogeneous group of disorders characterized by increased risk of infections, autoimmunity, autoinflammatory diseases, malignancy and allergy. Next-generation sequencing has revolutionized the identification of genetic background of these patients and assists in diagnosis and treatment. In this study, we identified a probable unique monogenic cause of IEI, and evaluated the immunological methods and pathogenic detections.MethodsA family with a member with a clinical diagnosis of IEI was screened by whole genomic sequencing (WGS). Demographic data, clinical manifestations, medical history, physical examination, laboratory findings and imaging features of the patient were extracted from medical records. Comprehensive immune monitoring methods include a complete blood count with differential, serum levels of cytokines and autoantibodies, T-cell and B-cell subsets analysis and measurement of serum immunoglobulins. In addition, metagenomic sequencing (mNGS) of blood, cerebrospinal fluid and biopsy from small intestine were used to detect potential pathogens.ResultsThe patient manifested with recurrent infections and autoimmune disorders, who was eventually diagnosed with IEI. Repetitive mNGS tests of blood, cerebrospinal fluid and biopsy from small intestine didn’t detect pathogenic microorganism. Immunological tests showed a slightly decreased level of IgG than normal, elevated levels of tumor necrosis factor and interleukin-6. Lymphocyte flow cytometry showed elevated total B cells and natural killer cells, decreased total T cells and B-cell plasmablasts. WGS of the patient identified a novel heterozygous mutation in IRF2BP2 (c.439_450dup p. Thr147_Pro150dup), which was also confirmed in his father. The mutation was classified as variant of uncertain significance (VUS) according to the American College of Medical Genetics and Genomics guidelines.ConclusionWe identified a novel IRF2BP2 mutation in a family with a member diagnosed with IEI. Immune monitoring and WGS as auxiliary tests are helpful in identifying genetic defects and assisting diagnosis in patients with clinically highly suspected immune abnormalities and deficiencies in inflammation regulation. In addition, mNGS techniques allow a more comprehensive assessment of the pathogenic characteristics of these patients. This report further validates the association of IRF2BP2 deficiency and IEI, and expands IEI phenotypes.

Dissolved organic matter (DOM) plays a major role in ecological systems, affecting the fate and transportation of iron (Fe) and phosphorus (P). To better understand the geochemical cycling of these components, soil and sediment samples were collected around a reservoir downstream of a typical temperate forest in Northeast China. The DOM fractions from these soils, river, and reservoir sediments were extracted and then characterized by spectroscopic techniques. Comparative characterization data showed that the DOM pool of the Xishan Reservoir was partly autochthonous and derived from runoff and deposition of material in terrestrial ecosystems upstream. The upper reaches of the reservoir had significantly lower total Fe (TFe) content in the DOM extracts than those found in the reservoir (p

The COVID-19 pandemic, caused by the SARS-CoV-2, is the most serious global health calamity since the 2 nd World War. The COVID-19 pandemic threatens public health systems worldwide, both in developed and developing countries. In the present report we discuss various effects of the pandemic on the status of neglected tropical diseases (NTDs). COVID-19 will be a public health issue for an extended period. COVID-19 presented several challenges and opportunities for NTD prevention and control. Significant alterations include impact of the pandemic on preventive/control measures and poverty-related plans, service failures and injury to health workers, delayed treatment of NTDs, health service funding, and worsening poverty in marginalized societies. Additionally, the COVID-19 pandemic necessitated school and university closures on public education and research institutes. Furthermore, the COVID-19 pandemic has also provided opportunities, such as improving health literacy, changing approaches to NTD treatments, restructuring the health system and emergency responses, and enhancing science communication.

Abstract Background Gait disturbances may appear prior to cognitive dysfunction in the early stage of silent cerebrovascular disease (SCD). Subtle changes in gait characteristics may provide an early warning of later cognitive decline. Our team has proposed a vision-based artificial intelligent gait analyzer for the rapid detection of spatiotemporal parameters and walking pattern based on videos of the Timed Up and Go (TUG) test. The primary objective of this study is to investigate the relationship between gait features assessed by our artificial intelligent gait analyzer and cognitive function changes in patients with SCD. Methods This will be a multicenter prospective cohort study involving a total of 14 hospitals from Shanghai and Guizhou. One thousand and six hundred patients with SCD aged 60–85 years will be consecutively recruited. Eligible patients will undergo the intelligent gait assessment and neuropsychological evaluation at baseline and at 1-year follow-up. The intelligent gait analyzer will divide participant into normal gait group and abnormal gait group according to their walking performance in the TUG videos at baseline. All participants will be naturally observed during 1-year follow-up period. Primary outcome are the changes in Mini-Mental State Examination (MMSE) score. Secondary outcomes include the changes in intelligent gait spatiotemporal parameters (step length, gait speed, step frequency, step width, standing up time, and turning back time), the changes in scores on other neuropsychological tests (Montreal Cognitive Assessment, the Stroop Color Word Test, and Digit Span Test), falls events, and cerebrovascular events. We hypothesize that both groups will show a decline in MMSE score, but the decrease of MMSE score in the abnormal gait group will be more significant. Conclusion This study will be the first to explore the relationship between gait features assessed by an artificial intelligent gait analyzer and cognitive decline in patients with SCD. It will demonstrate whether subtle gait abnormalities detected by the artificial intelligent gait analyzer can act as a cognitive-related marker for patients with SCD. Trial registration This trial was registered at ClinicalTrials.gov ( NCT04456348 ; 2 July 2020).

Abstract With the continuous development of terahertz (THz) detection technology, the use of terahertz spectroscopy to study chemical samples has become one of the indispensable tools in the field of biochemistry. While most biomolecules biological activity can only be expressed in aqueous solutions, water as a polar molecule has strong absorption properties for terahertz waves, making it difficult to use terahertz technology to study the activity of biological samples in aqueous solutions. In this study, a sandwich-type terahertz microfluidic chip with high terahertz wave transmission was designed and combined with a terahertz time domain spectroscopy (THz-TDS) system to test the terahertz spectra of distilled water, 0.9 mol/L NH4Cl, (NH4)2SO4, (NH4)2CO3 and CH3COONH4 solutions, respectively, and to investigate the effect of the electric field action time on the hydrogen bond in the solution under the action of an external electric field. The experimental results show that the terahertz spectra of different ammonium solutions at the same concentration differ significantly, indicating that the ion hydration process affects the intermolecular hydrogen bonding in water, while the applied electric field also affects the hydrogen bonding in water, resulting in a change in the terahertz waves water absorption.

Selective conversion of methane into value-added chemicals is a promising approach for utilization of hydrocarbon sources. Here the authors develop dimeric copper centers supported on graphitic carbon nitride (denoted as Cu2@C3N4) with >10% conversion and >98% selectivity toward methyl oxygenates in both thermo- and photo- catalytic reactions.