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The precursor ribosomal RNA is processed by multiple steps of nucleolytic cleavage to generate mature rRNAs. Utp24 is a PIN domain endonuclease in the early 90S precursor of small ribosomal subunit and is proposed to cleave at sites A1 and A2 of pre-rRNA. Here we determine the crystal structure of Utp24 from Schizosaccharomyces pombe at 2.1 angstrom resolution. Utp24 structurally resembles the ribosome assembly factor Utp23 and both contain a Zn-finger motif. Functional analysis in Saccharomyces cerevisiae shows that depletion of Utp24 disturbs the assembly of 90S and abolishes cleavage at sites A0, A1 and A2. The 90S assembled with inactivated Utp24 is arrested at a post-A0-cleavage state and contains enriched nuclear exosome for degradation of 5' ETS. Despite of high sequence conservation, Utp24 from other organisms is unable to form an active 90S in S. cerevisiae, suggesting that Utp24 needs to be precisely positioned in 90S. Our study provides biochemical and structural insight into the role of Utp24 in 90S assembly and activity.

Eukaryotic small ribosomal subunits are first assembled into 90S pre-ribosomes. The complete 90S is a gigantic complex with a molecular mass of approximately five megadaltons. Here, we report the nearly complete architecture of Saccharomyces cerevisiae 90S determined from three cryo-electron microscopy single particle reconstructions at 4.5 to 8.7 angstrom resolution. The majority of the density maps were modeled and assigned to specific RNA and protein components. The nascent ribosome is assembled into isolated native-like substructures that are stabilized by abundant assembly factors. The 5' external transcribed spacer and U3 snoRNA nucleate a large subcomplex that scaffolds the nascent ribosome. U3 binds four sites of pre-rRNA, including a novel site on helix 27 but not the 3' side of the central pseudoknot, and crucially organizes the 90S structure. The 90S model provides significant insight into the principle of small subunit assembly and the function of assembly factors.

Abstract Hypoxia, characterized by reduced oxygen concentration, is a significant stressor that affects the survival of aerobic species and plays a prominent role in cardiovascular diseases. From the research history and milestone events related to hypoxia in cardiovascular development and diseases, The "hypoxia-inducible factors (HIFs) switch" can be observed from both temporal and spatial perspectives, encompassing the occurrence and progression of hypoxia (gradual decline in oxygen concentration), the acute and chronic manifestations of hypoxia, and the geographical characteristics of hypoxia (natural selection at high altitudes). Furthermore, hypoxia signaling pathways are associated with natural rhythms, such as diurnal and hibernation processes. In addition to innate factors and natural selection, it has been found that epigenetics, as a postnatal factor, profoundly influences the hypoxic response and progression within the cardiovascular system. Within this intricate process, interactions between different tissues and organs within the cardiovascular system and other systems in the context of hypoxia signaling pathways have been established. Thus, it is the time to summarize and to construct a multi-level regulatory framework of hypoxia signaling and mechanisms in cardiovascular diseases for developing more therapeutic targets and make reasonable advancements in clinical research, including FDA-approved drugs and ongoing clinical trials, to guide future clinical practice in the field of hypoxia signaling in cardiovascular diseases.

Abstract Although chimeric antigen receptor (CAR) T cells have become an important treatment option for patients with relapsed/refractory B-cell malignancies, more than 60% of patients with diffuse large B-cell lymphoma (DLBCL) treated with CAR-T cell therapies fail to achieve a durable response. To reveal changes in CAR-T cell therapy and identify response biomarkers, we conducted a retrospective analysis of pre-manufacture source T cells and CAR-T cell products and their association with outcome in 58 patients with r/rDLBCL who received tandem CD19/CD20 CAR-T cell therapy. We performed bulk RNA-Seq, single-cell RNA-Seq, and paired T cell receptor sequencing on CAR-T cell products and pre-manufacture T cells from DLBCL patients. We note that a CD8+ stem cell-like memory T cell population with a higher proportion and enhanced activating capacity of the CAR-T cell products was key to achieving durable clinical response. By analysing autologously-derived, pre-manufacture T cells, our data suggest that heterogeneity in the cellular and molecular features of pre-manufacture T cells contribute to the variation in efficacy after CAR-T cell therapy in DLBCL. The differences in anti-tumour efficacy of CAR-T cells among patients with different clinical outcomes appear to be due to the loss of CCR7 gene expression, coupled with increased expression of activation- and inhibitor-related genes in the CD8+ naïve-T cell populations among the apheresis T cells from patients with a poor molecular response. These findings significantly advance our understanding of the underlying molecular determinants of pre-manufacture T cell function.

Abstract In light of the rapid expansion of the marine aquaculture industry, there has been widespread and irregular usage of aquatic drugs to combat biological diseases, which significantly impact the neighboring aquatic ecosystems. This study delves into the impact of the antibiotic aquatic drug known as doxycycline hydrochloride (DOX) on offshore soft corals, providing valuable data for the responsible use and management of aquatic drugs. In this investigation, we subjected Sarcophyton trocheliophorum to acute exposure to varying concentrations of DOX (0, 1, 5, and 10 mg L−1). We meticulously assessed critical parameters and observed alterations in protein levels, superoxide dismutase (SOD) activity, catalase (CAT) activity, lipid peroxidation (LPO), malondialdehyde (MDA) levels, Acid phosphatase (ACP) activity, alkaline phosphatase (AKP) activity, glutathione (GSH) concentration, glutathione S-transferase (GST) activity, glutathione Peroxidase (GSH-Px) activity, zooxanthellae density, and chlorophyll content. Our findings reveal that in the presence of DOX-induced environmental stress, there is a significant increase in LPO, MDA, chlorophyll, carotenoid levels, and the activities of ACP, GST, and GSH-Px in soft corals. Simultaneously, there is a noteworthy decrease in zooxanthellae density. Additionally, the protein concentration and SOD activity in soft corals experience substantial reduction when exposed to 5 mg L−1 DOX. Notably, CAT activity varies significantly in environments with 1 and 10 mg L−1 DOX. Moreover, these conditions exhibit a discernible influence on AKP activity, GSH content, and chlorophyll levels. These findings suggest that DOX exposure carries the potential for toxicity in aquaculture settings, affecting protein synthesis in soft corals and influencing oxidative stress, lipid peroxidation, immunity, and detoxification processes within these organisms. There is also a risk of compromising the coral defense system, potentially leading to coral bleaching. Furthermore, this study underscores the significant impact on photosynthesis, growth, and the metabolic dynamics of the coral-zooxanthellae symbiotic system. Consequently, our research offers vital insights into the mortality and bleaching effects of aquatic drugs on marine corals, offering a foundation for the prudent use and management of such substances.

Abstract Reversing ventricular remodeling represents a promising treatment for the post-myocardial infarction (MI) heart failure (HF). Here, we report a novel small molecule HHQ16, an optimized derivative of astragaloside IV, which effectively reversed infarction-induced myocardial remodeling and improved cardiac function by directly acting on the cardiomyocyte to reverse hypertrophy. The effect of HHQ16 was associated with a strong inhibition of a newly discovered Egr2-affiliated transcript lnc9456 in the heart. While minimally expressed in normal mouse heart, lnc9456 was dramatically upregulated in the heart subjected to left anterior descending coronary artery ligation (LADL) and in cardiomyocytes subjected to hypertrophic stimulation. The critical role of lnc9456 in cardiomyocyte hypertrophy was confirmed by specific overexpression and knockout in vitro. A physical interaction between lnc9456 and G3BP2 increased NF-κB nuclear translocation, triggering hypertrophy-related cascades. HHQ16 physically bound to lnc9456 with a high-affinity and induced its degradation. Cardiomyocyte-specific lnc9456 overexpression induced, but knockout prevented LADL-induced, cardiac hypertrophy and dysfunction. HHQ16 reversed the effect of lnc9456 overexpression while lost its protective role when lnc9456 was deleted, further confirming lnc9456 as the bona fide target of HHQ16. We further identified the human ortholog of lnc9456, also an Egr2-affiliated transcript, lnc4012. Similarly, lnc4012 was significantly upregulated in hypertrophied failing hearts of patients with dilated cardiomyopathy. HHQ16 also specifically bound to lnc4012 and caused its degradation and antagonized its hypertrophic effects. Targeted degradation of pathological increased lnc4012/lnc9456 by small molecules might serve as a novel promising strategy to regress infarction-induced cardiac hypertrophy and HF.

Abstract Mining entity and relation from unstructured text is important for knowledge graph construction and expansion. Recent approaches have achieved promising performance while still suffering from inherent limitations, such as the computation efficiency and redundancy of relation prediction. In this paper, we propose a novel hybrid attention and dilated convolution network (HADNet), an end-to-end solution for entity and relation extraction and mining. HADNet designs a novel encoder architecture integrated with an attention mechanism, dilated convolutions, and gated unit to further improve computation efficiency, which achieves an effective global receptive field while considering local context. For the decoder, we decompose the task into three phases, relation prediction, entity recognition and relation determination. We evaluate our proposed model using two public real-world datasets that the experimental results demonstrate the effectiveness of the proposed model.

Abstract Damage to the intestinal epithelial barrier (IEB) has been reported under high-altitude (HA) conditions and may be responsible for HA-associated gastrointestinal (GI) disorders. However, this pathogenetic mechanism does not fully explain the GI stress symptoms, such as flatulence and motility diarrhea, which accompany the IEB damage under HA conditions, especially for the people exposed to HA acutely. In the present study, we collected the blood samples from the people who lived at HA and found the concentration of enteric glial cells (EGCs)-associated biomarkers increased significantly. HA mouse model was then established and the results revealed that EGCs were involved in IEB damage. Zona occludens (ZO)-1, occludin, and claudin-1 expression was negatively correlated with that of glial fibrillary acidic protein (GFAP) and S100β under HA conditions. In order to learn more about how EGCs influence IEB, the in vitro EGC and MODE-K hypoxia experiments that used hypoxic stimulation for simulating in vivo exposure to HA was performed. We found that hypoxia increased S100β secretion in EGCs. And MODE-K cells cultured in medium conditioned by hypoxic EGCs showed low ZO-1, occludin, and claudin-1 levels of expression. Furthermore, treatment of MODE-K cells with recombinant mouse S100β resulted in diminished levels of ZO-1, occludin, and claudin-1 expression. Thus, HA exposure induces greater S100β secretion by EGCs, which aggravates the damage to the IEB. This study has revealed a novel mechanism of IEB damage under HA conditions, and suggest that EGCs may constitute a fresh avenue for the avoidance of GI disorders at HA.

Copper can be toxic at very high intracellular concentrations and can inhibit prostate cancer (PCa) progression. Recently, a study reported the mechanism of cuproptosis and the potentially associated genes. However, the function of these cuproptosis-related genes in PCa remains unknown. Based on the RNA sequence and clinical data from public databases, we analyzed the clinical value of cuproptosis-related genes in PCa. DLD, DLAT, PDHA1, and CDKN2A were expressed differently between normal and PCa tissues. The FDX1, LIAS, DLAT, GLS, and CDKN2A genes can affect PCa progression, while PDHA1 and CDKN2A influence the patients’ disease-free survival (DFS) status. The expression of LIAS, LIPT1, DLAT, and PDHB did not alter upon the incidence of PCa in Chinese patients. A constructed regression model showed that FDX1, PDHA1, MTF1, and CDKN2A can be risk factors leading to PCa in both Western and Chinese patients with PCa. The lasso regression model reflected that these genes can affect the patients’ DFS status. Additionally, the cuproptosis-related genes were associated with immune cell infiltration. We also verified the high expression of PDHA1 and CDKN2A, in clinical samples. In conclusion, we identified a novel cuproptosis-related gene signature for predicting the development of PCa.

Abstract Adenosine N1 methylation (m1A) of RNA, a type of post-transcriptional modification, has been shown to play a significant role in the progression of cancer. The objective of the current research was to analyze the genetic alteration and prognostic significance of m1A regulators in kidney renal clear cell carcinoma (KIRC). Genomic and clinicopathological characteristics were obtained from 558 KIRC patients in the Cancer Genome Atlas (TCGA) and Gene Omnibus Expression (GEO) databases. Alterations in the gene expression of ten m1A-regulators were analyzed and survival analysis was performed using the Cox regression method. We also identified three clusters of patients based on their distinct m1A alteration patterns, using integrated analysis of the ten m1A-related regulators, which were significantly related to overall survival (OS), disease-free survival (DFS) and tumor microenvironment (TME) immune cell infiltration cells in KIRC. Our findings showed that m1A alteration patterns have critical roles in determining TME complexity and its immune cell composition. Furthermore, different m1A expression patterns were significantly associated with DFS and OS rates in KIRC patients. In conclusion, the identified m1A RNA modification patterns offer a potentially effective way to classify KIRC patients based on their TME immune cell infiltration, enabling the development of more personalized and successful treatment strategies for these patients.

Abstract Calorie restriction (CR) or a fasting regimen is considered one of the most potent non-pharmacological interventions to prevent chronic metabolic disorders, ameliorate autoimmune diseases, and attenuate aging. Despite efforts, the mechanisms by which CR improves health, particularly brain health, are still not fully understood. Metabolic homeostasis is vital for brain function, and a detailed metabolome atlas of the brain is essential for understanding the networks connecting different brain regions. Herein, we applied gas chromatography-mass spectrometry-based metabolomics and lipidomics, covering 797 structurally annotated metabolites, to investigate the metabolome of seven brain regions in fasted (3, 6, 12, and 24 h) and ad libitum fed mice. Using multivariate and univariate statistical techniques, we generated a metabolome atlas of mouse brain on the global metabolic signature dynamics across multiple brain regions following short-term fasting (STF). Significant metabolic differences across brain regions along with STF-triggered region-dependent metabolic remodeling were identified. We found that STF elicited triacylglycerol degradation and lipolysis to compensate for energy demand under fasting conditions. Besides, changes in amino acid profiles were observed, which may play crucial roles in the regulation of energy metabolism, neurotransmitter signaling, and anti-inflammatory and antioxidant in response to STF. Additionally, this study reported, for the first time, that STF triggers a significant elevation of N-acylethanolamines, a class of neuroprotective lipids, in the brain and liver. These findings provide novel insights into the molecular basis and mechanisms of CR and offer a comprehensive resource for further investigation.

Abstract Background Cell-based strategies focusing on replacement or protection of dopaminergic neurons have been considered as a potential approach to treat Parkinson’s disease (PD) for decades. However, despite promising preclinical results, clinical trials on cell-therapy for PD reported mixed outcomes and a thorough synthesis of these findings is lacking. We performed a systematic review and meta-analysis to evaluate cell-therapy for PD patients. Methods We systematically identified all clinical trials investigating cell- or tissue-based therapies for PD published before July 2023. Out of those, studies reporting transplantation of homogenous cells (containing one cell type) were included in meta-analysis. The mean difference or standardized mean difference in quantitative neurological scale scores before and after cell-therapy was analyzed to evaluate treatment effects. Results The systematic literature search revealed 106 articles. Eleven studies reporting data from 11 independent trials (210 patients) were eligible for meta-analysis. Disease severity and motor function evaluation indicated beneficial effects of homogenous cell-therapy in the ‘off’ state at 3-, 6-, 12-, or 24-month follow-ups, and for motor function even after 36 months. Most of the patients were levodopa responders (61.6–100% in different follow-ups). Cell-therapy was also effective in improving the daily living activities in the ‘off’ state of PD patients. Cells from diverse sources were used and multiple transplantation modes were applied. Autografts did not improve functional outcomes, while allografts exhibited beneficial effects. Encouragingly, both transplantation into basal ganglia and to areas outside the basal ganglia were effective to reduce disease severity. Some trials reported adverse events potentially related to the surgical procedure. One confirmed and four possible cases of graft-induced dyskinesia were reported in two trials included in this meta-analysis. Conclusions This meta-analysis provides preliminary evidence for the beneficial effects of homogenous cell-therapy for PD, potentially to the levodopa responders. Allogeneic cells were superior to autologous cells, and the effective transplantation sites are not limited to the basal ganglia. PROSPERO registration number: CRD42022369760

Background: To evaluate the efficacy of stent-assisted coiling (SAC) for the treatment of carotid ophthalmic segment aneurysm segment aneurysms (OSAs) of the internal carotid artery (ICA) through detailed long-term follow-up of a large patient cohort. Methods: We retrospectively analyzed 88 consecutive patients with OSAs between January 2009 and January 2020 ​at our center. Angiographic results were evaluated using the modified Raymond grading system and clinical outcomes were evaluated using the mRS scale. The primary endpoints were major aneurysm recurrence and poor clinical outcomes for at least 18 months of follow-up. The patients were asked to attend clinical follow-up assessments and possibly undergo DSA or MR via telephone. Results: We enrolled 88 patients with 99 OSAs treated with coiling, of whom 76 were treated with SAC. The coiling procedures were successful in all 88 patients. Overall, complications occurred in 8 patients (9.1%). No procedure-related mortality was observed. 67 (76.1%) experienced immediate aneurysm occlusion at the end of the procedure. Long-term angiographic follow-up (18 months) was available in 45/88 aneurysms (51%) (average 18.7 ​± ​5.2 months). Four patients continued their follow-up for 5 years after initial aneurysm treatment. After a clinical follow-up time of 28.7 months (range, 12–51 months), 85 patients (95.5%) achieved favorable clinical outcomes (mRS scores of 0–2). Conclusions: This study indicates that SAC treatment is a safe and effective therapeutic alternative for ruptured and unruptured OSAs. The procedural risks are low with relatively long-term effectiveness.

Abstract Relation extraction is one of the important steps in building a knowledge graph. Its main objective is to extract semantic relationships from identified entity pairs in sentences, playing a crucial role in semantic understanding and knowledge graph construction. Remote supervised relation extraction aligns knowledge bases with natural language texts and generates labeled data, which alleviates the burden of manually annotating datasets. However, the labeled corpus obtained from remote supervision contains a large amount of noisy data, which greatly affects the training of relation extraction models. In this paper, we propose the hypothesis that key semantic information within the sentence plays a crucial role in entity relation extraction in the task of remote supervised relation extraction. Based on this hypothesis, we divide the sentence into three segments by splitting it according to the positions of entities, starting from within the sentence. Then, using intra-sentence attention mechanisms, we identify fine-grained semantic features within the sentence to reduce the interference of irrelevant noise information. We also improved the intra-bag attention mechanism by setting a threshold gate to filter out low-relevant noisy sentences, minimizing the impact of noise on the relation extraction model, and making full use of available positive semantic information. Experimental results show that the proposed relation extraction model in this paper achieves improvements in precision-recall curve, P@N value, and AUC value compared to existing methods, demonstrating the effectiveness of this model.

Abstract Background Ankylosing spondylitis (AS) is an autoimmune disease with a genetic correlation and is characterized by inflammation in the axial skeleton and sacroiliac joints. Many AS patients also have inflammatory bowel diseases (IBD), but the underlying causes of intestinal inflammation and osteoporosis in AS are not well understood. CX3CL1, a protein involved in inflammation, has been found to be up-regulated in AS patients and AS-model mice. Methods The authors investigated the effects of CX3CL1 on AS by studying its impact on macrophage polarization, inflammation factors, and osteoclast differentiation. Furthermore, the effects of inhibiting the NF-κB pathway and blocking CX3CL1 were assessed using BAY-117082 and anti-CX3CL1 mAb, respectively. AS model mice were used to evaluate the effects of anti-CX3CL1 mAb on limb thickness, spine rupture, and intestinal tissue damage. Results The authors found that CX3CL1 increased the expression of M1-type macrophage markers and inflammation factors, and promoted osteoclast differentiation. This effect was mediated through the NF-κB signaling pathway. Inhibition of the NF-κB pathway prevented M1-type macrophage polarization, reduced inflammation levels, and inhibited osteoclast differentiation. Injection of anti-CX3CL1 mAb alleviated limb thickness, spine rupture, and intestinal tissue damage in AS model mice by inhibiting M1-type macrophage polarization and reducing intestinal tissue inflammation. Conclusions The study demonstrated that up-regulated CX3CL1 promotes M1-type macrophage polarization and osteoclast differentiation through the NF-κB signaling pathway. Inhibition of this pathway and blocking CX3CL1 can alleviate inflammation and bone destruction in AS. These findings contribute to a better understanding of the pathogenesis of AS and provide a basis for clinical diagnosis and treatment.

Abstract Renal cancer is a common malignancy of the urinary system, and renal clear cell carcinoma (RCCC) is the most common pathological type. Transmembrane channel-like (TMC) protein is an evolutionarily conserved gene family containing 8 members, however there is still a lack of comprehensive analysis about TMC family members in RCCC. In this study, we analyzed the expression of TMC family members in RCCC from TCGA and investigated the prognosis values and immune infiltration of TMC family members in RCCC. We found that TMC2, TMC3, TMC5, TMC7 and TMC8 were significantly related with overall survival (OS) of RCCC patients. TMC3, TMC6, and TMC8 was positively correlated with the degree of immune infiltration in RCCC. TMC2, TMC6, TMC7, and TMC8 were positively correlated with immune checkpoint genes, whereas TMC4 was negative. According to KEGG and GO analysis, almost all TMCs except TMC4 were involved in the immune response. Thus, we may regard the TMC family members as novel biomarkers to predict potential prognosis and immunotherapeutic response in RCCC patients.

Abstract This phase I/II trial characterized the tolerability, safety, and antitumor activities of unecritinib, a novel derivative of crizotinib and a multi-tyrosine kinase inhibitor targeting ROS1, ALK, and c-MET, in advanced tumors and ROS1 inhibitor-naive advanced or metastatic non-small cell lung cancer (NSCLC) harboring ROS1 rearrangements. Eligible patients received unecritinib 100, 200, and 300 mg QD, and 200, 250, 300, and 350 mg BID in a 3 + 3 design during dose escalation and 300 and 350 mg BID during expansion. Phase II trial patients received unecritinib 300 mg BID in continuous 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) per independent review committee (IRC). Key secondary endpoints included intracranial ORR and safety. The ORR of 36 efficacy evaluable patients in the phase I trial was 63.9% (95% CI 46.2%, 79.2%). In the phase II trial, 111 eligible patients in the main study cohort received unecritinib. The ORR per IRC was 80.2% (95% CI 71.5%, 87.1%) and the median progression-free survival (PFS) per IRC was 16.5 months (95% CI 10.2, 27.0). Additionally, 46.9% of the patients who received recommended phase II dose of 300 mg BID experienced grade 3 or higher treatment-related adverse events. Treatment-related ocular disorders and neurotoxicity occurred in 28.1% and 34.4% of patients, respectively, but none was grade 3 or higher. Unecritinib is efficacious and safe for ROS1 inhibitor-naive patients with ROS1-positive advanced NSCLC, particularly patients with brain metastases at baseline, strongly supporting that unecritinib should become one of the standards of care for ROS1-positive NSCLC. ClinicalTrials.gov identifier: NCT03019276 and NCT03972189.

Abstract Although more adeno-associated virus AAV-based drugs enter the clinic, vector tissue tropism remains an unresolved challenge that limits its full potential despite that the tissue tropism of naturally occurring AAV serotypes can be altered by genetic engineering capsid vie DNA shuffling, or molecular evolution. To further expand the tropism and thus potential applications of AAV vectors, we utilized an alternative approach that employs chemical modifications to covalently link small molecules to reactive exposed Lysine residues of AAV capsids. We demonstrated that AAV9 capsid modified with N-ethyl Maleimide (NEM) increased its tropism more towards murine bone marrow (osteoblast lineage) while decreased transduction of liver tissue compared to the unmodified capsid. In the bone marrow, AAV9-NEM transduced Cd31, Cd34, and Cd90 expressing cells at a higher percentage than unmodified AAV9. Moreover, AAV9-NEM localized strongly in vivo to cells lining the calcified trabecular bone and transduced primary murine osteoblasts in culture, while WT AAV9 transduced undifferentiated bone marrow stromal cells as well as osteoblasts. Our approach could provide a promising platform for expanding clinical AAV development to treat bone pathologies such as cancer and osteoporosis. Thus, chemical engineering the AAV capsid holds great potential for development of future generations of AAV vectors.

Background/Aims Although the conversion from tacrolimus (TAC) to cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (CTLA4-Ig) is effective in reducing TAC-induced nephrotoxicity, it remains unclear whether CTLA4-Ig has a direct effect on TAC-induced renal injury. In this study, we evaluated the effects of CTLA4-Ig on TAC-induced renal injury in terms of oxidative stress. Methods in vitro study was performed to assess the effect of CTLA4-Ig on TAC-induced cell death, reactive oxygen species (ROS), apoptosis, and the protein kinase B (AKT)/forkhead transcription factor (FOXO) 3 pathway in human kidney 2 cells. In the in vivo study, the effect of CTLA4-Ig on TAC-induced renal injury was evaluated using renal function, histopathology, markers of oxidative stress (8-hydroxy-2’-deoxyguanosine) and metabolites (4-hydroxy-2-hexenal, catalase, glutathione S-transferase, and glutathione reductase), and activation of the AKT/FOXO3 pathway with insulin-like growth factor 1 (IGF-1). Results CTLA4-Ig significantly decreased cell death, ROS, and apoptosis caused by TAC. TAC treatment increased apoptotic cell death and apoptosis-related proteins (increased Bcl-2-associated X protein and caspase-3 and decreased Bcl-2), but it was reversed by CTLA4-Ig treatment. The activation of p-AKT and p-FOXO3 by TAC decreased with CTLA4-Ig treatment. TAC-induced renal dysfunction and oxidative marker levels were significantly improved by CTLA4-Ig in vivo. Concomitant IGF-1 treatment abolished the effects of CTLA4-Ig. Conclusions CTLA4-Ig has a direct protective effect on TAC-induced renal injury via the inhibition of AKT/FOXO3 pathway.

Abstract Based on the epidemiological characteristics of susceptibility and age selectivity for women in Xp11.2 translocation renal cell carcinoma (Xp11.2 tRCC), we inferred that estrogen was to be blamed. Rad54 like 2 (Rad54l2) which might be one of key effector proteins of DNA damage mediated by estrogen was downregulated in numerous cancers, however, its role in epidemiological characteristics of Xp11.2 tRCC was needed to further study. We reviewed 1005 Xp11.2 tRCC cases and collected estrogen data and then compared the onset time of Xp11.2 tRCC cases in female with estrogen changing trend. An RNA-sequencing was performed in estrogen treated HK-2 cells and subsequently bioinformatic analysis was applied based on the Cancer Genome Atlas (TCGA) and GEO database. The male-to-female ratio of Xp11.2 tRCC was 1:1.4 and the median age of onset was 29.7 years old. The onset trend of female was similar to estrogen physiological rhythm (r = 0.67, p

Abstract The purpose of our study was to compare the short-term outcomes of early (within 3 months after stroke) and nonearly (more than 3 months after stroke) radical colorectal cancer surgery to find an appropriate time to surgery for these colorectal cancer patients complicated with new-onset cerebral infarction. A retrospective analysis of patients with stroke who underwent curative colorectal cancer surgery between January 2010 and December 2020 was conducted. Propensity score matching (PSM) analysis was performed to overcome patient selection bias between the two groups. A total of 395 patients were reviewed. After PSM, 40 patients in the early group and 40 patients in the nonearly group were compared. The median time to surgery was 4 weeks in the early group. The overall incidence of postoperative complications between the groups was not significantly different (p = 0.745). The early group was associated with less intraoperative blood loss (50 vs. 100, p = 0.029 ml), with no difference in 30-day morbidity and mortality. Additionally, multivariate logistic regression analysis showed that previous abdominal surgery (p = 0.049) was an independent risk factor for postoperative complications after matching. Before matching, multivariate logistic analysis showed that ESRS (p = 0.028) and MRS (p = 0.039) were independent risk factors. Radical surgery after 4 weeks of cerebral infarction may be feasible for colorectal cancer patients with new onset stroke, as it appear not to increase the perioperative complications of Clavien–Dindo grade II or higher, while strengthening the preoperative evaluation and perioperative monitoring.

Abstract Immunogenic cell death (ICD) is the trigger of adaptive immune responses. However, the role of ICD-related genes in clear cell renal carcinoma (ccRCC) remains unclear. We aimed to identify biomarkers associated with ICD and develop an ICD-related predictive model that predicts the immune microenvironment, prognosis, and response to immunotherapy in ccRCC. Our study included 739 patients (603 in the training set and 136 in the validation set) with clinicopathologic information and transcriptome sequencing data. Consensus clustering, principal component analysis (PCA), weighted gene co-expression network analysis (WGCNA), univariate COX analysis, multivariate COX analysis, and the Lasso-Cox algorithm were applied to shrink predictors and construct a predictive signature of overall survival (OS). We used CIBERSORT, ESTIMATE, and TIMER in the R package IOBR to evaluate the tumor microenvironment and immune infiltration pattern of each sample. Finally, the single cell sequencing results of immune cells in ccRCC were used to verify the results of immune infiltration analysis, and the performance of the prognostic model was evaluated by calibration curves and c-index. This study revealed that inability of the initial immune response and primary immunodeficiency were significantly enriched in the ICD subgroup with poor prognosis. We found that the ten candidate ICD genes (CALR, ENTPD1, FOXP3, HSP90AA1, IFNB1, IFNG, IL6, LY96, PIK3CA, and TLR4) could affect the prognosis of ccRCC (p

BackgroundCommonly used noninvasive serological indicators serve as a step before endoscope diagnosis and help identify the high-risk gastric cancer (GC) population. However, they are associated with high false positives and high false negatives. Alternative noninvasive approaches, such as cancer-related features in cell-free DNA (cfDNA) fragments, have been gradually identified and play essential roles in early cancer detection. The integrated analysis of multiple cfDNA features has enhanced detection sensitivity compared to individual features. ObjectiveThis study aimed to develop and validate an assay based on assessing genomic-scale methylation and fragmentation profiles of plasma cfDNA for early cancer detection, thereby facilitating the early diagnosis of GC. The primary objective is to evaluate the overall specificity and sensitivity of the assay in predicting GC within the entire cohort, and subsequently within each clinical stage of GC. The secondary objective involved investigating the specificity and sensitivity of the assay in combination with possible serological indicators. MethodsThis is an observational case-control study. Blood samples will be prospectively collected before gastroscopy from 180 patients with GC and 180 nonmalignant control subjects (healthy or with benign gastric diseases). Cases and controls will be randomly divided into a training and a testing data set at a ratio of 2:1. Plasma cfDNA will be isolated and extracted, followed by bisulfite-free low-depth whole methylome sequencing. A multidimensional model named Thorough Epigenetic Marker Integration Solution (THEMIS) will be constructed in the training data set. The model includes features such as the methylated fragment ratio, chromosomal aneuploidy of featured fragments, fragment size index, and fragment end motif. The performance of the model in distinguishing between patients with cancer and noncancer controls will then be evaluated in the testing data set. Furthermore, GC-related biomarkers, such as pepsinogen, gastrin-17, and Helicobacter pylori, will be measured for each patient, and their predictive accuracy will be assessed both independently and in combination with the THEMIS model ResultsRecruitment began in November 2022 and will be ended in April 2024. As of August 2022,250 patients have been enrolled. The final data analysis is anticipated to be completed by September 2024. ConclusionsThis is the first registered case-control study designed to investigate a stacked ensemble model integrating several cfDNA features generated from a bisulfite-free whole methylome sequencing assay. These features include methylation patterns, fragmentation profiles, and chromosomal copy number changes, with the aim of identifying the GC population. This study will determine whether multidimensional analysis of cfDNA will prove to be an effective strategy for distinguishing patients with GC from nonmalignant individuals within the Chinese population. We anticipate the THEMIS model will complement the standard-of-care screening and aid in identifying high-risk patients for further diagnosis. Trial RegistrationClinicalTrial.gov NCT05668910; https://www.clinicaltrials.gov/study/NCT05668910 International Registered Report Identifier (IRRID)DERR1-10.2196/48247

Scientists have made great efforts to understand the evolution of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) to provide crucial information to public health experts on strategies to control this viral pathogen. The pandemic of the coronavirus disease that began in 2019, COVID-19, lasted nearly three years, and nearly all countries have set different epidemic prevention policies for this virus. The continuous evolution of SARS-CoV-2 alters its pathogenicity and infectivity in human hosts, thus the policy and treatments have been continually adjusted. Based on our previous study on the dynamics of binding ability prediction between the COVID-19 spike protein and human ACE2, the present study mined over 10 million sequences and epidemiological data of SARS-CoV-2 during 2020-2022 to understand the evolutionary path of SARS-CoV-2. We analyzed and predicted the mutation rates of the whole genome and main proteins of SARS-CoV-2 from different populations to understand the adaptive relationship between humans and COVID-19. Our study identified a correlation of the mutation rates from each protein of SARS-CoV-2 and various human populations. Overall, this analysis provides a scientific basis for developing data-driven strategies to confront human pathogens.

Sanghuangporus vaninii is a medicinal macrofungus that is increasingly cultivated in China. During cultivation, it was found that the fruiting body of S. vaninii was susceptible to pathogenic fungi, resulting in significant economic losses to the industry. The symptoms of the disease occur in the initial stage of fruiting body development. The isolate YZB-1 was obtained from the junction of the diseased and healthy areas of the fruiting body. In order to verify the pathogenicity of YZB-1, its purified spore suspension was inoculated into the exposed area nearby the developing fruiting body of S. vaninii. After 10 days, the same disease symptoms appeared in the inoculated area. Morphological identification and molecular analysis of rDNA ITS region confirmed that the isolate YZB-1 was identified as Trichoderma virens. The temperature stability assay revealed that the mycelia of YZB-1 grew the fastest at 25 °C, with growth slowing down gradually as the temperature increased or decreased. Dual-culture tests of T. virens and S. vaninii showed that the inhibition rate of T. virens on S. vaninii mycelium was the highest (79.01 ± 2.79%) at 25 °C, and more green spores were produced at the intersection of T. virens and S. vaninii.

Abstract. Remarkable improvement relative to traditional approaches in the treatment of hematological malignancies by chimeric antigen receptor (CAR) T-cell therapy has promoted sequential approvals of eight commercial CAR T products within last 5 years. Although CAR T cells’ productization is now rapidly boosting their extensive clinical application in real-world patients, the limitation of their clinical efficacy and related toxicities inspire further optimization of CAR structure and substantial development of innovative trials in various scenarios. Herein, we first summarized the current status and major progress in CAR T therapy for hematological malignancies, then described crucial factors which possibly compromise the clinical efficacies of CAR T cells, such as CAR T cell exhaustion and loss of antigen, and finally, we discussed the potential optimization strategies to tackle the challenges in the field of CAR T therapy.

Abstract Background Hepatocellular carcinoma is one of the most common and deadly cancers. The aim of this study was to elucidate the role of tRNA methyltransferase 6 (TRMT6) during HCC progression. Methods The role of TRMT6 in the progression and prognosis of HCC was confirmed by analysis of online databases and clinical human samples. The effects of up-regulation or down-regulation of TRMT6 on HCC cell proliferation and PI3K/AKT pathway-related protein expressions were verified. The molecular mechanism was investigated in vivo by constructing subcutaneous xenograft tumor model. Results TRMT6 was overexpressed in HCC tissues and associated with Tumour-Node-Metastasis (TNM) stage, primary tumor (T) and regional lymph node (N) classification. TRMT6 expressions in HCC cell lines were higher than that in normal liver cell. TRMT6 overexpression can promote HCC cell proliferation, increase the number of S phase cells. Interference with TRMT6 reduced the PI3K/AKT pathway-related protein expressions, and was reversed by the addition of IGF1. Interference with TRMT6 inhibited tumor growth in vivo and was related to PI3K/AKT pathway. Conclusions Overexpression of TRMT6 promote HCC cell proliferation in vivo and in vitro through PI3K/AKT/mTOR axis, which provides a potential choice for the treatment of HCC in clinical practice.

Abstract Cross-domain few-shot learning is one of the research highlights in machine learning. The difficulty lies in the accuracy drop of cross-domain network learning on a single domain due to the differences between the domains. To alleviate the problem, according to the idea of contour cognition and the process of human recognition, we propose a few-shot learning method based on pseudo-Siamese convolution neural network. The original image and the sketch map are respectively sent to the branch network in the pre-training and meta-learning process. While maintaining the original image features, the contour features are separately extracted as branch for training at the same time to improve the accuracy and generalization of learning. We conduct cross-domain few-shot learning experiments and good results have been achieved using mini-ImageNet as source domain, EuroSAT and ChestX as the target domains. Also, the results are qualitatively analyzed using a heatmap to verify the feasibility of our method.

Abstract Background Clear cell renal cell carcinoma (ccRCC), the most common urological malignancy, has an unfavorable prognosis and an unknown mechanism of progression. Through survival analyses screening of The Cancer Genome Atlas (TCGA) dataset, we identified Visual system homeobox1 (VSX1) as a novel potential prognostic biomarker in ccRCC and subsequently investigated the oncogenic role of VSX1 in ccRCC. Methods The differential expression of VSX1 in human tumors and the clinical prognoses were analyzed in the TCGA dataset and Gene Expression Omnibus. Spearman’s correlation coefficient was determined for the correlation analysis of VSX1 expression and other genes of interest. The roles of VSX1 in cell proliferation, invasion, and migration of ccRCC cells were evaluated via the CCK-8 assay, colony formation assay, and Transwell assay, respectively. Further results were demonstrated by western blotting, immunohistochemistry, qRT-PCR, tumor sphere formation, flow cytometry, and the dual‑luciferase reporter assay. Results VSX1 mRNA upregulation was generally observed in multiple human malignancies from the TCGA database and was confirmed in ccRCC clinical specimens from our department. High VSX1 expression usually indicated that overall and disease-free survival were unfavorable for patients with ccRCC. In terms of mechanism, knockdown or overexpression of VSX1 affected ccRCC aggressiveness in vitro. The dual-luciferase reporter gene assay implied that VSX1 overexpression significantly increased the luciferase activity of TMEM44, FKBP10, and TRIB3, which indicated that VSX1 promoted ccRCC invasiveness via transcriptional regulation of these genes. The significantly enhanced growth in vitro that was induced by stable VSX1 overexpression was almost restored to normal by the knockdown of FKBP10. Conclusions This study demonstrated that VSX1 was a novel prognostic biomarker in ccRCC and that high VSX1 expression promoted cell proliferation, invasion, and migration in ccRCC via transcriptional activation of downstream target genes.

Abstract Ferroptosis is a new form of programmed cell death, which achieved great breakthroughs in cell biology during past decade. However, the regulation of ferroptosis is yet to be identified thoroughly. The latest study published on Nature cell biology by Nguyen and colleagues found a new NADPH sensor, MARCHF6 an E3 ubiquitin ligase, mediates ferroptosis in tumor growth and animal development. This finding provides a novel insight into ubiquitin system and energy metabolism in regulation of ferroptosis, which may open up new avenues for tumor treatment.

Objective: Examine effect of sleep duration on children's risk of overweight and obesity; and study associations between activities in the last hour before bedtime and sleep outcomes (sleep duration, sleep quality, and sleep onset latency). Methods: Children's data were recruited using a questionnaire survey from a nationally representative sample of children (n = 10 279) in China in 2013‒2016. Mixed-effects models were used to test associations among variables stratified by sex. Results: Sleep duration was positively associated with BMI in boys (β = 0.04, P = 0.021). Girls with short sleep durations (< 8 h/d) tended to have higher BMI values than those with normal sleep durations (8‒9 h/d) (β = 0.12, P = 0.063). The top three activities were playing electronic devices (Factor 1), doing homework, and reading (combined as Factor 2). Factors 1 and 2 were both significantly associated with sleep duration (β = 0.17, P < 0.001; β = −0.26, P < 0.001, respectively). Conclusion: Sleep duration seems to affect BMI in Chinese children. Using electronic devices and reading before bedtime influenced sleep duration. Good bedtime habits and sleep duration can help weight management in children.

Abstract Spike sorting is a fundamental step in extracting single-unit activity from neural ensemble recordings, which play an important role in basic neuroscience and neurotechnologies. A few algorithms have been applied in spike sorting. However, when noise level or waveform similarity becomes relatively high, their robustness still faces a big challenge. In this study, we propose a spike sorting method combining Linear Discriminant Analysis (LDA) and Density Peaks (DP) for feature extraction and clustering. Relying on the joint optimization of LDA and DP: DP provides more accurate classification labels for LDA, LDA extracts more discriminative features to cluster for DP, and the algorithm achieves high performance after iteration. We first compared the proposed LDA-DP algorithm with several algorithms on one publicly available simulated dataset and one real rodent neural dataset with different noise levels. We further demonstrated the performance of the LDA-DP method on a real neural dataset from non-human primates with more complex distribution characteristics. The results show that our LDA-DP algorithm extracts a more discriminative feature subspace and achieves better cluster quality than previously established methods in both simulated and real data. Especially in the neural recordings with high noise levels or waveform similarity, the LDA-DP still yields a robust performance with automatic detection of the number of clusters. The proposed LDA-DP algorithm achieved high sorting accuracy and robustness to noise, which offers a promising tool for spike sorting and facilitates the following analysis of neural population activity.

Abstract The case assignment system is an essential system of case management and assignment within the procuratorate and is an important aspect of judicial fairness and efficiency. However, existing methods mostly use manual or random case assignment, which leads to unbalanced case distribution. Moreover, the relationship between prosecutors and case categories usually shows a power-law distribution in real-world data. Therefore, in this paper, we describe the case rationality assignment as a recommendation problem under the power-law distributed data. To solve the above problems, we propose an end-to-end Self-supervised Graph neural network model with Pre-training Generative learning for Recommendation (SGPGRec), the main idea of which is to capture self-supervised signals using intra-node features and inter-node correlations in the data, and generate the data representation by pre-training to improve the recommendation results. To be specific, we designed three auxiliary self-supervised tasks based on the prosecutor-case category interaction graph and the data distribution to obtain feature representations of prosecutors, case categories, and the interaction information between them. Then we constructed an end-to-end graph neural network recommendation model by the interaction information based on the data characteristics of the power-law distribution. Finally, extensive experimental consistency on a real-world dataset from three procuratorates shows that our method is effective compared to several yet competing baseline methods and further supports the development of an intelligent case assignment system with adequate performance.

Abstract Topological insulators (TIs) have attracted significant attention in photonics and acoustics due to their unique physical properties and promising applications. Electronics has recently emerged as an exciting arena to study various topological phenomena because of its advantages in building complex topological structures. Here, we explore TIs on an integrated circuit (IC) platform with a standard complementary metal-oxide-semiconductor technology. Based on the Su–Schrieffer–Heeger model, we design a fully integrated topological circuit chain using multiple capacitively-coupled inductor–capacitor resonators. We perform comprehensive post-layout simulations on its physical layout to observe and evaluate the salient topological features. Our results demonstrate the existence of the topological edge state and the remarkable robustness of the edge state against various defects. Our work shows the feasibility and promise of studying TIs with IC technology, paving the way for future explorations of large-scale topological electronics on the scalable IC platform.

Abstract Migraine is the second most common form of headache disorder and the second leading cause of disability worldwide. Cognitive symptoms ranked second resulting in migraine-related disability, after pain. P2X7 receptor (P2X7R) was recently shown to be involved in hyperalgesia in migraine. However, the role of P2X7R in migraine-related cognitive impairment is still ill-defined. The aim of this study was to explore the molecular mechanisms underlying migraine-related cognitive impairment and the role of P2X7R in it. Here we used a well-established mouse model of migraine that triggered migraine attacks by application of inflammatory soup (IS) to the dura. Our results showed that repeated dural IS stimulation triggered upregulation of P2X7R, activation of NLRP3 inflammasome, release of proinflammatory cytokines (IL-1β and IL-18) and activation of pyroptotic cell death pathway. Gliosis (microgliosis and astrogliosis), neuronal loss and cognitive impairment also occurred in the IS-induced migraine model. No significant apoptosis or whiter matter damage was observed following IS-induced migraine attacks. These pathological changes occurred mainly in the cerebral cortex and to a less extent in the hippocampus, all of which can be prevented by pretreatment with a specific P2X7R antagonist Brilliant Blue G (BBG). Moreover, BBG can alleviate cognitive impairment following dural IS stimulation. These results identified P2X7R as a key contributor to migraine-related cognitive impairment and may represent a potential therapeutic target for mitigating cognitive impairment in migraine.

Abstract Toxoplasma gondii, one of the important zoonotic parasites, has been detected in lots of hosts including humans, with a widespread prevalence. The products of equids, such as meat and milk, have been closely related to humans’ life. As the intermediate hosts, little is known about equids toxoplasmosis in Jilin province. Therefore, the present study aimed to evaluate the occurrence and risk factors of Toxoplasma gondii infections in equids from Jilin, northeastern China. In this study, a total of 245 blood samples of equids (192 horses, 25 donkeys and 28 mules) were collected from six localities in Jilin Province from March 2018 to August 2020 and detected by PCR. The occurrence rate of T. gondii B1 gene was analyzed using multivariable logistic regression to evaluate risk factors associated with the positive rates in equids. Among 245equids, T. gondii molecular occurrence was 9.0% (22/245). The highest positive rate was observed in equids from Dongfeng (16.3%) followed by Taonan (10.0%), Wangqing (8.3%), Antu (8.0%), Tonghua (8.0%) and Shulan (2.3%). Statistical analysis revealed that farming model and region may be two main risk factors. Data analysis indicated that the positive rate in captive farm (3.2%, 95% CI: 0.0–6.7%) was significantly lower than those in cage-free farm (P

Abstract In this study, we investigated the process of preconcentrate and determine trace amounts of Auramine O (AO) and methylene blue (MB) dyes in environmental water samples. For this purpose, the ultrasound-assisted dispersive-magnetic nanocomposites-solid-phase microextraction (UA-DMNSPME) method was performed to extract AO and MB from aqueous samples by applying magnesium oxide nanoparticles (MgO-NPs). The proposed technique is low-cost, facile, fast, and compatible with many existing instrumental methods. Parameters affecting the extraction of AO and MB were optimized using response surface methodology (RSM). Short extraction time, low experimental tests, low consumption of organic solvent, low limits of detection (LOD), and high preconcentration factor (PF) was the advantages of method. The PF was 44.5, and LOD for AO and MB was 0.33 ng mL−1 and 1.66 ng mL−1, respectively. The linear range of this method for AO and MB were 1–1000 ng mL−1 and 5–2000 ng mL−1, respectively. In addition, the relative standard deviation (RSD; n = 5) of the mentioned analytes was between 2.9% and 3.1%. The adsorption–desorption studies showed that the efficiency of adsorbent extraction had not declined significantly up to 6 recycling runs, and the adsorbent could be used several times. The interference studies revealed that the presence of different ions did not interfere substantially with the extraction and determination of AO and MB. Therefore, UA-DMNSPME-UV/Vis method can be proposed as an efficient method for preconcentration and extraction of AO and MB from water and wastewater samples.

Abstract Evidence from previous epidemiological studies on the effect of physical activity on the risk of Alzheimer’s disease (AD) is conflicting. We performed a two-sample Mendelian randomization analysis to verify whether physical activity is causally associated with AD. This study used two-sample Mendelian randomization (MR) analysis to estimate the association between physical activity (including overall activity, sedentary behavior, walking, and moderate-intensity activity) and AD. Genetic instruments for physical activity were obtained from published genome-wide association studies (GWAS) including 91,105 individuals from UK Biobank. Summary-level GWAS data were extracted from the International Genomics of Alzheimer’s Project IGAP (21,982 patients with AD and 41,944 controls). Inverse Variance Weighted (IVW) was used to estimate the effect of physical activity on AD. Sensitivity analyses including weighted median, MR-Egger, MR-PRESSO, and leave-one-out analysis were used to estimate pleiotropy and heterogeneity. Mendelian randomization evidences suggested a protective relationship between walking and AD (odds ratio (OR) = 0.30, 95% confidence interval (CI), 0.13–0.68, P = 0.0039). Genetically predicted overall activity, sedentary behavior, and moderate-intensity activity were not associated with AD. In summary, this study provided evidence that genetically predicted walking might associate with a reduced risk of AD. Further research into the causal association between physical activity and AD could help to explore the real relationship and provide more measures to reduce AD risk.

Abstract Prostate cancer (PCa) affects millions of men globally. Due to advances in understanding genomic landscapes and biological functions, the treatment of PCa continues to improve. Recently, various new classes of agents, which include next-generation androgen receptor (AR) signaling inhibitors (abiraterone, enzalutamide, apalutamide, and darolutamide), bone-targeting agents (radium-223 chloride, zoledronic acid), and poly(ADP-ribose) polymerase (PARP) inhibitors (olaparib, rucaparib, and talazoparib) have been developed to treat PCa. Agents targeting other signaling pathways, including cyclin-dependent kinase (CDK)4/6, Ak strain transforming (AKT), wingless-type protein (WNT), and epigenetic marks, have successively entered clinical trials. Furthermore, prostate-specific membrane antigen (PSMA) targeting agents such as 177Lu-PSMA-617 are promising theranostics that could improve both diagnostic accuracy and therapeutic efficacy. Advanced clinical studies with immune checkpoint inhibitors (ICIs) have shown limited benefits in PCa, whereas subgroups of PCa with mismatch repair (MMR) or CDK12 inactivation may benefit from ICIs treatment. In this review, we summarized the targeted agents of PCa in clinical trials and their underlying mechanisms, and further discussed their limitations and future directions.

Abstract Factories swiftly and precisely grasp the real-time data of the production instrumentation, which is the foundation for the development and progress of industrial intelligence in industrial production. Weather, light, angle, and other unknown circumstances, on the other hand, impair the image quality of meter dials in natural environments, resulting in poor dial image quality. The remote meter reading system has trouble recognizing dial pictures in extreme settings, challenging it to meet industrial production demands. This paper provides multiple attention and encoder–decoder-based gas meter recognition networks (MAEDR) for this problem. First, from the acquired dial photos, the dial images with extreme conditions such as overexposure, artifacts, blurring, incomplete display of characters, and occlusion are chosen to generate the gas meter dataset. Then, a new character recognition network is proposed utilizing multiple attention and an encoder–decoder structure. Convolutional neural networks (CNN) extract visual features from dial images, encode visual features employing multi-head self-attention and position information, and facilitate feature alignment using the connectionist temporal classification (CTC) method. A novel two-step attention decoder is presented to improve the accuracy of recognition results. convolutional block attention module (CBAM) reweights the visual features from the CNN and the semantic features computed by the encoder to improve model performance; long short-term memory attention (LSTM attention) focuses on the relationship between feature sequences. According to experimental data, our system can effectively and efficiently identify industrial gas meter picture digits with 91.1% identification accuracy, faster inference speed, and higher accuracy than standard algorithms. The accuracy and practicality of the recognition can fulfill the needs of instrument data detection and recognition in industrial production, and it has a wide range of applications.

CD8+ exhausted T cells (Tex) are heterogeneous. PD-1 inhibitors reinvigorate progenitor Tex, which subsequently differentiate into irresponsive terminal Tex. The ability to maintain a capacity for durable proliferation of progenitor Tex is important, but the mechanism remains unclear. Here, we showed CD8+ progenitor Tex pretreated with decitabine, a low-dose DNA demethylating agent, had enhanced proliferation and effector function against tumors after anti–PD-1 treatment in vitro. Treatment with decitabine plus anti–PD-1 promoted the activation and expansion of tumor-infiltrated CD8+ progenitor Tex and efficiently suppressed tumor growth in multiple tumor models. Transcriptional and epigenetic profiling of tumor-infiltrated T cells demonstrated that the combination of decitabine plus anti–PD-1 markedly elevated the clonal expansion and cytolytic activity of progenitor Tex compared with anti–PD-1 monotherapy and restrained CD8+ T cell terminal differentiation. Strikingly, decitabine plus anti–PD-1 sustained the expression and activity of the AP-1 transcription factor JunD, which was reduced following PD-1 blockade therapy. Downregulation of JunD repressed T cell proliferation, and activation of JNK/AP-1 signaling in CD8+ T cells enhanced the antitumor capacity of PD-1 inhibitors. Together, epigenetic agents remodel CD8+ progenitor Tex populations and improve responsiveness to anti–PD-1 therapy.

Objectives The aims of the study were to assess the management of low-density lipoprotein cholesterol (LDL-C) and the goal achievement, as well as to investigate the association between baseline LDL-C level, lipid-lowering treatment (LLT), and stroke recurrence in patients with ischaemic stroke or transient ischaemic attack (TIA).Design Our study was a post hoc analysis of the Third China National Stroke Registry (CNSR-III).Setting We derived data from the CNSR-III - a nationwide clinical registry of ischaemic stroke and TIA based on 201 participating hospitals in mainland China.Participants 15,166 patients were included in this study with demographic characteristics, etiology, imaging, and biological markers from August 2015 to March 2018.Primary and secondary outcome measures The primary outcome was a new stroke, LDL-C goal (LDL-C

During October 2020, we identified 13 highly pathogenic avian influenza A(H5N8) clade 2.3.4.4b viruses from wild ducks in Ningxia, China. These viruses were genetically related to H5N8 viruses circulating mainly in poultry in Europe during early 2020. We also determined movements of H5N8 virus‒infected wild ducks and evidence for spreading of viruses.

Abstract Sparganium longifolium was reported as a hybrid between S. emersum and S. gramineum based on its intermediate type or the common characteristics of its parent species. Its hybrid origin needs to be confirmed using molecular technology. We investigated the origin of S. longifolium based on 10 populations of S. emersum, S. gramineum and S. longifolium from five lakes in European Russia, using sequences of six nuclear loci and one chloroplast DNA fragment. Haplotype network, principal coordinate analysis and genetic clustering based on data of nuclear loci confirmed that S. longifolium is the hybrid between S. emersum and S. gramineum. We found that the natural hybridization between S. emersum and S. gramineum is bidirectional but asymmetrical, and the latter mainly acts as maternal species. We also found that all samples of S. longifolium were F1 generations, and thus hypothesized that S. emersum and S. gramineum could likely maintain their species boundary through the post-zygote reproductive isolation mechanism of F1 generation sterility.

Abstract Background Limited data exist regarding the potential impact of assisted reproductive technology (ART) on cardiac remodeling. In particular, whether different ART techniques are related to different cardiac alterations remains unclear. We aimed to evaluate cardiac changes in fetuses and infants arising from ART and fetal cardiac alterations in fetuses conceived by specific ART procedures. Methods This prospective and observational cohort study recruited 111 fetuses conceived by ART and 106 spontaneously conceived controls between December 2017 and April 2019. Echocardiography was performed between 28+0 and 32+6 weeks-of-gestation and at 0–2 and 6 months after birth. Results A total of 88 ART fetuses and 85 controls were included in the final analysis. Compared to controls, ART fetuses demonstrated a globular enlarged left ventricle (LV) (LV sphericity index of mid-section, 2.29 ± 0.34 vs. 2.45 ± 0.39, P = 0.006; LV area, 262.33 ± 45.96 mm2 vs. 244.25 ± 47.13 mm2, P = 0.002), a larger right ventricle (RV) (RV area, 236.10 ± 38.63 mm2 vs. 221.14 ± 42.60 mm2, P = 0.003) and reduced LV systolic deformation (LV global longitudinal strain (GLS), −19.56% ± 1.90% vs. −20.65% ± 1.88%, P = 0.013; LV GLS rate S, −3.32 ± 0.36 s-1 vs. −3.58 ± 0.39 s-1, P = 0.023). There were no significant differences between the ART and control groups at postnatal follow-ups. Furthermore, we found fetal cardiac morphometry and function were comparable between different ART procedures. Compared to controls, the fetuses derived from various ART procedures all exhibited impairments in the LV GLS and the LV GLS rate S. Conclusions Our analysis demonstrated that subclinical cardiac remodeling and dysfunction were evident in ART fetuses, although these alterations did not persist in early infancy. In addition, various ART procedures may cause the same unfavorable changes in the fetal heart. Trial registration This trial was registered at the Chinese Clinical Trial Registry ( www.chictr.org.cn ) ( ChiCTR1900021672 ) on March 4, 2019, retrospectively registered.

Objective The goal of this study was to investigate the effect of the Toll-like receptor-4 (TLR-4) inhibitor TAK-242 on bone resorption in severe periodontitis in rats in order to provide an experimental basis for finding new adjuvant treatments for severe periodontitis.Methods Eighteen three-week-old male Wistar rats were randomly divided into three groups (n=6). One group was the control group, and the other two groups were modelled with severe periodontitis in bilateral maxillary molars ligated with 5-0 silk thread containing P. gingivalis ATCC33277 (periodontitis and TAK-242 groups, respectively). The TAK-242 group was injected with TAK-242 (2 mg/kg) in DMSO every other day through the tail vein from the first day of silk ligation, and the other two groups were injected with DMSO solvent at the same proportion of body weight for 8 consecutive weeks. At the end of the 8th week, rats in the 3 groups were sacrificed, and maxillary specimens were taken. Three-dimensional reconstruction was achieved after micro-CT scanning to measure the distance between the enamel cementum boundary and alveolar crest at specific sites to assess the amount of bone loss. The parameters related to alveolar bone and bone microstructure were analyzed, and the pathological changes of periodontal tissue were observed by hematoxylin-eosin (HE) staining. Alveolar bone resorption was observed by Methyl Green staining, and the distribution of osteoclasts was observed by anti-tartrate acid phosphatase double staining (TRAP).Results Micro-CT quantitative analysis showed that alveolar bone resorption in the periodontitis group and TAK-242 group was significantly higher than that in the control group. Compared with the periodontitis group, bone loss of the mesial and distal root resorption sites of maxillary first molars was significantly reduced in the TAK-242 group (P < 0.001), the bone mineral density (P < 0.05) and bone volume/total volume fraction (P < 0.01) were significantly increased, and the number of trabeculae and the trabeculae thickness (P < 0.01) were relatively increased. The trabecular separation (P < 0.01) and trabecular structure model index were significantly decreased. In the periodontitis group, the bone exhibited a sparse and porous honeycomb structure, with deterioration of the trabecular structure and a shift towards a rod-strength structure. In the TAK-242 group, the bone microstructure was improved, the bone volume was enriched, the distribution of trabeculae was relatively denser and the trabecular structure shared more similarities with the control group. HE staining displayed that the attachment loss and bone absorption were significantly higher in the periodontitis group and TAK-242 group than in the control group. Compared with the periodontitis group, MG staining displayed significantly alleviated bone absorption in the TAK-242 group. TRAP staining showed that osteoclast infiltration decreased in the TAK-242 group compared with the periodontitis group (P < 0.001).Conclusions The TLR-4 inhibitor TAK-242 can alleviate bone resorption in severe periodontitis and improve the porous, sparse and disorganized inflammatory bone trabecular structure in rats.

Abstract Compound Kushen injection (CKI) is the most widely used traditional Chinese medicine preparation for the comprehensive treatment of colorectal cancer (CRC) in China, but its underlying molecular mechanisms of action are still unclear. The present study employed a network pharmacology approach, in which we constructed a “bioactive compound-target-pathway” network. Experimental RNA sequencing (RNA-Seq) analysis was performed to identify a key “bioactive compound-target-pathway” network for subsequent experimental validation. Cell cycle, proliferation, autophagy, and apoptosis assays and a model of azoxymethane/dextran sodium sulfate-induced colorectal carcinogenesis in mice were employed to detect the biological effect of CKI on CRC. Real-time reverse-transcription polymerase chain reaction, Western blot, and immunohistochemistry were performed to verify the selected targets and pathways. We constructed a predicted network that included 82 bioactive compounds, 34 targets, and 33 pathways and further screened an anti-CRC CKI “biological compound (hesperetin 7-O-rutinoside, genistein 7-O-rutinoside, and trifolirhizin)-target (p53 and checkpoint kinase 1 [CHEK1])” network that targeted the “cell cycle pathway”. Validation experiments showed that CKI effectively induced the cell-cycle arrest of CRC cells in vitro and suppressed the development of CRC in vivo by downregulating the expression of p53 and CHEK1. Our findings confirmed that inducing cell-cycle arrest by CKI is an important mechanism of its anti-CRC action, which provides a direct and scientific experimental basis for the clinical application of CKI.

Abstract After the spread of COVID-19, surgical masks became highly recommended to the public. They tend to be handled and used multiple times, which may impact their performance. To evaluate this risk, surgical masks of Type IIR were submitted to four simulated treatments: folding, ageing with artificial saliva or sweat and washing cycles. The air permeability, mechanical integrity, electrostatic potential, and filtration efficiency (FE) of the masks were measured to quantify possible degradation. Overall, air permeability and mechanical integrity were not affected, except after washing, which slightly degraded the filtering layers. Electrostatic potential and FE showed a strong correlation, highlighting the role of electrostatic charges on small particle filtration. A slight decrease in FE for 100 nm particles was found, from 74.4% for the reference masks to 70.6% for the mask treated in saliva for 8 h. A strong effect was observed for washed masks, resulting in FE of 46.9% (± 9.5%), comparable to that of a control group with no electrostatic charges. A dry store and reuse strategy could thus be envisaged for the public if safety in terms of viral and bacterial charge is ensured, whereas washing strongly impacts FE and is not recommended.