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Fibrosis is significantly associated with a wide variety of diseases and is involved in their progression. Fibrosis activated under the influence of different combinations of factors is considered a double-edged sword. Although there has been much research on organ fibrosis in recent years, a variety of organ fibrosis diseases and cancers are not well controlled in terms of prevention, treatment, and prognosis. Clinical studies still lack exploration and discovery of effective targets for the pathogenesis of organ fibrosis. Prolyl 4-hydroxylase subunit alpha 1 (P4HA1) is a protein kinase and the synthesis and secretion of collagen are related to the sustained activation of P4HA1. As further studies are being conducted, the potential role of P4HA1 in the development of fibrosis-associated diseases and cancer is becoming clear. Consequently, we conducted a systematic review and discussion on the role of P4HA1 in the pathogenesis of various fibrosis-related diseases and cancers. We reviewed the possible strategies of P4HA1 in the diagnosis and treatment of fibrosis-related diseases and cancers, and analyzed its potential relevance as a biomarker in the diagnosis and treatment of fibrosis-related diseases and cancer.

Donkey milk has attracted attention due to its distinctive nutritional composition and potential health advantages, particularly because of its whey protein content, which includes lysozyme, α-lactalbumin, lactoferrin, and β-lactoglobulin and vitamin C, among other components. These elements contribute to immunoregulatory, antimicrobial, antioxidant, and anti-inflammatory properties, positioning donkey milk as a possible therapeutic option. In addition, due to the low levels of caseins, the casein-to-whey protein ratio, and the β-lactoglobulin content in donkey milk, it presents an optimal alternative for infant formula for individuals with cow’s milk allergies. Moreover, research into donkey milk’s potential for cancer prevention, diabetes management, and as a treatment for various diseases is ongoing, thanks to its bioactive peptides and components. Nevertheless, challenges such as its low production yield and the not fully understood mechanisms behind its potential therapeutic role necessitate more thorough investigation. This review consolidates the existing knowledge on the therapeutic possibilities of donkey milk, emphasizing its importance for human health and the need for more detailed studies to confirm its health benefits.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is characterized by a widespread maculopapular rash, lymphadenopathy, fever, and multisystem involvement. Conversely, hemophagocytic lymphohistiocytosis (HLH) is an infrequent yet critical condition presenting with fever, hepatosplenomegaly, cytopenias, coagulation abnormalities, and elevated inflammatory markers. The overlapping clinical and laboratory features between DRESS and HLH poses a significant diagnostic challenge. Secondary HLH (sHLH) typically occurs in adults triggered by viral infections, malignancies, rheumatologic diseases, or immune deficiencies. Recently, COVID-19 has also been identified as one of the triggers for sHLH. Herein, we present a case of Sulfasalazine-induced DRESS coinfected with COVID-19 that subsequently progressed into HLH. Our patient exhibited common hepatorenal and splenic involvement along with rare cholecystitis and appendicitis. However, a significant improvement was observed upon the addition of etoposide and azathioprine. We hypothesize that excessive activation of the immune system and cytokine storm due to DRESS combined with COVID-19 infection led to more extensive systemic damage resulting in HLH development. This highlights the potential for severe consequences when DRESS coincides with HLH during a COVID-19 infection.

In rice cultivation, the traits of semi-dwarfism and glutinous texture are pivotal for optimizing yield potential and grain quality, respectively. Xiangdaowan (XDW) rice, renowned for its exceptional aromatic properties, has faced challenges due to its tall stature and high amylose content, resulting in poor lodging resistance and suboptimal culinary attributes. To address these issues, we employed CRISPR/Cas9 technology to precisely edit the SD1 and Wx genes in XDW rice, leading to the development of stable genetically homozygous lines with desired semi-dwarf and glutinous characteristics. The sd1-wx mutant lines exhibited reduced gibberellin content, plant height, and amylose content, while maintaining hardly changed germination rate and other key agronomic traits. Importantly, our study demonstrated that exogenous GA3 application effectively promoted growth by compensating for the deficiency of endogenous gibberellin. Based on this, a semi-dwarf glutinous elite rice (Oryza sativa L.) Lines was developed without too much effect on most agronomic traits. Furthermore, a comparative transcriptome analysis unveiled that differentially expressed genes (DEGs) were primarily associated with the anchored component of the membrane, hydrogen peroxide catabolic process, peroxidase activity, terpene synthase activity, and apoplast. Additionally, terpene synthase genes involved in catalyzing the biosynthesis of diterpenoids to gibberellins were enriched and significantly down-regulated. This comprehensive study provides an efficient method for simultaneously enhancing rice plant height and quality, paving the way for the development of lodging-resistant and high-quality rice varieties.

BackgroundCoronary microvascular dysfunction (CMD) is associated with increased cardiovascular events in patients with angina with non-obstructive coronary (ANOCA), especially heart failure. Conventional echocardiography is difficult to identify early alterations in cardiac function due to CMD.MethodsWe recruited 78 ANOCA patients. All patients underwent conventional echocardiography examination, adenosine stress echocardiography and examination of coronary flow reserve (CFR) by transthoracic echocardiography. Based on the CFR results, patients were divided into the CMD group (CFR

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an aggressive variant of inflammatory myofibroblastic tumor (IMT) and has a poor prognosis. EIMS is characterized by epithelioid morphology, neutrophilic infiltrate and specific fusion partners of anaplastic lymphoma kinase (ALK). Despite no standard therapy for EIMS, ALK tyrosine kinase inhibitors (TKIs) are recommended for these tumors. The present case describes an abdominal mass that presented in a 31-year-old male. The patient suffered from recurrence and multiple metastases 2 months after surgery. Ensartinib was administered and RANBP2-ALK fusion was detected. A partial response has been observed for 4 months and there has been no recurrence. This study provided a successful case with sustained response of targeted therapy.

The distinctive flavor compounds of donkey meat are unknown. Accordingly, in the present study, the volatile compounds (VOCs) in the meat from SanFen (SF) and WuTou (WT) donkeys were comprehensively analyzed by gas chromatography–ion mobility spectrometry (GC-IMS) combined with multivariate analysis. A total of 38 VOCs, of which 33.33% were ketones, 28.89% were alcohols, 20.00% were aldehydes, and 2.22% were heterocycles, were identified. Ketones and alcohols were significantly more abundant for SF than for WT, whereas aldehydes showed the opposite trend. The donkey meats from the two strains were well differentiated using topographic plots, VOC fingerprinting, and multivariate analysis. A total of 17 different VOCs were identified as potential markers for distinguishing the different strains, including hexanal-m, 3-octenal, oct-1-en-3-ol, and pentanal-d. These results indicate that GC–IMS combined with multivariate analysis is a convenient and powerful method for characterizing and discriminating donkey meat.

As the third most common cancer and the second leading cause of cancer death worldwide, colorectal cancer (CRC) poses a serious threat to people’s health. In recent years, circRNA has been widely reported as a new biomarker in CRC, but a comprehensive summary and analysis is lacking. This study aims to evaluate the diagnostic, therapeutic and prognostic significance of circRNAs in CRC by systematically analysing their expression patterns, biological functions and clinical significance in CRC. The literature on circRNA in CRC was searched in the PubMed database and included for analysis after screening according to strict inclusion and exclusion criteria. The UALCAN online tool was used to obtain host gene expression data. The miRTargetLink 2.0 was used to predict target genes for miRNAs action in CRC patients. Cytoscape was used to construct circRNA-miRNA-mRNA interaction networks. From the 236 included papers, we identified 217 circRNAs and their associated 108 host genes and 145 miRNAs. Among the 145 miRNAs, 27 miRNAs had no corresponding target genes. After prediction of target genes and differential analysis, a total of 25 target genes were obtained and a circRNA-miRNA-mRNA interaction network was constructed. Among the 217 circRNAs, 74 were associated with diagnosis, 160 with treatment and 51 with prognosis. And 154 of them function as oncogenes while 58 as tumour suppressor genes. In addition, these circRNAs include 32 exosomal circRNAs, which have unique advantages as biomarkers. In total, we summarize and analyze the expression patterns, biological functions and clinical significance of circRNAs in CRC. In addition, we constructed some new circRNA-miRNA-mRNA regulatory axes based on the miRNAs sponged by circRNAs.

BackgroundEGFR exon 20 insertions (EGFR ex20ins) constitute a heterogeneous subset of EGFR-activating alterations. However, the effectiveness of standard therapy in patients with EGFR ex20ins remains poor.MethodsIn our study, we retrospectively collected next-generation sequencing (NGS) data from 7,831 Chinese NSCLC patients and analyzed the relationship between EGFR ex20ins variations and medical records.ResultsOur data showed that EGFR ex20ins account for up to 3.5% of all EGFR mutation non-small-cell lung cancer (NSCLC) patients and 1.6% of all NSCLC patients in China. Thirty-eight different variants of EGFR ex20ins were identified in 129 NSCLC patients. We observed that the patients with EGFR ex20ins may benefit from the anti-angiogenesis agents significantly (P = 0.027). In the EGFR ex20ins near-loop group, patients who received second-/third-generation EGFR-TKI therapy treatment as first-line treatment had a longer median progression-free survival (PFS) than those who initiated treatment with first-generation EGFR-TKI or chemotherapy. Patients with co-mutations of EGFR ex20ins near-loop and TP53 tended to have a shorter OS in second-/third-generation EGFR-TKI therapy (P = 0.039). Additionally, median PFS was significantly longer in patients harboring EGFR ex20ins far-loop variants who received chemotherapy as a first-line setting (P = 0.037).ConclusionsOverall survival was significantly longer in EGFR ex20ins patients with anti-angiogenesis agents. For the choice of first-line strategy, NSCLC with EGFR ex20ins near-loop variants may benefit from second-/third-generation EGFR-TKI, while patients harboring EGFR ex20ins far-loop variants might have better outcomes from chemotherapy. TP53 could serve as a potential predictive marker in poor prognosis for EGFR ex20ins near-loop patients.

BackgroundMultimorbidity, polypharmacy and inappropriate prescribing is common in elderly patients worldwide. We aimed to explore the current status of multimorbidity, polypharmacy and the appropriateness of pharmacological therapy among elderly patients with atrial fibrillation (AF) in China.Materials and methodsWe randomly selected 500 patients aged 65 years or older from the China AF Registry study. Multimorbidity was defined as ≥2 comorbidities and polypharmacy was defined as ≥5 long-term prescribed drugs. Appropriateness of prescribing was evaluated using the Screening Tool of Older People’s Prescriptions/Screening Tool to Alert to Right Treatment (STOPP/START) criteria version 2. Patients’ attitudes toward polypharmacy were evaluated by the Patients’ Attitudes Towards Deprescribing (PATD) questionnaire.ResultsAmong the 500 patients included (mean age 75.2 ± 6.7 years, 49.0% male), 98.0% had multimorbidity and 49.4% had polypharmacy. The prevalence of potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs) was 43.6% (n = 218) and 71.6% (n = 358), respectively. Traditional Chinese medicine attributed largely to PIMs. Anticoagulants were the most common PPOs. Many clinical factors increased the risk of PIMs and PPOs. However, polypharmacy increased the risk of PIMs (OR 2.70, 95%CI 1.78–4.11; p < 0.0001), but not PPOs. In addition, 73.7% patients with polypharmacy were willing to have one or more of their medications prescribed if advised by their doctor.ConclusionMultimorbidity and polypharmacy were highly prevalent in elderly patients with AF in China. A high prevalence of inappropriate prescribing was also observed. Therefore, much more attention should be paid to the serious health problem in the elderly population.

Radiotherapy for rectal cancer has received increasing research attention in recent years; however, no bibliometric assessment has been conducted on the progress of research in this field. This study aimed to visualize the research evolution and emerging research hotspots in the field of rectal cancer radiotherapy using bibliometric methods. Data were collected from the Web of Science Core Collection database, including countries, institutions, authors, keywords, and co-citations of references, and the CiteSpace software was used for bibliometric analysis. A total of 5,372 publications on radiotherapy for rectal cancer, published between January 2000 and January 2022, were included. An increasing trend in the number of published articles was observed. There is an overall upward trend in the number of publications published, with the US publishing the most in this field, followed by China and the Netherlands. Italian writer Vincenzo Valentini and German writer R. Sauer ranked first in terms of published articles and co-cited authors, respectively. Literature co-citation and keyword co-occurrence analyses showed that early studies focused on topics such as preoperative radiotherapy, combined radiotherapy and chemotherapy, and total mesorectal excision. In recent years, gradually increasing attention has been paid to short-course radiotherapy, x-ray brachytherapy, and stereotactic systemic radiotherapy. Burst analysis suggested that magnetic resonance (MR)-guided neoadjuvant radiotherapy studies, mechanistic studies, and clinical trials may emerge as new research hotspots. Rectal cancer radiotherapy has been widely studied and the research hotspots have considerably changed in recent years. Future research hotspots may include MR-guided neoadjuvant radiotherapy studies, mechanistic studies, and clinical trials.

Previous studies have demonstrated that short-term exposure to ambient air pollution was associated with hospital admissions for cardiovascular diseases, but the evidence of its effects on acute myocardial infarction (AMI) in East Asian countries is limited and inconsistent. We aimed to investigate the association between air pollution and AMI hospitalizations in Chongqing, China. This time-stratified case-crossover study included 872 patients with AMI from three hospitals in Chongqing from January 2015 to December 2016. Exposures were compared between days with AMI (case days) and days without AMI (control days). Spearman’s correlation coefficient was applied to explore the correlation between air pollutants and meteorological conditions. Conditional logistic regression was used to assess the associations between air pollution exposure with different lag periods and AMI hospitalizations. Stratification analysis was further implemented by sex, age, and season. Hospitalizations for AMI were signifficantly associated with air pollution. All analyzed air pollutants showed lag-specific at lag 0 day and lag 01 day, whereas a 10 μg/m3 increase of average concentrations in PM2.5, PM10, SO2, NO2, and CO was associated with 1.034% (95% CI: 1.003–1.067%), 1.035% (95% CI:1.015–1.056%), 1.231% (95% CI: 1.053–1.438%), 1.062% (95% CI: 1.018–1.107%), and 1.406% (95% CI: 1.059–1.866%) increase in hospitalizations for AMI, respectively. No effect modifications were detected for sex, age, and season. Our findings suggest that short-term exposure to PM2.5, PM10, SO2, NO2, and CO contributes to increase AMI hospitalizations, which have public health implications for primary prevention and emergency health services.

Calcium phosphate (CaP) is the principal inorganic constituent of bone and teeth in vertebrates and has various applications in biomedical areas. Among various types of CaPs, amorphous calcium phosphate (ACP) is considered to have superior bioactivity and biodegradability. With regard to the instability of ACP, the phosphorus-containing molecules are usually adopted to solve this issue, but the specific roles of the molecules in the formation of nano-sized CaP have not been clearly clarified yet. Herein, alendronate, cyclophosphamide, zoledronate, and foscarnet are selected as the model molecules, and theoretical calculations were performed to elucidate the interaction between calcium ions and different model molecules. Subsequently, CaPs were prepared with the addition of the phosphorus-containing molecules. It is found that cyclophosphamide has limited influence on the generation of CaPs due to their weak interaction. During the co-precipitation process of Ca2+ and PO43-, the competitive relation among alendronate, zoledronate, and foscarnet plays critical roles in the produced inorganic-organic complex. Moreover, the biocompatibility of CaPs was also systematically evaluated. The DFT calculation provides a convincing strategy for predicting the structure of CaPs with various additives. This work is promising for designing CaP-based multifunctional drug delivery systems and tissue engineering materials.

Background and AimsEmergency endoscopy is recommended for patients with acute esophageal variceal bleeding (EVB) and their prognosis has improved markedly over past decades due to the increased specialization of endoscopic practice. The study aimed to compare outcomes following emergency endoscopic injection sclerotherapy (EIS) and endoscopic variceal ligation (EVL) in cirrhotic patients with acute EVB.MethodsCirrhotic patients with acute EVB who underwent emergency endoscopy were retrospectively enrolled from 2013 to 2020 across 34 university hospitals from 30 cities. The primary outcome was the incidence of 5-day rebleeding after emergency endoscopy. Subgroup analysis was stratified by Child-Pugh class and bleeding history. A 1:1 propensity score matching (PSM) analysis was performed.ResultsA total of 1,017 and 382 patients were included in EIS group and EVL group, respectively. The 5-day rebleeding incidence was similar between EIS group and EVL group (4% vs. 5%, P = 0.45). The result remained the same after PSM (P = 1.00). Among Child-Pugh class A, B and C patients, there were no differences in the 5-day rebleeding incidence between the two groups after PSM (P = 0.25, 0.82, and 0.21, respectively). As for the patients with or without bleeding history, the differences between EIS group and EVL group were not significant after PSM (P = 1.00 and 0.26, respectively).ConclusionThe nationwide cohort study indicates that EIS and EVL are both efficient emergency endoscopic treatment strategies for acute EVB. EIS should not be dismissed as an economical and effective emergency endoscopic treatment strategy of acute EVB. ClincialTrials.gov number NCT04307264.

Heat cooking of meat gives it a specific taste and flavor which are favored by many consumers. While the characteristic taste components of chicken, duck, pig, and seafood have been studied, there is a lack of information about the molecular components that give donkey meat its unique taste. Here, the characterization profiles of raw donkey meat (RDM) and cooked donkey meat (CDM) meat by metabonomics and lipidomics. The results showed that a total of 186 metabolites belonging to 8 subclasses were identified in CDM and RDM, including carbohydrates (27.42%), amino acids (17.20%), lipids (13.44%), and nucleotides (9.14%). In total, 37 differential metabolites were identified between CDM and RDM. Among these, maltotriose, L-glutamate, and L-proline might predominantly contribute to the unique umami and sweet taste of donkey meat. Comprehensive biomarker screening detected 9 potential metabolite markers for the discrimination among RDM and CDM, including L-glutamate, gamma-aminobutyric acid, and butane-1, 2, 3, 4-tetrol. Moreover, a total of 992 and 1,022 lipids belonging to 12 subclasses were identified in RDM and CDM, respectively, mainly including triglycerides (TGs) and glycerophospholipids (GPs). Of these lipids, 116 were significantly different between CDM and RDM. The abundances of 61 TGs rich in saturated and monounsaturated fatty acids were retained in CDM, whereas the abundances of 37 GPs rich in polyunsaturated fatty acids were reduced, suggesting that TGs and GPs might be the predominant lipids for binding and generating aroma compounds, respectively. A total of 13 lipids were determined as potential markers for the discrimination among RDM and CDM, including PC(O-16:2/2:0), LPE(22:5/0:0), and PC(P-16:0/2:0). In conclusion, this study provided useful information about the metabolic and lipid profiles of donkey meat which may explain its unique taste and flavor, which could serve as a basis for the development and quality control of donkey meat and its products.

PurposeTo assess the ocular surface and meibomian gland (MG) of patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and to explore the effects of surgery for OSAHS on the ocular surface and MG.MethodsBased on the apnea hypopnea index (AHI), 21 patients with mild OSAHS (Group A, 5/h ≤ AHI < 15/h), 20 patients with moderate OSAHS (Group B, 15/h ≤ AHI < 30/h), 62 patients with severe OSAHS (Group C, AHI ≥ 30/h) were examined. The ocular surface and MG were evaluated using Keratograph 5M. In addition, detailed Ophthalmic examination including visual acuity, refraction, slit-lamp examination of the anterior segment, corneal fluorescein staining (CFS), ocular surface disease index (OSDI) scoring, Schirmer I test (SIT) and serum lipid measurement was performed. For OSAHS patients with dry eye syndrome (DES) who underwent uvulopalatopharyngoplasty for improving AHI, the conditions of the ocular surface and MG were compared before surgery and 3 months after surgery. Only the data of the right eyes were analyzed.ResultsThere were no significantly different in the OSDI score, tear meniscus height (TMH), or loss ratio of the lower eyelid (LRLE) among these groups. The first non-invasive tear film breakup time (fNIBUT), average non-invasive tear film breakup time (avNIBUT), bulbar redness index (BRI), lipid layer grading (LLG), CFS, plugged orifices and distortion in MG, the loss ratio of upper eyelid (LRUE), and the incidence of DES, floppy eyelid syndrome (FES) and meibomian gland dysfunction (MGD) showed significant differences between Groups A and C (p = 0.015, p = 0.018, p < 0.001, p = 0.022, p = 0.036, p = 0.007, p = 0.019, p = 0.017, p = 0.045, p = 0.013, and p = 0.029, respectively). The SIT in the Group A was significantly higher than in Group B (p = 0.025) and in Group C (p < 0.001). In the correlation analyses, the fNIBUT, avNIBUT, SIT and LLG had negative correlations with the AHI (p = 0.013, p = 0.010, p = 0.003, p < 0.001, and p = 0.006, respectively). The BRI, CFS and LRUE were positively correlated with the AHI (p = 0.006, p = 0.007, and p = 0.046, respectively). Three months after surgery, there were no significant differences in the ocular surface or MG.ConclusionPatients with severe OSAHS have poor stability of tear film and are prone to lipid-deficient dry eye as a result of the loss of meibomian gland. By improving the AHI, the ocular surface damage of OSAHS patients cannot be reversed in a short time.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. Gemcitabine is the most commonly used chemotherapy for the treatment of PDAC, but the development of drug resistance still remains challenging. Recently, exosomes have emerged as important mediators for intercellular communication. Exosomes affect recipient cells’ behavior through the engulfed cargos, however the specific cargos responsible for gemcitabine resistance in PDAC are poorly understood. Here, we reported that exosomes could transfer gemcitabine resistance via a metalloproteinase 14 (MMP14)-dependent mechanism. MMP14 was identified as a major differentially secreted protein from the gemcitabine-resistant PDAC cells by comparative secretome. It was packaged into the exosomes and transmitted from the chemoresistant cells to the sensitive ones. The exosome-transferred MMP14 could enhance drug resistance and promotes the sphere-formation and migration abilities of the recipient sensitive PDAC cells. Mechanically, exosome-transferred MMP14 promotes the stability of CD44, the cancer stem cell marker in the recipient cells. Our results indicate that MMP14 is a key player for exosome-mediated transfer of gemcitabine resistance, thus targeting MMP14 in exosomes may represent a novel strategy to limit gemcitabine resistance in PDAC.

PurposeTo investigate the clinical characteristics of acute symptomatic seizures and the predictors of the development of epilepsy in patients with anti-NMDAR, anti-LGI1, and anti-GABABR encephalitis.MethodsWe retrospectively screened the medical records of 86 hospitalized patients with confirmed autoimmune encephalitis (AE). The clinical characteristics of acute symptomatic seizures were analyzed. The predictors of the development of epilepsy were investigated using logistic regression analysis.ResultsA total of 86 patients with AE were finally included. Eighty-six percent of patients (n = 74) experienced acute symptomatic seizures, and 28.4% of patients developed epilepsy during follow-up. Abnormal EEG findings were more frequent in AE patients with acute symptomatic seizures. A greater number of anti-seizure medications (ASMs), abnormal EEG findings, and delayed immunotherapy were found to be independently associated with the development of epilepsy.ConclusionAcute symptomatic seizures are a common manifestation in AE patients. During follow-up, 28.4% of AE patients developed epilepsy. The independent factors that predicted the development of epilepsy after the acute phase included a larger number of ASMs, EEG abnormalities, and delayed immunotherapy. In clinical practice, we should prioritize immunotherapy to control acute seizures as soon as possible. For AE patients with an increased risk of developing epilepsy, early withdrawal of ASM is not recommended.

Introduction:CHEK2 (Checkpoint kinase 2) germline mutations were associated with an elevated risk of breast cancer, colorectal cancer, and other familiar cancers. Loss-of-function variants in CHEK2 are known to be pathogenic. Germline CHEK2 mutations have also been observed in medulloblastoma and primary glioblastomas. Currently, there is no direct evidence supporting the relationship of CHEK2 with central nervous system tumors.Case presentation: A case of an oligodendroglioma patient harboring the germline CHEK2 p.R137* mutation was reported. CHEK2 p.R137* mutation occurred in the forkhead-associated domain. Given the absence of other known genetic predisposing risk factors, we considered that oligodendroglioma might be associated with the CHEK2 mutation. The patient in our case might have a high risk of breast cancer and other multiple primary tumors. Her siblings and offspring would have a 50% chance of having the same variant.Conclusion: We reported a case of an oligodendroglioma patient with a family history of gastrointestinal tumors harboring the germline CHEK2 pathogenic variation. This is the first report of the association between the CHEK2 pathogenic variation and brain tumors that warrants further validation in larger cohorts.

There has been a rapid development of biomimetic platforms using cell membranes as nanocarriers to camouflage nanoparticles for enhancing bio-interfacial capabilities. Various sources of cell membranes have been explored for natural functions such as circulation and targeting effect. Biomedical applications of cell membranes-based delivery systems are expanding from cancer to multiple diseases. However, the natural properties of cell membranes are still far from achieving desired functions and effects as a nanocarrier platform for various diseases. To obtain multi-functionality and multitasking in complex biological systems, various functionalized modifications of cell membranes are being developed based on physical, chemical, and biological methods. Notably, many research opportunities have been initiated at the interface of multi-technologies and cell membranes, opening a promising frontier in therapeutic applications. Herein, the current exploration of natural cell membrane functionality, the design principles for engineered cell membrane-based delivery systems, and the disease applications are reviewed, with a special focus on the emerging strategies in engineering approaches.

Short-term exposure to air pollution has been associated with ischemic stroke (IS) hospitalizations, but the evidence of its effects on IS in low- and middle-income countries is limited and inconsistent. We aimed to quantitatively estimate the association between air pollution and hospitalizations for IS in Chongqing, China. This time series study included 2,299 inpatients with IS from three hospitals in Chongqing from January 2015 to December 2016. Generalized linear regression models combined with a distributed lag nonlinear model (DLNM) were used to investigate the impact of air pollution on IS hospitalizations. Stratification analysis was further implemented by sex, age, and season. The maximum lag-specific and cumulative percentage changes of IS were 1.2% (95% CI: 0.4–2.1%, lag 3 day) and 3.6% (95% CI: 0.5–6.7%, lag 05 day) for each 10 μg/m3 increase in PM2.5; 1.0% (95% CI: 0.3–1.7%, lag 3 day) and 2.9% (95% CI: 0.6–5.2%, lag 05 day) for each 10 μg/m3 increase in PM10; 4.8% (95% CI: 0.1–9.7%, lag 4 day) for each 10 μg/m3 increase in SO2; 2.5% (95% CI: 0.3–4.7%, lag 3 day) and 8.2% (95% CI: 0.9–16.0%, lag 05 day) for each 10 μg/m3 increase in NO2; 0.7% (95% CI: 0.0–1.5%, lag 6 day) for each 10 μg/m3 increase in O3. No effect modifications were detected for sex, age, and season. Our findings suggest that short-term exposure to PM2.5, PM10, SO2, NO2, and O3 contributes to more IS hospitalizations, which warrant the government to take effective actions in addressing air pollution issues.

Largemouth bass virus (LMBV) is one of the most devastating viral pathogens in farmed Largemouth bass. Aptamers are novel molecule probes and have been widely applied in the field of efficient therapeutic and diagnostic agents development. LMBV-infected fathead minnow cells (LMBV-FHM) served as target cells in this study, and three DNA aptamers (LBVA1, LBVA2, and LBVA3) were generated against target cells by SELEX technology. The selected aptamers could specifically bind to LMBV-FHM cells, with rather high calculated dissociation constants (Kd) of 890.09, 517.22, and 249.31 nM for aptamers LBVA1, LBVA2, and LBVA3, respectively. Three aptamers displayed efficient antiviral activities in vitro. It indicates that the selected aptamers have great potentials in developing efficient anti-viruses treatments. The targets of aptamers LBVA1, LBVA2, and LBVA3 could be membrane proteins on host cells. The targets of aptamers (LBVA1, LBVA2, and LBVA3) come out on the cells surface at 8, 10, 8 h post-infection. As novel molecular probes for accurate recognition, aptamer LBVA3 could detect LMBV infection in vitro and in vivo, it indicates that the selected aptamers could be applied in the development of rapid detective technologies, which are characterized by high sensitivity, accuracy, and easy operation.

Despite that androgen-deprivation therapy results in long-lasting responses, the disease inevitably progresses to metastatic castration-resistant prostate cancer. In this study, we identified miR-33b-3p as a tumor suppressor in prostate cancer. miR-33b-3p was significantly reduced in prostate cancer tissues, and the low expression of miR-33b-3p was correlated with poor overall survival of prostate cancer patients. Overexpression of miR-33b-3p inhibited both migration and invasion of highly metastatic prostate cancer cells whereas inhibition of miR-33b-3p promoted those processes in lowly metastatic cells. The in vivo results demonstrate that miR-33b-3p suppresses metastasis of tail vein inoculated prostate cancer cells to lung and lymph nodes in mice. DOCK4 was validated as the direct target of miR-33b-3p. miR-33b-3p decreased the expression of DOCK4 and restoration of DOCK4 could rescue miR-33b-3p inhibition on cell migration and invasion. Moreover, downregulation of miR-33b-3p was induced by bortezomib, the clinically used proteasome inhibitor, and overexpression of miR-33b-3p enhanced the insufficient inhibition of bortezomib on migration and invasion as well as metastasis of prostate cancer cells. In summary, our findings demonstrate that miR-33b-3p suppresses metastasis by targeting DOCK4 in prostate cancer. Our results suggest that enhancing miR-33b-3p expression may provide a promising therapeutic strategy for overcoming that proteasome inhibitor’s poor efficacy against metastatic prostate cancer.

No study has examined myocardial work in subjects with cancer therapy-related cardiac dysfunction (CTRCD). Myocardial work, as a new ultrasonic indicator, reflects the metabolism and oxygen consumption of the left ventricle. The aim of this study was to test the relative value of new indices of myocardial work and global longitudinal strain (GLS) in detecting changes in myocardial function during the treatment of breast cancer by two-dimensional and three-dimensional echocardiography. We enrolled 79 breast cancer patients undergoing different tumor treatment regimens. Follow-up observation was conducted before and after chemotherapy. The effects of breast cancer chemotherapy and targeted therapy on the development of CTRCD [defined as an absolute reduction in left ventricular ejection fraction (LVEF) of >5% to

Abundant empirical research has demonstrated the relationship between parenting style and adolescent problematic online game use (POGU), but the direction and underlying mechanism of this association remain unclear. Using a 1-year longitudinal design across three time points, the present study explored interrelations among parenting styles, depressive symptoms, and POGU from the theoretical perspective of the developmental cascade model and examined whether depressive symptoms mediate the relationship between parenting style and POGU. A sample of 1,041 children was recruited from two junior middle schools in China, of which 46.3% were boys. Results confirmed the cascade effects and showed that the reciprocal effect of parenting style, depressive symptoms, and POGU was significant, and parental control and POGU can predict each other via depressive symptoms. Knowledge regarding the direct and underlying mechanisms between parenting style, depressive symptoms, and POGU provides reference suggestions for the prevention and intervention of adolescent depressive symptoms and problematic online game use.

Intramuscular fat (IMF) and visceral adipose tissue (VAT) are both lipids, but have significantly different deposition processes. Furthermore, the heterogeneity of lipid molecular characteristics and mechanisms is unclear. Accordingly, this study used non-targeted lipidomics and transcriptomics to analyze the lipid profiles and metabolism of longissimus dorsi muscle (LDM) and VAT from donkeys. A total of 1,146 and 1,134 lipids belonging to 18 subclasses were identified in LDM and VAT, respectively, with LDM having higher glycerophospholipid (GP) and lower glycerolipid (GL) contents. Polyunsaturated fatty acids (PUFAs) were distributed preferentially at the sn-1 positions in triglycerides (TGs), and sn-2 positions in phosphatidylcholine (PC) and phosphatidylethanolamine (PE). The percentage PUFA content in TGs was significantly lower in LDM than in VAT, while the opposite trend was observed for PUFAs in PC and PE. A total of 110 different lipid molecules (72 downregulated and 38 upregulated) were identified in LDM compared with VAT, of which 11 were considered potential lipid markers. These different lipids were involved in 17 metabolic pathways, including GL and GP metabolisms. Of the 578 differentially expressed genes screened, 311 were downregulated and 267 were upregulated in LDM compared with VAT. Enriched ontology analysis of the differentially expressed genes mainly involved sphingolipid signaling pathways, and GP, GL, and sphingolipid metabolisms. Overall, lipidomics and transcriptomics indicated differences in lipid profiles and metabolism in LDM and VAT, providing new perspectives for the study of heterogeneity in IMF and VAT.

Tongxinluo (TXL), a traditional Chinese medication, plays a key role in the formation and progression of plaques in atherosclerosis. The formation of foam cells by macrophages accelerates the destabilisation of plaques. In previous research, we had found that TXL significantly inhibits ox-LDL-induced apoptosis in macrophages in vitro by improving the dissociation of the Beclin-1-Bcl-2 complex. Therefore, here, we explored the effect of TXL on lipid metabolism in macrophages and the mechanism involved. To evaluate the role of TXL in atherosclerotic plaques, we construct the atherosclerotic animal model with lentiviral injection and performed immunofluorescence staining analysis in vivo. Western blot, immunofluorescence staining and microscopy were performed to elucidate the mechanism underlying TXL-mediated regulation of autophagy in THP-1 macrophages in vitro. Immunofluorescence assay revealed that TXL treatment inhibited lipid deposition in advanced atherosclerotic plaques. In vitro TXL treatment inhibited lipid deposition in THP-1 macrophages by enhancing autophagy via Beclin-1. TXL reversed the high expression of class I histone deacetylases (HDACs) induced by ox-LDL (p < 0.05). Compared with the TXL + ox-LDL group, TXL failed to promote intracellular lipid droplet decomposition after the addition of the histone deacetylase agonist. We found that TXL attenuates the accumulation of lipids in macrophage by enhancing Beclin-1-induced autophagy, and additionally, it inhibits the inhibitory effect of class I HDAC on the expression of Beclin-1.

After the biological pesticide Bacillus thuringiensis (Bt) is applied to the field, it has to remain on the surface of plants to have the insecticidal activities against insect pests. Bt can form biofilms on the surface of vegetable leaves, which were rich in polysaccharides. However, the relationship between polysaccharides of the leaves and the biofilm formation as well as the insecticidal activities of Bt is still unknown. Herein, this study focused on the effects of plant polysaccharides pectin and xylan on biofilm formation and the insecticidal activities of Bt strains. By adding pectin, there were 88 Bt strains with strong biofilm formation, 69 strains with weak biofilm formation, and 13 strains without biofilm formation. When xylan was added, 13 Bt strains formed strong biofilms, 98 strains formed weak biofilms, and 59 strains did not form biofilms. This indicated that two plant polysaccharides, especially pectin, modulate the biofilm formation of Bt strains. The ability of pectin to induce biofilm formation was not related to Bt serotypes. Pectin promoted the biofilms formed by Bt cells in the logarithmic growth phase and lysis phase at the air–liquid interface, while it inhibited the biofilms formed by Bt cells in the sporangial phase at the air–liquid interface. The dosage of pectin was positively correlated with the yield of biofilms formed by Bt cells in the logarithmic growth phase or lysis phase at the solid–liquid interfaces. Pectin did not change the free-living growth and the cell motility of Bt strains. Pectin can improve the biocontrol activities of the spore–insecticidal crystal protein mixture of Bt and BtK commercial insecticides, as well as the biofilms formed by the logarithmic growth phase or lysis phase of Bt cells. Our findings confirmed that plant polysaccharides modulate biofilm formation and insecticidal activities of Bt strains and built a foundation for the construction of biofilm-type Bt biopesticides.

Background:SCN1A and SCN2A genes have been reported to be associated with the efficacy of single and combined antiepileptic therapy, but the results remain contradictory. Previous meta-analyses on this topic mainly focused on the SCN1A rs3812718 polymorphism. However, meta-analyses focused on SCN1A rs2298771, SCN1A rs10188577, SCN2A rs17183814, or SCN2A rs2304016 polymorphisms are scarce or non-existent.Objective: We aimed to conduct a meta-analysis to determine the effects of SCN1A rs2298771, SCN1A rs10188577, SCN2A rs17183814, and SCN2A rs2304016 polymorphisms on resistance to antiepileptic drugs (AEDs).Methods: We searched the PubMed, Embase, Cochrane Library, WANFANG, and CNKI databases up to June 2020 to collect studies on the association of SCN1A and SCN2A polymorphisms with reactivity to AEDs. We calculated the pooled odds ratios (ORs) under the allelic, homozygous, heterozygous, dominant, and recessive genetic models to identify the association between the four single-nucleotide polymorphisms (SNPs) and resistance to AEDs.Results: Our meta-analysis included 19 eligible studies. The results showed that the SCN1A rs2298771 polymorphism was related to AED resistance in the allelic, homozygous, and recessive genetic models (G vs. A: OR = 1.20, 95% CI: 1.012–1.424; GG vs. AA: OR = 1.567, 95% CI: 1.147–2.142; GG vs. AA + AG: OR = 1.408, 95% CI: 1.053–1.882). The homozygous model remained significant after Bonferroni correction (P < 0.0125). Further subgroup analyses demonstrated the significance of the correlation in the dominant model in Caucasians (South Asians) after Bonferroni correction (GG + GA vs. AA: OR = 1.620, 95% CI: 1.165–2.252). However, no association between SCN1A rs2298771 polymorphism and resistance to AEDs was found in Asians or Caucasians (non-South Asians). For SCN1A rs10188577, SCN2A rs17183814, and SCN2A rs2304016 polymorphisms, the correlations with responsiveness to AEDs were not significant in the overall population nor in any subgroup after conducting the Bonferroni correction. The results for SCN1A rs2298771, SCN1A rs10188577, and SCN2A rs2304016 polymorphisms were stable and reliable according to sensitivity analysis and Begg and Egger tests. However, the results for SCN2A rs17183814 polymorphism have to be treated cautiously owing to the significant publication bias revealed by Begg and Egger tests.Conclusions: The present meta-analysis indicated that SCN1A rs2298771 polymorphism significantly affects resistance to AEDs in the overall population and Caucasians (South Asians). There were no significant correlations between SCN1A rs10188577, SCN2A rs17183814, and SCN2A rs2304016 polymorphisms and resistance to AEDs.

Mechanical stretch promotes deregulation of vascular smooth muscle cell (VSMC) functions during hypertension-induced vascular remodeling. ACE2 has a wide range of cardiovascular and renal protective effects. Loss of ACE2 is associated with cardiovascular disease, but little is known about the regulation of its expression, especially by abnormal mechanical stretch during hypertension. The present study was designed to investigate the contribution of ACE2 to vascular remodeling under mechanical stretch and to assess the possible underlying mechanisms. The abdominal aortic constriction model was established to mimic the environment in vivo. FX-5000T Strain Unit provided mechanical stretch in vitro. Overexpression was used to analyze the role of ACE2 played in the proliferation, migration, apoptosis, and collagen metabolism of the VSMCs. RT-qPCR, Western blot, luciferase assay, and ChIP assay were used to elucidate the molecular mechanism of ACE2 expression regulated by stretch. We found that mechanical stretch modulated the expression of the ACE2/Ang-(1–7) and ACE/AngII axis. ACE2 was mechanically sensitive and was involved in the stretch-induced dysfunction of VSMCs. The p38 MAPK/ATF3 pathway and miR-421 participated in the regulation of ACE2. Thus, ACE2 may contribute to the development of vascular remodeling under conditions of mechanical stretch.

Substitution of feed protein source with defatted black soldier fly larvae meal (BSFM) has been evaluated intensively in poultry, but information about full-fatted BSFM is still very limited. The aim of the present study was to investigate the effect of dietary low inclusion of full-fatted BSFM on the growth performance, plasma antioxidant ability, nutrient digestibility, and gut health of layer chickens during 1–42 days of age. A total of 480 female 1-day-old Hy-Line Brown chickens were divided into four dietary treatments, with the inclusion of 0, 3, 6, and 9% of full-fatted BSFM. Each treatment included six replicates and 20 birds per replicate. As dietary full-fatted BSFM inclusion levels increased, there was a quadratic increase in final weight and average daily gain and a quadratic decrease in feed/gain ratio. Dietary full-fatted BSFM inclusion levels increased the digestibility of crude protein and ether extract quadratically as well as ileum mucosal sIgA concentration linearly, but these had no effect on intestinal morphology. Additionally, an increase in dietary full-fatted BSFM inclusion levels resulted in a linear increase in glutathione peroxidase and total superoxide dismutase activities and a linear decrease in malondialdehyde content in plasma. The encouraging results of the improvement of growth performance, nutrient digestibility, antioxidant ability, and gut health parameters suggested that partially full-fatted BSFM inclusion can be suitable protein ingredients for layer chickens' diets at the starter period.

Cognitive impairment (CI) occurs in people with epilepsy, affecting their quality of life. This study aimed to identify factors associated with CI in adult patients with newly diagnosed epilepsy. Additionally, we sought to determine whether any particular cognitive function is impaired predominantly by anti-seizure medications or by other factors. We enrolled 229 patients with newly diagnosed epilepsy and 191 participants were followed up for 1 y. We used the Montreal Cognitive Assessment as a tool to quantify CI. The sub-item scores were also collected to assess whether any aspects of CI are predominantly affected by anti-seizure medication treatment. Subjective memory decline due to anti-seizure medications was also recorded. One-hundred-and-two participants (44.5%) had CI onset before anti-seizure medication treatment. Aging, low education level, stroke or brain surgery etiology, and anxious symptoms were identified as risk factors for CI before anti-seizure medications use. Brain surgery for the young, anxious status for the middle-aged, and depressive status for the elderly were risk factors for CI at different ages. The elderly PWE had worse memory than the others. PWE with TLE had worse cognition, especially in memory and naming. The overall impact of anti-seizure medications on cognition was mild. Refractory epilepsy was a predictor of cognitive decline. Subjective memory decline was predicted by high-risk treatment and by a finding of refractory epilepsy. Clarifying the risk factors for CI can help the physician to assess the probable risk of CI for each individual before the start of anti-seizure medication treatment, which may lead to better compliance.

Ovarian cancer is the leading cause of gynecologic cancer-related deaths. Emerging research has revealed a close relationship between circular RNAs (circRNAs) and ovarian cancer development, metastasis, and prognosis. The objective of our research was to further explore the relationship between circASH2L and ovarian cancer. Quantitative real-time polymerase chain reaction was used to detect the differential expression of circRNAs between normal ovaries and ovarian cancer tissues. The impact of circASH2L on the proliferation, invasion, and tumorigenicity of ovarian cancer cells was evaluated using gain- and loss-of-function experiments. The molecular mechanisms of circASH2L function were investigated using bioinformatics analysis, RNA fluorescence in situ hybridization, western blots, and dual-luciferase reporter assays. The results showed that circASH2L was remarkably upregulated in ovarian cancer. The invasion and growth of ovarian cancer cells were suppressed by circASH2L knockdown in vitro, and downregulation of circASH2L restrained both angiogenesis and lymphangiogenesis of tumor xenografts in vivo. Furthermore, circASH2L was mostly distributed in the cytoplasm, where it competes with vascular endothelial growth factor A (VEGFA) for binding to miR-665. These findings indicate that circASH2L has an oncogenic function in ovarian cancer. In conclusion, circASH2L plays a critical role in regulating ovarian cancer cell tumorigenesis, angiogenesis, and lymphangiogenesis through the miR-665/VEGFA axis and, therefore, is a possible candidate target for ovarian cancer treatment.

BackgroundSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) induced Coronavirus Disease 2019 (COVID-19) has posed a global threat to public health. The immune system is crucial in defending and eliminating the virus and infected cells. However, immune dysregulation may result in the rapid progression of COVID-19. Here, we evaluated the subsets, phenotypic and functional characteristics of natural killer (NK) and T cells in patients with COVID-19 and their associations with disease severity.MethodsDemographic and clinical data of COVID-19 patients enrolled in Wuhan Union Hospital from February 25 to February 27, 2020, were collected and analyzed. The phenotypic and functional characteristics of NK cells and T cells subsets in circulating blood and serum levels of cytokines were analyzed via flow cytometry. Then the LASSO logistic regression model was employed to predict risk factors for the severity of COVID-19.ResultsThe counts and percentages of NK cells, CD4+ T cells, CD8+ T cells and NKT cells were significantly reduced in patients with severe symptoms. The cytotoxic CD3-CD56dimCD16+ cell population significantly decreased, while the CD3-CD56dimCD16- part significantly increased in severe COVID-19 patients. More importantly, elevated expression of regulatory molecules, such as CD244 and programmed death-1 (PD-1), on NK cells and T cells, as well as decreased serum cytotoxic effector molecules including perforin and granzyme A, were detected in patients with COVID-19. The serum IL-6, IL-10, and TNF-α were significantly increased in severe patients. Moreover, the CD3-CD56dimCD16- cells were screened out as an influential factor in severe cases by LASSO logistic regression.ConclusionsThe functional exhaustion and other subset alteration of NK and T cells may contribute to the progression and improve the prognosis of COVID-19. Surveillance of lymphocyte subsets may in the future enable early screening for signs of critical illness and understanding the pathogenesis of this disease.

Singapore grouper iridovirus (SGIV) causes high mortality rates in mariculture, and effective treatments against SGIV infection are urgently required. Illicium verum Hook. f. (I. verum) is a well-known medicinal plant with a variety of biological activities. The natural ingredient quercetin isolated from I. verum could effectively inhibit SGIV infection in a dose-dependent manner. The possible antiviral mechanism of quercetin was further analyzed in this study. It showed that quercetin did obvious damages to SGIV particles. Furthermore, quercetin could interfere with SGIV binding to targets on host cells (by 76.14%), disturb SGIV invading into host cells (by 56.03%), and effect SGIV replication in host cells (by 52.73%), respectively. Quercetin had the best antiviral effects during the SGIV life cycle of binding to the receptors on host cells’ membranes. Overall, the results suggest that quercetin has direct and host-mediated antiviral effects against SGIV and holds great potential for developing effective drugs to control SGIV infection in aquaculture.

Reinforced concrete is one of the most critical composite materials in the modern civil engineering and can improve the tensile resistance of concrete. Its passivation film plays an important role in the durability of concrete and the steel corrosion. But, due to the size limitations, the destruction of micro-scale steel bars has not been well studied. In this work, the reactive molecular dynamics simulation was employed to studying the mechanical properties of the steel and its passivation film. The uniaxial stretching of different compounds of γ-FeOOH, γ-Fe2O3 and Fe was performed. We found that the oxidation can reduce the tensile strength of steel. For the three compounds of γ-FeOOH, γ-Fe2O3 and Fe, the order of tensile strength from high to low is Fe > γ-Fe2O3 > γ-FeOOH. But, the ductility of γ-FeOOH under x direction is increased. The detail microstructure analysis shown that the difference of tensile strength is origin from the coordination in the materials. The two kinds of stretching processes of whole system stretching (in the Fe phase and x direction of γ-FeOOH phase) and partly area stretching (in the Fe2O3 phase and z direction of γ-FeOOH phase) were clarified. The external force is dispersed in whole system stretching but opposite in partly area stretching. This investigation leads to possible new direction for studying the tensile strength of materials, and the strategy of evaluating materials tensile strength can supply valuable information in evaluating and improving the mechanical properties of reinforced concrete.

Objective: Data on changes in bone mineral density (BMD) from valproate (VPA) therapy are ambiguous and conflicting. Thus, the aim of this study was to systematically review the existing data and carry out a meta-analysis to investigate the effect of VPA as a monotherapy on BMD in people with epilepsy (PWE).Methods: We systematically searched PubMed, EMBASE, and MEDLINE for eligible studies. We calculated the standardized mean difference (SMD) with 95% confidence interval (CI) to investigate the statistical power of the association between VPA treatment and BMD.Results: Nineteen studies were included in this systematic review and meta-analysis. We found that BMD was lower in the VPA group than in the control group (SMD: −0.44; 95% CI: −0.65 to −0.22). A significant association was found in adult patients (SMD: −0.57; 95% CI: −0.88 to −0.26; I2 = 69.8%) and pediatric patients (SMD: −0.32; 95% CI: −0.60 to −0.03; I2 = 67.8%) by subgroup analysis. This study indicated that BMD was significantly lower in patients treated for more than 36 months than in controls (SMD: −0.52; 95% CI: −0.76 to −0.27; I2 = 61.8%). However, a significant difference was not found between patients who were treated for less than 36 months and controls (SMD: −0.36; 95% CI: −0.72 to 0.01; I2 = 74.8%).Conclusion and significance: The present study provided evidence that VPA treatment was significantly associated with BMD loss in PWE. Thus, for patients at a high risk of osteoporosis and fracture, especially for patients who need long-term treatment, VPA may not be a good choice.

Here, we describe the first case of familial hemiplegic migraine type 1 (FHM1) resulting from a T666M mutation in the CACNA1A gene of a Chinese individual. A 54-year-old female patient demonstrated extensive clinical manifestations, including transient paropsia, hemianesthesia, logaphasia, hemiplegia, migraine, fever, impaired consciousness, and progressive cerebellar ataxia. At admission, neurological examination showed a fever of 38.6°C, coma, bilateral pupillary constriction, left-sided deviation of both eyes, meningeal irritation, and bilateral positive Chaddock's sign. Brain magnetic resonance imaging (MRI) displayed only cerebellar atrophy. The pressure and white blood cells of the cerebrospinal fluid (CSF) were elevated. Her nine relatives also had similar clinical spectra. To further clarify the diagnosis, we conducted a genetic analysis on the family. The results of genetic testing showed that all seven living affected members carried the T666M mutation in the CACNA1A gene. This case report indicates that the diagnosis of FHM should be taken into account when a patient manifests migraine accompanied with hemiplegia, acute encephalopathy, and abnormal CSF. In addition, genetic testing is indispensable for the identification of some atypical attacks of hemiplegic migraine.

Background: In recent years, increasing attention has been paid to the association between C-reactive protein (CRP) levels and epilepsy. However, studies concerning CRP levels in epilepsy have also yielded conflicting results. Thus, the objective of the present study is to systematically review the evidence and conduct a meta-analysis to investigate CRP levels in epileptic patients compared with healthy controls.Methods: A systematic search of PubMed, EMBASE, and the Cochrane Library was performed for eligible studies. Standardized mean differences (SMDs) with 95% confidence intervals (95% CIs) were used as a measure to assess the association between CRP and epilepsy.Results: In total, 16 case–control studies were included in the present meta-analysis, which comprised 1918 individuals. Combined results indicated that epileptic patients had significantly increased CRP levels in peripheral blood compared with healthy controls (SMD = 0.43; 95% CI: 0.19–0.67). In addition, subgroup analyses by age demonstrated that significant differences in blood CRP levels between epileptic patients and healthy controls could be found in adults (SMD = 0.47; 95% CI: 0.21–0.73) but not children (SMD = 0.26; 95% CI: −0.48–0.99).Conclusion: The present meta-analysis shows that the CRP levels in peripheral blood were significantly increased in epileptic patients compared to healthy controls, indicating a significant association between inflammation and epilepsy. Epileptic seizures may be associated with the inflammatory response.

Background: Epilepsy is one of the most prevalent chronic brain diseases worldwide and is often accompanied by cognitive impairment. Event-related potentials (ERPs) are an objectively non-invasive approach for studying information processing and cognitive functions in the brain. The P300 is an important and extensively explored late component of ERPs that has been widely applied to assess cognitive function in epilepsy in previous studies. However, consistent conclusions have not yet been reached for various reasons.Objective: We conducted a comprehensive systematic review and meta-analysis of P300-related studies to assess the latency and amplitude of the P300 in epileptic patients.Methods: PubMed, EMBASE, and Cochrane Library databases were systematically searched for eligible studies. The standard mean difference (SMD) and the 95% confidence interval (CI) were calculated as the effect size of the P300 component.Results: The main results of the present meta-analysis indicated that epileptic patients have a longer P300 latency and a lower P300 amplitude than controls. Subgroup analysis based on age group demonstrated that these differences can be observed in both children and adult patients compared with healthy controls. In addition, the P300 latency was longer in patients with the five main types of epileptic seizures than in controls.Conclusion: This study revealed that epileptic patients have abnormalities in the P300 component, which may reflect deficits in cognitive function. Thus, the P300 may be a potential objective approach for evaluating cognitive function in epileptic patients.

Small peptides secreted to the extracellular matrix control many aspects of the plant’s physiological activities which were identified in Arabidopsis thaliana, called ATSPs. Here, we isolated and characterized the small peptide gene Bna.SP6 from Brassica napus. The BnaC.SP6 promoter was cloned and identified. Promoter deletion analysis suggested that the -447 to -375 and -210 to -135 regions are crucial for the silique septum and pollen expression of BnaC.SP6, respectively. Furthermore, the minimal promoter region of p158 (-210 to -52) was sufficient for driving gene expression specifically in pollen and highly conserved in Brassica species. In addition, BnaA.bZIP1 was predominantly expressed in anthers where BnaC.SP6 was also expressed, and was localized to the nuclei. BnaA.bZIP1 possessed transcriptional activation activity in yeast and protoplast system. It could specifically bind to the C-box in p158 in vitro, and negatively regulate p158 activity in vivo. BnaA.bZIP1 functions as a transcriptional repressor of BnaC.SP6 in pollen activity. These results provide novel insight into the transcriptional regulation of BnaC.SP6 in pollen activity and the pollen/anther-specific promoter regions of BnaC.SP6 may have their potential agricultural application for new male sterility line generation.

BackgroundIn the tumor microenvironment (TME), the transforming growth factor-β (TGF-β) and programmed cell death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling axes are complementary, nonredundant immunosuppressive signaling pathways. Studies have revealed that active TGF-β is mainly released from the glycoprotein A repetitions predominant (GARP)-TGF-β complex on the surface of activated regulatory T cells (Tregs), B cells, natural killer (NK) cells, and tumor cells. The currently available antibodies or fusion proteins that target TGF-β are limited in their abilities to simultaneously block TGF-β release and neutralize active TGF-β in the TME, thus limiting their antitumor effects.MethodsWe designed and constructed a bispecific, trifunctional antibody, namely, BPB-101, that specifically targets the GARP-TGF-β complex and/or small latent complex (SLC), active TGF-β, and PD-L1. The binding ability of BPB-101 to the different antigens was determined by ELISA, FACS, and biolayer interferometry (BLI). The blocking ability of BPB-101 to the TGF-β and PD-1/PD-L1 signaling axes was determined by reporter gene assay (RGA). The antitumor effect and biosafety of BPB-101 were determined in a transgenic mouse tumor model and cynomolgus monkeys, respectively. Stability assessments, including stability in serum, after exposure to light, after repeated freeze-thaw cycles, and after high-temperature stress tests had been completed to evaluate the stability of BPB-101.ResultsBPB-101 bound efficiently to different antigenic proteins: the GARP-TGF-β complex and/or SLC, active TGF-β, and PD-L1. Data showed that BPB-101 not only effectively inhibited the release of TGF-β from human Tregs, but also blocked both the TGF-β and PD-1/PD-L1 signaling pathways. In an MC38-hPD-L1 tumor-bearing C57BL/6-hGARP mouse model, BPB-101 at a dose of 5 mg/kg significantly inhibited tumor growth, with a complete elimination rate of 50%. Stability assessments confirmed the robustness of BPB-101. Furthermore, BPB-101 showed a favorable safety profile in nonhuman primate (NHP) toxicity studies.ConclusionBPB-101 is a potentially promising therapeutic candidate that may address unmet clinical needs in cancer immunotherapy, thus, BPB-101 warrants further clinical investigation.

BackgroundTumor antigen peptide vaccines have shown remarkable efficacy, safety, and reliability in recent studies. However, the screening process for immunopotent antigenic peptides is cumbersome, limiting their widespread application. Identifying neoantigen peptides that can effectively trigger an immune response is crucial for personalized cancer treatment.MethodsWhole exome sequencing was performed on patient-derived colon cancer cells to predict 9-amino-acid (9aa) neoantigen peptides. In vitro simulation of endogenous antigen presentation by antigen-presenting cells (dendritic cells) to CD8+ T cells was conducted, aiming to activate the CD8+ immune response to the predicted antigens. The immunological effects of each neoantigen were assessed using flow cytometry and ELISpot assays, while the relationship between neoantigen immunogenicity and MHC molecular affinity was examined.Results1. Next-generation sequencing (NGS) predicted 9-amino acid (9aa) neoantigen peptides for subsequent immunological analysis.2. Higher mDC Levels in Experimental Group: CD11c+CD83+ mature dendritic cells (mDCs) were 96.6% in the experimental group, compared to 0.051% in the control group. CD80 fluorescence intensity was also significantly higher in the experimental group, confirming a greater mDC presence.3. Neoantigen Peptides Promote CD4+, CD8+ T, and NK Cell Proliferation: After 14 days, flow cytometry showed higher percentages of CD4+ T (37.41% vs 7.8%), CD8+ T (16.67% vs 14.63%), and NK cells (33.09% vs 7.81%) in the experimental group, indicating that the neoantigen peptides induced proliferation of CD4+, CD8+ T cells, and NK cells. 4. The results, analyzed using two-way ANOVA, showed that the standardized T-value for HLA molecular affinity variation in the 1-4 range (Group B) was significantly higher than for ≤1 (Group A, p < 0.0001) and >4 (Group C, p < 0.05). Regarding HLA-allele genotypes, HLA-Type 1 had a significantly higher standardized T-value than HLA-Type 2 (p < 0.05) and HLA-Type 3 (p < 0.0001). HLA-Type 1 was identified as the allele associated with the highest T-value.Conclusion1. The most immunogenic neoantigens typically exhibit an MHC molecular affinity variation between 1 and 4, indicating that stronger immunogenicity correlates with higher MHC molecular affinity variation. 2. Each patient's HLA molecules were classified into Types 1, 2, and 3, with Type 1 showing the highest binding capacity for neoantigens. Our findings indicate that the most immunogenic neoantigens were associated with HLA Type 1. 3. Neoantigen peptides were shown to activate the proliferation of both CD8+ T-cells and induce proliferation of CD4+ T-cells and NK cells. 4. Variation in MHC molecular affinity and HLA neoantigen genotype are anticipated to serve as valuable variables for screening highly immunogenic neoantigens, facilitating more efficient preparation of effective polypeptide tumor vaccines.

BackgroundThe majority of patients with lung cancer exhibit drug resistance after anti-PD-1 immunotherapy, leading to shortened patient survival time. Previous studies have suggested an association between epigenetic abnormalities such as methylation and clinical response to anti-PD-1 immunotherapy, while the role of SUMOylation in resistance to anti-PD-1 antibody immunotherapy is still unclear.MethodsHere, the mRNA expression of 15 SUMO machinery components in PBMC from lung cancer patients receiving anti-PD-1 immunotherapy were analyzed using real-time PCR. Base on the percentage change in mRNA levels, the relationship between the expression of SUMO machinery components and outcomes of anti-PD-1 immunotherapy, and the influencing factors of SUMOylation were evaluated. PBMC was treated with different concentrations of 2-D08 (a specific inhibitor of SUMOylation) in vitro, and analyzed the activation and the death rates of lymphocyte subsets by flow cytometry analysis.ResultsA predictive method, base on the gene expression of three SUMO machinery components (SUMO1, SUMO3 and UBE2I), were developed to distinguish non-responders to PD-1 inhibitors. Furthermore, the number of lymphocytes in peripheral blood significantly reduced in the dysregulated SUMOylation groups (the percentage change >100 or -50 ~ -100 groups). In vitro studies confirmed that lightly low SUMOylation level improved the activation status of T and NK lymphocytes, but extremely low SUMOylation level lead to the increased death rates of lymphocytes.ConclusionOur findings implied that dysregulated gene expression of SUMO machinery components could induce the resistance of anti-PD-1 immunotherapy in lung cancer by upregulating the death of peripheral blood lymphocytes. These data might provide effective circulating biomarkers for predicting the efficacy of anti-PD-1 immunotherapy, and uncovered a novel regulatory mechanism of resistance to anti-PD-1 immunotherapy.