Foreign ownership, subjective willing, and internal control level.

Foreign shareholders are essential in the capital market. The study on A-share listed firms from 2012 to 2021 examines the impact of foreign ownership on internal control and its transmission effect. Using text analysis and machine learning methods, we construct a variable named "internal control willingness" to explore the impact of subjective willingness. The findings indicate that foreign shareholding significantly enhances internal control quality, with a more pronounced effect observed in samples demonstrating a more positive internal control willingness. Moreover, foreign shareholders contribute to the invested firm's sustainable development by enhancing internal control quality. Further research demonstrates that the positive impact of foreign shareholding is more significant in firms with legal foreign shareholders, highly competitive industries, and sound legal environments. These findings can aid host country firms in more efficiently leveraging foreign resources and provide empirical evidence for opening up China's capital market and formulating foreign investment regulations.

An optimal combined slow-release nitrogen fertilizer and urea can enhance the decomposition rate of straw and the yield of maize by improving soil bacterial community and structure under full straw returning system.

Under a full straw returning system, the relationship between soil bacterial community diversity and straw decomposition, yield, and the combined application of slow-release nitrogen and urea remains unclear. To evaluate these effects and provide an effective strategy for sustainable agricultural production, a 2-year field positioning trial was conducted using maize as the research object. Six experimental treatments were set up: straw returning + no nitrogen fertilizer (S1N0), straw returning + slow-release nitrogen fertilizer:urea = 0:100% (S1N1), straw returning + slow-release nitrogen fertilizer:urea = 30%:70% (S1N2), straw returning + slow-release nitrogen fertilizer:urea = 60%:40% (S1N3), straw returning + slow-release nitrogen fertilizer:urea = 90%:10% (S1N4), and straw removal + slow-release nitrogen fertilizer:urea = 30%:70% (S0N2). Significant differences (p < 0.05) were observed between treatments for Proteobacteria, Acidobacteriota, Myxococcota, and Actinobacteriota at the jointing stage; Proteobacteria, Acidobacteriota, Myxococcota, Bacteroidota, and Gemmatimonadota at the tasseling stage; and Bacteroidota, Firmicutes, Myxococcota, Methylomirabilota, and Proteobacteria at the maturity stage. The alpha diversity analysis of the soil bacterial community showed that the number of operational taxonomic units (OTUs) and the Chao1 index were higher in S1N2, S1N3, and S1N4 compared with S0N2 at each growth stage. Additionally, the alpha diversity measures were higher in S1N3 and S1N4 compared with S1N2. The beta diversity analysis of the soil bacterial community showed that the bacterial communities in S1N3 and S1N4 were more similar or closely clustered together, while S0N2 was further from all treatments across the three growth stages. The cumulative straw decomposition rate was tested for each treatment, and data showed that S1N3 (90.58%) had the highest decomposition rate. At the phylum level, straw decomposition was positively correlated with Proteobacteria, Actinobacteriota, Myxococcota, and Bacteroidota but significantly negatively correlated with Acidobacteriota. PICRUSt2 function prediction results show that the relative abundance of bacteria in soil samples from each treatment differed significantly. The maize yield of S1N3 was 15597.85 ± 1477.17 kg/hm2, which was 12.80 and 4.18% higher than that of S1N1 and S0N2, respectively. In conclusion, a combination of slow-release nitrogen fertilizer and urea can enhance the straw decomposition rate and maize yield by improving the soil bacterial community and structure within a full straw returning system.

Highly sensitive turn-on electrochemical sensing of organophosphorus pesticides by integration of homogeneous reaction and heterogeneous catalytic signal amplification.

Enzyme-inhibited electrochemical sensor is a promising strategy for detecting organophosphorus pesticides (OPs). However, the poor stability of enzymes and the high oxidation potential of thiocholine signal probe limit their potential applications. To address this issue, an indirect strategy was proposed for highly sensitive and reliable detection of chlorpyrifos by integrating homogeneous reaction and heterogeneous catalysis. In the homogeneous reaction, Hg2+ with low oxidation potential was employed as signal probe for chlorpyrifos detection since its electroactivity can be inhibited by thiocholine, which was the hydrolysate of acetylthiocholine catalyzed by acetylcholinesterase. Additionally, Co,N-doped hollow porous carbon nanocage@carbon nanotubes (Co,N-HPNC@CNT) derived from ZIF-8@ZIF-67 was utilized as high-performance electrode material to amplify the stripping voltammetry signal of Hg2+. Thanks to their synergistic effect, the sensor exhibited outstanding sensing performance, excellent stability and good anti-interference ability. This strategy paves the way for the development of high-performance OP sensors and their application in food safety.

Injectable bio-multifunctional hyaluronic acid-based hydrogels loaded with poly ADP-ribose polymerase inhibitors for ovarian cancer therapy.

The recent use of PARP inhibitors (PARPi) in the maintenance treatment of ovarian tumor has significantly improved the survival rates of cancer patients. However, the current oral administration of PARP inhibitors fails to realize optimal therapeutic effects due to the low bioavailability in cancerous tissues, and often leads to a range of systemic adverse effects including hematologic toxicities, digestive system reactions, and neurotoxicities. Therefore, the demand for an advanced drug delivery system that can ensure effective drug administration while minimizing these unfavorable reactions is pressing. Injectable hydrogel emerges as a promising solution for local administration with the capability of sustainable drug release. In this study, we developed an injectable hydrogel made from aminated hyaluronic acid and aldehyde-functionalized pluronic127 via Schiff base reaction. This hydrogel exhibits excellent injectability with short gelation time and remarkable self-healing ability, and is applied to load niraparib. The drug-loaded hydrogel (HP@Nir hydrogel) releases drugs sustainably as tested in vitro as well as displays significant anti-proliferation and anti-migratory properties on human epithelial ovarian cancer cell line. Notably, HP@Nir hydrogel effectively suppresses the growth of ovarian cancer, without significant adverse reactions as demonstrated in animal studies. Additionally, the developed hydrogel is gradually degraded in vivo for around 20 d, while maintaining good biocompatibility. Overall, the injectable hydrogel loaded with niraparib provides a secure and efficient strategy for the treatment and management of ovarian cancer.

High expression of SLC7A1 in high-grade serous ovarian cancer promotes tumor progression and is involved in MAPK/ERK pathway and EMT.

Our previous studies have shown that upregulation of SLC7A1 in epithelial ovarian cancer (EOC) tumor cells significantly increases cancer cell proliferation, migration, and cisplatin resistance; however, the molecular mechanism by which SLC7A1 functions in EOC remains unknown. In later studies, we found that SLC7A1 is also highly expressed in the interstitial portion of high-grade serous ovarian cancer (HGSOC), but the significance of this high expression in the interstitial remains unclear. Here, we showed the Interstitial high expression of SLC7A1 in HGSOC by immunohistochemistry. SLC7A1 enriched in cancer-associated fibroblasts (CAFs) was upregulated by TGF-ß1. Transwell assay, scratch assay, cck8 assay and cell adhesion assay showed that SLC7A1 highly expressed in CAFs promoted tumor cells invasion, migration and metastasis in vitro. The effect of SLC7A1 on MAPK and EMT pathway proteins in ovarian cancer (OC) was verified by RNA sequencing and western blotting. Overexpression of SLC7A1 in OC is involved in MAPK/ ERK pathway and EMT. In general, in HGSOC, CAFs overexpressing SLC7A1 supported the migration and invasion of tumor cells; SLC7A1 is highly expressed in ovarian cancer and is involved in ERK phosphorylation and EMT signaling in MAPK signaling pathway. This suggests that SLC7A1 may be a potential therapeutic target for OC metastasis.

Correlation study of serum lipid levels and lipid metabolism-related genes in cervical cancer.

Objective: Lipid metabolism plays an important role in cancer. The aim of this study was to investigate the relationship between lipid metabolism and the development of cervical cancer, and to explore the prognostic significance of lipid metabolism-related genes in patients with cervical cancer. Methods: Initially, we retrospectively collected data from 1589 cervical cancer patients treated at the Affiliated Hospital of Qingdao University, with 1589 healthy individuals from the physical examination center serving as the control group. The correlation between their serum lipid levels and cervical cancer was analyzed. Subsequently, leveraging public databases, we conducted comprehensive studies on lipid metabolism-related genes. Additionally, we analyzed RNA expression profiling and clinical information sourced from TCGA and GTEx databases. Finally, we established a prognostic model integrating 9 genes associated with lipid metabolism and generated a nomogram model using R. GO and KEGG were performed to explore the functions and pathways of lipid metabolism-related genes. Results: Our findings revealed that patients with cervical cancer exhibited dyslipidemia, characterized by elevated levels of TC, TG, and LDL-C, alongside reduced HDL-C levels compared to controls (P<0.05). Interestingly, compared with early-stage patients, advanced patients had lower HDL-C level and higher LDL-C level. Regression analysis further highlighted high TC, TG, and LDL-C as significant risk factors for cervical cancer. Then a total of 188 lipid metabolism-related genes were identified and a prognostic signature based on 9 genes was established and validated. The results of the GO and KEGG functional analysis indicated that the lipid metabolism-related genes are primarily concentrated on pathways associated with fatty acid metabolism. Conclusion: Our study underscores the varying degrees of dyslipidemia observed in patients with cervical cancer, emphasizing the relevance of serum lipids in disease development. Our prognostic riskScore model predicted the overall survival time of patients based on 9 genes associated with lipid metabolism. These 9 genes may be tumor biomarkers and new targets for the treatment of cervical cancer.

Effects of slow-release nitrogen and urea combined application on soil physicochemical properties and fungal community under total straw returning condition.

Under the system of full straw returning, the relationship between soil fungal community diversity and soil physiochemical properties, and the combined application of slow-release nitrogen and urea is unclear. To evaluate its effect and provide an effective strategy for sustainable agricultural production, a 2-year field positioning trial was conducted using maize as the research object. The experiment was designed with two factors: straw treatment(S) and nitrogen fertilizer treatment(N),Six experimental treatments were set up,S1N0,S1N1,S1N2,S1N3,S1N4,S0N2,respectively.Analysis of 54 soil samples revealed 15 fungal phyla and 49 fungal classes. The composition of fungal communities in each treatment was basically the same, but there were significant differences in species abundance. Under total straw returning conditions, the combined application of slow-release nitrogen fertilizer and normal nitrogen fertilizer significantly increased the relative abundance of Ascomycota. During the jointing stage, tasseling stage and maturity stage, S1N4, S1N3 and S1N2 increased by 25.76%, 22.97%, 20.74%; 25.11%, 30.02%, 23.64% and 22.47%, 28.14%, 22.71% respectively compared with S0N2.The relative abundance of Basidiomycota was significantly reduced. Alpha diversity analysis showed that the straw returning mode significantly increased the Shannon index and decreased the Simpson index, which was obvious in the jointing stage and tasseling stage. The principal coordinate analysis analysis results showed that the fungal communities formed different clusters in the horizontal and vertical directions at the three growth stages of corn jointing, tasseling and maturity. At the jointing stage and tasseling stage, the communities of the straw return treatment and the straw removal treatment were separated, and the community distribution of each treatment was not significantly different in the mature stage. Total straw returning combined with slow-release fertilizer significantly (P＜0.05) increased the soil organic carbon, nitrate nitrogen and ammonia nitrogen content in each growth period, and increased the soil total nitrogen and hydrolyzable nitrogen content (P＞0.05).After the straw was returned to the field, the combined application of slow-release nitrogen fertilizer and common urea had a significant impact on soil urease, catalase, and sucrase activities. Among them, the three enzyme activities were the highest in the S1N3 treatment at the jointing stage and maturity stage, and the S1N4 treatment at the tasseling stage had the highest enzyme activity. Fungal community composition is closely related to environmental factors. Soil organic carbon, urease and catalase are positively correlated with Ascomycota and negatively correlated with Basidiomycota.

The top 100 highly cited articles on surgery-first orthognathic surgery between 2009 and 2022: a bibliometric and visualized analysis.

OBJECTIVES: To reveal research focuses on surgery-first orthognathic surgery by a bibliometric and visualized analysis of the top 100 highly cited articles. STUDY DESIGN: Published papers related to surgery-first orthognathic surgery were retrospectively retrieved from the Web of Science Core Collection from 2009 to 2022. The number of articles, journals, countries/regions, institutions, authors, and keywords were assessed and visualized using CiteSpace software. RESULTS: The top 100 cited articles included 89 research papers and 11 reviews. The average total citation was 21. The most influential article with 146 citations was published by Dr. Liou E.J.W. in 2011. The most common level of evidence was level IV (36 articles). The Journal of Oral and Maxillofacial Surgery had the largest number of papers and the highest total citation frequency. The most productive countries and institutions were Korea/China and Chang Gung Memorial Hospital, respectively. Chen Yu-ray and Choi Jong Woo published 13 and 11 articles with 434 and 299 total citations, respectively. Research interests shifted from skeletal class III malocclusion, accuracy, stability, and relapse to quality of life and virtual surgical planning. CONCLUSION: Our bibliometric analyses provide a comprehensive landscape of the influential topics and developmental trends in surgery-first orthognathic surgery and inspire future studies in this booming field.

Neglected function of gastrin to reduce feeding in Siberian sturgeon (Acipenser baerii) via cholecystokinin receptor B.

Gastrin is an important intragastrointestinal hormone, but reports on its regulation of feeding behavior in fish are still scarce. This study aimed to determine the feeding regulatory function of gastrin in sturgeon. In this study, a gastrin/cholecystokinin-like peptide was identified in the genomes of sturgeon and proved to be gastrin by evolutionary tree analysis. Tissue distribution of gastrin and its receptor, cholecystokinin receptor B (CCKRB), showed that both had high mRNA abundance in the hypothalamus and gastrointestinal tract. In the duodenum, gastrin and CCKRB mRNAs were reduced at 1 h of fasting, and both were also observed in the stomach and hypothalamus in response to changes in feeding status. Sulfated gastrin 17 is the major form of gastrin in vivo. Therefore, we investigated the effect of sulfated gastrin 17 on feeding by intraperitoneal injection into Siberian sturgeon using sulfated gastrin 17. The results showed that gastrin 17 significantly reduced the cumulative feeding of Siberian sturgeon in the short term (1, 3 and 6 h) and long term (1, 2, 3, 4, 5 and 7 days). Finally, we explored the potential mechanism of feeding inhibition after intraperitoneal injection of gastrin 17 for 7 consecutive days. The results showed that gastrin 17 treatment significantly increased the mRNA levels of anorexigenic peptides (cart, cck and pyy), while it had no significant effect on the mRNA abundance of orexigenic peptides (npy and agrp). In addition, gastrin 17 treatment significantly affected the expression of appetite signaling pathways in the hypothalamus, such that the mRNA expression of ampkα1 was significantly reduced, whereas the mRNA abundance of stat3, mtor and s6k was significantly increased. In conclusion, the present study confirmed the anorectic effect of gastrin on Siberian sturgeon.

Development of a novel senescence-related gene signature to predict clinical outcomes, immune landscape, and chemotherapeutic sensitivity in oral squamous cell carcinoma.

BACKGROUND: Cellular senescence significantly associates with tumor initiation, progression, and therapeutic response across multiple cancers. Here, we sought to develop a novel senescence-related genes (SRGs)-derived signature for oral squamous cell carcinoma (OSCC) prognostication and therapeutic response prediction. METHODS: OSCC-specific SRG prognostic signature was established with univariate Cox regression, Kaplan-Meier survival, and LASSO-penalized multivariate Cox regression analyses. A SRG nomogram integrating this signature and selected clinicopathological parameters were constructed by multivariate Cox regression. SiRNA-mediated gene knockdown was exploited to validate its function in vitro. The utilities of SRG signature in predicting immune status and chemotherapeutic sensitivities were analyzed. RESULTS: The prognostic performance of SRG signature/nomogram was satisfactory in multiple independent cohorts. CDK1 knockdown induced senescence phenotype in vitro. Moreover, SRG signature scores negatively correlated with tumor-infiltrating immune cells and associated with multiple chemotherapeutic drug sensitivities. CONCLUSIONS: Our results established SRG-derived signature/nomogram as powerful predictors for prognosis and chemotherapeutic response for OSCC.

Beta cell specific cannabinoid 1 receptor deletion counteracts progression to hyperglycemia in non-obese diabetic mice.

OBJECTIVE: Type 1 diabetes (T1D) occurs because of islet infiltration by autoreactive immune cells leading to destruction of beta cells and it is becoming evident that beta cell dysfunction partakes in this process. We previously reported that genetic deletion and pharmacological antagonism of the cannabinoid 1 receptor (CB1) in mice improves insulin synthesis and secretion, upregulates glucose sensing machinery, favors beta cell survival by reducing apoptosis, and enhances beta cell proliferation. Moreover, beta cell specific deletion of CB1 protected mice fed a high fat high sugar diet against islet inflammation and beta cell dysfunction. Therefore, we hypothesized that it would mitigate the dysfunction of beta cells in the precipitating events leading to T1D. METHODS: We genetically deleted CB1 specifically from beta cells in non-obese diabetic (NOD; NOD RIP Cre+ Cnr1fl/fl) mice. We evaluated female NOD RIP Cre+ Cnr1fl/fl mice and their NOD RIP Cre-Cnr1fl/fl and NOD RIP Cre+ Cnr1Wt/Wt littermates for onset of hyperglycemia over 26 weeks. We also examined islet morphology, islet infiltration by immune cells and beta cell function and proliferation. RESULTS: Beta cell specific deletion of CB1 in NOD mice significantly reduced the incidence of hyperglycemia by preserving beta cell function and mass. Deletion also prevented beta cell apoptosis and aggressive insulitis in NOD RIP Cre+ Cnr1fl/fl mice compared to wild-type littermates. NOD RIP Cre+ Cnr1fl/fl islets maintained normal morphology with no evidence of beta cell dedifferentiation or appearance of extra islet beta cells, indicating that protection from autoimmunity is inherent to genetic deletion of beta cell CB1. Pancreatic lymph node Treg cells were significantly higher in NOD RIP Cre+ Cnr1fl/flvs NOD RIP Cre-Cnr1fl/fl. CONCLUSIONS: Collectively these data demonstrate how protection of beta cells from metabolic stress during the active phase of T1D can ameliorate destructive insulitis and provides evidence for CB1 as a potential pharmacologic target in T1D.

Soil pH and carbon quality index regulate the biogeochemical cycle couplings of carbon, nitrogen and phosphorus in the profiles of Isohumosols.

Soil biogeochemical cycles are essential for regulating ecosystem functions and services. However, little knowledge has been revealed on microbe-driven biogeochemical processes and their coupling mechanisms in soil profiles. This study investigated the vertical distribution of soil functional composition and their contribution to carbon (C), nitrogen (N) and phosphorus (P) cycling in the humus horizons (A-horizons) and parent material horizons (C-horizons) in Udic and Ustic Isohumosols using shotgun sequencing. Results showed that the diversity and relative abundance of microbial functional genes was influenced by soil horizons and soil types. In A-horizons, the relative abundances of N mineralization and liable C decomposition genes were significantly greater, but the P cycle-related genes, recalcitrant C decomposition and denitrification genes were lower compared to C-horizons. While, Ustic Isohumosols had lower relative abundances of C decomposition genes but higher relative abundances of N mineralization and P cycling-related pathways compared to Udic Isohumosols. The network analysis revealed that C-horizons had more interactions and stronger stability of functional gene networks than in A-horizons. Importantly, our results provide new insights into the potential mechanisms for the coupling processes of soil biogeochemical cycles among C, N and P, which is mediated by specific microbial taxa. Soil pH and carbon quality index (CQI) were two sensitive indicators for regulating the relative abundances and the relationships of functional genes in biogeochemical cycles. This study contributes to a deeper understanding of the ecological functions of soil microorganisms, thus providing a theoretical basis for the exploration and utilization of soil microbial resources and the development of soil ecological control strategies.

Next-generation sequencing-based analysis of homologous recombination repair gene variant in ovarian cancer.

Background: Ovarian cancer is the leading cause of death from gynecological malignancies. Investigating the HRR-related gene status, notably BRCA1/2 in different regions and populations is of great significance for formulating accurate target therapy. Methods: We collected 124 ovarian cancer cases from the Affiliated Hospital of.Qingdao University, detected the genomic alteration of 32 genes by NGS, including.19 HRR-related genes, 9 proto-oncogenes and 4 tumor suppressor genes. Clinicopathological characteristics, variants, clinical significance, and correlation with prognosis were analyzed. Results: The incidence of HRR-related gene mutation was 59.68 % and no statistical significance was found with multiple clinicopathological characteristics. BRCA1/2 (27.42 %) were the most frequent mutated HRR genes. 23 (18.55 %) cases harbored gBRCA1/2 mutation, with all BRCA1 mutations were pathogenic/likely pathogenic and 2 cases of BRCA2 mutation was variant of uncertain significance. Somatic BRCA1/2 mutations were found in 12 (9.68 %) cases, and sBRCA1/2 had a higher frequency in less common ovarian cancer than high-grade serous carcinoma. HRR-related gene mutation status was associated with better prognosis than HRR wild-type. Conclusions: Somatic BRCA1/2 mutation has higher incidence in less common ovarian cancer. HRR gene mutation status is an independent prognosis factor in ovarian cancer. Clarifying the HRR gene status is important for the selection of target therapy as well as the evaluation of prognosis.

Identification of C1q/TNF-related protein 4 as a novel appetite-regulating peptide that reduces food intake in Siberian sturgeon (Acipenser baerii).

Emerging findings point to a role for C1q/TNF-related protein 4 (CTRP4) in feeding in mammals. However, it remains unknown whether CTRP4 regulates feeding in fish. This study aimed to determine the feeding regulation function of CTRP4 in Siberian sturgeon (Acipenser baerii). In this study, the Siberian sturgeon ctrp4 (Abctrp4) gene was cloned, and Abctrp4 mRNA was shown to be highly expressed in the hypothalamus. In the hypothalamus, Abctrp4 mRNA decreased during fasting and reversed after refeeding. Subsequently, we obtained the AbCTRP4 recombinant protein by prokaryotic expression and optimized the expression and purification conditions. Siberian sturgeon (81.28 ± 14.75 g) were injected intraperitoneally using 30, 100, and 300 ng/g Body weight (BW) AbCTRP4 to investigate its effect on feeding. The results showed that 30, 100, and 300 ng/g BW of the AbCTRP4 significantly reduced the cumulative food intake of Siberian sturgeon at 1, 3, and 6 h. Finally, to investigate the potential mechanism of CTRP4 feeding inhibition, 300 ng/g BW AbCTRP4 was injected intraperitoneally. The findings demonstrated that AbCTRP4 treatment for 1 h significantly promoted the mRNA levels of anorexigenic peptides (pomc, cart, and leptin) while suppressing the mRNA abundances of orexigenic peptides (npy and agrp).In addition, the jak2/stat3 pathway in the hypothalamus was significantly activated after 1 h of AbCTRP4 treatment. In conclusion., this study confirms the anorexigenic effect of CTRP4 in Siberian sturgeon.

Status risk factors and prevention and control strategies of familial aggregation of Helicobacter pylori infection / 公共卫生与预防医学

Objective To investigate the status of familial aggregation of Helicobacter pylori (Hp) infection in Jinniu District, Chengdu, and analyze its risk factors so as to provide a basis for developing prevention and control strategies of family aggregation of Hp infection. Methods A total of 172 subjects in the Second Affiliated Hospital of Chengdu Medical College · 416 Hospital of Nuclear Industry from January 2022 to January 2023 were selected as the research subjects. All subjects underwent 13C-urea breath test (13C-UBT) to diagnose whether there was Hp infection. Analyze the current situation of family aggregation of Hp infection in the region, collect general data of survey subjects, analyze the relevant factors affecting Hp family aggregation infection, and develop prevention and control strategies based on this. Results A total of 242 people from 97 households were surveyed, and the Hp family aggregation rate was 29.33%. Univariate analysis showed that there were statistically significant differences in family aggregation of Hp infection in terms of different age groups (χ2=9.719, P=0.008), marital status (χ2=8.496, P=0.014), occupations (χ2=19.462, P2=5.457, P=0.019), previous Hp test results (χ2 =4.131, P=0.042) and test results after treatment (χ2=12.000, P=0.001), with statistical significance (P<0.05). Multivariate logistic regression analysis showed that the frequency of dining out 2 days or more per week and a positive Hp test results in the past were risk factors for family aggregation of Hp infection, while the occupation of teachers/medical staff/management/technology personnel and a negative Hp results after treatment were protective factors (P<0.05). Conclusion Family aggregation of Hp infection is related to family members' occupation, frequency of dining out, previous Hp test results and Hp test results after eradication, which deserves attention in clinical practice.

A novel role for microtubule affinity-regulating kinases in neuropathic pain.

BACKGROUND AND PURPOSE: Neuropathic pain affects millions of patients, but there are currently few viable therapeutic options available. Microtubule affinity-regulating kinases (MARKs) regulate the dynamics of microtubules and participate in synaptic remodelling. It is unclear whether these changes are involved in the central sensitization of neuropathic pain. This study examined the role of MARK1 or MARK2 in regulating neurosynaptic plasticity induced by neuropathic pain. EXPERIMENTAL APPROACH: A rat spinal nerve ligation (SNL) model was established to induce neuropathic pain. The role of MARKs in nociceptive regulation was assessed by genetically knocking down MARK1 or MARK2 in amygdala and systemic administration of PCC0105003, a novel small molecule MARK inhibitor. Cognitive function, anxiety-like behaviours and motor coordination capability were also examined in SNL rats. Synaptic remodelling-associated signalling changes were detected with electrophysiological recording, Golgi-Cox staining, western blotting and qRT-PCR. KEY RESULTS: MARK1 and MARK2 expression levels in amygdala and spinal dorsal horn were elevated in SNL rats. MARK1 or MARK2 knockdown in amygdala and PCC0105003 treatment partially attenuated pain-like behaviours along with improving cognitive deficit, anxiogenic-like behaviours and motor coordination in SNL rats. Inhibition of MARKs signalling reversed synaptic plasticity at the functional and structural levels by suppressing NR2B/GluR1 and EB3/Drebrin signalling pathways both in amygdala and spinal dorsal horn. CONCLUSION AND IMPLICATIONS: These results suggest that MARKs-mediated synaptic remodelling plays a key role in the pathogenesis of neuropathic pain and that pharmacological inhibitors of MARKs such as PCC0105003 could represent a novel therapeutic strategy for the management of neuropathic pain.

The age-related obesity paradigm: results from two large prospective cohort studies.

BACKGROUND: The obesity paradigm has been a health concern globally for many years, its meaning is controversial. In this study, we assess the characteristics and causes of obesity paradigm and detail the mediation of obesity and inflammation on survival. METHODS: The original cohort included participants from the US National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018, a prospective cohort of a nationally representative sample of adult participants; the oncology validation cohort included patients from the Investigation on Nutrition Status and Clinical Outcome of Common Cancers (INSCOC) from 2013 to 2021, a prospective cohort of Chinese patients with cancer. Survival analysis was performed using weighted (NHANES) or unweighted (INSCOC) Cox survival analyses. The normal BMI group was used as a reference for all comparisons. Systemic inflammation was defined as neutrophil-to-lymphocyte ratio (NLR) > 3. Model-based causal mediation analysis was used to identify the mediators. RESULTS: A total of 52 270 (weighted population: 528506229) participants of the NHANES [mean follow-up times: 10.2 years; mean age (SD): 47 (19.16) years] were included in the original cohort; and a total of 17 418 patients with cancer of INSCOC [mean follow-up times: 2.9 years; mean age (SD): 57.37 (11.66) years] were included in the validation cohort. In the subgroups of all the participants, the obesity paradigm was more apparent in older participants and participants with disease [HR (95% CI): age ≥ 65 years, 0.84 (0.76, 0.93); with cancer, 0.84 (0.71, 0.99); with CVD, 0.74 (0.65, 0.85)]. As aged, the protective effect of a high BMI on survival gradually increased and a high BMI showed the effect of a protective factor on older participants [for obese II, HR (95% CI): young adults, 1.91 (1.40, 2.62); middle age, 1.56 (1.28, 1.91); old adults, 0.85 (0.76, 0.96]). The aged-related obesity paradigm in patients with cancer from the NHANES was verified in the INSCOC cohorts [for obese, HR (95%CI): 0.65 (0.52, 0.81)]. The NLR is an important mediator of the effect of BMI on survival (proportion of mediation = 15.4%). CONCLUSIONS: The obesity paradigm has a strong correlation with age. Relative to normal weight, obese in young people was association with higher all-cause mortality, and obese in elderly people was not association with higher mortality. The protection of obesity is association with systemic inflammation.

Long-Term Dysfunction of Taste Papillae in SARS-CoV-2.

BACKGROUND: We sought to determine whether ongoing taste disturbance in the postacute sequelae of coronavirus disease 2019 period is associated with persistent virus in primary taste tissue. METHODS: We performed fungiform papillae biopsies on 16 patients who reported taste disturbance lasting more than 6 weeks after molecularly determined severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Then, on multiple occasions, we rebiopsied 10 of those patients who still had taste complaints for at least 6 months postinfection. Fungiform papillae obtained from other patients before March 2020 served as negative controls. We performed hematoxylin and eosin staining to examine fungiform papillae morphology and immunofluorescence and fluorescence in situ hybridization to look for evidence of persistent viral infection and immune response. RESULTS: In all patients, we found evidence of SARS-CoV-2, accompanying immune response and misshapen or absent taste buds with loss of intergemmal neurite fibers. Six patients reported normal taste perception by 6 months postinfection and were not further biopsied. In the remaining 10, the virus was eliminated in a seemingly random fashion from their fungiform papillae, but four patients still, by history, reported incomplete return to preinfection taste perception by the time we wrote this report. CONCLUSIONS: Our data show a temporal association in patients between functional taste, taste papillae morphology, and the presence of SARS-CoV-2 and its associated immunological changes. (Funded by Intramural Research Program/National Institute on Aging/National Institute of Allergy and Infectious Diseases/National Institutes of Health; ClinicalTrials.gov numbers NCT03366168 and NCT04565067.).

HPLC for simultaneous quantification of free mannose and glucose concentrations in serum: use in detection of ovarian cancer.

Background: Abnormal levels of monosaccharides in blood have been linked to tumorigenesis. In this study, a novel high-performance liquid chromatography (HPLC) method was established for the simultaneous determination of free mannose and glucose in the serum. Methods: The serum was directly derivatized by 1-phenyl-3-methyl-5-pyrazolone under alkaline conditions using L-rhamnose as an internal standard. The chromatographic separation was then performed on a Poroshell EC-C18 chromatographic column (4.6 × 100 mm, particle size 2.7 µm, Agilent) with gradient elution using NH4Ac-HAc and acetonitrile as the mobile phases. The method was thereafter validated according to international guidelines. The serum samples obtained from 200 healthy individuals and 200 ovarian cancer (OC) patients were analyzed for free mannose and glucose. Results: The method was found to be reproducible for quantification within 20 min and included online sample purification. The method displayed excellent linearity in the concentration range (for mannose: 0.5-500 µg/mL; glucose: 0.5-1500 µg/mL). The precision, recovery, and stability met the FDA bioanalytical method validation acceptance criteria. Overall, the measurement of glucose content by HPLC correlated well with the different enzymatic methods. Ovarian cancer mannose levels in the serum were significantly higher in the advanced stage (61.22 µmol/L, p < 0.0001) than those in healthy volunteers and early-stage patients (44.51 µmol/L versus 50.09 µmol/L, p < 0.0001). The AUC for the ratio of serum free glucose to mannose (G/M) was 0.98 (p < 0.0001), with a sensitivity of 91.46% and a specificity of 98.50%, which served as a biomarker for OC diagnosis. Conclusion: We report a simple, repeatable, and attractive analytical method by HPLC, which can be used for quantitative estimation of free mannose and glucose simultaneously in human serum. Our results indicate that the serum level of mannose could be used as a potential biomarker of ovarian cancer.