Quercetin improves the protection of hydroxysafflor yellow a against cerebral ischemic injury by modulating of blood-brain barrier and src-p-gp-mmp-9 signalling.

Protection of the structural and functional integrity of the blood-brain barrier (BBB) is crucial for treating ischemic stroke (IS). Hydroxysafflor yellow A (HSYA) and quercetin (Quer), two main active components in the edible and medicinal plant Carthamus tinctorius L., have been reported to exhibit neuroprotective effects. We investigated the anti-IS and BBB-protective properties of HSYA and Quer and the underlying mechanisms. They decreased neurological deficits in middle cerebral artery occlusion (MCAO) mice, while their combination showed better effects. Importantly, HSYA and Quer ameliorated BBB permeability. Their effects on reduction of both EB leakage and infarct volume were similar, which may contribute to improved locomotor activities. Moreover, HSYA and Quer showed protective effects for hCMEC/D3 monolayer against oxygen-glucose deprivation. Src, p-Src, MMP-9, and P-gp were associated with ingredients treatments. Furthermore, molecular docking and molecular dynamics simulations revealed stable and tight binding modes of ingredients with Src and P-gp. The current study supports the potential role of HSYA, Quer, and their combination in the treatment of IS by regulating BBB integrity.

A novel score for early prediction of urinary tract infection risk in patients with acute ischemic stroke: a nomogram-based retrospective cohort study.

This study aimed to construct and externally validate a user-friendly nomogram-based scoring model for predicting the risk of urinary tract infections (UTIs) in patients with acute ischemic stroke (AIS). A retrospective real-world cohort study was conducted on 1748 consecutive hospitalized patients with AIS. Out of these patients, a total of 1132 participants were ultimately included in the final analysis, with 817 used for model construction and 315 utilized for external validation. Multivariate regression analysis was applied to develop the model. The discriminative capacity, calibration ability, and clinical effectiveness of the model were evaluated. The overall incidence of UTIs was 8.13% (92/1132), with Escherichia coli being the most prevalent causative pathogen in patients with AIS. After multivariable analysis, advanced age, female gender, National Institute of Health Stroke Scale (NIHSS) score ≥ 5, and use of urinary catheters were identified as independent risk factors for UTIs. A nomogram-based SUNA model was constructed using these four factors (Area under the receiver operating characteristic curve (AUC) = 0.810), which showed good discrimination (AUC = 0.788), calibration, and clinical utility in the external validation cohort. Based on four simple and readily available factors, we derived and externally validated a novel and user-friendly nomogram-based scoring model (SUNA score) to predict the risk of UTIs in patients with AIS. The model has a good predictive value and provides valuable information for timely intervention in patients with AIS to reduce the occurrence of UTIs.

Streptomyces umbrella toxin particles block hyphal growth of competing species.

Streptomyces are a genus of ubiquitous soil bacteria from which the majority of clinically utilized antibiotics derive1. The production of these antibacterial molecules reflects the relentless competition Streptomyces engage in with other bacteria, including other Streptomyces species1,2. Here we show that in addition to small-molecule antibiotics, Streptomyces produce and secrete antibacterial protein complexes that feature a large, degenerate repeat-containing polymorphic toxin protein. A cryo-electron microscopy structure of these particles reveals an extended stalk topped by a ringed crown comprising the toxin repeats scaffolding five lectin-tipped spokes, which led us to name them umbrella particles. Streptomyces coelicolor encodes three umbrella particles with distinct toxin and lectin composition. Notably, supernatant containing these toxins specifically and potently inhibits the growth of select Streptomyces species from among a diverse collection of bacteria screened. For one target, Streptomyces griseus, inhibition relies on a single toxin and that intoxication manifests as rapid cessation of vegetative hyphal growth. Our data show that Streptomyces umbrella particles mediate competition among vegetative mycelia of related species, a function distinct from small-molecule antibiotics, which are produced at the onset of reproductive growth and act broadly3,4. Sequence analyses suggest that this role of umbrella particles extends beyond Streptomyces, as we identified umbrella loci in nearly 1,000 species across Actinobacteria.

Anxiety symptoms without depression are associated with cognitive control network (CNN) dysfunction: An fNIRS study.

Anxiety is a common psychological disorder associated with other mental disorders, with depression being the most common comorbidity. Few studies have examined the neural mechanisms underlying anxiety after controlling for depression. This study aimed to explore whether there are differences in cortical activation in anxiety patients with different severities whose depression are normal. In the current study, depression levels were normal for 366 subjects-139 healthy subjects, 117 with mild anxiety, and 110 with major anxiety. Using the Hospital Anxiety and Depression Scale (HADS) and a verbal fluency task (VFT) to test subjects' anxiety and depression and cognitive function, respectively. A 53-channel guided near-infrared spectroscopic imaging technology (fNIRS) detected the concentration of oxyhemoglobin (oxy-Hb). Correlation analysis between anxiety severity and oxy-Hb concentration in the brain cortex was performed, as well as ANOVA analysis of oxy-Hb concentration among the three anxiety severity groups. The results showed that anxiety severity was significantly and negatively correlated with oxy-Hb concentrations in the left frontal eye field (lFEF) and in the right dorsolateral prefrontal area (rDLPFC). The oxy-Hb concentration in the lFEF and the rDLPFC were significantly lower in the major anxiety disorder group than that in the control group. This suggests that decreased cortical activity of the lFEF and rDLPFC may be neural markers of anxiety symptoms after controlling for depression. Anxiety symptoms without depression may be result from the dysfunction of the cognitive control network (CCN) which includes the lFEF and rDLPFC.

Small-molecule antiviral treatments for COVID-19: A systematic review and network meta-analysis.

OBJECTIVE: This study aimed to explore the efficacy and safety of small-molecule antivirals for treating coronavirus disease 2019 (COVID-19). METHODS: Seven databases were searched from their inception to 01 June 2023. The risk of bias in randomised controlled trials and retrospective studies was evaluated individually using the Cochrane risk-of-bias tool and Newcastle Ottawa Scale. RESULTS: In total, 160 studies involving 933 409 COVID-19 patients were evaluated. Compared with placebo or standard of care, proxalutamide demonstrated remarkable efficacy in reducing mortality rates, hospitalisation rates, serious adverse events, and the need for mechanical ventilation. Furthermore, it significantly enhanced both the rate of clinical improvement and expedited the duration of clinical recovery when compared with control groups. In patients with mild-to-moderate COVID-19, proxalutamide exhibited the above advantages, except for mortality reduction. Triazavirin was the most effective treatment for reducing the time required for viral clearance and improving the discharge rate. Leritrelvir and VV116 were ranked first in terms of enhancing the viral clearance rate on days 7 and 14, respectively. Molnupiravir was the most effective treatment for reducing the need for oxygen support. Overall, these findings remained consistent across the various subgroups. CONCLUSIONS: A thorough evaluation of effectiveness, applicable to both mild-to-moderate and unstratified populations, highlights the specific advantages of proxalutamide, nirmatrelvir/ritonavir, triazavirin, azvudine, molnupiravir, and VV116 in combating COVID-19. Additional clinical data are required to confirm the efficacy and safety of simnotrelvir/ritonavir and leritrelvir. The safety profiles of these antivirals were deemed acceptable.

Association between immunoglobulin G N-glycosylation and lupus nephritis in female patients with systemic lupus erythematosus: a case-control study.

Background: Lupus nephritis (LN) is a crucial complication of systemic lupus erythematosus (SLE) and has important clinical implications in guiding treatment. N-glycosylation of immunoglobulin G (IgG) plays a key role in the development of SLE by affecting the balance of anti-inflammatory and proinflammatory responses. This study aimed to evaluate the performance of IgG N-glycosylation for diagnosing LN in a sample of female SLE patients. Methods: This case-control study recruited 188 women with SLE, including 94 patients with LN and 94 age-matched patients without LN. The profiles of plasma IgG N-glycans were detected by hydrophilic interaction chromatography with ultra-performance liquid chromatography (HILIC-UPLC). A multivariate logistic regression model was used to explore the associations between IgG N-glycans and LN. A diagnostic model was developed using the significant glycans as well as demographic factors. The performance of IgG N-glycans in the diagnosis of LN was evaluated by receiver operating characteristic (ROC) curve analysis, and the area under the curve (AUC) and its 95% confidence interval (CI) were calculated. Results: There were significant differences in 9 initial glycans (GP2, GP4, GP6, GP8, GP10, GP14, GP16, GP18 and GP23) between women with SLE with and without LN (P < 0.05). The levels of sialylated, galactosylated and fucosylated glycans were significantly lower in the LN patients than in the control group, while bisected N-acetylglucosamine (GlcNAc) glycans were increased in LN patients (P < 0.05). GP8, GP10, GP18, and anemia were included in our diagnostic model, which performed well in differentiating female SLE patients with LN from those without LN (AUC = 0.792, 95% CI: 0.727 to 0.858). Conclusion: Our findings indicate that decreased sialylation, galactosylation, and core fucosylation and increased bisecting GlcNAc might play a role in the development of LN by upregulating the proinflammatory response of IgG. IgG N-glycans can serve as potential biomarkers to differentiate individuals with LN among SLE patients.

Dual-Signal Integrated Aptasensor for Microcystin-LR Detection via In Situ Generation of Silver Nanoclusters Induced by Circular DNA Strand Displacement Reactions.

Inspired by the signal accumulation of circular DNA strand displacement reactions (CD-SDRs) and the in situ generation of silver nanoclusters (AgNCs) from signature template sequences, a dual-signal integrated aptasensor was designed for microcystin-LR (MC-LR) detection. The aptamer was programmed to be included in an enzyme-free CD-SDR, which utilized MC-LR as the primer and outputted the H1/H2 dsDNA in a continuous manner according to the ideal state. Ingeniously, H1/H2 dsDNA was enriched with signature template sequences, allowing in situ generation of AgNCs signal probes. To enhance the signal amplification performance, co-reaction acceleration strategies and CRISPR-Cas12a nucleases were invoked. The H1/H2 dsDNA could trigger the incidental cleavage performance of CRISPR-Cas12a nucleases: cis-cleavage reduced signature template sequences for the synthetic AgNCs, while trans-cleavage enabled fluorescence (FL) analysis. Meanwhile, AuPtAg was selected as the substrate material to facilitate the S2O82- reduction reaction for enhancing the electrochemiluminescence (ECL) basal signals. ECL and FL detection do not interfere with each other and have improved accuracy and sensitivity, with limits of detection of 0.011 and 0.023 pmol/L, respectively. This widens the path for designing dual-mode sensing strategies for signal amplification.

Is Azvudine Comparable to Nirmatrelvir-Ritonavir in Real-World Efficacy and Safety for Hospitalized Patients with COVID-19? A Retrospective Cohort Study.

INTRODUCTION: Azvudine and nirmatrelvir-ritonavir are more extensively used to treat COVID-19 in China due to their earlier approval by the National Medical Products Administration. However, there has been a scarcity of research directly comparing the clinical outcomes between azvudine and nirmatrelvir-ritonavir till now. We aimed to make a head-to-head comparison of the efficacy and safety of azvudine or nirmatrelvir-ritonavir in hospitalized patients with COVID-19 in China. METHODS: This retrospective cohort study was conducted using data collected from Tongde Hospital of Zhejiang Province between December 2022 and January 2023. All-cause mortality, risk of progressing to a critical condition, proportion with nucleic-acid negative conversion (PNANC), time to first nucleic-acid negative conversion (TFNANC), length of hospital stay and incidence of adverse events were systematically assessed as outcomes. Multi-model regression analysis, propensity-score-matching analysis, subgroup analysis and several sensitivity analyses were applied to compare these outcomes. RESULTS: This study included a total of 1571 hospitalized patients with COVID-19, among whom 272 received nirmatrelvir-ritonavir and 156 received azvudine. We found no significant differences in all-cause mortality (HR 1.41; 95% CI 0.56-3.56; P = 0.471), risk of progressing to critical COVID-19 (HR 1.67; 95% CI 0.78-3.60; P = 0.189), PNANC (HR 0.87; 95% CI 0.69-1.09; P = 0.220), length of stay (ß - 0.82; 95% CI - 2.78 to 1.15; P = 0.414) and adverse event rate (3.21% vs. 4.41%, P = 0.538) between the two groups, although azvudine was slightly less effective than nirmatrelvir-ritonavir. Meanwhile, the azvudine group exhibited a significantly longer TFNANC (ß 2.53; 95% CI 0.76-4.29; P = 0.005) than the nirmatrelvir-ritonavir group. Results were similar for propensity-score matching and multiple sensitivity analyses. CONCLUSION: Azvudine probably possessed comparable efficacy and safety to nirmatrelvir-ritonavir, although it was less effective than nirmatrelvir-ritonavir for some outcomes.

Strain improvement of Trichoderma harzianum for enhanced biocontrol capacity: Strategies and prospects.

In the control of plant diseases, biocontrol has the advantages of being efficient and safe for human health and the environment. The filamentous fungus Trichoderma harzianum and its closely related species can inhibit the growth of many phytopathogenic fungi, and have been developed as commercial biocontrol agents for decades. In this review, we summarize studies on T. harzianum species complex from the perspective of strain improvement. To elevate the biocontrol ability, the production of extracellular proteins and compounds with antimicrobial or plant immunity-eliciting activities need to be enhanced. In addition, resistance to various environmental stressors should be strengthened. Engineering the gene regulatory system has the potential to modulate a variety of biological processes related to biocontrol. With the rapidly developing technologies for fungal genetic engineering, T. harzianum strains with increased biocontrol activities are expected to be constructed to promote the sustainable development of agriculture.

The interaction between the histone acetyltransferase complex Hat1-Hat2 and transcription factor AmyR provides a molecular brake to regulate amylase gene expression.

The chromatin structure is generally regulated by chromatin remodelers and histone modifiers, which affect DNA replication, repair, and levels of transcription. The first identified histone acetyltransferase was Hat1/KAT1, which belongs to lysine (K) acetyltransferases. The catalytic subunit Hat1 and the regulatory subunit Hat2 make up the core HAT1 complex. In this study, the results of tandem affinity purification and mass spectrometry and bimolecular fluorescence complementation proved that the Penicillium oxalicum PoHat1-Hat2 is the transcriptional cofactor of the sequence-specific transcription factor PoAmyR, a transcription activator essential for the transcription of amylase gene. ChIP-qPCR results demonstrated that the complex PoHat1-Hat2 is recruited by PoAmyR to the promoters of prominent amylase genes Poamy13A and Poamy15A and performs histone H4 lysine12 acetylation. The result of the yeast two-hybrid test indicated that PoHat2 is the subunit that directly interacts with PoAmyR. PoHat1-Hat2 acts as the molecular brake of the PoAmyR-regulating transcription of amylase genes. A putative model for amylase gene regulation by PoAmyR-Hat2-Hat1 was constructed. Our paper is the first report that the Hat1-Hat2 complex acts as a cofactor for sequence-specific TF to regulate gene expression and explains the mechanism of TF AmyR regulating amylase genes expression.

Combined Transcriptomic and Proteomic Analyses Reveal the Different Responses to UVA and UVB Radiation in Human Keratinocytes.

Ultraviolet (UV) radiation from sunlight is a major risk factor for many cutaneous pathologies including skin aging and cancers. Despite decades of research, the different responses to UVA and UVB in human keratinocytes have not been systemically investigated. Here, we performed multi-omics to characterize the common and different changes in gene transcription and protein expression after exposure to UVB and UVA, respectively. Keratinocyte cells, treated with or without UV, were analyzed by TMT-labeled MS/MS spectra and RNA-sequencing. A common set of genes/proteins was found to be impacted by both UVA and UVB and the other differential genes/proteins showed wavelength specificity. The common set of genes/proteins were mainly involved in keratinization, lipid metabolic processes and stimulus response. The UVB specifically responsive genes/proteins were mainly related to RNA processing, gene silencing regulation and cytoskeleton organization. The UVA specifically responsive genes/proteins were mainly involved in vesicle-mediated transport and oxygen-containing compound response. Meanwhile, the hub differential genes/proteins in each set were identified by protein-protein interaction networks and cluster analysis. This work provided a global view of the similar and differential molecular mechanisms of UVB- and UVA-induced cell damage in keratinocytes, which would be beneficial for further studies in the prevention or treatment of UV-related pathologies.

Structure-guided engineering of transcriptional activator XYR1 for inducer-free production of lignocellulolytic enzymes in Trichoderma reesei.

The filamentous fungus Trichoderma reesei is widely used for the production of lignocellulolytic enzymes in industry. XYR1 is the major transcriptional activator of cellulases and hemicellulases in T. reesei. However, rational engineering of XYR1 for improved lignocellulolytic enzymes production has been limited by the lack of structure information. Here, alanine 873 was identified as a new potential target for the engineering of XYR1 based on its structure predicted by AlphaFold2. The mutation of this residue to tyrosine enabled significantly enhanced production of xylanolytic enzymes in the medium with cellulose as the carbon source. Moreover, xylanase and cellulase production increased by 56.7- and 3.3-fold, respectively, when glucose was used as the sole carbon source. Under both conditions, the improvements of lignocellulolytic enzyme production were higher than those in the previously reported V821F mutant. With the enriched hemicellulases and cellulases, the crude enzymes secreted by the A873Y mutant strain produced 51 % more glucose and 52 % more xylose from pretreated corn stover than those of the parent strain. The results provide a novel strategy for engineering the lignocellulolytic enzyme-producing capacity of T. reesei, and would be helpful for understanding the molecular mechanisms of XYR1 regulation.

Customized optimization of lignocellulolytic enzyme cocktails for efficient conversion of pectin-rich biomass residues.

Pectin is a major component in many agricultural feedstocks. Despite the wide use in industrial production of cellulases and hemicellulases, the fungus Trichoderma reesei lacks a complete enzyme set for pectin degradation. In this study, three representative pectinolytic enzymes were expressed and screened for their abilities to improve the efficiency of T. reesei enzymes on the conversion of different agricultural residues. By replacing 5 % of the T. reesei proteins, endopolygalacturonase and pectin lyase remarkably increased the release of sugars from inferior tobacco leaves. In contrast, pectin methylesterase showed the strongest improving effect (by 31.1 %) on the hydrolysis of beetroot residue. The pectin in beetroot residue was only mildly degraded with the supplementation of pectin methylesterase, which allowed the extraction of pectin keeping the original emulsifying activity with a 51.1 % higher yield. The results provide a basis for precise optimization of lignocellulolytic enzyme systems for targeted valorization of pectin-rich agricultural residues.

Management of dermatologic adverse events associated with tumor treating fields in patients with glioblastoma multiforme: A 27-case series.

Objective: This study summarized the clinical management of 27 patients with glioblastoma multiforme who tumor treating fields therapy for the healthcare providers. Methods: Glioblastoma multiforme patients who experienced dermatologic adverse events after tumor treating fields therapy from April 2019 to May 2021 were included. The clinical management involved educating patients and their caregivers on the prevention of dermatologic adverse events, scalp assessment and preparation, and removal and replacement of the transducer array. Informed consent for participating in the study including the taking of pictures was obtained from all patients. Results: The dermatologic adverse events were successfully managed in all 27 patients, with no severe dermatologic adverse events were reported. Conclusions: Data on tumor treating fields-related dermatologic adverse events is rarely reported, and published reports of management of scalp dermatologic adverse events are lacking. This case series summarizes a clinically individualized management for tumor treating fields-related dermatologic adverse events.

Incidence, trend and risk factors associated with suicide among patients with malignant intracranial tumors: a surveillance, epidemiology, and end results analysis.

BACKGROUND: Cancer patients are associated with an elevated risk of suicide. This study aims to investigate the suicide rates and identify risk factors for suicide among patients with malignant intracranial tumors (MITs). METHODS: Patients diagnosed with MITs during the years of 1975-2015 were identified from the Surveillance, Epidemiology, and End Results (SEER) program. Suicide rates and standardized mortality ratios (SMR) were calculated. Cox regression analyses were used to identified risk factors for suicide among MIT patients. RESULTS: Among 115,668 patients with MITs collected from the SEER program, 99 committed suicide. The rate of suicide was 23.02 per 100,000 person-years, and SMR of suicide was 1.90. Diagnosis in recent era (years 2000-2015, SMR = 2.01), male gender (SMR = 1.78), older age (60-79 years, SMR = 3.54), white race (SMR = 1.86), married persons (SMR = 2.31), living in rural areas (SMR = 2.50), history of other malignancy (SMR = 3.81), diagnosis of glioblastoma (SMR = 4.05) and supratentorial location (SMR = 2.45) were associated with an increased incidence of suicide. In addition, the risk of suicide increased significantly within the first year after diagnosis (SMR = 13.04). Multivariate Cox regressions showed that older age, male sex, and supratentorial location were independent risk factors for suicide. CONCLUSIONS: The suicide mortality among patients with MITs steadily elevated in the past decades. Male sex, older age, and supratentorial location were significantly associated with risk of suicide, especially within the first year following diagnosis. Healthcare providers should early identify and effectively intervene with MIT patients at risk.

[Situation of nurses in China]. / La situation des infirmières en Chine.

Nurses play an essential role in the People's Republic of China. In particular, they are essential to meet the challenges of an aging population. While there has been little change in their situation for many years, change is now underway. The National Health Commission of the People's Republic of China has announced the upcoming implementation of strategies essential to the development of the profession.

Genetic engineering and raising temperature enhance recombinant protein production with the cdna1 promoter in Trichoderma reesei.

The fungus Trichoderma reesei is a powerful host for secreted production of proteins. The promoter of cdna1 gene, which encodes a small basic protein of unknown function and high expression, is commonly used for constitutive protein production in T. reesei. Nevertheless, the production level of proteins driven by this promoter still needs to be improved. Here, we identified that the region 600- to 700-bp upstream of the start codon is critical for the efficiency of the cdna1 promoter. Increasing the copy number of this region to three improved the production of a heterologous ß-mannanase by 37.5%. Screening of several stressful conditions revealed that the cdna1 promoter is heat inducible. Cultivation at 37 °C significantly enhanced the production of ß-mannanase as well as a polygalacturonase with the cdna1 promoter compared with those at 30 °C. Combing the strategies of promoter engineering, multi-copy gene insertion, and control of cultivation temperature, ß-mannanase of 199.85 U/mL and relatively high purity was produced in shake flask, which was 6.6 times higher than that before optimization. Taken together, the results advance the understanding of the widely used cdna1 promoter and provide effective strategies for enhancing the production of recombinant proteins in T. reesei.

Risk factors for postoperative cerebrospinal fluid leakage after transsphenoidal surgery for pituitary adenoma: a meta-analysis and systematic review.

OBJECTIVE: Postoperative cerebrospinal fluid (CSF) leakage represents a challenge even for experienced pituitary surgeons. We aimed to quantitatively synthesize data from studies regarding the risk factors for postoperative CSF leakage after transsphenoidal surgery (TSS) for pituitary adenoma (PA). METHODS: PubMed, Web of Science, The Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Wanfang database, and VIP database were searched for case-control and cohort studies, focusing on the risk factors associated with postoperative CSF leakage after TSS for PA. Pooled odds ratios (ORs) and 95% confidence intervals were calculated to determine the risk factors. RESULTS: A total of 34 case-control and cohort studies involving a total of 9,144 patients with PA were included in this systematic review. The overall rate of postoperative CSF leakage after TSS for PA was 5.6%. Tumor size, adenoma consistency, revision surgery, and intraoperative CSF leakage were independent risk factors for postoperative CSF leakage (ORs, 3.18-6.33). By contrast, the endoscopic approach showed a slight protective benefit compared with the microscopic approach in TSS (OR, 0.69). CONCLUSIONS: This review provides a comprehensive overview of the quality of the evidence base, informing clinical staff of the importance of screening risk factors for postoperative CSF leakage after TSS for PA. More attention should be paid to PA patients at high risk for CSF leakage after TSS to reduce complications and improve prognosis.