Model-based precision dosing and remedial dosing recommendations for delayed or missed doses of isoniazid in Chinese patients with tuberculosis.

AIMS: Isoniazid (INH) has been used as a first-line drug to treat tuberculosis (TB) for more than 50 years. However, large interindividual variability was found in its pharmacokinetics, and effects of nonadherence to INH treatment and corresponding remedy regime remain unclear. This study aimed to develop a population pharmacokinetic (PPK) model of INH in Chinese patients with TB to provide model-informed precision dosing and explore appropriate remedial dosing regimens for nonadherent patients. METHODS: In total, 1012 INH observations from 736 TB patients were included. A nonlinear mixed-effects modelling was used to analyse the PPK of INH. Using Monte Carlo simulations to determine optimal dosage regimens and design remedial dosing regimens. RESULTS: A 2-compartmental model, including first-order absorption and elimination with allometric scaling, was found to best describe the PK characteristics of INH. A mixture model was used to characterize dual rates of INH elimination. Estimates of apparent clearance in fast and slow eliminators were 28.0 and 11.2 L/h, respectively. The proportion of fast eliminators in the population was estimated to be 40.5%. Monte Carlo simulations determined optimal dosage regimens for slow and fast eliminators with different body weight. For remedial dosing regimens, the missed dose should be taken as soon as possible when the delay does not exceed 12 h, and an additional dose is not needed. delay for an INH dose exceeds 12 h, the patient only needs to take the next single dose normally. CONCLUSION: PPK modelling and simulation provide valid evidence on the precision dosing and remedial dosing regimen of INH.

Prevotella intermedia boosts OSCC progression through ISG15 upregulation: a new target for intervention.

PURPOSE: Periodontitis-associated bacteria, such as Porphyromonas gingivalis and Fusobacterium nucleatum, are closely linked to the risk of oral squamous cell carcinoma (OSCC). Emerging studies have indicated that another common periodontal pathogen, Prevotella intermedia (P. intermedia), is enriched in OSCC and could affect the occurrence and progression of OSCC. Our aim is to determine the effects of P. intermedia on the progression of OSCC and the role of antibiotics in reversing these effects. METHODS: In this study, a murine xenograft model of OSCC was established, and the mice were injected intratumorally with PBS (control group), P. intermedia (P.i group), or P. intermedia combined with an antibiotic cocktail administration (P.i + ABX group), respectively. The effects of P. intermedia and ABX administration on xenograft tumor growth, invasion, angiogenesis, and metastasis were investigated by tumor volume measurement and histopathological examination. Enzyme-linked immunosorbent assay (ELISA) was used to investigate the changes in serum cytokine levels. Immunohistochemistry (IHC) was adopted to analyze the alterations in the levels of inflammatory cytokines and infiltrated immune cells in OSCC tissues of xenograft tumors. Transcriptome sequencing and analysis were conducted to determine differential expression genes among various groups. RESULTS: Compared with the control treatment, P. intermedia treatment significantly promoted tumor growth, invasion, angiogenesis, and metastasis, markedly affected the levels of inflammatory cytokines, and markedly altered M2 macrophages and regulatory T cells (Tregs) infiltration in the tumor microenvironment. However, ABX administration clearly abolished these effects of P. intermedia. Transcriptome and immunohistochemical analyses revealed that P. intermedia infection increased the expression of interferon-stimulated gene 15 (ISG15). Correlation analysis indicated that the expression level of ISG15 was positively correlated with the Ki67 expression level, microvessel density, serum concentrations and tissue expression levels of inflammatory cytokines, and quantities of infiltrated M2 macrophages and Tregs. However, it is negatively correlated with the quantities of infiltrated CD4+ and CD8+ T cells. CONCLUSION: In conclusion, intratumoral P. intermedia infection aggravated OSCC progression, which may be achieved through upregulation of ISG15. This study sheds new light on the possible pathogenic mechanism of intratumoral P. intermedia in OSCC progression, which could be a prospective target for OSCC prevention and treatment.

The application of Moore's online learning interactions model in learning outcomes: The SOR (stimulus-organism-response) paradigm perspective.

This study presents an in-depth exploration of the impact of online learning interactions on student learning outcomes. Drawing from the Stimulus-Organism-Response (SOR) paradigm, our study focuses on the effects of online learning interactions on learners' perception usefulness and ease of use, subsequently impacting their learning outcomes. The study employs a quantitative research methodology, gathering data from a sample of 397 students enrolled in various higher education institutions across China. Data collection involved administering structured questionnaires that were designed to quantitatively assess the three components of the SOR model: stimulus (online learning interactions), organism (students' perceptions), and response (learning outcomes). The measurement model assessment and structural model assessment were conducted. Our findings reveal that online learning interactions can effectively enhance learners' perception of online learning (usefulness and ease of use), thereby influencing their learning outcomes. Notably, perceived usefulness negatively mediates the relationship between online learning interactions and learning outcomes, while perceived ease of use positively mediates this relationship. These findings offer both theoretical and practical implications.

Allosteric regulation of nitrate transporter NRT via the signaling protein PII.

Coordinated carbon and nitrogen metabolism is crucial for bacteria living in the fluctuating environments. Intracellular carbon and nitrogen homeostasis is maintained by a sophisticated network, in which the widespread signaling protein PII acts as a major regulatory hub. In cyanobacteria, PII was proposed to regulate the nitrate uptake by an ABC (ATP-binding cassette)-type nitrate transporter NrtABCD, in which the nucleotide-binding domain of NrtC is fused with a C-terminal regulatory domain (CRD). Here, we solved three cryoelectron microscopy structures of NrtBCD, bound to nitrate, ATP, and PII, respectively. Structural and biochemical analyses enable us to identify the key residues that form a hydrophobic and a hydrophilic cavity along the substrate translocation channel. The core structure of PII, but not the canonical T-loop, binds to NrtC and stabilizes the CRD, making it visible in the complex structure, narrows the substrate translocation channel in NrtB, and ultimately locks NrtBCD at an inhibited inward-facing conformation. Based on these results and previous reports, we propose a putative transport cycle driven by NrtABCD, which is allosterically inhibited by PII in response to the cellular level of 2-oxoglutarate. Our findings provide a distinct regulatory mechanism of ABC transporter via asymmetrically binding to a signaling protein.

Heat-killed Prevotella intermedia promotes the progression of oral squamous cell carcinoma by inhibiting the expression of tumor suppressors and affecting the tumor microenvironment.

BACKGROUND: Oral microbial dysbiosis contributes to the development of oral squamous cell carcinoma (OSCC). Our previous study showed that Prevotella intermedia (P. intermedia) were enriched in the oral mucosal surface, plaque, and saliva of patients with OSCC. Intratumoral microbiome could reshape the immune system and influence the development of various tumors. However, the invasion status of human OSCC tissues by P. intermedia and the pathway through which intratumoral P. intermedia potentiates tumor progression remain unexplored. METHODS: P. intermedia in human OSCC or normal tissues was detected by FISH. A mouse OSCC cell line SCC7 was adopted to investigate the effects of heat-killed P. intermedia treatment on cell proliferation, invasion, and cytokine release by using CCK-8 assay, transwell invasion assay and ELISA. Moreover, we established a mouse transplanted tumor model by using SCC7 cells, injected heat-killed P. intermedia into tumor tissues, and investigated the effects of heat-killed P. intermedia on tumor growth, invasion, cytokine levels, immune cell infiltrations, and expression levels by using gross observation, H&E staining, ELISA, immunohistochemistry, mRNA sequencing, and transcriptomic analysis. RESULTS: Our results indicated that P. intermedia were abundant in OSCC and surrounding muscle tissues. Heat-killed P. intermedia promoted SCC7 cell proliferation, invasion and proinflammatory cytokine secretions, accelerated transplanted tumor growth in mice, exacerbate muscle and perineural invasion of OSCC, elevated the serum levels of IL-17A, IL-6, TNF-α, IFN-γ, and PD-L1, induced Treg cells M2 type macrophages in mouse transplanted tumors. The data of transcriptomic analysis revealed that heat-killed P. intermedia increased the expression levels of inflammatory cytokines and chemokines while reduced the expression levels of some tumor suppressor genes in mouse transplanted tumors. Additionally, IL-17 signaling pathway was upregulated whereas GABAergic system was downregulated by heat-killed P. intermedia treatment. CONCLUSIONS: Taken together, our results suggest that P. intermedia could inhibit the expression of tumor suppressors, alter the tumor microenvironment, and promote the progression of OSCC.

Effects of the SEMA4B gene on hexavalent chromium [Cr(VI)]-induced malignant transformation of human bronchial epithelial cells.

Our previous study identified the potential of SEMA4B methylation level as a biomarker for hexavalent chromium [Cr(VI)] exposure. This study aimed to investigate the role of the SEMA4B gene in Cr(VI)-mediated malignant transformation of human bronchial epithelial (BEAS-2B) cells. In our population survey of workers, the geometric mean [95% confidence intervals (CIs)] of Cr in blood was 3.80 (0.42, 26.56) µg/L. Following treatment with various doses of Cr(VI), it was found that 0.5 µM had negligible effects on the cell viability of BEAS-2B cells. The expression of SEMA4B was observed to decrease in BEAS-2B cells after 7 days of treatment with 0.5 µM Cr(VI), and this downregulation continued with increasing passages of Cr(VI) treatment. Chronic exposure to 0.5 µM Cr(VI) enhanced the anchorage-independent growth ability of BEAS-2B cells. Furthermore, the use of a methylation inhibitor suppressed the Cr(VI)-mediated anchorage-independent growth in BEAS-2B cells. Considering that Cr levels exceeding 0.5 µM can be found in human blood due to occupational exposure, the results suggested a potential carcinogenic risk associated with occupational Cr(VI) exposure through the promotion of malignant transformation. The in vitro study further demonstrated that Cr(VI) exposure might inhibit the expression of the SEMA4B gene to promote the malignant transformation of BEAS-2B cells.

Low frequency of SLC26A4 c.919-2A > G variant among patients with nonsyndromic hearing loss in Yunnan of Southwest China.

BACKGROUND: Gene variants are responsible for more than half of hearing loss, particularly in nonsyndromic hearing loss (NSHL). The most common pathogenic variant in SLC26A4 gene found in East Asian populations is c.919-2A > G followed by c.2168A > G (p.H723R). This study was to evaluate their variant frequencies in patients with NSHL from special education schools in nine different areas of Southwest China's Yunnan. METHODS: We performed molecular characterization by PCR-products directly Sanger sequencing of the SLC26A4 c.919-2AG and c.2168 A > G variants in 1167 patients with NSHL including 533 Han Chinese and 634 ethnic minorities. RESULTS: The SLC26A4 c.919-2A > G variant was discovered in 8 patients with a homozygous state (0.69%) and twenty-five heterozygous (2.14%) in 1167 patients with NSHL. The total carrier rate of the c.919-2A > G variant was found in Han Chinese patients with 4.50% and ethnic minority patients with 1.42%. A significant difference existed between the two groups (P < 0.05). The c.919-2A > G allele variant frequency was ranged from 3.93% in Kunming to zero in Lincang and Nvjiang areas of Yunnan. We further detected the SLC26A4 c.2168 A > G variant in this cohort with one homozygotes (0.09%) and seven heterozygotes (0.60%), which was detected in Baoshan, Honghe, Licang and Pu`er areas. Between Han Chinese group (0.94%) and ethnic minority group (0.47%), there was no statistical significance (P > 0.05). Three Han Chinese patients (0.26%) carried compound heterozygosity for c.919-2A > G and c.2168 A > G. CONCLUSION: These data suggest that the variants in both SLC26A4 c.919-2A > G and c.2168 A > G were relatively less frequencies in this cohort compared to the average levels in most regions of China, as well as significantly lower than that in Han-Chinese patients. These results broadened Chinese population genetic information resources and provided more detailed information for regional genetic counselling for Yunnan.

Preventing Dissolution of Cathode Active Materials by Ion-anchoring Zeolite-based Separators for Durable Aqueous Zinc Batteries.

Aqueous zinc batteries have emerged as promising energy storage devices due to their safety and low cost. However, they face challenges such as anodic dendrite formation and cathodic compound dissolution. Here, we present the development of a polymer-matrixed zeolite separator (SZ) by synthesizing zeolite materials on a flexible polymeric membrane. This separator acts as an effective ionic barrier, preventing the leaching and shuttling of vanadium from the cathode, while significantly inhibiting the formation of by-products and zinc dendrites. The SZ cells demonstrate stable operation for more than 400 cycles at 0.5 A g-1 , with an initial capacity of 375.4 mAh g-1 , and over 10,000 cycles at 15 A g-1 . Notably, when pre-anchored with vanadium ions, the SZ-V cells exhibited excellent capacity retention of up to 94.6 % over 1000 cycles. The SZ separator featuring an ion barrier represents a crucial advancement towards the commercialization of zinc storage devices.

Rational design, synthesis and binding mechanisms of novel benzyl geranate derivatives as potential eco-friendly aphid repellents.

BACKGROUND: The push-pull strategy is considered as a promising eco-friendly method for pest management. Plant volatile organic compounds (PVOCs) act as semiochemicals constitute the key factor in implementing this strategy. Benzyl alcohol and geraniol, as functional PVOCs, were reported to regulate insect behavior, showing the potential application in pest control. Using geraniol as lead, a geraniol derivative 5i with fine repellent activity was discovered in our previous work. In order to explore novel, eco-friendly aphid control agents, a series of benzyl geranate derivatives was designed and synthesized using 5i as the lead and benzyl alcohol as the active fragment. RESULTS: Benzyl alcohol was firstly evaluated to have repellent activity to Acyrthosiphon pisum. Based on this repellent fragment, a series of novel benzyl geranate derivatives was rationally designed and synthesized using a scaffold-hopping strategy. Among them, compound T9, with a binding affinity (Kd = 0.43 µm) and a substantial repellency of 64.7% against A. pisum, is the most promising compound. Molecule docking showed that hydrophobic and hydrogen-bonding interactions substantially influenced the binding affinity of compounds with ApisOBP9. Additionally, T9 exhibited low-toxicity to honeybees and ladybugs. CONCLUSION: Using a simple scaffold-hopping strategy combined with active fragment benzyl alcohol, a new derivative T9, with high aphid-repellency and low-toxicity to nontarget organisms, can be considered as a novel potential eco-friendly aphid control agent for sustainable agriculture. © 2023 Society of Chemical Industry.

Inulin alleviates perfluorooctanoic acid-induced intestinal injury in mice by modulating the PI3K/AKT/mTOR signaling pathway.

Perfluorooctanoic acid (PFOA) is a widely used industrial compound that has been found to induce intestinal toxicity. However, the underlying mechanisms have not been fully clarified and effective interventions are rarely developed. Inulin, a prebiotic, has been used as a supplement in human daily life as well as in gastrointestinal diseases and metabolic disorders. In this study, male mice were exposed to PFOA with or without inulin supplementation to investigate the enterotoxicity and potential intervention effects of inulin. Mice were administered PFOA at 1 mg/kg/day, PFOA with inulin at 5 g/kg/day, or Milli-Q water for 12 weeks. Histopathological analysis showed that PFOA caused colon shortening, goblet cell reduction, and inflammatory cell infiltration. The expression of the tight junction proteins ZO-1, occludin and claudin5 significantly decreased, indicating impaired barrier function. According to the RNA-sequencing analysis, PFOA exposure resulted in 917 differentially expressed genes, involving 39 significant pathways, such as TNF signaling and cell cycle pathways. In addition, the protein expression of TNF-α, IRG-47, cyclinB1, and cyclinB2 increased, while Gadd45γ, Lzip, and Jam2 decreased, suggesting the involvement of the TNF signaling pathway, cell cycle, and cell adhesion molecules in PFOA-associated intestinal injury. Inulin intervention alleviated PFOA-induced enterotoxicity by activating the PI3K/AKT/mTOR signaling pathway and increasing the protein expression of Wnt1, ß-catenin, PI3K, Akt3, and p62, while suppressing MAP LC3ß, TNF-α, and CyclinE expression. These findings suggested that PFOA-induced intestinal injury, including inflammation and tight junction disruption, was mitigated by inulin through modifying the PI3K/AKT/mTOR signaling pathways. Our study provides valuable insights into the enterotoxic effects of PFOA and highlights the potential therapeutic role of inulin.

miR-9 promotes canine endothelial-like cell migration by targeting COL15A1.

BACKGROUND: Endothelial cell migration is the initial stage of angiogenesis. In previous studies, miR-9 has been found to regulate angiogenesis and cell migration in human medicine. OBJECTIVES: This study aimed to reveal the regulatory effect of miR-9 on canine endothelial cell migration. METHODS: Embryonic canine ventricle myocardium tissues were collected and induced to differentiate into endothelial-like cells (ELCs). A transwell and invasion assay were used to evaluate the impact of miR-9 on the migration capacity of ELCs, after which a luciferase reporter assay, western blotting, RNA sequencing and reverse transcription-polymerase chain reaction were conducted to explore the regulatory mechanism. RESULTS: Our results showed that we successfully induced the primary cells derived from canine cardiac embryo tissues into ELCs. MiR-9 also promoted the migration and invasion of canine ELCs, and inhibited the expression of collagen XV, an angiogenic inhibitor, at the translational level by targeting the 3' untranslated region of COL15A1 gene. Furthermore, RNA sequencing showed that overexpression of miR-9 impacted several signalling pathways and eight genes involved in angiogenesis and cell migration in canine ELCs. CONCLUSIONS: These findings suggest that miR-9 enhances the migration of canine ELCs and may serve as a potential diagnostic and therapeutic target for canine diseases involved in endothelial cells migration and angiogenesis, but more further studies are needed.

Risky working conditions and chronic kidney disease.

BACKGROUND: Individuals in the workplace are exposed to various environments, tasks, and schedules. Previous studies have indicated a link between occupational exposures and an increased risk of chronic kidney disease (CKD). However, the social conditions of the work environment may also be a crucial contributing factor to CKD. Furthermore, individuals may encounter multiple occupational-related risk factors simultaneously, underscoring the importance of investigating the joint risk of different working conditions on CKD. METHODS: A prospective analysis of 65,069 UK Biobank participants aged 40 to 69 years without CKD at baseline (2006-2010) was performed. A self-administered questionnaire assessed working conditions and a working conditions risk score were developed. Participants who answered "sometimes" or "often" exposure to occupational heat or occupational secondhand cigarette smoke; involved in shift work or heavy workloads ("usually" or "always"), were grouped as high-risk working conditions. Each working condition was scored as 1 if grouped as high-risk, and 0 if not. The working conditions risk score was equal to the sum of these four working conditions. Cox proportional hazard regression models were used to estimate the associations between working conditions and CKD incidence. RESULTS: The mean follow-up time was 6.7 years. After adjusting for demographic, lifestyle, and working time factors, the hazard ratios for the development of CKD for heavy workloads, shift work, occupational secondhand cigarette smoke exposure, and occupational heat exposure were 1.24 (95%CI = 1.03, 1.51), 1.33 (95%CI = 1.10, 1.62), 1.13 (95%CI = 1.01, 1.26), 1.11 (95%CI = 0.99, 1.24), respectively. The risk of CKD was found to be significantly associated with an increasing working conditions risk score. Individuals with a working conditions risk score of 4 had an 88.0% (95% CI = 1.05, 3.35) higher risk of developing CKD when compared to those with a working conditions risk score of 0. CONCLUSIONS: Adverse working conditions, particularly when considered in combination, can significantly elevate the risk of chronic kidney disease (CKD). These results provide a reference for implementing measures to prevent CKD.

Functional characterization of alkaline phosphatases involved alarm pheromone in the vetch aphid Megoura viciae.

The alkaline phosphatases (ALPs) are highly promiscuous enzymes and have been extensively investigated in mammals for their medical significance, but their functional promiscuity is relatively poorly understood in insects. Here, we first identified four ALP genes (designated as MvALP1-4) in the vetch aphid Megoura viciae that contained one alkaline phosphatase site, three metal-binding sites, and varied other functional sites. Phylogenetic analysis, molecular docking and the spatiotemporal expression profiling of MvALP1-4 were very different, indicating a promiscuous functionality. We also found that MvALP4 involved the biosynthesis of aphid alarm pheromones (EßF) in vitro and in vivo. Finally, transcriptome analysis in the stimulated and unstimulated aphids supported the involvement of MvALPs in the biosynthesis of aphid alarm pheromones. Our study identified a multifunctional ALP involved terpene synthase enzyme activity in the aphid, which contributes to the understanding of the functional plasticity of ALPs in insects.

Screening strategies and dynamic risk prediction models for Alzheimer's disease.

BACKGROUND: Characterizing the progression from Mild cognitive impairment (MCI) to Alzheimer's disease (AD) is essential for early AD prevention and targeted intervention. Our goal was to construct precise screening schemes for individuals with different risk of AD and to establish prognosis models for them. METHODS: We constructed a retrospective cohort by reviewing individuals with baseline diagnosis of MCI and at least one follow-up visits between November 2005 and May 2021. They were stratified into high-risk and low-risk groups with longitudinal cognitive trajectory. Then, we established a screening framework and obtained optimal screening strategies for two risk groups. Cox and random survival forest (RSF) models were developed for dynamic prognosis prediction. RESULTS: In terms of screening strategies, the combination of Clinical Dementia Rating Sum of Boxes (CDRSB) and hippocampus volume was recommended for the high-risk MCI group, while the combination of Alzheimer's Disease Assessment Scale Cognitive 13 items (ADAS13) and FAQ was recommended for low-risk MCI group. The concordance index (C-index) of the Cox model for the high-risk group was 0.844 (95% CI: 0.815-0.873) and adjustments for demographic information and APOE ε4. The RSF model incorporating longitudinal ADAS13, FAQ, and demographic information and APOE ε4 performed for the low-risk group. CONCLUSION: This precise screening scheme will optimize allocation of medical resources and reduce the economic burden on individuals with low risk of MCI. Moreover, dynamic prognosis models may be helpful for early identification of individuals at risk and clinical decisions, which will promote the secondary prevention of AD.

Controllable release of nitric oxide from an injectable alginate hydrogel.

Currently, the controlled release of nitric oxide (NO) plays a crucial role in various biomedical applications. However, injectable NO-releasing materials remain an underexplored research field to date. In this study, via the incorporation of S-nitroso-N-acetyl-penicillamine (SNAP) as an NO donor, a family of NO-releasing injectable hydrogels was synthesized through the in situ cross-linking between sodium alginate and calcium ion induced by D-(+)-gluconate δ-lactone as an initiator. Initially, the organic functional groups and the corresponding morphologies of the resulting injectable hydrogels were characterized by IR and SEM spectroscopies, respectively. The NO release times of hydrogels with different SNAP loading amounts could reach up to 36-47 h. Due to the release of NO, the highest antibacterial rates of these injectable hydrogels against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) were up to 95 %, respectively. Furthermore, the matrix of these hydrogels demonstrated great water absorption ability, swelling behavior, and degradation performance. Finally, we expect that these NO-releasing injectable hydrogels could have great potential applications various biomedical material fields.

Independent and Combined Associations of Blood Manganese, Cadmium and Lead Exposures with the Systemic Immune-Inflammation Index in Adults.

Manganese (Mn), cadmium (Cd) and lead (Pb) have toxic effects on the immune system. However, their independent and combined effects on immune-inflammation responses are unclear. In recent years, the systemic immune-inflammation index (SII) has been developed as an integrated and novel inflammatory indicator. A retrospective cross-sectional study of 2174 adults ≥20 years old from the National Health and Nutrition Examination Survey (NHANES) 2015-2016 was conducted. Generalized linear models were used to evaluate the independent and combined associations of SII with blood Mn, Cd and Pb levels. As continuous variables, both blood Cd and Mn showed dose-dependent relationships with the SII before and after adjusting for all potential confounding factors. Metal concentrations were then converted into categorical variables. Compared with the adults in the lowest Cd or Mn tertile, those in the highest tertile had higher risks of elevated SII. Furthermore, co-exposure to Mn and Cd also showed a positive relationship with the SII after adjusting for all confounding factors. However, the single effect of Pb exposure and the joint effect of Pb and other metal exposures on the SII were not observed. This study provides important epidemiological evidence of the associations of SII with single and co-exposure effects of blood Mn, Cd, and Pb.

Unveiling the role of bZIP transcription factors CREB and CEBP in detoxification metabolism of Nilaparvata lugens (Stål).

The basic leucine zipper (bZIP) superfamily is a crucial group of xenobiotics in insects. However, little is known about the function of CAAT enhancer binding proteins (CEBP) and cAMP response element binding protein (CREB) in Nilaparvata lugens. In the present study, NlCEBP and NlCREB were cloned and identified. Quantitative polymerase real-time chain reaction (qRT-PCR) analysis showed the expression of NlCEBP and NlCREB was significantly induced after chemical insecticides exposure. Silencing of NlCEBP and NlCREB increased the susceptibility of N. lugens to insecticides, and the detoxification enzyme activities were also significantly decreased. In addition, comparative transcriptome analysis revealed that 174 genes were significantly co-down-regulated after interfering with the two transcription factors. GO analysis showed that co-down-regulated genes are mostly related to energy transport and metabolic functions indicating the potential regulatory role of NlCEBP and NlCREB in detoxification metabolism. Our research shed lights on the functional roles of transcription factors NlCEBP and NlCREB in the detoxification metabolism of N. lugens, providing a theoretical basis for pest management and comprehensive control of this pest and increasing our understanding of insect toxicology.

Prognostic Factors and Survival Outcomes Among Patients With Mycosis Fungoides in China: A 12-Year Review.

Importance: There are limited prognostic statistics and data available on survival outcomes for patients with mycosis fungoides (MF) in Asia. Objective: To determine the prognostic factors and survival outcomes of patients with MF among a cohort in China. Design, Setting, and Participants: This was a retrospective cohort study of patients with MF who received treatment at a tertiary referral center for skin lymphoma (Peking University First Hospital, Beijing, China) from August 1, 2009, to August 31, 2021. Data were analyzed from September 1, 2021, to December 31, 2022. Main Outcomes and Measures: Overall survival (OS), disease-specific survival (DSS), and progression-free survival (PFS); for prognostic factors, hazard ratios (HRs), and adjusted HRs (aHRs; adjusted for sex, age, and overall TNMB [tumor, node, metastasis, blood] stage) determined using the Cox proportional hazards model. Results: The study cohort comprised 461 patients with MF (median [range] age at diagnosis, 46 [5-87] years; 275 [59.7%] men and 186 [40.3%] women; 461 [100%] Chinese). The overall 5-year rate was 82.2% for OS, 83.5% for DSS, and 79.6% for PFS. Stage-specific 5-year OS rates were 95.7% for stage IA, 93.2% for IB, 95.7% for IIA, 70.1% for IIB, 55.3% for III, and 23.6% for IV. Compared with a UK cohort, our Chinese cohort had a younger median age at diagnosis (46 years vs 54 years) and a more favorable 5-year OS (82.2% vs 75.0%); however, after adjusting for age, the discrepancy in the 5-year OS rate was diminished (77.3% vs 76.4%). Cox models revealed that unfavorable predictors of OS, PFS, and DSS, respectively, were: age older than 60 years (aHR [95% CI], 2.25 [1.28-3.96]; 2.09 [1.16-3.76]; 2.27 [1.39-3.72]); advanced TNMB stage; advanced overall stage; large-cell transformation (aHR [95% CI], 2.16 [1.17-3.99]; 2.29 [1.21-4.33]; 2.21 [1.26-3.86]); and elevated lactate dehydrogenase levels (aHR [95% CI], 3.92 [1.64-9.36]; 4.77 [1.86-12.22]; 5.05 [2.23-11.42]). Biological sex and plaque lesion type were not associated with prognosis among this study cohort. Conclusion and Relevance: The findings of this retrospective cohort study of patients with MF in China suggest that Asian patients are diagnosed at a younger age and have a higher 5-year OS compared with patients of other races in studies in other countries (predominantly White). Prognostic factors were similar to those of previous studies, except for patient sex and plaque lesion type.

XGBoost-SHAP-based interpretable diagnostic framework for alzheimer's disease.

BACKGROUND: Due to the class imbalance issue faced when Alzheimer's disease (AD) develops from normal cognition (NC) to mild cognitive impairment (MCI), present clinical practice is met with challenges regarding the auxiliary diagnosis of AD using machine learning (ML). This leads to low diagnosis performance. We aimed to construct an interpretable framework, extreme gradient boosting-Shapley additive explanations (XGBoost-SHAP), to handle the imbalance among different AD progression statuses at the algorithmic level. We also sought to achieve multiclassification of NC, MCI, and AD. METHODS: We obtained patient data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including clinical information, neuropsychological test results, neuroimaging-derived biomarkers, and APOE-ε4 gene statuses. First, three feature selection algorithms were applied, and they were then included in the XGBoost algorithm. Due to the imbalance among the three classes, we changed the sample weight distribution to achieve multiclassification of NC, MCI, and AD. Then, the SHAP method was linked to XGBoost to form an interpretable framework. This framework utilized attribution ideas that quantified the impacts of model predictions into numerical values and analysed them based on their directions and sizes. Subsequently, the top 10 features (optimal subset) were used to simplify the clinical decision-making process, and their performance was compared with that of a random forest (RF), Bagging, AdaBoost, and a naive Bayes (NB) classifier. Finally, the National Alzheimer's Coordinating Center (NACC) dataset was employed to assess the impact path consistency of the features within the optimal subset. RESULTS: Compared to the RF, Bagging, AdaBoost, NB and XGBoost (unweighted), the interpretable framework had higher classification performance with accuracy improvements of 0.74%, 0.74%, 1.46%, 13.18%, and 0.83%, respectively. The framework achieved high sensitivity (81.21%/74.85%), specificity (92.18%/89.86%), accuracy (87.57%/80.52%), area under the receiver operating characteristic curve (AUC) (0.91/0.88), positive clinical utility index (0.71/0.56), and negative clinical utility index (0.75/0.68) on the ADNI and NACC datasets, respectively. In the ADNI dataset, the top 10 features were found to have varying associations with the risk of AD onset based on their SHAP values. Specifically, the higher SHAP values of CDRSB, ADAS13, ADAS11, ventricle volume, ADASQ4, and FAQ were associated with higher risks of AD onset. Conversely, the higher SHAP values of LDELTOTAL, mPACCdigit, RAVLT_immediate, and MMSE were associated with lower risks of AD onset. Similar results were found for the NACC dataset. CONCLUSIONS: The proposed interpretable framework contributes to achieving excellent performance in imbalanced AD multiclassification tasks and provides scientific guidance (optimal subset) for clinical decision-making, thereby facilitating disease management and offering new research ideas for optimizing AD prevention and treatment programs.

Inhibiting mechanism of Alpiniae oxyphyllae fructus polysaccharide 3 against the replication of porcine epidemic diarrhea virus.

Porcine epidemic diarrhea virus (PEDV) causes diarrhea, vomiting, and death in piglets. Our previous study has revealed the anti-PEDV activity of Alpiniae oxyphyllae fructus polysaccharide 3 (AOFP3). However, it is still unknown whether AOFP3 can inhibit the replication of PEDV. Therefore, the effect of AOFP3 on PEDV replication was investigated in the present study, along with analysis of viral RdRp activity and expression of hnRNP A1 by RNA polymerase activity assay in vitro, RIP assay, and Western blotting. The results showed that both the PEDV gene and protein levels in IPEC-J2 cells decreased with AOFP3 treatment. In addition, AOFP3 significantly reduced PEDV's replication by down-regulating the activity of PEDV RdRp and reducing the expression of hnRNP A1, whereas only the bind of RdRp to PEDV 3'UTR was inhibited in AOFP3 treated cells.