Formononetin derivatives containing benzyl piperidine: A brand new, highly efficient inhibitor targeting Xanthomonas spp.

INTRODUCTION: Plant bacterial diseases take an incalculable toll on global food security. The indiscriminate use of chemical synthetic pesticide not only facilitates pathogen resistance of pathogenic bacteria, but also poses a major threat to human health and environmental protection. Therefore, it is of great economic value and scientific significance to develop a new antibacterial drug with environmental friendliness and unique mechanism of action. OBJECTIVES: To design and synthesize formononetin derivatives based on natural products, evaluate their in vitro and in vivo antibacterial activities and elucidate the mechanisms involved. METHODS: The synthesis was carried out by classical active group splicing method. The antibacterial activities were evaluated using turbidimetry and pot experiments. The antibacterial mechanism was further investigated using scanning electron microscopy (SEM), virulence factors, defense enzymes activities, proteomics and metabolomics. RESULTS: 40 formononetin derivatives containing benzyl piperidine were designed and synthesized. The antibacterial results demonstrated that H32 exhibited the most potent inhibitory effect against Xanthomonas oryzae pv. Oryzae (Xoo) with the EC50 of 0.07 µg/mL, while H6 displayed the highest inhibitory activity against Xanthomonas axonopodis pv. Citri (Xac) with the EC50 of 0.24 µg/mL. Furthermore, the control efficacy of H32 against rice bacterial leaf blight (BLB) and H6 against citrus canker (CC) was validated through pot experiments. SEM, virulence factors and host enzyme activities assay indicated that H32 could not only reduce the virulence of Xoo, but also activate the activities of defense enzymes and improve the disease resistance of host plants. The proteomics and metabolomics analysis demonstrated that H32 could inhibit the synthesis of branched-chain amino acids, make Xoo cells in a starvation state, inhibit its proliferation, weaken its virulence and reduce its colonization and infection of host cells. CONCLUSION: Formononetin derivatives containing benzyl piperidine could be used as potentially effective inhibitors against Xanthomonas spp.

Development and Validation of a Risk Mortality Prediction Model for Patients with Pulmonary Tuberculosis Complicated by Severe Community-Acquired Pneumonia in the Intensive Care Unit.

Purpose: The mortality rate from pulmonary tuberculosis (PTB) complicated by severe community-acquired pneumonia (SCAP) in the intensive care unit (ICU) remains high. We aimed to develop a rapid and simple model for the early assessment and stratification of prognosis in these patients. Patients and Methods: All adult patients with PTB complicated by SCAP admitted to the ICU of a tertiary hospital in Chengdu, Sichuan, China between 2019 and 2021 (development cohort) and 2022 (validation cohort) were retrospectively included. Data on demographics, comorbidities, laboratory values, and interventions were collected. The outcome was the 28-day mortality. Stepwise backward multivariate Cox analysis was used to develop a mortality risk prediction score model. Receiver operating characteristic (ROC) and calibration curves were used to evaluate the model's predictive efficiency. Decision curve analysis (DCA) was used to validate the model's clinical value and impact on decision making. Results: Overall, 357 and 168 patients were included in the development and validation cohorts, respectively. The Pulmonary Tuberculosis Severity Index (PTSI) score included long-term use of glucocorticoid, body mass index (BMI) <18.5 kg/m2, diabetes, blood urea nitrogen (BUN) ≥7.14 mmol/L, PO2/FiO2 <150 mmHg, and vasopressor use. The area under the ROC curve (AUC) values were 0.817 (95% CI: 0.772-0.863) and 0.814 for the development and validation cohorts, respectively. The PTSI score had a higher AUC than the APACHE II, SOFA, and CURB-65 score. The calibration curves indicated good calibration in both cohorts. The DCA of the PTSI score indicated the high clinical application of the model compared with the APACHE II and SOFA scores. Conclusion: This prognostic tool was designed to rapidly evaluate the 28-day mortality risk in individuals with PTB complicated by SCAP. It can stratify this patient group into relevant risk categories, guide targeted interventions, and enhance clinical decision making, thereby optimizing patient care and improving outcomes.

The association between blood urea nitrogen to albumin ratio and the 28 day mortality in tuberculosis patients complicated by sepsis.

The relationship between blood urea nitrogen to albumin ratio (BAR) and the prognosis of patients with tuberculosis (TB) complicated by sepsis remains unclear. This study aimed to explore the association between BAR and overall patient prognosis. This was a retrospective cohort study of patients with TB complicated by sepsis who were admitted to the intensive care unit (ICU) of the Public Health Clinical Center of Chengdu between January 2019 and February 2023. The relationship between BAR values and prognosis in these patients was investigated using multivariate Cox regression, stratified analysis with interaction, restricted cubic spline (RCS), and threshold effect analysis. Sensitivity analyses were conducted to assess the robustness of the results. Our study included 537 TB patients complicated by sepsis admitted in the ICU, with a median age of 63.0 (48.0, 72.0) years; 76.7% of whom were men. The multivariate-restricted cubic spline analysis showed a non-linear association between BAR and patient prognosis. In the threshold analysis, we found that TB patients complicated by sepsis and a BAR < 7.916 mg/g had an adjusted hazard ratio (HR) for prognosis of 1.163 (95% CI 1.038-1.303; P = 0.009). However, when the BAR was ≥ 7.916 mg/g, there was no significant increase in the risk of death. The results of the sensitivity analysis were stable.

Aggregation Mechanisms and Molecular Structures of Amyloid-ß in Alzheimer's Disease.

Amyloid plaques are a major pathological hallmark involved in Alzheimer's disease and consist of deposits of the amyloid-ß peptide (Aß). The aggregation process of Aß is highly complex, which leads to polymorphous aggregates with different structures. In addition to aberrant aggregation, Aß oligomers can undergo liquid-liquid phase separation (LLPS) and form dynamic condensates. It has been hypothesized that these amyloid liquid droplets affect and modulate amyloid fibril formation. In this review, we briefly introduce the relationship between stress granules and amyloid protein aggregation that is associated with neurodegenerative diseases. Then we highlight the regulatory role of LLPS in Aß aggregation and discuss the potential relationship between Aß phase transition and aggregation. Furthermore, we summarize the current structures of Aß oligomers and amyloid fibrils, which have been determined using nuclear magnetic resonance (NMR) and cryo-electron microscopy (cryo-EM). The structural variations of Aß aggregates provide an explanation for the different levels of toxicity, shed light on the aggregation mechanism and may pave the way towards structure-based drug design for both clinical diagnosis and treatment.

Blockage of L2HGDH-mediated S-2HG catabolism orchestrates macrophage polarization to elicit antitumor immunity.

The high infiltration of tumor-associated macrophages (TAMs) in the immunosuppressive tumor microenvironment prominently attenuates the efficacy of immune checkpoint blockade (ICB) therapies, yet the underlying mechanisms are not fully understood. Here, we investigate the metabolic profile of TAMs and identify S-2-hydroxyglutarate (S-2HG) as a potential immunometabolite that shapes macrophages into an antitumoral phenotype. Blockage of L-2-hydroxyglutarate dehydrogenase (L2HGDH)-mediated S-2HG catabolism in macrophages promotes tumor regression. Mechanistically, based on its structural similarity to α-ketoglutarate (α-KG), S-2HG has the potential to block the enzymatic activity of 2-oxoglutarate-dependent dioxygenases (2-OGDDs), consequently reshaping chromatin accessibility. Moreover, S-2HG-treated macrophages enhance CD8+ T cell-mediated antitumor activity and sensitivity to anti-PD-1 therapy. Overall, our study uncovers the role of blockage of L2HGDH-mediated S-2HG catabolism in orchestrating macrophage antitumoral polarization and, further, provides the potential of repolarizing macrophages by S-2HG to overcome resistance to anti-PD-1 therapy.

Association Between Age and the 28-Day All-Cause Mortality in Tuberculosis Complicated by Sepsis in ICU Patients: A Retrospective Cohort Study.

Purpose: Age is considered a vital factor in intensive care units (ICUs) because of its association with physiological frailty, comorbidities, and immune system function. Previous studies have examined the association between age and prognosis in patients with tuberculosis (TB) or sepsis; however, the association between age and prognosis in ICU patients with TB complicated by sepsis is rare. This study aimed to assess the association between age and the prognosis of patients in the ICU with TB complicated by sepsis. Patients and Methods: Data from the ICU of the Public Health Clinical Center of Chengdu were analyzed using the multivariable Cox regression model, stratified analysis with interaction, restricted cubic spline (RCS), and threshold effect analysis to investigate the association between age and 28-day all-cause mortality in patients with TB complicated by sepsis. Results: In total, 520 patients diagnosed with TB and sepsis were enrolled (120 women [23.1%]; median age, 64 years). The association between age and risk of death exhibited a J-shaped curve on the RCS (P for nonlinearity = 0.001). In the threshold analysis, the hazard ratio for the risk of death was 1.104 (95% confidence interval, 1.05-1.16) in participants aged ≥66.2 years. The risk of death increased by 10.4% with every 1-year increase in age in patients with TB complicated by sepsis. No significant association was found between age and 28-day all-cause mortality in patients aged <66.2 years. Conclusion: A nonlinear relationship was observed between age and short-term all-cause mortality in patients in the ICU with TB complicated by sepsis. Patients with a higher age at admission may have a higher risk of death and require focused attention, close monitoring, and early treatment to reduce mortality.

AabHLH48, a novel basic helix-loop-helix transcription factor from Adonis amurensis, promotes early flowering in Arabidopsis by activating FRUITFULL expression.

Basic helix-loop-helix (bHLH) transcription factors play various important roles in plant growth and development. In this study, a AabHLH48 was identified in the floral organ of Adonis amurensis, a perennial herb that can naturally complete flowering at extreme low temperatures. AabHLH48 was widely expressed in various tissues or organs of A. amurensis and was localized in the nucleus. Overexpression of AabHLH48 promotes early flowering in Arabidopsis under both photoperiod (12 h light/12 h dark and 16 h light/8 h dark) and temperature (22 and 18 °C) conditions. Transcriptome sequencing combined with quantitative real-time PCR analysis showed that overexpression of AabHLH48 caused a general upregulation of genes involved in floral development in Arabidopsis, especially for AtAGAMOUS-LIKE 8/FRUITFULL (AtAGL8/FUL). The yeast one-hybrid assay revealed that AabHLH48 has transcriptional activating activity and can directly bind to the promoter region of AtAGL8/FUL. These results suggest that the overexpression of AabHLH48 promoting early flowering in Arabidopsis is associated with the upregulated expression of AtAGL8/FUL activated by AabHLH48. This indicates that AabHLH48 can serve as an important genetic resource for improving flowering-time control in other ornamental plants or crops.

Fluoride induces pyroptosis via IL-17A-mediated caspase-1/11-dependent pathways and Bifidobacterium intervention in testis.

Fluoride, a ubiquitous environmental pollutant, poses a significant public health threat. Our previous study revealed a correlation between fluoride-induced testicular pyroptosis and male reproductive dysfunction. However, the underlying mechanism remains unclear. Wild-type and interleukin 17A knockout mice were exposed to sodium fluoride (100 mg/L) in deionized drinking water for 18 weeks. Bifidobacterium intervention (1 × 109 CFU/mL, 0.2 mL/day, administered via gavage) commenced in the 10th week. Sperm quality, testicular morphology, key pyroptosis markers, spermatogenesis key genes, IL-17A signaling pathway, and pyroptosis pathway related genes were determined. The results showed that fluoride reduced sperm quality, damaged testicular morphology, affected spermatogenesis, elevated IL-17A levels, and induced testicular pyroptosis. Bifidobacterium intervention alleviated adverse reproductive outcomes. Fluoride-activated testicular pyroptosis through both typical and atypical pathways, with IL-17A involvement. Bifidobacterium supplementation attenuated pyroptosis by downregulating IL-17A, inhibiting NLRP3 and PYRIN-mediated caspase-1 and caspase-11 dependent pathways in testis, thereby alleviating fluoride-induced male reproductive damage. In summary, this study uncovers the mechanism underlying fluorine-induced testicular pyroptosis and illustrates the novel protecting feature of Bifidobacterium against fluoride-induced harm to male reproduction, along with its potential regulatory mechanism. These results provide fresh perspectives on treating male reproductive dysfunction resulting from fluoride or other environmental toxins.

The Heterogeneity of Symptom Burden and Fear of Progression Among Kidney Transplant Recipients: A Latent Class Analysis.

Purpose: Kidney transplant recipients (KTRs) may experience symptoms that increase their fear of progression (FoP), but a dearth of research examines the issue from a patient-centered perspective. Our study aimed to first determine the category of symptom burden, then to explore the differences in characteristics of patients in different subgroups, and finally to analyze the impact of symptom subgroup on FoP. Patients and Methods: Sociodemographic and Clinical Characteristics, Symptom Experience Scale, and Fear of Progression Questionnaire-Short Form were used. Latent class analysis was used to group KTRs according to the occurrence of symptoms. We used multivariate logistic regression to analyze the predictors of different subgroups. The differences in FoP among symptom burden subgroups were analyzed by hierarchical multiple regression. Results: Three subgroups were identified, designated all-high (20.5%), moderate (39.9%), and all-low (39.6%) according to their symptom occurrence. Multivariate logistic regression showed that gender, post-transplant time, per capita monthly income, and hyperuricemia were the factors that distinguished and predicted the all-high subgroup (P < 0.05). Hierarchical multiple regression showed that symptom burden had a significant effect on FoP (class1 vs class3: ß = 0.327, P < 0.001; class2 vs class3: ß = 0.104, P = 0.046), explaining the 8.0% variance of FoP (ΔR2 = 0.080). Conclusion: KTRs generally experience moderate or low symptom burden, and symptom burden is an influencing factor in FoP. Identifying the traits of KTRs with high symptom burden can help clinicians develop targeted management strategies and ease FoP of KTRs.

h-MBenes: Promising Two-Dimensional Material Family for Room-Temperature Antiferromagnetic and Hydrogen Evolution Reaction Applications.

Recently, a new class of two-dimensional (2D) hexagonal transition-metal borides (h-MBenes) was discovered through a combination of ab initio predictions and experimental studies. These h-MBenes are derived from ternary hexagonal MAB (h-MAB) phases and have demonstrated promising potential for practical applications. In this study, we conducted first-principles calculations on 15 h-MBenes and identified four antiferromagnetic metals and 11 electrocatalysts for the hydrogen evolution reaction (HER). Notably, the h-MnB material exhibited a remarkable Néel temperature of 340 K and a high magnetic anisotropy energy of 154 µeV/atom. Additionally, the hydrogen adsorption Gibbs free energies (ΔGH*) for h-ZrBO, h-MoBO, and h-Nb2BO2 are close to the ideal value of 0 eV, indicating their potential as electrochemical catalysts for HER. Further investigations revealed that the electronic structure, Néel temperature, and HER activity of the studied h-MBenes can be tuned by applying biaxial strains. These findings suggest that h-MBenes have wide-ranging applicability in areas such as antiferromagnetic spintronics, flexible electronic devices, and electrocatalysis, thereby expanding the potential applications of 2D transition-metal borides.

Novel flavonol derivatives containing benzoxazole as potential antiviral agents: design, synthesis, and biological evaluation.

A series of flavonol derivatives containing benzoxazole were designed and synthesized, and the structures of all the target compounds were determined by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). The structure of X2 was further confirmed by single crystal X-ray diffraction analysis. The results of the bioactivity tests showed that some of the target compounds possessed excellent antiviral activity against tobacco mosaic virus (TMV) in vivo. In particular, the median effective concentration (EC50) values for the curative and protective activities of X17 against TMV were 127.6 and 101.2 µg/mL, respectively, which were superior to those of ningnanmycin (320.0 and 234.6 µg/mL). The results of preliminary mechanism study indicated that X17 had a strong binding affinity for TMV coat protein (TMV-CP), which might hinder the self-assembly and replication of TMV particles. In addition, X17 was able to effectively inhibit tobacco leaf membrane lipid peroxidation and facilitate the removal of O2- from the body, thereby improving the disease resistance of tobacco plants. Therefore, the design and synthesis of flavonol derivatives containing benzoxazole provides value for the development of new antiviral drugs.

Cell number regulator 8 from Salix linearistipularis enhances cadmium tolerance in poplar by reducing cadmium uptake and accumulation.

Trace metals have relatively high density and high toxicity at low concentrations. Willow (Salix genus) is an excellent phytoremediation species for soil contaminated by trace metal ions. This study identified a cell number regulator (CNR) gene family member in Salix linearistipularis exhibiting strong metal ion resistance: SlCNR8. SlCNR8 expression was affected by various metal ions, including cadmium (Cd), zinc (Zn), copper (Cu), iron (Fe), and manganese (Mn). SlCNR8 overexpression enhanced Cd, Zn, Cu, and Fe resistance in transgenic poplar seedlings (84K) compared with the wild-type (WT). Moreover, transgenic poplar seedlings showed lower root Cd uptake and less Cd accumulation than WT under Cd stress. SlCNR8 was primarily localized to the nucleus and the plasma membrane-like cell periphery. Furthermore, SlCNR8 had transcriptional activation activity in yeast. The transcript levels of multiple metal ion transporters were altered in the roots of transgenic poplar seedlings compared to WT roots under Cd stress. These results suggest that SlCNR8 may enhance Cd resistance in transgenic poplar by reducing Cd uptake and accumulation. This may be related to altered transcription levels of other transporters or to itself. Our study suggests that SlCNR8 can be used as a candidate gene for genetic improvement of phytostabilisation of trace metals by genetic engineering.

Harmonizing T1-Weighted Images to Improve Consistency of Brain Morphology Among Different Scanner Manufacturers in Alzheimer's disease.

BACKGROUND: Brain MRI scanner variability can introduce bias in measurements. Harmonizing scanner variability is crucial. PURPOSE: To develop a harmonization method aimed at removing scanner variability, and to evaluate the consistency of results in multicenter studies. STUDY TYPE: Retrospective. POPULATION: Multicenter data from 170 healthy participants (males/females = 98/72; age = 73.8 ± 7.3) and 170 Alzheimer's disease patients (males/females = 98/72; age = 76.2 ± 8.5) were compared with reference data from another 340 participants. FIELD STRENGTH/SEQUENCE: 3-T, magnetization prepared rapid gradient echo and turbo field echo; 1.5-T, inversion recovery prepared fast spoiled gradient echo T1-weighted sequences. ASSESSMENT: Gray matter (GM) brain images, obtained through segmentation of T1-weighted images, were utilized to evaluate the performance of the harmonization method using common orthogonal basis extraction (HCOBE) and four other methods (removal of artificial voxel effect by linear regression, RAVEL; Z_score; general linear model, GLM; ComBat). Linear discriminant analysis (LDA) was used to access the effectiveness of different methods in reducing scanner variability. The performance of harmonization methods in preserving GM volumes heterogeneity was evaluated by the similarity of the relationship between GM proportion and age in the reference and multicenter data. Furthermore, the consistency of the harmonized multicenter data with the reference data were evaluated based on classification results (train/test = 7/3) and brain atrophy. STATISTICAL TESTS: Two-sample t-tests, area under the curve (AUC), and Dice coefficients were used to analyze the consistency of results from the reference and harmonized multicenter data. A P-value <0.01 was considered statistically significant. RESULTS: HCOBE reduced the scanner variability from 0.09 before harmonization to 0.003 (ideal: 0, RAVEL/Z_score/GLM/ComBat = 0.087/0.003/0.006/0.013). GM volumes showed no significant difference (P = 0.52) between the reference and HCOBE-harmonized multicenter data. Consistency evaluation showed that AUC values of 0.95 for both reference and HCOBE-harmonized multicenter data (RAVEL/Z_score/GLM/ComBat = 0.86/0.86/0.84/0.89), and the Dice coefficient increased from 0.73 before harmonization to 0.82 (ideal: 1, RAVEL/Z_score/GLM/ComBat = 0.39/0.64/0.59/0.74). DATA CONCLUSION: HCOBE may help to remove scanner variability and could improve the consistency of results in multicenter studies. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 1.

Ultrasound Combined With Continuous Microbubble Injection to Enhance Catheter-Directed Thrombolysis in Vitro and in Vivo.

OBJECTIVES: To investigate the influence of microbubble perfusion mode on catheter-directed thrombolysis (CDT), we evaluated the effect of two different types of microbubble perfusion modes (continuous injection versus bolus injection) on the thrombolytic efficacy of CDT in vitro and further assessed the effect of continuous microbubble injection on CDT in vivo. METHODS: In an in vitro experimental setup, 50 fresh bovine whole blood clots were randomized into five groups: ultrasound and continuous microbubble injection-enhanced CDT (US + cMB + CDT), ultrasound and bolus microbubble injection-enhanced CDT (US + bMB + CDT), US + CDT, US + cMB, and CDT. In a porcine femoral vein thrombosis model, 16 completely obstructive thrombi were randomly assigned to the CDT group and the US + cMB + CDT group, respectively. Thrombolysis rate, vascular recanalization rate, hematoxylin-eosin, and immunofluorescence staining were used to evaluate the thrombolytic effect in vitro and in vivo. RESULTS: In vitro, US + cMB + CDT group resulted in a significantly higher thrombolysis rate compared with the other four groups (P < .05). Meanwhile, this group also demonstrated a looser clot structure and more disrupted fibrin structures. In vivo, US + cMB + CDT contributed to a significantly higher vascular recanalization rate compared with CDT (87.50% versus 25.00%, P < .05). CONCLUSIONS: US + cMB + CDT was more effective than US + bMB + CDT in thrombolysis, and ultrasound combined with continuous microbubble injection could enhance the thrombolytic efficacy of CDT.

Treatment of Unstable Sacral Fractures with Robotically-aided Minimally Invasive Triangular Fixation.

OBJECTIVE: The treatment of unstable sacral fractures is huge challenge to surgeons. Robotically-aided minimally invasive triangular fixation (RoboTFX) is the most advanced technique up to now. This study is to evaluate the clinical outcomes of unstable sacral fractures treated with RoboTFX. METHODS: From March 2017 to October 2021, 48 consecutive patients with unstable sacral fractures were included in the study. All patients received surgical treatment with triangular fixation (TFX). Patients were divided into four groups according to the number of fractures (uni- or bilateral) and surgical method employed (RoboTFX or traditional open TFX). Between these four groups, clinical data on operation time, intraoperative bleeding, intraoperative fluoroscopy time, infection rate, fracture healing rates, insertion accuracy, Majeed pelvic outcome score, Mears' criterion, and Gibbons score were compared. Quantitative data were expressed as mean ± standard deviation and compared using Student's t-test. Categorical variable were compared using the Pearson's χ2 test. RESULTS: Comparing unilateral RoboTFX versus open TFX, neither fracture healing rate, infection rate, Majeed pelvic outcome score, Mears' radiological evaluation criterion, nor Gibbons score of the two groups were statistically significantly different (p > 0.05). However, operation time, intraoperative bleeding, intraoperative fluoroscopy time, and insertion accuracy in the RoboTFX group were all significantly better than those of the traditional open group (p < 0.05). Likewise, operation time, intraoperative bleeding, intraoperative fluoroscopy time, and accuracy of fixation insertion of the bilateral RoboTFX group were significantly better than those of the bilateral open group (p < 0.05). Meanwhile infection rate, fracture healing rate, Majeed score, Mears' criterion, and Gibbons score of two groups were not significantly different (p > 0.05). CONCLUSION: RoboTFX has the advantages of less operation time, less intraoperative bleeding and fluoroscopy, more accurate fixation insertion, and a higher healing rate compared to traditional open methods in the treatment of unstable sacral fractures. However, RoboTFX requires a few critical considerations, and the indications of its operation should be strictly evaluated.

Dopaminergic damage pattern predicts phenoconversion time in isolated rapid eye movement sleep behavior disorder.

PURPOSE: The exact phenoconversion time from isolated rapid eye movement (REM) sleep behavior disorder (iRBD) to synucleinopathies remains unpredictable. This study investigated whole-brain dopaminergic damage pattern (DDP) with disease progression and predicted phenoconversion time in individual patients. METHODS: Age-matched 33 iRBD patients and 20 healthy controls with 11C-CFT-PET scans were enrolled. The patients were followed up 2-10 (6.7 ± 2.0) years. The phenoconversion year was defined as the base year, and every 2 years before conversion was defined as a stage. Support vector machine with leave-one-out cross-validation strategy was used to perform prediction. RESULTS: Dopaminergic degeneration of iRBD was found to occur about 6 years before conversion and then abnormal brain regions gradually expanded. Using DDP, area under curve (AUC) was 0.879 (90% sensitivity and 88.3% specificity) for predicting conversion in 0-2 years, 0.807 (72.7% sensitivity and 83.3% specificity) in 2-4 years, 0.940 (100% sensitivity and 84.6% specificity) in 4-6 years, and 0.879 (100% sensitivity and 80.7% specificity) over 6 years. In individual patients, predicted stages correlated with whole-brain dopaminergic levels (r = - 0.740, p < 0.001). CONCLUSION: Our findings suggest that DDP could accurately predict phenoconversion time of individual iRBD patients, which may help to screen patients for early intervention.

Chlorpyrifos-mediated mitochondrial calcium overload induces EPC cell apoptosis via ROS/AMPK/ULK1.

Chlorpyrifos (CPF) is a typical organophosphate insecticide known to has serious toxicological effects on aquatic animals and causes many environmental contamination problems. To assess the effects of CPF on the epithelioma papulosum cyprini (EPC) cells of the common carps from the point of calcium ion (Ca2+) transport, the CPF-exposed EPC models were primarily established, and both AO/EB staining and Annexin V/PI assay with flow cytometry analysis were subsequently implemented to identify that CPF-induced EPC cell apoptosis, in consistent with the up-regulated expression of BAX, Cyt-c, CASP3 and CASP9, and down-regulated BCL-2 expression. Then, Mag-Fluo-4 AM, Fluo-4 AM and Rhod-2 AM staining probes were co-stained with ER-Tracker Red and Mito-Tracker Green applied to image cellular Ca2+ flux, illuminating Ca2+ depleted from ER and flux into mitochondria, resulting in ER stress and mitochondrial dysfunction. Additionally, 2-Aminoethyl Diphenylborinate (2-APB), 4-Phenylbutyric acid (4-PBA) and Dorsomorphin (Compound C) were performed as the inhibitor of Ca2+ transition, ER stress and AMPK phosphorylation, suggesting CPF-mediated Ca2+ overload triggered ER stress. And the over-generation of Mito-ROS intensified oxidative stress, promoting the phosphorylation of AMPK and deteriorating cell apoptotic death. The results of this study demonstrated Ca2+ overload-dependent mitochondrial dysfunction engages in the CPF-induced apoptosis, providing a novel concept for investigating the toxicity of CPF as environmental pollution on aquatic organisms.

A Campylobacteriosis Outbreak Caused by One Asymptomatic Food Handler Carrier.

In August 2021, three students with diarrhea from the same school visited a local hospital in the S district of Beijing. An epidemic investigation showed that there were more students with diarrhea in the same school and they had one meal together. Campylobacter jejuni was isolated from both patients with diarrhea and asymptomatic food handlers; however, the latter also carried Campylobacter coli. Phylogenomic analysis showed that there was a campylobacteriosis outbreak among the students, and the asymptomatic food handler may have been the source of the infection. Routine inspection and surveillance for Campylobacter is needed for the food producing staff, particularly those cooking in the cafeteria in schools or other public food services.

Clonal MDS/AML cells with enhanced TWIST1 expression reprogram the differentiation of bone marrow MSCs.

Bone marrow-derived mesenchymal stem cells (BMMSCs) derived from myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients often show a shift in the balance between osteoblastogenesis and adipogenesis. It was suggested that BMMSCs can potentially undergo reprogramming or educational processes. However, the results of reprogrammed differentiation have been inconclusive. In this study, clinical samples, co-culture models and mouse models were employed to explore the association of MDS/AML clonal cells and BMMSCs differentiation. We found that clonal MDS/AML cells promoted adipogenic differentiation and inhibited osteogenic differentiation of BMMSCs, which in turn promoted MDS expansion. Mass spectrometry and cytokine array were used to identify the molecules to drive the BMMSCs differentiation in MDS/AML. Mechanistically, highly expressed transcription factor TWIST1 in clonal MDS/AML cells induces MDS/AML cells to secrete more IFN-γ, which can induce oxidative stress through STAT1-dependent manner, ultimately causing enhanced adipogenic differentiation and inhibited osteogenic differentiation in BMMSCs. Overall, our findings suggest that targeting the driving oncogenes in malignant clonal cells, such as TWIST1, may offer new therapeutic strategies by remodeling the surrounding bone marrow microenvironment in the treatment of MDS/AML and other hematopoietic malignancies.