Biofilm-producing ability of methicillin-resistant Staphylococcus aureus clinically isolated in China.

BACKGROUND: Staphylococcus aureus, a commensal bacterium, colonizes the skin and mucous membranes of approximately 30% of the human population. Apart from conventional resistance mechanisms, one of the pathogenic features of S. aureus is its ability to survive in a biofilm state on both biotic and abiotic surfaces. Due to this characteristic, S. aureus is a major cause of human infections, with Methicillin-Resistant Staphylococcus aureus (MRSA) being a significant contributor to both community-acquired and hospital-acquired infections. RESULTS: Analyzing non-repetitive clinical isolates of MRSA collected from seven provinces and cities in China between 2014 and 2020, it was observed that 53.2% of the MRSA isolates exhibited varying degrees of ability to produce biofilm. The biofilm positivity rate was notably high in MRSA isolates from Guangdong, Jiangxi, and Hubei. The predominant MRSA strains collected in this study were of sequence types ST59, ST5, and ST239, with the biofilm-producing capability mainly distributed among moderate and weak biofilm producers within these ST types. Notably, certain sequence types, such as ST88, exhibited a high prevalence of strong biofilm-producing strains. The study found that SCCmec IV was the predominant type among biofilm-positive MRSA, followed by SCCmec II. Comparing strains with weak and strong biofilm production capabilities, the positive rates of the sdrD and sdrE were higher in strong biofilm producers. The genetic determinants ebp, icaA, icaB, icaC, icaD, icaR, and sdrE were associated with strong biofilm production in MRSA. Additionally, biofilm-negative MRSA isolates showed higher sensitivity rates to cefalotin (94.8%), daptomycin (94.5%), mupirocin (86.5%), teicoplanin (94.5%), fusidic acid (81.0%), and dalbavancin (94.5%) compared to biofilm-positive MRSA isolates. The biofilm positivity rate was consistently above 50% in all collected specimen types. CONCLUSIONS: MRSA strains with biofilm production capability warrant increased vigilance.

A dual-energy computed tomography-based radiomics nomogram for predicting time since stroke onset: a multicenter study.

OBJECTIVES: We aimed to develop and validate a radiomics nomogram based on dual-energy computed tomography (DECT) images and clinical features to classify the time since stroke (TSS), which could facilitate stroke decision-making. MATERIALS AND METHODS: This retrospective three-center study consecutively included 488 stroke patients who underwent DECT between August 2016 and August 2022. The eligible patients were divided into training, test, and validation cohorts according to the center. The patients were classified into two groups based on an estimated TSS threshold of ≤ 4.5 h. Virtual images optimized the visibility of early ischemic lesions with more CT attenuation. A total of 535 radiomics features were extracted from polyenergetic, iodine concentration, virtual monoenergetic, and non-contrast images reconstructed using DECT. Demographic factors were assessed to build a clinical model. A radiomics nomogram was a tool that the Rad score and clinical factors to classify the TSS using multivariate logistic regression analysis. Predictive performance was evaluated using receiver operating characteristic (ROC) analysis, and decision curve analysis (DCA) was used to compare the clinical utility and benefits of different models. RESULTS: Twelve features were used to build the radiomics model. The nomogram incorporating both clinical and radiomics features showed favorable predictive value for TSS. In the validation cohort, the nomogram showed a higher AUC than the radiomics-only and clinical-only models (AUC: 0.936 vs 0.905 vs 0.824). DCA demonstrated the clinical utility of the radiomics nomogram model. CONCLUSIONS: The DECT-based radiomics nomogram provides a promising approach to predicting the TSS of patients. CLINICAL RELEVANCE STATEMENT: The findings support the potential clinical use of DECT-based radiomics nomograms for predicting the TSS. KEY POINTS: Accurately determining the TSS onset is crucial in deciding a treatment approach. The radiomics-clinical nomogram showed the best performance for predicting the TSS. Using the developed model to identify patients at different times since stroke can facilitate individualized management.

Associations between atherosclerotic luminal stenosis in the distal internal carotid artery and diffuse wall thickening in its upstream segment.

OBJECTIVES: Significant atherosclerotic stenosis or occlusion in the distal internal carotid artery (ICA) may induce diffuse wall thickening (DWT) in the upstream arterial wall. This study aimed to assess the association of atherosclerotic steno-occlusive diseases in the distal ICA with DWT in the upstream ipsilateral ICA. METHODS: Individuals with atherosclerotic stenosis in the distal ICA, detected by carotid MR vessel wall imaging using 3D pre- and post-contrast T1 volume isotropic turbo spin-echo acquisition (T1-VISTA) sequence, were enrolled. The associations of vessel wall thickening, the longitudinal extent of DWT, enhancement of the upstream ipsilateral ICA, and stenosis degree in the distal ICA were examined. RESULTS: Totally 64 arteries in 55 patients with atherosclerotic steno-occlusive distal ICAs were included. Significant correlations were found between distal ICA stenosis and DWT in the petrous ICA (r = 0.422, p = 0.001), DWT severity (r = 0.474, p < 0.001), the longitudinal extent of DWT in the ICA (r = 0.671, p < 0.001), enhancement in the petrous ICA (r = 0.409, p = 0.001), and enhancement degree (r = 0.651, p < 0.001). In addition, high degree of enhancement was correlated with both increased wall thickness and increased prevalence of DWT in the petrous ICA (both p < 0.001). CONCLUSIONS: DWT of the petrous ICA is commonly detected in patients with atherosclerotic steno-occlusive disease in the distal ICA. The degree of stenosis in the distal ICA is associated with wall thickening and its longitudinal extent in the upstream segments. CLINICAL RELEVANCE STATEMENT: Diffuse wall thickening is a common secondary change in atherosclerotic steno-occlusive disease in the intracranial carotid. This phenomenon constitutes a confounding factor in the distinction between atherosclerosis and inflammatory vasculopathies, and could be reversed after alleviated atherosclerotic stenosis. KEY POINTS: • Diffuse wall thickening of the petrous internal carotid artery is commonly detected in patients with atherosclerotic steno-occlusive disease in the distal internal carotid artery. • The phenomenon of diffuse wall thickening could be reversed after stenosis alleviation. • Carotid artery atherosclerosis with diffuse wall thickening should warrant a differential diagnosis from other steno-occlusive diseases, including moyamoya diseases and Takayasu aortitis.

Optimizing timing for quantification of intracranial aneurysm enhancement: a multi-phase contrast-enhanced vessel wall MRI study.

OBJECTIVES: Aneurysm wall enhancement (AWE) on high-resolution contrast-enhanced vessel wall MRI (VWMRI) is an emerging biomarker for intracranial aneurysms (IAs) stability. Quantification methods of AWE in the literature, however, are variable. We aimed to determine the optimal post-contrast timing to quantify AWE in both saccular and fusiform IAs. MATERIALS AND METHODS: Consecutive patients with unruptured IAs were prospectively recruited. VWMRI was acquired on 1 pre-contrast and 4 consecutive post-contrast phases (each phase was 9 min). Signal intensity values of cerebrospinal fluid (CSF) and aneurysm wall on pre- and 4 post-contrast phases were measured to determine the aneurysm wall enhancement index (WEI). AWE was also qualitatively analyzed on post-contrast images using previous grading criteria. The dynamic changes of AWE grade and WEI were analyzed for both saccular and fusiform IAs. RESULTS: Thirty-four patients with 42 IAs (27 saccular IAs and 15 fusiform IAs) were included. The changes in AWE grade occurred in 8 (30%) saccular IAs and 6 (40%) in fusiform IAs during the 4 post-contrast phases. The WEI of fusiform IAs decreased 22.0% over time after contrast enhancement (p = 0.009), while the WEI of saccular IAs kept constant during the 4 post-contrast phases (p > 0.05). CONCLUSIONS: When performing quantitative analysis of AWE, acquiring post-contrast VWMRI immediately after contrast injection achieves the strongest AWE for fusiform IAs. While the AWE degree is stable for 36 min after contrast injection for saccular IAs. CLINICAL RELEVANCE STATEMENT: The standardization of imaging protocols and analysis methods for AWE will be helpful for imaging surveillance and further treatment decisions of patients with unruptured IAs. KEY POINTS: Imaging protocols and measurements of intracranial aneurysm wall enhancement are reported heterogeneously. Aneurysm wall enhancement for fusiform intracranial aneurysms (IAs) is strongest immediately post-contrast, and stable for 36 min for saccular IAs. Future multi-center studies should investigate aneurysm wall enhancement as an emerging marker of aneurysm growth and rupture.

Gadolinium-enhanced intracranial aneurysm wall imaging and risk of aneurysm growth and rupture: a multicentre longitudinal cohort study.

OBJECTIVES: In patients with an unruptured intracranial aneurysm, gadolinium enhancement of the aneurysm wall is associated with growth and rupture. However, most previous studies did not have a longitudinal design and did not adjust for aneurysm size, which is the main predictor of aneurysm instability and the most important determinant of wall enhancement. We investigated whether aneurysm wall enhancement predicts aneurysm growth and rupture during follow-up and whether the predictive value was independent of aneurysm size. MATERIALS AND METHODS: In this multicentre longitudinal cohort study, individual patient data were obtained from twelve international cohorts. Inclusion criteria were as follows: 18 years or older with ≥ 1 untreated unruptured intracranial aneurysm < 15 mm; gadolinium-enhanced aneurysm wall imaging and MRA at baseline; and MRA or rupture during follow-up. Patients were included between November 2012 and November 2019. We calculated crude hazard ratios with 95%CI of aneurysm wall enhancement for growth (≥ 1 mm increase) or rupture and adjusted for aneurysm size. RESULTS: In 455 patients (mean age (SD), 60 (13) years; 323 (71%) women) with 559 aneurysms, growth or rupture occurred in 13/194 (6.7%) aneurysms with wall enhancement and in 9/365 (2.5%) aneurysms without enhancement (crude hazard ratio 3.1 [95%CI: 1.3-7.4], adjusted hazard ratio 1.4 [95%CI: 0.5-3.7]) with a median follow-up duration of 1.2 years. CONCLUSIONS: Gadolinium enhancement of the aneurysm wall predicts aneurysm growth or rupture during short-term follow-up, but not independent of aneurysm size. CLINICAL RELEVANCE STATEMENT: Gadolinium-enhanced aneurysm wall imaging is not recommended for short-term prediction of growth and rupture, since it appears to have no additional value to conventional predictors. KEY POINTS: • Although aneurysm wall enhancement is associated with aneurysm instability in cross-sectional studies, it remains unknown whether it predicts risk of aneurysm growth or rupture in longitudinal studies. • Gadolinium enhancement of the aneurysm wall predicts aneurysm growth or rupture during short-term follow-up, but not when adjusting for aneurysm size. • While gadolinium-enhanced aneurysm wall imaging is not recommended for short-term prediction of growth and rupture, it may hold potential for aneurysms smaller than 7 mm.

Antagonizing roles of SHP1 in the pathogenesis of Helicobacter pylori infection.

BACKGROUND: SHP1 has been documented as a tumor suppressor and it was thought to play an antagonistic role in the pathogenesis of Helicobacter pylori infection. In this study, the exact mechanism of this antagonistic action was studied. MATERIALS AND METHODS: AGS, MGC803, and GES-1 cells were infected with H. pylori, intracellular distribution changes of SHP1 were first detected by immunofluorescence. SHP1 overexpression and knockdown were then constructed in these cells to investigate its antagonistic roles in H. pylori infection. Migration and invasion of infected cells were detected by transwell assay, secretion of IL-8 was examined via ELISA, the cells with hummingbird-like alteration were determined by microexamination, and activation of JAK2/STAT3, PI3K/Akt, and ERK pathways were detected by immunoblotting. Mice infection model was established and gastric pathological changes were evaluated. Finally, the SHP1 activator sorafenib was used to analyze the attenuating effect of SHP1 activation on H. pylori pathogenesis in vitro and in vivo. RESULTS: The sub-localization of SHP1 changed after H. pylori infection, specifically that the majority of the cytoplasmic SHP1 was transferred to the cell membrane. SHP1 inhibited H. pylori-induced activation of JAK2/STAT3 pathway, PI3K/Akt pathway, nuclear translocation of NF-κB, and then reduced EMT, migration, invasion, and IL-8 secretion. In addition, SHP1 inhibited the formation of CagA-SHP2 complex by dephosphorylating phosphorylated CagA, reduced ERK phosphorylation and the formation of CagA-dependent hummingbird-like cells. In the mice infection model, gastric pathological changes were observed and increased IL-8 secretion, indicators of cell proliferation and EMT progression were also detected. By activating SHP1 with sorafenib, a significant curative effect against H. pylori infection was obtained in vitro and in vivo. CONCLUSIONS: SHP1 plays an antagonistic role in H. pylori pathogenesis by inhibiting JAK2/STAT3 and PI3K/Akt pathways, NF-κB nuclear translocation, and CagA phosphorylation, thereby reducing cell EMT, migration, invasion, IL-8 secretion, and hummingbird-like changes.

EEG microstate correlates of emotion dynamics and stimulation content during video watching.

INTRODUCTION: EEG microstates have been widely adopted to understand the complex and dynamic-changing process in dynamic brain systems, but how microstates are temporally modulated by emotion dynamics is still unclear. An investigation of EEG microstates under video-evoking emotion dynamics modulation would provide a novel insight into the understanding of temporal dynamics of functional brain networks. METHODS: In the present study, we postulate that emotional states dynamically modulate the microstate patterns, and perform an in-depth investigation between EEG microstates and emotion dynamics under a video-watching task. By mapping from subjective-experienced emotion states and objective-presented stimulation content to EEG microstates, we gauge the comprehensive associations among microstates, emotions, and multimedia stimulation. RESULTS: The results show that emotion dynamics could be well revealed by four EEG microstates (MS1, MS2, MS3, and MS4), where MS3 and MS4 are found to be highly correlated to different emotion states (emotion task effect and level effect) and the affective information involved in the multimedia content (visual and audio). CONCLUSION: In this work, we reveal the microstate patterns related to emotion dynamics from sensory and stimulation dimensions, which deepens the understanding of the neural representation under emotion dynamics modulation and will be beneficial for the future study of brain dynamic systems.

Characterization difference of typical KL1, KL2 and ST11-KL64 hypervirulent and carbapenem-resistant Klebsiella pneumoniae.

Almost all the formation of hypervirulent and carbapenem-resistant Klebsiella pneumoniae follow two major patterns: KL1/KL2 hvKP strains acquire carbapenem-resistance plasmids (CR-hvKP), and carbapenem-resistant Klebsiella pneumoniae (CRKP) strains obtain virulence plasmids (hv-CRKP). These two patterns may pose different phenotypes. In this study, three typical resistance and hypervirulent K. pneumoniae (KL1, KL2, and ST11-KL64), isolating from poor prognosis patients, were selected. Compared with ST11-KL64 hv-CRKP, KL1/KL2 hypervirulent lineages harbor significantly fewer resistance determinants and exhibited lower-level resistance to antibiotics. Notably, though the blaKPC gene could be detected in all these isolates, KL1/KL2 hvKP strain did not exhibit corresponding high-level carbapenem resistance. Unlike the resistance features, we did not observe significant virulence differences between the three strains. The ST11-KL64 hv-CRKP (1403) in this study, showed similar mucoviscosity, siderophores production, and biofilm production compared with KL1 and KL2 hvKP. Moreover, the hypervirulent of ST11-KL64 hvKP also verified with the human lung epithelial cells infection and G. mellonella infection models. Moreover, we found the pLVPK-like virulence plasmid and IncF blaKPC-2 plasmid was crucial for the formation of hypervirulent and carbapenem-resistant K. pneumoniae. The conservation of origin of transfer site (oriT) in these virulence and blaKPC-2 plasmids, indicated the virulence plasmids could transfer to CRKP with the help of blaKPC-2 plasmids. The co-existence of virulence plasmid and blaKPC-2 plasmid facilitate the formation of ST11-KL64 hv-CPKP, which then become nosocomial epidemic under the antibiotic stress. The ST11-KL64 hv-CPKP may poses a substantial threat to healthcare networks, urgent measures were needed to prevent further dissemination in nosocomial settings.

De novo design of dual-target JAK2, SMO inhibitors based on deep reinforcement learning, molecular docking and molecular dynamics simulations.

Triple-negative breast cancer (TNBC) and HER2-positive breast cancer are particularly aggressive and the effectiveness of current therapies for them is limited. TNBC lacks effective therapies and HER2-positive cancer is often resistant to HER2-targeted drugs after an initial response. The recent studies have demonstrated that the combination of JAK2 inhibitors and SMO inhibitors can effectively inhibit the growth and metastasis of TNBC and HER2-positive drug resistant breast cancer cells. In this study, deep reinforcement learning was used to learn the characteristics of existing small molecule inhibitors of JAK2 and SMO, and to generate a novel library of small molecule compounds that may be able to inhibit both JAK2 and SMO. Subsequently, the molecule library was screened by molecular docking and a total of 7 compounds were selected out as dual inhibitors of JAK2 and SMO. Molecular dynamics simulations and binding free energies showed that the top three compounds stably bound to both JAK2 and SMO proteins. The binding free energies and hydrogen bond occupancy of key amino acids indicate that A8976 and A10625 has good properties and could be a potential dual-target inhibitor of JAK2 and SMO.

Cerebral hemodynamics in symptomatic anterior circulation intracranial stenosis measured by angiography-based quantitative flow ratio: association with CT perfusion.

OBJECTIVES: Cerebral hemodynamics is important for the management of intracranial atherosclerotic stenosis (ICAS). This study aimed to determine the utility of angiography-based quantitative flow ratio (QFR) to reflect cerebral hemodynamics in symptomatic anterior circulation ICAS by evaluating its association with CT perfusion (CTP). METHODS: Sixty-two patients with unilateral symptomatic stenosis in the intracranial internal carotid artery or middle cerebral artery who received percutaneous transluminal angioplasty (PTA) or PTA with stenting were included. Murray law-based QFR (µQFR) was computed from a single angiographic view. CTP parameters including cerebral blood flow, cerebral blood volume, mean transit time (MTT), and time to peak (TTP) were calculated, and relative values were obtained as the ratio between symptomatic and contralateral hemispheres. Relationships between µQFR and perfusion parameters, and between µQFR and perfusion response after intervention, were analyzed. RESULTS: Thirty-eight patients had improved perfusion after treatment. µQFR was significantly correlated with relative values of TTP and MTT, with correlation coefficients of -0.45 and -0.26, respectively, on a per-patient basis, and -0.72 and -0.43, respectively, on a per-vessel basis (all p < 0.05). Sensitivity and specificity for µQFR to diagnose hypoperfusion at a cut-off value of 0.82 were 94.1% and 92.1%, respectively. Multivariate analysis revealed that µQFRpost (adjusted odds ratio [OR], 1.48; p = 0.002), collateral score (adjusted OR, 6.97; p = 0.01), and current smoking status (adjusted OR, 0.03; p = 0.01) were independently associated with perfusion improvement after treatment. CONCLUSIONS: µQFR was associated with CTP in patients with symptomatic anterior circulation ICAS and may be a potential marker for real-time hemodynamic evaluation during interventional procedures. KEY POINTS: • Murray law-based QFR (µQFR) is associated with CT perfusion parameters in intracranial atherosclerotic stenosis and can differentiate hypoperfusion from normal perfusion. • Post-intervention µQFR, collateral score, and current smoking status are independent factors associated with improved perfusion after treatment.

Elevated Hemoglobin A1c Is Associated With Leaky Plaque Neovasculature as Detected by Dynamic Contrast-Enhanced Magnetic Resonance Imaging.

BACKGROUND: Patients with diabetes have accelerated atherosclerosis progression, but the underlying mechanisms are not fully understood. Dynamic contrast-enhanced magnetic resonance imaging has allowed in vivo characterization of plaque neovasculature, which plays a critical role in plaque progression. We aimed to evaluate the impact of diabetes on carotid plaque neovasculature as assessed by dynamic contrast-enhanced magnetic resonance imaging. METHODS: Patients with recent ischemic stroke and ipsilateral carotid plaque underwent multicontrast magnetic resonance imaging for characterizing plaque morphology and dynamic contrast-enhanced magnetic resonance imaging for pharmacokinetic parameters of plaque neovasculature, including transfer constant (Ktrans, reflecting flow, endothelial surface area, and permeability) and fractional plasma volume (νp). RESULTS: Sixty-five patients were enrolled, including 30 patients with diabetes (years since diagnosis: median 5.0 [interquartile range, [3.0-12.0]) and 35 patients without diabetes. Subjects with diabetes had a greater plaque burden and a higher prevalence of high-risk characteristics. Additionally, carotid plaques in the subjects with diabetes showed higher Ktrans than those in the subjects without diabetes (0.100±0.048 min-1 versus 0.067±0.042 min-1, P=0.005) but νp was numerically lower in the subjects with diabetes (5.2±3.7% versus 6.2±4.3%, P=0.31). The association of diabetes with high Ktrans (ß=0.033, P=0.005) was independent of patient and plaque characteristics and remained largely intact after adjusting for serum lipids, glucose, or hs-CRP (high-sensitivity C-reactive protein). However, it became nonexistent after adjusting for hemoglobin A1c (ß=-0.010, P=0.49). CONCLUSIONS: Dynamic contrast-enhanced magnetic resonance imaging of carotid plaques suggested that plaque neovasculature in patients with diabetes is leaky, indicating enhanced capability of bringing blood constituents and facilitating extravasation of inflammatory cells, erythrocytes, and plasma proteins. Leaky plaque neovasculature correlated with hemoglobin A1c and may play a role in accelerated atherosclerosis progression in diabetes.

Fusion data from FT-IR and MALDI-TOF MS result in more accurate classification of specific microbiota.

Microbes are usually present as a specific microbiota, and their classification remains a challenge. MALDI-TOF MS is particularly successful in library-based microbial identification at the species level as it analyzes the molecular weight of peptides and ribosomal proteins. FT-IR allows more accurate classification of bacteria at the subspecies level due to the high sensitivity, specificity and repeatability of FT-IR signals from bacteria, which is not achievable with MALDI-TOF MS. Previous studies have shown that more accurate identification results can be obtained by the fusion of FT-IR and MALDI-TOF MS spectral data. Here, we constructed 20 groups of model microbiota samples and used FT-IR, MALDI-TOF MS, and their fusion data to classify them. Hierarchical clustering analysis (HCA) showed that the classification accuracy of FT-IR, MALDI-TOF MS, and the fusion data was 85%, 90%, and 100%, respectively. These results indicate that both FT-IR and MALDI-TOF MS can effectively classify specific microbiota, and the fusion of their spectral data could improve the classification accuracy. The FT-IR and MALDI-TOF MS data fusion strategy may be a promising technology for specific microbiota classification.

Detection of Advanced Lesions of Atherosclerosis in Carotid Arteries Using 3-Dimensional Motion-Sensitized Driven-Equilibrium Prepared Rapid Gradient Echo (3D-MERGE) Magnetic Resonance Imaging as a Screening Tool.

BACKGROUND AND PURPOSE: Two-dimensional high-resolution multicontrast magnetic resonance imaging (2D-MC MRI) is currently the most reliable and reproducible noninvasive carotid vessel wall imaging technique. However, the long scan time required for 2D-MC MRI restricts its practical clinical application. Alternatively, 3-dimensional motion-sensitized driven-equilibrium prepared rapid gradient echo (3D-MERGE) vessel wall MRI can provide high isotropic resolution with extensive coverage in two minutes. In this study, we sought to prove that 3D-MERGE alone can serve as a screening tool to identify advanced carotid lesions. METHODS: Two hundred twenty-seven subjects suspected of recent ischemic stroke or transient ischemic attack were imaged using 2D-MC MRI with an imaging time of 30 minutes, then with 3D-MERGE with an imaging time of 2 minutes, on 3T-MRI scanners. Two experienced reviewers interpreted plaque components using 2D-MC MRI as the reference standard and categorized plaques using a modified American Heart Association lesion classification for MRI. Plaques of American Heart Association type IV and above were classified as advanced. Arteries of American Heart Association types I to II and III were categorized as normal or with early lesions, respectively. One radiologist independently reviewed only 3D-MERGE and labeled the plaques as advanced if they had a wall thickness of >2 mm with high or low signal intensity compared with the adjacent sternocleidomastoid muscle. Sensitivity, specificity, and accuracy for 3D-MERGE were calculated. RESULTS: Four hundred forty-nine arteries from 227 participants (mean age 61.2 years old, 64% male) were included in the analysis. Sensitivity, specificity, and accuracy for identification of advanced lesions on 3D-MERGE were 95.0% (95% CI, 91.8-97.2), 86.9% (95% CI, 81.4-92.0), 93.8% (95% CI, 91.1-95.8), respectively. CONCLUSIONS: 3D-MERGE can accurately identify advanced carotid atherosclerotic plaques in patients suspected of stroke or transient ischemic attack. It has a more extensive coverage and higher sensitivity and specificity for advanced plaque detection with a much shorter acquisition time than 2D-MC MRI. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02017756.

Virtual screening and molecular dynamics simulation for identification of natural antiviral agents targeting SARS-CoV-2 NSP10.

New variations of SARS-CoV-2 continue to emerge in the global pandemic, which may be resistant to at least some vaccines in COVID-19, indicating that drug and vaccine development must be continuously strengthened. NSP10 plays an essential role in SARS-CoV-2 viral life cycle. It stimulates the enzymatic activities of NSP14-ExoN and NSP16-O-MTase by the formation of NSP10/NSP14 and NSP10/NSP16 complexes. Inhibiting NSP10 can block the binding of NSP10 to NSP14 and NSP16. This study has identified potential natural NSP10 inhibitors from ZINC database. The protein druggable pocket was identified for screening candidates. Molecular docking of the selected compounds was performed and MM-GBSA binding energy was calculated. After ADMET assessment, 4 hits were obtained for favorable druggability. The analysis of site interactions suggested that the hits all had excellent binding. Molecular dynamics studies revealed that selected natural compounds stably bind to NSP10. These compounds were identified as potential leads against NSP10 for the development of strategies to combat SARS-CoV-2 replication and could serve as the basis for further studies.

Effects of Levodopa Therapy on Cerebral Arteries and Perfusion in Parkinson's Disease Patients.

BACKGROUND: Levodopa is the most-commonly used therapy for Parkinson's Disease (PD). Imaging findings show increased cerebral blood flow (CBF) response to levodopa, but the artery morphological change is less studied. PURPOSE: To investigate the effect of levodopa on cerebral arteries and CBF. STUDY TYPE: Prospective. POPULATION: 57 PD patients (56 ± 10 years, 26 males) and 17 age-matched healthy controls (AMC, 57 ± 9 years, 9 males) were scanned at baseline (OFF). Patients were rescanned 50 minutes after taking levodopa (ON). FIELD STRENGTH AND SEQUENCE: 3 T; Simultaneous noncontrast angiography intraplaque imaging (SNAP) based on turbo field echo; Pseudo-continuous arterial spin labeling (PCASL) based on echo-planner imaging. ASSESSMENT: The Unified Parkinson's Disease Rating Scale (UPDRS-III) was used to assess the disease severity. Length and radius of arteries were measured from SNAP images. CBF was calculated from PCASL images globally and regionally. STATISTICAL TESTS: Mann Whitney U tests were conducted in comparing PD vs. AMC. Wilcoxon matched-pairs signed rank tests were used in comparing OFF vs. ON, and the more-affected vs. the less-affected hemisphere in PD. Linear regressions were performed to test the correlations of neuroimaging findings with behavioral changes. Significance threshold was P < 0.05 with Bonferroni correction. RESULTS: PD patients were identified with significantly lower CBF (PD OFF Mean = 40.15 ± 5.99, AMC Mean = 43.48 ± 6.21 mL/100 g/min) and shortened total artery length (PD OFF Mean = 5851.07 ± 1393.45, AMC Mean = 7479.16 ± 1335.93 mm). Levodopa elevated CBF of PD brains (PD ON Mean = 41.48 ± 6.32 mL/100 g/min) and expanded radius of proximal arteries. Artery radius change significantly correlated with CBF change in corresponding territories (r = 0.559 for Internal Carotid Arteries, r = 0.448 for Basilar Artery, and r = 0.464 for Middle Cerebral Artery M1). Global CBF significantly related to UPDRS-III (r = -0.391) post-levodopa. DATA CONCLUSION: Levodopa can increase CBF by dilating proximal arteries. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 4.

Carotid vulnerable plaque coexisting with cerebral small vessel disease and acute ischemic stroke: a Chinese Atherosclerosis Risk Evaluation study.

OBJECTIVES: We aimed to investigate the associations between carotid vulnerable plaque features coexisting with cerebral small vessel diseases (CSVDs) and acute ischemic stroke (AIS) and, furthermore, to determine whether coexisting diseases had a stronger association with AIS than a single disease. METHODS: Patients with cerebrovascular symptoms and carotid plaque were recruited from the cross-sectional, multicenter CARE-II study. The population was divided into two groups (AIS and transient ischemic stroke (TIA)). MRI features of carotid plaques (including luminal stenosis and plaque vulnerabilities) and CSVDs (such as white matter hyperintensities (WMHs) and lacunes) were evaluated. Coexisting diseases were defined as the presence of at least one carotid plaque features and one or more CSVDs feature. Multivariate logistic regression was performed to examine the associations between coexisting diseases and AIS. RESULTS: Of the recruited 634 patients (mean age: 59.1 ± 11.3 years; 429 males), 312 (49.2%) patients had AIS. These subjects had a higher prevalence of carotid vulnerable plaques, lacunes, and moderate-to-severe WMHs (a total Fazekas score of 3-6) than those with TIA (42.6% vs. 29.5%, 59.6% vs. 26.4%, 69.9% vs. 60.6%, respectively, all p < 0.05). Multivariate analysis revealed that carotid plaque features coexisting with lacunes or moderate-to-severe WMHs had a stronger association with AIS compared to carotid lesions alone (all p < 0.05) (i.e., vulnerable plaque coexisting with lacunes vs. vulnerable plaque alone, adjusted odds ratio: 3.67 vs. 1.62). CONCLUSIONS: Carotid vulnerable plaque features coexisting with CSVDs, particularly lacunes, had a stronger association with AIS compared to carotid lesions alone in a large, symptomatic, cohort. TRIAL REGISTRATION: Clinical trial registration URL: http://www. CLINICALTRIALS: gov , unique identifier: NCT02017756 KEY POINTS: • Carotid vulnerable plaque features coexisting with cerebral small vessel diseases, such as lacunes, had a stronger association with acute ischemic stroke compared to single diseases in symptomatic patients. • A comprehensive assessment of coexisting cerebrovascular diseases may help stratify the risk of acute ischemic stroke.

Oceanospirillum sediminis sp. nov., Isolated From Coastal Sediment in the Yellow Sea.

A novel Gram-negative, motile, aerobic, spiral-shaped bacterium designated D5T, was isolated from a coastal sediment collected in the Yellow Sea. Optimal growth occurred at 30 °C, pH 7.0-8.0 and in the presence of 1-3% (w/v) NaCl. Strain D5T contained ubiquinone 8 (Q-8) as the predominant respiratory quinone. The major fatty acids (> 10%) were C16:0, C16:1 ω7c/C16:1 ω6c and C18:1w7c/C18:1w6c. The main polar lipids were phosphatidylglycerol and phosphatidylethanolamine. The draft genome is 5.6 Mb in length, and DNA G + C content is 47.2 mol%. 16S rRNA gene sequences showed that strain D5T is most closely related to Oceanospirillum beijerinckii NBRC 15445T (97.8%, sequence similarity). However, the digital DNA-DNA hybridization (dDDH) value and average nucleotide identity (ANI) between strain D5T and O. beijerinckii is only 27.8% and 77.1%. Phylogenetic trees based on 16S rRNA gene sequences and whole genomes all indicated that strain D5T formed a separate branch in the genus Oceanospirillum. Combined results of the polyphasic analyses suggested that strain D5T represents a novel species in the genus Oceanospirillum, for which the name Oceanospirillum sediminis sp. nov. is proposed. The type strain is D5T (= MCCC 1K06061T = KCTC 62987T).

Blood oxygenation level-dependent cardiovascular magnetic resonance of the skeletal muscle in healthy adults: Different paradigms for provoking signal alterations.

PURPOSE: Stress blood oxygenation level-dependent (BOLD) cardiovascular magnetic resonance allows for quantitative evaluation of blood flow reserve in skeletal muscles. This study aimed to prospectively compare three commonly used skeletal BOLD cardiovascular magnetic resonance paradigms in healthy adults: gas inhalation, cuff compression-induced ischemia and postocclusive reactive hyperemia, and exercise. METHODS: Twelve young (22 ± 0.9 years) and 10 elderly (58 ± 5.0 years) healthy subjects underwent BOLD cardiovascular magnetic resonance under the three paradigms. T2∗ signal intensity time curves were generated and quantitative parameters were calculated. Meanwhile, stress transcutaneous oxygen pressure measurements were obtained as comparison. Measurement reproducibility was assessed with intraclass correlation coefficients. Differences in the T2∗ BOLD variation, the correlation with transcutaneous oxygen pressure, and the age-related change between paradigms were statistically analyzed. RESULTS: Minimum ischemic value and maximum hyperemic peak value showed the highest interobserver and interscan reproducibilities (intraclass correlation coefficient >0.90). The plantar dorsiflexion exercise paradigm elicited the largest T2∗ BOLD variation (15.48% ± 10.56%), followed by ischemia (8.30% ± 6.33%). Negligible to weak changes were observed during gas inhalation. Correlations with transcutaneous oxygen pressure measurements were found in the ischemic phase (r = 0.966; P < .001) and in the postexercise phase (r = -0.936; P < .001). Minimum ischemic value, maximum hyperemic peak value, maximum postexercise value, and slope of postexercise signal decay showed significant differences between young and elderly subjects (P < .01). CONCLUSION: Ischemia and reactive hyperemia have superior reproducibility, and exercise could induce the largest T2∗ variation. Key parameters from the two paradigms show age-related differences.

Domain adaptive and fully automated carotid artery atherosclerotic lesion detection using an artificial intelligence approach (LATTE) on 3D MRI.

PURPOSE: To develop and evaluate a domain adaptive and fully automated review workflow (lesion assessment through tracklet evaluation, LATTE) for assessment of atherosclerotic disease in 3D carotid MR vessel wall imaging (MR VWI). METHODS: VWI of 279 subjects with carotid atherosclerosis were used to develop LATTE, mainly convolutional neural network (CNN)-based domain adaptive lesion classification after image quality assessment and artery of interest localization. Heterogeneity in test sets from various sites usually causes inferior CNN performance. With our novel unsupervised domain adaptation (DA), LATTE was designed to accurately classify arteries into normal arteries and early and advanced lesions without additional annotations on new datasets. VWI of 271 subjects from four datasets (eight sites) with slightly different imaging parameters/signal patterns were collected to assess the effectiveness of DA of LATTE using the area under the receiver operating characteristic curve (AUC) on all lesions and advanced lesions before and after DA. RESULTS: LATTE had good performance with advanced/all lesion classification, with the AUC of >0.88/0.83, significant improvements from >0.82/0.80 if without DA. CONCLUSIONS: LATTE can locate target arteries and distinguish carotid atherosclerotic lesions with consistently improved performance with DA on new datasets. It may be useful for carotid atherosclerosis detection and assessment on various clinical sites.

The small molecule ZY-214-4 may reduce the virulence of Staphylococcus aureus by inhibiting pigment production.

BACKGROUND: In recent years, clinical Staphylococcus aureus isolates have become highly resistant to antibiotics, which has raised concerns about the ability to control infections by these organisms. The aim of this study was to clarify the effect of a new small molecule, ZY-214-4 (C19H11BrNO4), on S. aureus pigment production. RESULTS: At the concentration of 4 µg/mL, ZY-214-4 exerted a significant inhibitory effect on S. aureus pigment synthesis, without affecting its growth or inducing a toxic effect on the silkworm. An oxidant sensitivity test and a whole-blood killing test indicated that the S. aureus survival rate decreased significantly with ZY-214-4 treatment. Additionally, ZY-214-4 administration significantly reduced the expression of a pigment synthesis-related gene (crtM) and the superoxide dismutase genes (sodA) as determined by real-time quantitative polymerase chain reaction (RT-qPCR) analysis. ZY-214-4 treatment also improved the survival rate of S. aureus-infected silkworm larvae. CONCLUSIONS: The small molecule ZY-214-4 has potential for the prevention of S. aureus infections by reducing the virulence associated with this bacterium.