Integrated metagenomic and metabolomic analysis reveals distinctive stage-specific gut-microbiome-derived metabolites in intracranial aneurysms.

OBJECTIVE: Our study aimed to explore the influence of gut microbiota and their metabolites on intracranial aneurysms (IA) progression and pinpoint-related metabolic biomarkers derived from the gut microbiome. DESIGN: We recruited 358 patients with unruptured IA (UIA) and 161 with ruptured IA (RIA) from two distinct geographical regions for conducting an integrated analysis of plasma metabolomics and faecal metagenomics. Machine learning algorithms were employed to develop a classifier model, subsequently validated in an independent cohort. Mouse models of IA were established to verify the potential role of the specific metabolite identified. RESULTS: Distinct shifts in taxonomic and functional profiles of gut microbiota and their related metabolites were observed in different IA stages. Notably, tryptophan metabolites, particularly indoxyl sulfate (IS), were significantly higher in plasma of RIA. Meanwhile, upregulated tryptophanase expression and indole-producing microbiota were observed in gut microbiome of RIA. A model harnessing gut-microbiome-derived tryptophan metabolites demonstrated remarkable efficacy in distinguishing RIA from UIA patients in the validation cohort (AUC=0.97). Gut microbiota depletion by antibiotics decreased plasma IS concentration, reduced IA formation and rupture in mice, and downregulated matrix metalloproteinase-9 expression in aneurysmal walls with elastin degradation reduction. Supplement of IS reversed the effect of gut microbiota depletion. CONCLUSION: Our investigation highlights the potential of gut-microbiome-derived tryptophan metabolites as biomarkers for distinguishing RIA from UIA patients. The findings suggest a novel pathogenic role for gut-microbiome-derived IS in elastin degradation in the IA wall leading to the rupture of IA.

An Optimized Ni-catalyzed Chan-Lam Type Coupling: Enantioretentive Access to Chiral N-Aryl Sulfinamides.

C-N bond formation takes on a critical significance in reactions of organic synthesis, material production and pharmaceutical manufactory. Chan-Lam has proposed a useful methodology to furnish secondary arylamides under mild conditions. However, when chiral sulfinamides serve as the coupling precursors, the Cu-catalyzed coupling reaction is found with low efficacy. Complex side-products are generated under classic conditions. Moreover, it led to the racemization of the coupling product. In this study, an optimized Ni-catalyzed Chan-Lam type coupling conditions were proposed, which resulted in clean conversion from chiral sulfinamides and arylboronic acids to offer N-aryl sulfinamides efficiently and enantioretentively. The trans-N1 ,N2 -dimethylcyclohexane-1,2-diamine was proven as the most efficient ligand. Under the optimized conditions, a series of chiral N-aryl sulfinamides was prepared with high chemical yield without racemization. Furthermore, a plausible and novel mechanism was proposed. Interestingly, the method could efficiently furnish a wide variety of C-X bonds by coupling arylboronic acids with different nucleophiles.

Study on Sentinel Lymph Node and Its Lymphatic Drainage Pattern of Breast Cancer by Contrast-Enhanced Ultrasound.

OBJECTIVES: Sentinel lymph node (SLN) and its lymphatic drainage pattern (LDP) of breast cancer were studied by contrast-enhanced ultrasound (CEUS). METHODS: From July 2017 to December 2019, patients with SLN localization of breast cancer in Sichuan Academy of Medical Sciences·Sichuan Provincial People's Hospital were selected. The sentinel lymph system of breast cancer was observed by CEUS before both operation and blue staining in the surgery. The location, number, and route of sentinel lymphatic channel (SLC) were recorded, along with the number, size, and the depth from skin of SLN. LDPs were summarized according to these basic characteristics of SLC and SLN. RESULTS: A total of 368 cases were included; 465 SLCs and 423 SLNs were detected. Most of the SLCs were originated from the outer upper quadrant of areola. Eleven LDPs were found, including 31 subtypes of LDPs. There were 6 cases of type A (1.63%), 15 cases of type B (4.08%), 223 cases of type C (57.88%), 38 cases of type D (10.33%), 2 cases of type E (0.54%), 3 cases of type F (0.82%), 50 cases of type G (13.59%), 30 cases of type H (8.15%), 2 cases of type I (0.54%), 6 cases of type J (1.63%), and 3 cases of type K (0.82%). CONCLUSIONS: The most common LDP of breast cancer was one SLC originated from the upper quadrant of areola with one SLN. CEUS can identify the LDP before surgery to reduce the false negative rate of SLN biopsy.

Realgar and cinnabar are essential components contributing to neuroprotection of Angong Niuhuang Wan with no hepatorenal toxicity in transient ischemic brain injury.

Realgar and cinnabar are commonly used mineral medicine containing arsenic and mercury in Traditional Chinese Medicine (TCM). Angong Niuhuang Wan (AGNHW) is a representative realgar- and cinnabar-containing TCM formula for treating acute ischemic stroke, but its toxicology and neuropharmacological effects are not well addressed. In this study, we compared the neuropharmacological effects of AGNHW and modified AGNHW in an experimental ischemic stroke rat model. Male SD rats were subjected to 2 h of middle cerebral artery occlusion (MCAO) plus 22 h of reperfusion. Although oral administration of AGNHW for 7 days in the rats increased arsenic level in the blood and liver tissue, there were no significant changes in the arsenic level in kidney, mercury level in the blood, liver and kidney as well as hepatic and renal functions in MCAO rats. AGNHW revealed neuroprotective properties by reducing infarction volume, preserving blood-brain barrier integrity and improving neurological functions against cerebral ischemia-reperfusion injury. Interestingly, removing realgar and/or cinnabar from AGNHW abolished the neuroprotective effects. Meanwhile, AGNHW could scavenge peroxynitrite, down-regulate the expression of p47phox, 3-NT and MMP-9 and up-regulate the expression of ZO-1 and claudin-5 in the ischemic brains, which were abolished by removing realgar and/or cinnabar from AGNHW. Notably, realgar or cinnabar had no neuroprotection when used alone. Taken together, oral administration of AGNHW for one week should be safe for treating ischemic stroke with neuroprotective effects. Realgar and cinnabar are necessary elements with synergetic actions with other herbal materials for the neuroprotective effects of AGNHW against cerebral ischemia-reperfusion injury.

A self-assembly peptide nanofibrous scaffold reduces inflammatory response and promotes functional recovery in a mouse model of intracerebral hemorrhage.

UNLABELLED: Self-assembly peptide nanofibrous scaffold (SAPNS), such as RADA16-I, has been shown to reduce acute brain injury and enhance functional recovery in rat intracerebral hemorrhage (ICH) models. The acidic property of RADA16-I, however, limits its application in patients. In the present study, by using a modified neutral SAPNS (the RADA16mix) in collagenase IV induced ICH mice, we detected there were less microglial and apoptotic cells in mice injected with RADA16mix, meanwhile, more cells survived in this group. In addition, behavioral tests indicated that mice treated with RADA16mix showed better functional recovery than RADA16-I. Local delivery of RADA16mix reduces acute brain injury by lowering the number of apoptotic cells, decreasing glial reaction, reducing inflammatory response and, therefore promotes functional recovery. Moreover, new nerve fibers have grown into this new SAPNS, which indicates RADA16mix is able to serve as a bridge for nerve fibers to grow through. FROM THE CLINICAL EDITOR: Acute brain injury, such as intracerebral hemorrhage is a serious problem. In this work, self-assembly peptide nanofibrous scaffold (SAPNS) were tested in a rat model to aid functional recovery. Several items have been considered, such as histology, brain water content, hematoma volume, cell death and survival, inflammatory response, and nerve fiber growth. The positive data generated should pave the way towards better treatment options.

Review of Clinical Applications of Sonazoid Ultrasound Contrast for Liver Evaluation.

ABSTRACT: Sonazoid is a new ultrasound contrast agent with unique Kupffer phase imaging advantages and high mechanical index stability. This paper introduces the basic theories and advantages of Sonazoid ultrasound. Then, the application and latest advances of Sonazoid in the diagnosis and treatment of liver diseases are reviewed in detail. In addition, the advantages and disadvantages of Sonazoid ultrasound and its future directions are discussed. Sonazoid is expected to become an important tool for clinical ultrasound diagnosis and treatment.

Ovonic threshold switching-based artificial afferent neurons for thermal in-sensor computing.

Artificial afferent neurons in the sensory nervous system inspired by biology have enormous potential for efficiently perceiving and processing environmental information. However, the previously reported artificial afferent neurons suffer from two prominent challenges: considerable power consumption and limited scalability efficiency. Herein, addressing these challenges, a bioinspired artificial thermal afferent neuron based on a N-doped SiTe ovonic threshold switching (OTS) device is presented for the first time. The engineered OTS device shows remarkable uniformity and robust endurance, ensuring the reliability and efficacy of the artificial afferent neurons. A substantially decreased leakage current of the SiTe OTS device by nitrogen doping results in ultra-low power consumption less than 0.3 nJ per spike for artificial afferent neurons. The inherent temperature response exhibited by N-doped SiTe OTS materials allows us to construct a highly compact artificial thermal afferent neuron over a wide temperature range. An edge detection task is performed to further verify its thermal perceptual computing function. Our work provides an insight into OTS-based artificial afferent neurons for electronic skin and sensory neurorobotics.

Enhanced Thermal Stability of Carbonyl Iron Nanocrystalline Microwave Absorbents by Pinning Grain Boundaries with SiBaFe Alloy Nanoparticles.

Nanocrystalline carbonyl iron (CI) particles are promising microwave absorbents at elevated temperature, whereas their excessive grain boundary energy leads to the growth of nanograins and a deterioration in permeability. In this work, we report a strategy to enhance the thermal stability of the grains and microwave absorption of CI particles by doping a SiBaFe alloy. Grain growth was effectively inhibited by the pinning effect of SiBaFe alloy nanoparticles at the grain boundaries. After heat treatment at 600 °C, the grain size of CI particles increased from ~10 nm to 85.1 nm, while that of CI/SiBaFe particles was only 32.0 nm; with the temperature rising to 700 °C, the grain size of CI particles sharply increased to 158.1 nm, while that of CI/SiBaFe particles was only 40.8 nm. Excellent stability in saturation magnetization and microwave absorption was also achieved in CI/SiBaFe particles. After heat treatment at 600 °C, the flaky CI/SiBaFe particles exhibited reflection loss below -10 dB over 7.01~10.11 GHz and a minimum of -14.92 dB when the thickness of their paraffin-based composite was 1.5 mm. We provided a low-cost and efficient kinetic strategy to stabilize the grain size in nanoscale and microwave absorption for nanocrystalline magnetic absorbents working at elevated temperature.

A terpenoids database with the chemical content as a novel agronomic trait.

Natural products play a pivotal role in drug discovery, and the richness of natural products, albeit significantly influenced by various environmental factors, is predominantly determined by intrinsic genetics of a series of enzymatic reactions and produced as secondary metabolites of organisms. Heretofore, few natural product-related databases take the chemical content into consideration as a prominent property. To gain unique insights into the quantitative diversity of natural products, we have developed the first TerPenoids database embedded with Content information (TPCN) with features such as compound browsing, structural search, scaffold analysis, similarity analysis and data download. This database can be accessed through a web-based computational toolkit available at http://www.tpcn.pro/. By conducting meticulous manual searches and analyzing over 10 000 reference papers, the TPCN database has successfully integrated 6383 terpenoids obtained from 1254 distinct plant species. The database encompasses exhaustive details including isolation parts, comprehensive molecule structures, chemical abstracts service registry number (CAS number) and 7508 content descriptions. The TPCN database accentuates both the qualitative and quantitative dimensions as invaluable phenotypic characteristics of natural products that have undergone genetic evolution. By acting as an indispensable criterion, the TPCN database facilitates the discovery of drug alternatives with high content and the selection of high-yield medicinal plant species or phylogenetic alternatives, thereby fostering sustainable, cost-effective and environmentally friendly drug discovery in pharmaceutical farming. Database URL: http://www.tpcn.pro/.

Klebsiella pneumoniae invasive syndrome with liver, lung, and brain abscesses complicated with pulmonary fungal infection: a case report and review of the literature.

BACKGROUND: Klebsiella pneumoniae invasion syndrome (KPIS) is a severe multi-site infection that is usually caused by hypervirulent Klebsiella pneumoniae. The bacteria are relatively common in Asian diabetics and can cause organ abscesses or sepsis. When patients develop intracranial infection, the prognosis is poor. After anti-infective treatment, the Klebsiella pneumoniae-induced liver and lung abscesses and pulmonary fungal infection were relieved, but the brain abscesses worsened. Such complex and severe infection cases are rarely reported. Early identification of intracranial infection, selection of antibiotics with high concentrations in cerebrospinal fluid, and active treatment of complications such as diabetes and fungal infection are of great significance for the prognosis of patients. CASE PRESENTATION: A 71-year-old patient diagnosed with liver abscess in another hospital was transferred to our hospital due to a worsening condition. On day 1 (day of admission), the patient was given invasive mechanical ventilation, continuous renal replacement therapy combined with endotoxin adsorption, antimicrobial treatment with imipenem-cilastatin, and percutaneous catheter drainage for liver abscess. Metagenomic next-generation sequencing in bronchoalveolar lavage fluid indicated Klebsiella pneumoniae (K. pneumoniae), Candida albicans, and Aspergillus flavus complex, and no viruses were detected. Blood and pus cultures revealed K. pneumoniae that was sensitive to piperacillin/tazobactam. The anti-infection therapy was adjusted to piperacillin/tazobactam combined with voriconazole. On day 14, a head computed tomography (CT) scan showed no significant changes, and a chest CT scan showed absorption of multiple abscesses in both lungs. The patient was still unconscious. After the endotracheal tube was removed, cranial magnetic resonance imaging (MRI) showed multiple brain abscesses. Finally, his family gave up, and the patient was discharged and died in a local hospital. CONCLUSION: In cases of K. pneumoniae infection, the possibility of intracranial, liver, lung, or other site infections should be considered, and physicians should be vigilant for the occurrence of KPIS. For patients suspected of developing an intracranial infection, cerebrospinal fluid should be tested and cultured as soon as possible, a head MRI should be performed, and antibiotics with high distribution in cerebrospinal fluid should be used early. When patients are complicated with diabetes, in addition to glycemic control, vigilance for concurrent fungal infections is also needed.

Oxymatrine ameliorates white matter injury by modulating gut microbiota after intracerebral hemorrhage in mice.

INTRODUCTION: White matter injury (WMI) significantly affects neurobehavioral recovery in intracerebral hemorrhage (ICH) patients. Gut dysbiosis plays an important role in the pathogenesis of neurological disorders. Oxymatrine (OMT) has therapeutic effects on inflammation-mediated diseases. Whether OMT exerts therapeutic effects on WMI after ICH and the role of gut microbiota involved in this process is largely unknown. METHODS: Neurological deficits, WMI, gut microbial composition, intestinal barrier function, and systemic inflammation were investigated after ICH. Fecal microbiota transplantation (FMT) was performed to elucidate the role of gut microbiota in the pathogenesis of ICH. RESULTS: OMT promoted long-term neurological function recovery and ameliorated WMI in the peri-hematoma region and distal corticospinal tract (CST) region after ICH. ICH induced significant and persistent gut dysbiosis, which was obviously regulated by OMT. In addition, OMT alleviated intestinal barrier dysfunction and systemic inflammation. Correlation analysis revealed that gut microbiota alteration was significantly correlated with inflammation, intestinal barrier permeability, and neurological deficits after ICH. Moreover, OMT-induced gut microbiota alteration could confer protection against neurological deficits and intestinal barrier disruption. CONCLUSIONS: Our study demonstrates that OMT ameliorates ICH-induced WMI and neurological deficits by modulating gut microbiota.

Plasma metabolic signatures for intracranial aneurysm and its rupture identified by pseudotargeted metabolomics.

BACKGROUND AND AIMS: The vital metabolic signatures for IA risk stratification and its potential biological underpinnings remain elusive. Our study aimed to develop an early diagnosis model and rupture classification model by analyzing plasma metabolic profiles of IA patients. MATERIALS AND METHODS: Plasma samples from a cohort of 105 participants, including 75 IA patients in unruptured and ruptured status (UIA, RIA) and 30 control participants were collected for comprehensive metabolic evaluation using ultra-high-performance liquid chromatography-mass spectrometry-based pseudotargeted metabolomics method. Furthermore, an integrated machine learning strategy based on LASSO, random forest and logistic regression were used for feature selection and model construction. RESULTS: The metabolic profiling disturbed significantly in UIA and RIA patients. Notably, adenosine content was significantly downregulated in UIA, and various glycine-conjugated secondary bile acids were decreased in RIA patients. Enriched KEGG pathways included glutathione metabolism and bile acid metabolism. Two sets of biomarker panels were defined to discriminate IA and its rupture with the area under receiver operating characteristic curve of 0.843 and 0.929 on the validation sets, respectively. CONCLUSIONS: The present study could contribute to a better understanding of IA etiopathogenesis and facilitate discovery of new therapeutic targets. The metabolite panels may serve as potential non-invasive diagnostic and risk stratification tool for IA.

Inappropriate Use of Proton Pump Inhibitors Increases Cardiovascular Events in Patients with Coronary Heart Disease.

Antiplatelet drugs, as the cornerstone of the treatment of coronary heart disease, control the progression of the disease, but bring a higher risk of gastrointestinal bleeding. Relevant guidelines recommend the use of proton pump inhibitors (PPIs) to minimize the risk of gastrointestinal bleeding in patients receiving dual antiplatelet therapy. But for people at low risk of gastrointestinal bleeding, the harms associated with routine use of PPIs may far outweigh the benefits. PPIs increase the risk of lower gastrointestinal bleeding, inhibit the effect of antiplatelet drugs, impair vascular endothelial function, meanwhile induce hypomagnesemia, iron deficiency, vitamins D and K deficiency, etc. Eventually, PPIs may lead to an increase in cardiovascular events. However, the situation is that PPIs are often overused. This review elucidates the mechanisms by which PPIs increase cardiovascular events, thereby reminding clinicians to rationally prescribe PPIs.

Comprehensive histological imaging of native microbiota in human glioma.

Mounting evidence suggests that distinct microbial communities reside in tumors and play important roles in tumor physiology. Recently, a previous study profiled the composition and localization of intratumoral bacteria using 16S ribosomal DNA (rDNA) sequencing and histological visualization methods across seven tumor types, including human glioblastoma. However, their results based on traditional histological examinations should be further validated considering potential sources of contamination originating from sample collection and processing. Here, we aim to propose a three-dimensional (3D) in situ intratumoral microbiota visualization and quantification protocol avoiding surface contamination and provide a comprehensive histological investigation on local bacteria within human glioma samples. We develop a 3D quantitative in situ intratumoral microbiota imaging strategy, combining tissue clearing, immunofluorescent labeling, optical sectioning microscopy, and image processing, to visualize bacterial lipopolysaccharide (LPS) within gliomas in a direct, contaminant-free, and unambiguous manner. Through an automated statistical algorithm, reliable signals can be distinguished for further analysis of their sizes, distribution, and fluorescence intensities. In tandem, we also combined 2D images obtained from thin-section histological methods, including immunohistochemistry and fluorescence in situ hybridization, to provide comprehensive histological imaging for local bacterial components within human glioma samples. We have, for the first time, achieved 3D quantitative imaging of bacterial LPS colonized in gliomas in a contamination-free manner within human glioma samples. We also built the multiple histological evidence chain demonstrating the irregular shapes and sparse distribution of bacterial components within human glioma samples, mostly localized near nuclear membranes or in the intercellular space. This study provides favorable evidence for the presence of microbiota in human gliomas and provides information on the feature and distribution of bacterial components. The results, along with the integrated 3D quantitative intratumoral microbiota imaging method, are promising to provide insightful information into the direct interactions between the microbial community and the host in the tumor microenvironment.

Altered gut microbiomes are associated with the symptomatic status of unruptured intracranial aneurysms.

Background: Gut microbiome has recently been recognized as an important environmental factor affecting the occurrence and development of unruptured intracranial aneurysms (UIA). This study aimed to investigate the relationship between gut microbiome and symptomatic UIA, which is a predictor of instability and a high propensity to rupture. Methods: A total of 132 patients including 86 asymptomatic UIA and 46 symptomatic UIA were recruited in the study. The composition of gut bacterial communities was determined by 16S ribosomal RNA gene sequencing. In addition, Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) was used to predict the functional composition of the gut microbiome. Results: There is no difference in the fecal microbial alpha diversity between symptomatic and asymptomatic UIA, but gut microbiome composition changed significantly. At the order level, the relative abundance of Clostridiales was significantly enriched in the symptomatic compared with asymptomatic UIA (p = 0.043). In addition, similar alterations were observed at the family levels of Ruminococcaceae. The Linear discriminant analysis (LEfSe) revealed Fournierella, Ruthenibacterium, and Anaerotruncus as discriminative features in the symptomatic group. Notably, functional differences in gut microbiome of patients with symptomatic UIA included decreased propionate metabolism pathway and enrichment of peptidoglycan biosynthesis pathways. Conclusion: The present study comprehensively characterizes gut microbiome in a large cohort of different risk statuses of UIA patients and demonstrates the potential biological function of gut microbiome involved in the development of UIA. It may provide additional benefits in guiding UIA management and improving patient outcomes.

Targeting NLRP3 inflammasome modulates gut microbiota, attenuates corticospinal tract injury and ameliorates neurobehavioral deficits after intracerebral hemorrhage in mice.

Intracerebral hemorrhage (ICH) has a high mortality and disability rate. Fewer studies focus on white matter injury (WMI) after ICH, especially the corticospinal tract (CST) injury located in the spinal cord, which correlates with motor impairments. Recent studies have shown that gut microbiota dysbiosis occurs after ICH. Furthermore, NLRP3 inflammasome can be activated after ICH, resulting in inflammatory cascade reactions and aggravating brain injury. However, no direct and causal correlation among NLRP3 inflammasome inhibition, altered gut microbiota, and CST injury following ICH has been reported. This study aimed to investigate the effect of MCC950, a selective NLRP3 inflammasome inhibitor, on the gut microbiota and CST injury after ICH. We observed that compared with the sham group, the members of Firmicutes, such as Faecalibaculum and Dubosiella, were depleted in the ICH + Vehicle group, whereas the members of Proteobacteria and Campilobacterota were enriched, such as Enterobacter and Helicobacter. After treatment with MCC950, the Bacteroides, Bifidobacterium and Paenibacillus were relatively abundant in the gut flora of mice. Moreover, we observed CST injury located in cervical enlargement of the spinal cord, and MCC950 alleviated it. Furthermore, treatment with MCC950 decreased the mNSS score and brain water content in ICH. Taken together, the present study showed that MCC950 modulated gut microbiota, effectively attenuated CST injury located in cervical enlargement of the spinal cord, and ameliorated neurological deficits after ICH. This study provided a novel report that links NLRP3 inflammasome inhibition, gut microbiota alteration and CST injury following ICH and profound implications for ICH treatment.

Mechanism of White Matter Injury and Promising Therapeutic Strategies of MSCs After Intracerebral Hemorrhage.

Intracerebral hemorrhage (ICH) is the most fatal subtype of stroke with high disability and high mortality rates, and there is no effective treatment. The predilection site of ICH is in the area of the basal ganglia and internal capsule (IC), where exist abundant white matter (WM) fiber tracts, such as the corticospinal tract (CST) in the IC. Proximal or distal white matter injury (WMI) caused by intracerebral parenchymal hemorrhage is closely associated with poor prognosis after ICH, especially motor and sensory dysfunction. The pathophysiological mechanisms involved in WMI are quite complex and still far from clear. In recent years, the neuroprotection and repairment capacity of mesenchymal stem cells (MSCs) has been widely investigated after ICH. MSCs exert many unique biological effects, including self-recovery by producing growth factors and cytokines, regenerative repair, immunomodulation, and neuroprotection against oxidative stress, providing a promising cellular therapeutic approach for the treatment of WMI. Taken together, our goal is to discuss the characteristics of WMI following ICH, including the mechanism and potential promising therapeutic targets of MSCs, aiming at providing new clues for future therapeutic strategies.

Neuregulin-1 Accelerates Functional Motor Recovery by Improving Motoneuron Survival After Brachial Plexus Root Avulsion in Mice.

Brachial plexus root avulsion (BPRA) results in the complete loss of motor function in the upper limb, mainly due to the death of spinal motoneurons (MNs). The survival of spinal MNs is the key to the recovery of motor function. Neuregulin-1 (Nrg1) plays fundamental roles in nervous system development and nerve repair. However, its functional role in BPRA remains unclear. On the basis of our findings that Nrg1 is down-regulated in the ventral horn in a mouse model of BPRA, Nrg1 may be associated with BPRA. Here, we investigated whether recombinant Nrg1ß (rNrg1ß) can enhance the survival of spinal MNs and improve functional recovery in mice following BPRA. In vitro studies on primary cultured mouse MNs showed that rNrg1ß increased the survival rate in a dose-dependent manner, reaching a peak at 5 nM, which increased the survival rate and enhanced the pERK levels in MNs under H2O2-induced oxidative stress. In vivo studies revealed that rNrg1ß improved the functional recovery of elbow flexion, promoted the survival of MNs, enhanced the re-innervation of biceps brachii, and decreased the muscle atrophy. These results suggest that Nrg1 may provide a potential therapeutic strategy for root avulsion.

Using deep-learning techniques for pulmonary-thoracic segmentations and improvement of pneumonia diagnosis in pediatric chest radiographs.

PURPOSE: To evaluate the efficacy of a deep-learning model to segment the lung and thorax regions in pediatric chest X-rays (CXRs). Validating the diagnosis of bacterial or viral pneumonia could be improved after lung segmentation. MATERIALS AND METHODS: A clinical-pediatric CXR set including 1351 patients was proposed to develop a deep-learning model for the pulmonary-thoracic segmentations. Model performance was evaluated by Jaccard's similarity coefficient (JSC) and Dice's coefficient (DC). Two adult CXR sets were used to assess the model's generalizability. According to the pulmonary-thoracic ratio, Pearson's correlation coefficient and the Bland-Altman plot were generated to demonstrate the correlation and agreement between manual and automatic segmentations. The receiver operating characteristic curves and areas under the curve (AUCs) were used to compare the pneumonia classification performance based on the lung-extracted images with that based on the original images. RESULTS: The model achieved JSCs of 0.910 and 0.950, DCs of 0.948 and 0.974 for lung and thorax segmentations, respectively. Pearson's r = 0.96, P < .0001. In the Bland-Altman plot, the mean difference was 0.0025 with a 95% confidence interval of (-0.0451, 0.0501). For testing with two adult CXR sets, the JSCs were 0.903 and 0.888, respectively, while the DCs were 0.948 and 0.937, respectively. After lung segmentation, the AUC of a classifier to identify bacterial or viral pneumonia increased from 0.815 to 0.879. CONCLUSION: We built a pediatric CXR dataset and exploited a deep-learning model for accurate pulmonary-thoracic segmentations. Lung segmentation can notably improve the diagnosis of bacterial or viral pneumonia.

Potential molecular targets of peroxynitrite in mediating blood-brain barrier damage and haemorrhagic transformation in acute ischaemic stroke with delayed tissue plasminogen activator treatment.

Tissue plasminogen activator (t-PA) remains to be the only FDA-approved drug for ischaemic stroke, but it has a restrictive therapeutic window with 4.5 hours. Beyond the golden time window, thrombolytic treatment carries the risk of haemorrhagic transformation (HT). The blood-brain barrier (BBB) disruption is a critical step in the t-PA-mediated HT. Although large efforts are made to explore the mechanisms of the BBB disruption and HT, the underlying mechanisms are largely unknown. Thrombolytic treatment for recanalization could produce reactive oxygen species (ROS) and reactive nitrogen species (RNS) and mediate cerebral ischaemia-reperfusion injury. RNS, including nitric oxide (NO) and peroxynitrite (ONOO-), are important players in cerebral ischaemia-reperfusion injury. In particular, ONOO- and its derivatives could mediate neurovascular unit damages and induce the BBB disruption and HT possibly through interacting with different cellular signalling pathways including matrix metalloproteinase (MMPs), high mobility group Box 1 (HMGB1), toll-like receptor2/4, poly(ADP-ribose) polymerase, Src, ROCK, and GSK-3ß. Herein, we review current progress about the roles of ONOO- in mediating those signalling pathways and their impacts on the t-PA-induced BBB disruption and HT. Subsequently, we discuss the values of natural compounds with the properties of scavenging ONOO- as adjunctive therapies to extend the therapeutic window of t-PA and attenuate haemorrhage transformation in ischaemic stroke.