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Background Whole-body metabolism is emerging as a critical player in the pathophysiology of intracranial aneurysms (IAs). However, the vital metabolic signatures for IA risk stratification and its potential biological underpinnings remain elusive. Therefore, our study aimed to develop an early diagnosis model and rupture classification model by analyzing plasma metabolic profiles of IA patients. Methods Plasma samples from a cohort of 105 participants, including 75 patients with IAs in ruptured and unruptured statuses and 30 control participants, were collected for analysis. A pseudotargeted metabolomics strategy based on LC-MS/MS was applied for integration analyses of plasma samples, and significant differential metabolites were identified through univariate and multivariate statistical analysis. Furthermore, an integrated machine learning strategy based on LASSO, random forest and logistic regression were used for feature selection and model construction. Results The composition of metabolites changed significantly with the severity of IA. Among them, glutathione metabolism and bile acid metabolism may play a crucial role. Two sets of biomarker panels (M6 & M5) were defined to discriminate IA and its rupture with the area under receiver operating characteristic curve (AUC) of 0.843 and 0.929 on the validation sets, respectively. Conclusion The present study comprehensively characterizes plasma metabolites in different statuses of IA and demonstrates the potential of metabolic markers as non-invasive risk diagnostic tools for IA.

Background 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 in this process is largely unknown. Methods ICH model was established by collagenase IV injection. OMT was daily administrated via oral gavage after ICH. Neurological deficits, WMI, the severity of corticospinal tract (CST) injury, intestinal barrier function and systemic inflammation were investigate after ICH. Microbial 16S rRNA sequencing was performed to reveal the dynamic microbial profiles. Fecal microbiota transplantation (FMT) was performed to elucidate the role of gut microbiota in the pathogenesis of ICH. Results OMT promoted a better long-term neurological function recovery and ameliorated axonal demyelination, microgliosis and glial scar formation in the peri-hematoma region and distal CST in the chronic phase after ICH. The significant and persistent alterations of gut microbial composition induced by ICH, which lasted more than two weeks, were obviously regulated by OMT via increasing the species richness and diversity. Additionally, treatment with OMT alleviated intestinal barrier dysfunction, accompanied by a significant down-regulation of the levels of pro-inflammatory cytokines. Correlation analysis revealed that gut microbiota alteration was correlated with inflammation, intestinal barrier permeability, and neurological deficits after ICH. Moreover, the therapeutic effects of OMT on ICH-induced WMI and intestinal barrier disruption were transferrable by fecal microbiota transplantation (FMT). Conclusion Our study showed that OMT ameliorates ICH-induced WMI, neurological deficits and intestinal barrier disruption, and OMT-modulated gut microbiota plays an important role in the underlying mechanism.

A robust Pd(0)-catalyzed decarboxylation alkylation has been developed to construct quaternary stereocenters through the use of chiral tert-butanesulfinamide as the directing group. This strategy provides a simple and efficient route to the construction of quaternary chiral centers at the α-position of chiral sulfinamides, with high diastereoselectivities and high yields.

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-N

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.

In this study, a robust and facile method for desulfonation to achieve secondary amines is demonstrated. Diphenylphosphine (Ph2PH) was shown to significantly expedite the cleavage of sulfonamides under basic conditions. Aromatic and aliphatic sulfonamides were cleanly converted, with a rapid reaction time, into the required amines with good to excellent chemical yields. Moreover, the functional groups tested were generally well tolerated.

Sentinel lymph node (SLN) and its lymphatic drainage pattern (LDP) of breast cancer were studied by contrast-enhanced ultrasound (CEUS).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.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%).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.

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.

We design a nominal controller for animating an articulated physics-based human arm model, including the hands and fingers, to catch and throw objects. The controller is based on a finite state machine that defines the target poses for proportional-derivative control of the hand, as well as the orientation and position of the center of the palm using the solution of an inverse kinematics solver. We then use reinforcement learning to train agents to improve the robustness of the nominal controller for achieving many different goals. Imitation learning based on trajectories output by a numerical optimization is used to accelerate the training process. The success of our controllers is demonstrated by a variety of throwing and catching tasks, including flipping objects, hitting targets, and throwing objects to a desired height, and for several different objects, such as cans, spheres, and rods. We also discuss ways to extend our approach so that more challenging tasks, such as juggling, may be accomplished.

A one-step catalytic and diastereoselective method for the synthesis of aziridines possessing multiple chiral substitutions by radical aminotrifluoromethylation of alkenes has been developed for the first time. The reaction utilizes a Cu(I)/L-proline complex as a catalyst and a chiral sulfinamide group performs the role of nucleophile and chiral directing group. This synthetic strategy provides one-step access to a wide variety of substituted aziridines with good chemical yield, excellent diastereoselectivity and broad functional group tolerance. A possible reaction mechanism is proposed based on DFT calculations. The method should be useful for the rapid synthesis of chiral CF3-containing building blocks and novel drug molecules.

In this paper, a Rh-catalyzed diastereoselective α-allylation of cycloenamines is demonstrated. During the reaction, commercially available Wilkinson's catalyst was employed, and a chiral sulfinamide group acted as the chiral directing group. Following such a synthetic method, unusual linear substituted products were achieved, instead of branched substituted products which were most reported previously. The reaction exhibits a good chemical yield and excellent diastereoselectivity. A possible reaction mechanism was proposed. The method should be conducive to synthesizing natural products and novel drug molecules.

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

This paper describes an efficient method for constructing cyclic β-amino acids bearing quaternary stereocenters. NaHMDS-promoted asymmetric α-alkylation was employed to obtain the key intermediates with quaternary stereogenic centers, which were subsequently reduced by NaBH4 in 10% methanol in THF, with high yields and high diastereoselectivities. By removing the allyl ester group and the chiral auxiliary, the corresponding cyclic β-amino acid hydrochlorides were finally obtained.

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.

In this paper, we reported for the first time that the diastereoselective Rh-catalyzed decarboxylative allylation of chiral sulfinimines could be used to form quaternary stereocenters. The key factor in giving rise to the successful development of this method was the application of the commercially available and achiral Wilkinson's Rh catalyst. Explained by a plausible mechanism, the sulfinimine group might be a potent directing group chelated with Rh to construct intramolecular steric hindrance. In addition, broad functional group tolerance was observed, and we subsequently revealed the various transformations verifying the utility of this method for rapidly accessing complex enantio-enriched polycyclic compounds.

In this article, we report the rapid and facile synthesis of chiral 3‐methyl‐2,5‐trans‐tetrahydrofurans. This reaction utilizes cheap and easily available starting materials. A domino hydrolysis and intramolecular Michael‐type ring closure reaction was the key step. As a result, synthesis of the desired 3‐methyl‐2,5‐trans‐tetrahydrofurans could be achieved in gram‐scale over seven linear steps with high chemical yield and high diastereoselectivity.

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

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 Nrg1β (rNrg1β) 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 rNrg1β 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 rNrg1β 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.

This study developed a facile and efficient synthetic strategy to construct quaternary chiral centers at the α-position of imines and ketones. High regioselectivity and diastereoselectivity were achieved through the synergetic effect of electron-withdrawing directing groups and N-tert-butyl sulfinamide as chiral auxiliaries. Either of them could be removed under the optimized conditions without any epimerization.

In the present study, an inexpensive but efficient Iron(III) and Copper(II) co-catalyst without ligands catalyzed arylation of sulfinamides with aryl iodide was primarily reported. In brief, in the presence of Fe(NO3)3·9H2O, CuO and K3PO4, the highly selective C–N cross coupling of several sulfinamides and aryl iodides was achieved in high chemical yield, while the aryl chlorides and bromides could not yield coupling products. It is noteworthy that through the arylation of chiral tert-butanesulfinamide with aryl iodides, N-aryl tert-butanesulfinamides are provided without racemization, even in gram-scale. The possible mechanism was that This oxidative addition process between copper catalyst and aryl-iodides might be significantly accelerated by active Fe(III) species. Moreover, using this synthetic method, a facile and efficient access was developed for the derivatives of N-phenyl sulfinamides, which might help to develop new drug molecules and material chemicals.

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.

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.