Two-dimensional materials provide extraordinary opportunities for exploring phenomena arising in atomically thin crystals. Beginning with the first isolation of graphene, mechanical exfoliation has ...been a key to provide high-quality two-dimensional materials, but despite improvements it is still limited in yield, lateral size and contamination. Here we introduce a contamination-free, one-step and universal Au-assisted mechanical exfoliation method and demonstrate its effectiveness by isolating 40 types of single-crystalline monolayers, including elemental two-dimensional crystals, metal-dichalcogenides, magnets and superconductors. Most of them are of millimeter-size and high-quality, as shown by transfer-free measurements of electron microscopy, photo spectroscopies and electrical transport. Large suspended two-dimensional crystals and heterojunctions were also prepared with high-yield. Enhanced adhesion between the crystals and the substrates enables such efficient exfoliation, for which we identify a gold-assisted exfoliation method that underpins a universal route for producing large-area monolayers and thus supports studies of fundamental properties and potential application of two-dimensional materials.
Neuroinflammation is closely associated with the poor prognosis in subarachnoid hemorrhage (SAH) patients. This study was aimed to determine the role of stimulator of IFN genes (STING), an essential ...regulator to innate immunity, in the context of SAH.
A total of 344 male C57BL/6 J mice were subjected to endovascular perforation to develop a model of SAH. Selective STING antagonist C-176 and STING agonist CMA were administered at 30 min or 1 h post-modeling separately. To investigate the underlying mechanism, the AMPK inhibitor compound C was administered intracerebroventricularly at 30 min before surgery. Post-SAH assessments included SAH grade, neurological test, brain water content, western blotting, RT-PCR, and immunofluorescence. Oxygenated hemoglobin was introduced into BV2 cells to establish a SAH model in vitro.
STING was mainly distributed in microglia, and microglial STING expression was significantly increased after SAH. Administration of C-176 substantially attenuated SAH-induced brain edema and neuronal injury. More importantly, C-176 significantly alleviated both short-term and persistent neurological dysfunction after SAH. Meanwhile, STING agonist CMA remarkably exacerbated neuronal injury and deteriorated neurological impairments. Mechanically, STING activation aggravated neuroinflammation via promoting microglial activation and polarizing into M1 phenotype, evidenced by microglial morphological changes, as well as the increased level of microglial M1 markers including IL-1β, iNOS, IL-6, TNF-α, MCP-1, and NLRP3 inflammasome, while C-176 conferred a robust anti-inflammatory effect. However, all the mentioned beneficial effects of C-176 including alleviated neuroinflammation, attenuated neuronal injury and the improved neurological function were reversed by AMPK inhibitor compound C. Meanwhile, the critical role of AMPK signal in C-176 mediated anti-inflammatory effect was also confirmed in vitro.
Microglial STING yielded neuroinflammation after SAH, while pharmacologic inhibition of STING could attenuate SAH-induced inflammatory injury at least partly by activating AMPK signal. These data supported the notion that STING might be a potential therapeutic target for SAH.
The NLRP3 inflammasome is activated in the early period following subarachnoid hemorrhage(SAH), resulting in inflammatory responses. Recent studies have shown that activation of NLRP3 inflammasome is ...suppressed by autophagy, but the potential mechanism is unclear. In this study, we examined whether mitophagy was involved in the beneficial effect of melatonin and its relationship with NLRP3 inflammasome activation after SAH. In total, 130 adult-male SD rats were randomly divided into four groups: sham group, SAH + vehicle group, SAH + melatonin group, and SAH + 3-methyladenine (3-MA) + melatonin group. Brain samples were used for brain water content analysis, ROS assay, Western blot, immunohistochemistry and transmission electron microscopy. The results showed that melatonin treatment markedly increased the expression of both autophagy markers(LC3-II/LC3-I and Atg 5), and mitophagy markers(Parkin and PINK-1) following SAH induction. Additionally, melatonin treatment attenuated pathological changes in mitochondria and reduced ROS generation, which are closely related to NLRP3 inflammasome activation. Consequently, melatonin-mediated upregulation of proteins associated with mitophagy inhibited NLRP3 inflammasome activation and significantly reduced pro-inflammatory cytokine levels after SAH. Conversely, 3-MA, an autophagy inhibitor, reversed these beneficial effects of melatonin on mitophagy and the NLRP3 inflammasome. These results suggest that mitophagy-associated NLRP3 inflammasome inhibition by melatonin is neuroprotective against early brain injury post-SAH in rats.
During the coronavirus disease 2019 (COVID-19) containment, primary health care (PHC) facilities inChina played an important role in providing both healthcare and public care services to community ...populations. The tasks of COVID-19 containment facilitated by PHC facilities were different among different regions and during different periods of COVID-19 pandemic. We sought to investigate the gaps on task participation, explore existing problems and provide corresponding solutions.
Semi-structured face-to-face interviews with COVID-19 prevention and control management teams of PHC facilities were conducted. Purposive stratified sampling was used and 32 team members of 22 PHC facilities were selected from Wuhan (as high-risk city), Shanghai (as medium-risk city) and Zunyi (as low-risk city). Framework analysis was employed to analyze the transcribed recordings.
The main tasks of PHC facilities during the early period of the pandemic included assisting in contact tracing and epidemiological investigation, screening of populations at high-risk at travel centers/internals, house-by-house, or pre-examination/triage within PHC facilities; at-home/ centralized quarantine management; the work of fever sentinel clinics. Further analyses revealed the existing problems and suggestions for improvement or resolutions. Regular medical supply reserves were recommended because of the medical supply shortage during the pre-outbreak period. Temporarily converted quarantine wards and centralized quarantine centers could be used to deal with pressures on patients' treatment and management of the febrile patients. Only after strict evaluation of nucleic acid testing (NAT) results and housing conditions, decision on quarantine at-home or centralized quarantine centers could be made. Settings of fever sentinel clinics at PHC facilities allowed fever patients with no COVID-19 infection risks for treatment without being transferred to fever clinics of the designed secondary hospitals. Psychological intervention was sometimes in need and really helped in addressing individuals' mental pressures.
During the COVID-19 containment, PHC facilities in China were responsible for different tasks and several problems were encountered in the working process. Accordingly, specific and feasible suggestions were put forward for different problems. Our findings are highly beneficial for healthcare teams and governments in handling similar situations.
Reirradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is often associated with substantial late toxicity, ...negating its overall benefit. We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy.
This multicentre, randomised, open-label, phase 3 trial was done in three centres in Guangzhou, China. Eligible patients were aged 18–65 years with histopathologically confirmed undifferentiated or differentiated, non-keratinising, advanced locally recurrent nasopharyngeal carcinoma. Participants were randomly assigned (1:1) to either receive hyperfractionation (65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 h) or standard fractionation (60 Gy in 27 fractions, given once a day). Intensity-modulated radiotherapy was used in both groups. A computer program generated the assignment sequence and randomisation was stratified by treatment centre, recurrent tumour stage (T2–T3 vs T4), and recurrent nodal stage (N0 vs N1–N2), determined at the time of randomisation. The two primary endpoints were the incidence of severe late complications defined as the incidence of grade 3 or worse late radiation-induced complications occurring 3 months after the completion of radiotherapy until the latest follow-up in the safety population, and overall survival defined as the time interval from randomisation to death due to any cause in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02456506.
Between July 10, 2015, and Dec 23, 2019, 178 patients were screened for eligibility, 144 of whom were enrolled and randomly assigned to hyperfractionation or standard fractionation (n=72 in each group). 35 (24%) participants were women and 109 (76%) were men. After a median follow-up of 45·0 months (IQR 37·3–53·3), there was a significantly lower incidence of grade 3 or worse late radiation-induced toxicity in the hyperfractionation group (23 34% of 68 patients) versus the standard fractionation group (39 57% of 68 patients; between-group difference –23% 95% CI –39 to –7; p=0·023). Patients in the hyperfractionation group had better 3-year overall survival than those in the standard fractionation group (74·6% 95% CI 64·4 to 84·8 vs 55·0% 43·4 to 66·6; hazard ratio for death 0·54 95% CI 0·33 to 0·88; p=0·014). There were fewer grade 5 late complications in the hyperfractionation group (five 7% nasal haemorrhage) than in the standard fractionation group (16 24%, including two 3% nasopharyngeal necrosis, 11 16% nasal haemorrhage, and three 4% temporal lobe necrosis).
Hyperfractionated intensity-modulated radiotherapy could significantly decrease the rate of severe late complications and improve overall survival among patients with locally advanced recurrent nasopharyngeal carcinoma. Our findings suggest that hyperfractionated intensity-modulated radiotherapy could be used as the standard of care for these patients.
Key-Area Research and Development of Guangdong Province, the National Natural Science Foundation of China, the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project, and the National Ten Thousand Talents Program Science and Technology Innovation Leading Talents, Sun Yat-Sen University Clinical Research 5010 Program.
In this work, a new open‐tubular capillary electrochromatography (OT‐CEC) column was prepared using β‐cyclodextrin covalent organic framework (β‐CD COF) as a stationary phase. Polydopamine was used ...to assist fabrication of β‐CD COF on an inner wall of a fused‐silica capillary. The coating layer on the capillary was characterized by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). Electroosmotic flow (EOF) was also studied to evaluate the variation of the inner wall of immobilized columns. Furthermore, the chiral separation effectiveness of the fabricated capillary column was evaluated by CEC using enantiomers of several related proton pump inhibitors as model analytes, including omeprazole, lansoprazole, pantoprazole and tenatoprazole. The effects of bonding time and concentration of β‐CD COF, the type, concentration and pH of buffer, applied voltage were investigated to obtain satisfactory enantioselectivity. In the optimum conditions, the enantiomers of four analytes were resolved within 15 min with resolutions of 1.63–2.62. The relative standard deviation values for migration times and resolutions of the analytes representing intraday and interday were less than 6.75% and 4.24%, respectively. The results reveal that β‐CD COF has great potential as chiral‐stationary phases for enantioseparation in CEC.
Objectives
Nasopharyngeal carcinoma (NPC) patients with retropharyngeal lymph node (RPLN) recurrence typically undergo reirradiation and experience severe radiotoxicity. Salvage open surgery is ...challenging because gaining access to the retropharyngeal space is complex and risky. Thus, only several centers can perform this procedure, and complications are common. We applied transoral robotic surgery RPLN dissection (TORS‐RPLND) to NPC patients with RPLN recurrence to address the problem with open surgery.
Materials and Methods
From March 2017 to October 2020, 10 NPC patients with RPLN recurrence underwent TORS‐RPLND using the da Vinci Si/Xi Surgical System. We applied the balloon occlusion test to protect the internal carotid artery, induction chemotherapy to shrink large tumors preoperatively, and ultrasound positioning to effectively locate unrecognizable RPLNs during surgery. Clinical characteristics, complications, and survival outcome data were retrospectively collected.
Results
Of 10 patients, 8 underwent en bloc resection via TORS‐RPLND, and the remaining 2 patients were converted to open surgery because we failed to identify the RPLN during TORS. After introducing intraoperative ultrasound positioning, no such failure occurred. The mean operative time and intraoperative blood loss were 297 ± 120 min and 40 ± 43 ml, respectively. All surgical margins were negative. TORS‐related complications were mild, and the most severe one was grade 3 dysphagia in one patient who underwent conversion to open surgery (10%). With a median follow‐up of 19 months, only 1 (10%) patient developed cervical recurrence.
Conclusions
TORS‐RPLND is feasible, safe, and effective in the treatment of NPC patients with RPLN recurrence, especially with the help of intraoperative ultrasound positioning.
Level of Evidence
4 Laryngoscope, 131:E1895–E1902, 2021
Melatonin is a strong antioxidant that has beneficial effects against early brain injury (EBI) following a subarachnoid hemorrhage (SAH) in rats; protection includes reduced mortality and brain water ...content. The molecular mechanisms underlying these clinical effects in the SAH model, however, have not been clearly identified. This study was undertaken to determine the influence of melatonin on neural apoptosis and the potential mechanism of these effects in EBI following SAH using the filament perforation model of SAH in male Sprague Dawley rats. Melatonin (150 mg/kg) or vehicle was given via an intraperitoneal injection 2 hr after SAH induction. Brain samples were extracted 24 hr after SAH. The results show that melatonin treatment markedly reduced caspase‐3 activity and the number of TUNEL‐positive cells, while the treatment increased the LC3‐II/LC3‐I, an autophagy marker, which indicated that melatonin‐enhanced autophagy ameliorated apoptotic cell death in rats subjected to SAH. To further identify the mechanism of autophagy protection, we demonstrated that melatonin administration reduced Bax translocation to the mitochondria and the release of cytochrome c into the cytosol. Taken together, this report demonstrates that melatonin improved the neurological outcome in rats by protecting against neural apoptosis after the induction of filament perforation SAH; moreover, the mechanism of these antiapoptosis effects was related to the enhancement of autophagy, which ameliorated cell apoptosis via a mitochondrial pathway.
Danggui Sini decoction (DSD), a traditional Chinese medicine formula, has the function of nourishing blood, warming meridians, and unblocking collaterals. Our clinical and animal studies had shown ...that DSD can effectively protect against oxaliplatin (OXA)-induced peripheral neuropathy (OIPN), but the detailed mechanisms remain uncertain. Multiple studies have confirmed that gut microbiota plays a crucial role in the development of OIPN. In this study, the potential mechanism of protective effect of DSD against OIPN by regulating gut microbiota was investigated.
The neuroprotective effects of DSD against OIPN were examined on a rat model of OIPN by determining mechanical allodynia, biological features of dorsal root ganglia (DRG) as well as proinflammatory indicators. Gut microbiota dysbiosis was characterized using 16S rDNA gene sequencing and metabolism disorders were evaluated using untargeted and targeted metabolomics. Moreover the gut microbiota mediated mechanisms were validated by antibiotic intervention and fecal microbiota transplantation.
DSD treatment significantly alleviated OIPN symptoms by relieving mechanical allodynia, preserving DRG integrity and reducing proinflammatory indicators lipopolysaccharide (LPS), IL-6 and TNF-α. Besides, DSD restored OXA induced intestinal barrier disruption, gut microbiota dysbiosis as well as systemic metabolic disorders. Correlation analysis revealed that DSD increased bacterial genera such as Faecalibaculum, Allobaculum, Dubosiella and Rhodospirillales_unclassified were closely associated with neuroinflammation related metabolites, including positively with short-chain fatty acids (SCFAs) and sphingomyelin (d18:1/16:0), and negatively with pi-methylimidazoleacetic acid, L-glutamine and homovanillic acid. Meanwhile, antibiotic intervention apparently relieved OIPN symptoms. Furthermore, fecal microbiota transplantation further confirmed the mediated effects of gut microbiota.
DSD alleviates OIPN by regulating gut microbiota and potentially relieving neuroinflammation related metabolic disorder.
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