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Xu-Fu Yuan,1 Yu-Qin Ji,2 Teng-Xiao Zhang,3 Hong-Bin Xiang,4 Zhuo-Yan Ye,5 Qiang Ye3 1School of Sports Training, Nanjing Sport Institute, Nanjing, Jiangsu, People’s Republic of China; 2School of Sport and Human Science, Nanjing Sport Institute, Nanjing, Jiangsu, People’s Republic of China; 3School of Physical Education and Humanities, Nanjing Sport Institute, Nanjing, Jiangsu, People’s Republic of China; 4School of Sport, Exercise and Health Sciences, Loughborough University, Leicestershire, UK; 5Nanjing Foreign Language School Xianlin Campus, Nanjing, Jiangsu, People’s Republic of ChinaCorrespondence: Qiang Ye, School of Physical Education and Humanities, Nanjing Sport Institute, No. 8 Linggusi Road, Xuanwu, Nanjing, Jiangsu Province, People’s Republic of China, Tel +86-19962033966, Fax +86-84755161, Email yeqiang@nsi.edu.cnBackground/Objective: In the post-epidemic era, an increasing number of individuals were accustomed to learning sports and physical activity knowledge online for fitness and health demands. However, most previous studies have examined the influence of e-learning materials and resources on learners and have neglected intrinsic factors such as experience and physiological characteristics. Therefore, we conducted a study to investigate the effect of exercise habits and gender on sports e-learning behavior via eye-tracking technology.Methods: We recruited a sample of 60 undergraduate students (mean age = 19.6) from a university in Nanjing, China. They were randomly assigned into 4 groups based on 2 genders × 2 exercise habits. Their gaze behavior was collected by an eye-tracking device during the experiment. The cognitive Load Test and Learning Effect Test were conducted at the end of the individual experiment.Results: (1) Compared to the non-exercise habit group, the exercise habit group had a higher fixation count (P< 0.05), a shorter average fixation duration (P< 0.05), a smaller average pupil diameter (P< 0.05), and a lower subjective cognitive load (P< 0.05) and better learning outcome (P< 0.05). (2) Male participants showed a greater tendency to process information from the video area of interest (AOIs), and had lower subjective cognitive load (P < 0.05) and better learning outcomes (P < 0.05). (3) There was no interaction effect between exercise habits and gender for any of the indicators (P > 0.05).Conclusion: Our results indicate that exercise habits effectively enhance sports e-learning outcomes and reduce cognitive load. The exercise habits group showed significant improvements in fixation counts, average fixation duration, and average pupil diameter. Furthermore, male subjects exhibited superior learning outcomes, experienced lower cognitive load, and demonstrated greater attentiveness to dynamic visual information. These conclusions are expected to improve sports e-learning success and address educational inequality.Keywords: e-learning, exercise habit, eye-tracking, gaze behavior, gender

5 d transition metal oxides, such as iridates, have attracted significant interest in condensed matter physics throughout the past decade owing to their fascinating physical properties that arise from intrinsically strong spin-orbit coupling (SOC) and its interplay with other interactions of comparable energy scales. Among the rich family of iridates, iridium dioxide (IrO 2 ), a simple binary compound long known as a promising catalyst for water splitting, has recently been demonstrated to possess novel topological states and exotic transport properties. The strong SOC and the nonsymmorphic symmetry that IrO 2 possesses introduce symmetry-protected Dirac nodal lines (DNLs) within its band structure as well as a large spin Hall effect in the transport. Here, we review recent advances pertaining to the study of this unique SOC oxide, with an emphasis on the understanding of the topological electronic structures, syntheses of high crystalline quality nanostructures, and experimental measurements of its fundamental transport properties. In particular, the theoretical origin of the presence of the fourfold degenerate DNLs in band structure and its implications in the angle-resolved photoemission spectroscopy measurement and in the spin Hall effect are discussed. We further introduce a variety of synthesis techniques to achieve IrO 2 nanostructures, such as epitaxial thin films and single crystalline nanowires, with the goal of understanding the roles that each key parameter plays in the growth process. Finally, we review the electrical, spin, and thermal transport studies. The transport properties under variable temperatures and magnetic fields reveal themselves to be uniquely sensitive and modifiable by strain, dimensionality (bulk, thin film, nanowire), quantum confinement, film texture, and disorder. The sensitivity, stemming from the competing energy scales of SOC, disorder, and other interactions, enables the creation of a variety of intriguing quantum states of matter., (Creative Commons Attribution license.)

Purpose: Dysregulated expression of microRNA (miRNAs) in lung cancer has been wildly reported. The clinicopathologic significance of miR-9-5p in non-small-cell lung cancer (NSCLC) patients and its effect on NSCLC progression were explored in this study., Patients and Methods: A total of 76 NSCLC patients were included. miR-9-5p expression was evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Then, in vitro experiments including cell growth curve assays, colony formation assays, and transwell migration assays were performed. Further clinicopathological and prognostic values were explored using bioinformatics analysis of the TCGA database., Results: miR-9-5p expression was significantly increased in tumor tissues (both P < 0.0001). miR-9-5p expression was relatively higher in larger tumors ( P = 0.0327) and in lung squamous carcinoma (LUSC) ( P = 0. 0143). In addition, miR-9-5p was significantly upregulated in the normal lung tissues of cigarette smokers ( P = 0.0099). In vitro , miR-9-5p was correlated with cell proliferation and migration. After that, bioinformatics analysis of the TCGA database indicated that miR-9-5p was correlated with tumor size ( P = 0.0022), lymphatic metastasis ( P = 0.0141), LUSC ( P < 0.0001), and smoking history ( P < 0.0001). Finally, a prognostic study indicated high miR-9-5p expression was correlated with poor prognosis in LUAD ( P = 0.0121)., Conclusion: Upregulation of miR-9-5p may have an oncogenic effect in NSCLC and may be related to smoking. The conclusion of this study may help find new prognostic and therapeutic targets for NSCLC and the exploration of the relationship between smoking and lung cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Duan, Cui, Zhang, Gu, Wang and Li.)

Purpose: Mannitol is one of the first-line drugs for reducing cerebral edema through increasing the extracellular osmotic pressure. However, long-term administration of mannitol in the treatment of cerebral edema triggers damage to neurons and astrocytes. Given that neural stem cell (NSC) is a subpopulation of main regenerative cells in the central nervous system after injury, the effect of mannitol on NSC is still elusive. The present study aims to elucidate the role of mannitol in NSC proliferation., Methods: C57 mice were derived from the animal house of Zunyi Medical University. A total of 15 pregnant mice were employed for the purpose of isolating NSCs in this investigation. Initially, mouse primary NSCs were isolated from the embryonic cortex of mice and subsequently identified through immunofluorescence staining. In order to investigate the impact of mannitol on NSC proliferation, both cell counting kit-8 assays and neurospheres formation assays were conducted. The in vitro effects of mannitol were examined at various doses and time points. In order to elucidate the role of Aquaporin 4 (AQP4) in the suppressive effect of mannitol on NSC proliferation, various assays including reverse transcription polymerase chain reaction, western blotting, and immunocytochemistry were conducted on control and mannitol-treated groups. Additionally, the phosphorylated p38 (p-p38) was examined to explore the potential mechanism underlying the inhibitory effect of mannitol on NSC proliferation. Finally, to further confirm the involvement of the p38 mitogen-activated protein kinase-dependent (MAPK) signaling pathway in the observed inhibition of NSC proliferation by mannitol, SB203580 was employed. All data were analyzed using SPSS 20.0 software (SPSS, Inc., Chicago, IL). The statistical analysis among multiple comparisons was performed using one-way analysis of variance (ANOVA), followed by Turkey's post hoc test in case of the data following a normal distribution using a Shapiro-Wilk normality test. Comparisons between 2 groups were determined using Student's t-test, if the data exhibited a normal distribution using a Shapiro-Wilk normality test. Meanwhile, data were shown as median and interquartile range and analyzed using the Mann-Whitney U test, if the data failed the normality test. A p < 0.05 was considered as significant difference., Results: Primary NSC were isolated from the mice, and the characteristics were identified using immunostaining analysis. Thereafter, the results indicated that mannitol held the capability of inhibiting NSC proliferation in a dose-dependent and time-dependent manner using cell counting kit-8, neurospheres formation, and immunostaining of Nestin and Ki67 assays. During the process of mannitol suppressing NSC proliferation, the expression of AQP4 mRNA and protein was downregulated, while the gene expression of p-p38 was elevated by reverse transcription polymerase chain reaction, immunostaining, and western blotting assays. Subsequently, the administration of SB203580, one of the p38 MAPK signaling pathway inhibitors, partially abrogated this inhibitory effect resulting from mannitol, supporting the fact that the p38 MAPK signaling pathway participated in curbing NSC proliferation induced by mannitol., Conclusions: Mannitol inhibits NSC proliferation through downregulating AQP4, while upregulating the expression of p-p38 MAPK., (Copyright © 2024. Production and hosting by Elsevier B.V.)

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory autoimmune disease of the central nervous system that involves B-cell receptor signaling as well as astrocyte-microglia interaction, which both contribute to evolution of NMOSD lesions., Main Body: Through transcriptomic and flow cytometry analyses, we found that Bruton's tyrosine kinase (BTK), a crucial protein of B-cell receptor was upregulated both in the blood and cerebrospinal fluid of NMOSD patients. Blockade of BTK with zanubrutinib, a highly specific BTK inhibitor, mitigated the activation and maturation of B cells and reduced production of causal aquaporin-4 (AQP4) autoantibodies. In a mouse model of NMO, we found that both BTK and pBTK expression were significantly increased in microglia. Transmission electron microscope scan demonstrated that BTK inhibitor ameliorated demyelination, edema, and axonal injury in NMO mice. In the same mice colocalization of GFAP and Iba-1 immunofluorescence indicated a noticeable increase of astrocytes-microglia interaction, which was alleviated by zanubrutinib. The smart-seq analysis demonstrated that treatment with BTK inhibitor instigated microglial transcriptome changes including downregulation of chemokine-related genes and genes involved in the top 5 biological processes related to cell adhesion and migration, which are likely responsible for the reduced crosstalk of microglia and astrocytes., Conclusions: Our results show that BTK activity is enhanced both in B cells and microglia and BTK inhibition contributes to the amelioration of NMOSD pathology. These data collectively reveal the mechanism of action of BTK inhibition and corroborate BTK as a viable therapeutic target., (© 2023. The Author(s).)

The environmental presence of polybrominated diphenyl ethers (PBDEs) is ubiquitous due to their wide use as brominated flame retardants in industrial products. As a common congener of PBDEs, decabromodiphenyl ether (BDE-209) can pose a health risk to animals as well as humans. However, to date, few studies have explored BDE-209's toxic effects on the intestinal tract, and its relevant mechanism of toxicity has not been elucidated. In this study, adult male zebrafish were exposed to BDE-209 at 6 μg/L, 60 μg/L and 600 μg/L for 28 days, and intestinal tissue and microbial samples were collected for analysis to reveal the underlying toxic mechanisms. Transcriptome sequencing results demonstrated a dose-dependent pattern of substantial gene differential expression in the group exposed to BDE-209, and the differentially expressed genes were mainly concentrated in pathways related to protein synthesis and processing, redox reaction, and steroid and lipid metabolism. In addition, BDE-209 exposure caused damage to intestinal structure and barrier function, and promoted intestinal oxidative stress, inflammatory response, apoptosis and steroid and lipid metabolism disorders. Mechanistically, BDE-209 induced intestinal inflammation by increasing the levels of TNF-α and IL-1β and activating the NFκB signaling pathway, and might induce apoptosis through the p53-Bax/Bcl2-Caspase3 pathway. BDE-209 also significantly inhibited the gene expression of rate-limiting enzymes such as Sqle and 3βhsd (p < 0.05) to inhibit cholesterol synthesis. In addition, BDE-209 induced lipid metabolism disorders through the mTOR/PPARγ/RXRα pathway. 16S rRNA sequencing results showed that BDE-209 stress reduced the richness and diversity of intestinal microbiota, and reduced the abundance of probiotics (e.g., Bifidobacterium and Faecalibacterium). Overall, the results of this study help to clarify the intestinal response mechanism of BDE-209 exposure, and provide a basis for evaluating the health risks of BDE-209 in animals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The development of new cryoprotectants for cryopreservation of cells has attracted considerable interest. Herein, five calixarene-based CPAs (SC4A, S-S-C4A, S-SO 2 -C4A, SBAC4A, and CAC4A) were developed, and their IRI activity, DIS property and cryoprotective effect were studied. SBAC4A with a sulphobetaine zwitterion and SC4A with sulfo group modification possessed better cryoprotective effects than the other calixarene-based CPAs, especially for SBAC4A with the enhanced cell viabilities of 16.16 ± 1.78%, 12.60 ± 1.15% and 14.90 ± 1.66% against MCF-7, hucMSCs and A549 cells, respectively. This result provides a supramolecular principle for developing novel CPAs with consideration of the factors of hydrogen bonding, the macromolecular crowding principle and the three-dimensional (3D) structure.

Levels of serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) are useful biomarkers of disease activity and disability in neuromyelitis optica spectrum disorder (NMOSD). Here we investigated the association of sNfL and sGFAP levels with brain and spinal cord volumes in patients with NMOSD. Fifteen patients with NMOSD were enrolled in this prospective study. The median baseline level of sNfL was 42.2 (IQR, 16.1-72.6) pg/mL and decreased to 8.5 (IQR, 7.4-16.6) pg/mL at the end of the study. The reduction in sNfL was associated with a 7.5% loss of cervical spinal cord volume (CSCV) (p = 0.001). The levels of sGFAP reduced from 239.2 (IQR, 139.0-3393.3) pg/mL at baseline to 108.5 (IQR, 74.2-154.6) pg/mL. However, there was no strong correlation between sGFAP levels and CSCV changes during the follow-up period. Our data suggested that sNfL level is a useful biomarker for predicting spinal cord atrophy in patients with NMOSD., Competing Interests: Declaration of Competing Interest The authors declared no potential conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The waste sector is a significant source of greenhouse gas(GHG) emissions and clarifying its emission trends and characteristics is the premise for formulating GHG emission reduction strategies. Using the IPCC inventory model, the GHG emissions from the municipal solid waste(MSW) sector in China during 2010 to 2020 were estimated. The results showed that GHG emissions increased from 42.5 Mt in 2010 to 75.3 Mt in 2019, then decreased to 72.1 Mt in 2020. MSW landfills were the main source of GHG emissions. Further, with the increase in the proportion of waste incineration, the proportion of GHG incineration increased rapidly from 16.5% in 2010 to 60.1% in 2020. In terms of regional distribution, East and South China were the regions with the highest emissions, and Guangdong, Shandong, Jiangsu, and Zhejiang were the provinces with the largest GHG emissions. Implementing MSW classification, changing the MSW disposal modes from landfilling to incineration, improving the LFG collection efficiency of landfills, and using biological functional materials as the cover soil to strengthen the methane oxidation efficiency are the main measures to achieve GHG emission reduction in waste sectors.

Aquatic invertebrates are the organisms most susceptible to ammonia toxicity. However, the toxic effects of ammonia on invertebrates are still poorly understood. This study reviews the research progress in ammonia toxicology for the period from 1986 to 2023, focusing on the effects on invertebrates. Through examining the toxic effects of ammonia at different levels of organization (community, individual, tissue and physiology, and molecular) as well as the results from omics studies, we determined that the most significant effects were on the reproductive capacity of invertebrates and the growth of offspring, although different populations show variation in their tolerance to ammonia, and tissues have varied potential to respond to ammonia stress. A multicomponent analysis is an in-depth technique employed in toxicological studies, as it can be used to explore the enrichment pathways and functional genes expressed under ammonia stress. This study comprehensively discusses ammonia toxicity from multiple aspects in order to provide new insights into the toxic effects of ammonia on aquatic invertebrates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The clinical and molecular genetic data of 6 patients with genetically confirmed tyrosine hydroxylase deficiency(THD) diagnosed in Department of Neurology, Qilu Hospital of Shandong University from March 2017 to February 2022 were retrospectively collected and analyzed. The 6 patients were from 5 families. Among them, 5 patients had persistent or paroxysmal abnormal walking posture, 4 patients had dystonia of head and face, including spasm of perioral and oculopharyngeal muscles, hyperactivity, and binocular upvision, 4 patients showed obvious morning light and evening heavy phenomenon, 2 patients had postural tremor of limbs, 2 patients had psychomotor retardation from childhood, 1 patient only had limb and cervical muscle weakness, 1 patient had epileptic seizures. Of the 6 patients, only 1 was adult-onset, and the rest were child-onset. Four patients had good response to low-dose dopa preparation, 2 patients from the same family had poor response to dopamine treatment, requiring extremely low dose initiation and multi-frequency titration treatment. However, the long-term treatment effect was poor with obvious abnormalities. Gene testing of 5 families revealed 8 mutations in the TH gene, with c.698G>A (p.R233H) being the hot spot mutation site. The clinical manifestations of THD are complex. Besides paroxysmal or persistent dystonia, it can also be accompanied by eye movement crisis, muscle weakness, epilepsy, and delayed mental and motor development. Most patients respond well to low-dose dopamine preparations, but a small number of patients require titration treatment with extremely low-dose dopamine preparations, and the long-term effect is not satisfactory.

Autoreactive CD4 + helper T cells are implicated in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD). Both PD-1 + CXCR5 + CD4 + T follicular helper (Tfh) cells and PD-1 + CXCR5 - CD4 + T peripheral helper (Tph) cells can contribute to B-cell immune responses and the production of antibodies. Here we show the effect of B-cell depletion with rituximab on the homeostasis of Tfh cells, Tph cells and their subsets in patients with NMOSD. After rituximab treatment, total Tph cells, total Tfh cells, Tph17 cells, Tph17.1 cells, Tph1 cells, and Tfh1 cells tended to decrease at month 1, but gradually increased at month 6 and restored at month 12. Besides, Tph17.1 cells and Tfh17.1 cells were correlated with the proportion of CD19 - antibody-secreting cells. Our data suggest that rituximab induced a fluctuation of proinflammatory Tph and Tfh subsets within one year after initiation of the treatment., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The history of mare volcanism critically informs the thermal evolution of the Moon. However, young volcanic eruptions are poorly constrained by remote observations and limited samples, hindering an understanding of mare eruption flux over time. The Chang'e-5 mission returned the youngest lunar basalts thus far, offering a window into the Moon's late-stage evolution. Here, we investigate the mineralogy and geochemistry of 42 olivine and pyroxene crystals from the Chang'e-5 basalts. We find that almost all of them are normally zoned, suggesting limited magma recharge or shallow-level assimilation. Most olivine grains record a short timescale of cooling. Thermal modeling used to estimate the thickness and volume of the volcanism sampled by Chang'e-5 reveals enhanced magmatic flux ~2 billion years ago, suggesting that while overall lunar volcanic activity may decrease over time, episodic eruptions at the final stage could exhibit above average eruptive fluxes, thus revising models of lunar thermal evolution., (© 2023. The Author(s).)

The municipal solid waste (MSW) sector is an important source of greenhouse gas (GHG) emissions. MSW classification can achieve waste reduction and improve resource utilization. However, few studies have investigated the effects of MSW classification on GHG emission reduction. Therefore, the GHG emissions under different MSW disposal modes before and after classification were studied based on the life cycle assessment method in the four districts of Qingdao City. The results showed that MSW classification could significantly reduce the GHG emissions during the whole MSW treatment process. The net carbon emissions(in CO 2 /MSW)during the whole process of waste treatment for mode 1 (mixed collection+landfill), mode 2 (mixed collection+incineration), mode 3 (waste classification+anaerobic digestion of food waste and other incineration), and mode 4 (waste classification+anaerobic digestion of food waste, recycling of recyclable waste, and other incineration) were 686.39, -130.12, -61.88, and -230.17 kg·t -1 , respectively. Improving the classification efficiency of food waste had no significant impact on carbon emissions. The reduction in carbon emissions increased linearly with the improvement of waste recycling efficiency. For every 10% increase in the recovery efficiency of recyclable waste, the net carbon emission decreased by 26.6%(16.5 kg·t -1 ). Appropriate separation of food waste, improving the recycling efficiency of recyclable waste, and reducing the leakage rate of biogas from anaerobic digestion are feasible strategies to reduce carbon emissions from MSW disposal units through the classification of MSW.

Background: This study aimed to observe the changes in the ocular surface after phacoemulsification in patients with age-related cataracts with respect to the addition of varying concentrations of hyaluronate., Methods: Patients with dry eye syndrome were treated with 0.3% and 0.1% sodium hyaluronate eye drops to evaluate the clinical improvement in each treatment group. A total of 73 patients (91 eyes) with age-related cataracts suffering from dry eye syndrome after phacoemulsification were divided into treatment group A (30 eyes), undergoing conventional therapy and treatment with 0.3% sodium hyaluronate; treatment group B (31 eyes), undergoing conventional therapy and treatment with 0.1% sodium hyaluronate; and the control group (group C; 30 eyes), undergoing conventional therapy only. Two groups were given different concentrations of sodium hyaluronate eye drops four times a day (should be completed between 8 AM and 8 PM), one drop at a time., Results: Seven days, 2 weeks, 1 month, and 2 months postoperatively, there were significant differences in the Schirmer I test (SIt), first noninvasive tear film break-up time (NIBUTf), average noninvasive tear film break-up time (NIBUTav), tear meniscus height (TMH), and irregularity (when the refractive force of different parts of different meridians on the same meridian is different. The main manifestation is that the two meridians on the anterior surface of the cornea do not show a 90-degree vertical distribution, which cannot be corrected by conventional astigmatism lenses) between the three groups (p < 0.05). When compared with group C, there were significant differences in the SIt, NIBUTf, NIBUTav, TMH, and irregularity of group A and group B (p < 0.05). When compared with group B, there were significant improvements in the SIt, NIBUTf, NIBUTav, and TMH in group A (p < 0.05)., Conclusions: In the early stage after phacoemulsification, the stability of the tear film is reduced. Adding sodium hyaluronate eye drops can restore tear film structure and improve corneal surface regularity, and a 0.3% solution of sodium hyaluronate eye drops is more effective than a 0.1% solution., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

It is well-established that the combined use of nanostructured substrates and immunoaffinity agents can enhance the cell-capture performance of the substrates, thus offering a practical solution to effectively capture circulating tumor cells (CTCs) in peripheral blood. Developing along this strategy, this study first demonstrated a top-down approach for the fabrication of tetrahedral DNA nanostructure (TDN)-NanoGold substrates through the hierarchical integration of three functional constituents at various length-scales: a macroscale glass slide, sub-microscale self-organized NanoGold, and nanoscale self-assembled TDN. The TDN-NanoGold substrates were then assembled with microfluidic chaotic mixers to give TDN-NanoGold Click Chips. In conjunction with the use of copper (Cu)-catalyzed azide-alkyne cycloaddition (CuAAC)-mediated CTC capture and restriction enzyme-triggered CTC release, TDN-NanoGold Click Chips allow for effective enumeration and purification of CTCs with intact cell morphologies and preserved molecular integrity. To evaluate the clinical utility of TDN-NanoGold Click Chips, we used these devices to isolate and purify CTCs from patients with human papillomavirus (HPV)-positive (+) head and neck squamous cell carcinoma (HNSCC). The purified HPV(+) HNSCC CTCs were then subjected to RT-ddPCR testing, allowing for detection of E6/E7 oncogenes, the characteristic molecular signatures of HPV(+) HNSCC. We found that the resulting HPV(+) HNSCC CTC counts and E6/E7 transcript copy numbers are correlated with the treatment responses in the patients, suggesting the potential clinical utility of TDN-NanoGold Click Chips for non-invasive diagnostic applications of HPV(+) HNSCC., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hsian-Rong Tseng reports a relationship with CytoLumina Technologies Corp. and Pulsar Therapeutics Corp. that includes: board membership.

Background and Aims: The sensitivity of current surveillance methods for detecting early-stage hepatocellular carcinoma (HCC) is suboptimal. Extracellular vesicles (EVs) are promising circulating biomarkers for early cancer detection. In this study, we aim to develop an HCC EV-based surface protein assay for early detection of HCC., Approach and Results: Tissue microarray was used to evaluate four potential HCC-associated protein markers. An HCC EV surface protein assay, composed of covalent chemistry-mediated HCC EV purification and real-time immuno-polymerase chain reaction readouts, was developed and optimized for quantifying subpopulations of EVs. An HCC EV ECG score, calculated from the readouts of three HCC EV subpopulations ( E pCAM + CD63 + , C D147 + CD63 + , and G PC3 + CD63 + HCC EVs), was established for detecting early-stage HCC. A phase 2 biomarker study was conducted to evaluate the performance of ECG score in a training cohort ( n  = 106) and an independent validation cohort ( n  = 72).Overall, 99.7% of tissue microarray stained positive for at least one of the four HCC-associated protein markers (EpCAM, CD147, GPC3, and ASGPR1) that were subsequently validated in HCC EVs. In the training cohort, HCC EV ECG score demonstrated an area under the receiver operating curve (AUROC) of 0.95 (95% confidence interval [CI], 0.90-0.99) for distinguishing early-stage HCC from cirrhosis with a sensitivity of 91% and a specificity of 90%. The AUROCs of the HCC EV ECG score remained excellent in the validation cohort (0.93; 95% CI, 0.87-0.99) and in the subgroups by etiology (viral: 0.95; 95% CI, 0.90-1.00; nonviral: 0.94; 95% CI, 0.88-0.99)., Conclusion: HCC EV ECG score demonstrated great potential for detecting early-stage HCC. It could augment current surveillance methods and improve patients' outcomes., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Optimizing outcomes in prostate cancer (PCa) requires precision in characterization of disease status. This effort was directed at developing a PCa extracellular vesicle (EV) Digital Scoring Assay (DSA) for detecting metastasis and monitoring progression of PCa. PCa EV DSA is comprised of an EV purification device (i.e., EV Click Chip) and reverse-transcription droplet digital PCR that quantifies 11 PCa-relevant mRNA in purified PCa-derived EVs. A Met score was computed for each plasma sample based on the expression of the 11-gene panel using the weighted Z score method. Under optimized conditions, the EV Click Chips outperformed the ultracentrifugation or precipitation method of purifying PCa-derived EVs from artificial plasma samples. Using PCa EV DSA, the Met score distinguished metastatic ( n = 20) from localized PCa ( n = 20) with an area under the receiver operating characteristic curve of 0.88 (95% CI:0.78-0.98). Furthermore, longitudinal analysis of three PCa patients showed the dynamics of the Met scores reflected clinical behavior even when disease was undetectable by imaging. Overall, a sensitive PCa EV DSA was developed to identify metastatic PCa and reveal dynamic disease states noninvasively. This assay may complement current imaging tools and blood-based tests for timely detection of metastatic progression that can improve care for PCa patients., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests, Hsian-Rong Tseng reports a relationship with CytoLumina Technologies Corp. that includes: equity or stocks. Hsian-Rong Tseng reports a relationship with Pulsar Therapeutics Corp. that includes: equity or stocks. Hsian-Rong Tseng, Yazhen Zhu, Na Sun has patent Covalent chemistry enables extracellular vesicle purification on nanosubstrates - toward early detection of hepatocellular carcinoma pending to Hsian-Rong Tseng, Yazhen ZHU, Na Sun, Vatche G. AGOPIAN. Corresponding author Dr. Edwin Posadas is an uncompensated advisor to CytoLumina Technologies Corp.

Assembly of the adenovirus capsid protein hexon depends on the assistance of the molecular chaperone L4-100K. However, the chaperone mechanisms remain unclear. In this study, we found that L4-100K was involved in the hexon translation process and could prevent hexon degradation by the proteasome in cotransfected human cells. Two nonadjacent domains, 84-133 and 656-697, at the N-terminal and C-terminal regions of human adenovirus type 5 L4-100K, respectively, were found to be crucial and cooperatively responsible for hexon trimer expression and assembly. These two chaperone-related domains were conserved in the sequence of L4-100K and in the function of hexon assembly across different adenovirus serotypes. Different degrees of cross-activity of hexon trimerization with different serotypes were detected in subgroups B, C, and D, which were proven to be controlled by the interaction between the C-terminal chaperone-related domain of L4-100K and hypervariable regions (HVR) of hexon. Additionally, HVR-chimeric hexon mutants were successfully assembled with the assistance of the 1-697 mutant. Structural analysis of 656-697 by nuclear magnetic resonance and structural prediction of L4-100K using Robetta showed that the two conserved domains are mainly composed of α-helices and are located on the surface of the highly folded core region. Our research provides a more complete understanding of hexon assembly and guidance for the development of hexon-chimeric adenovirus vectors that will be safer, smarter, and more efficient. IMPORTANCE Adenovirus vectors have been widely used in clinical trials of vaccines and gene therapy, although some deficiencies remain. Chimeric modification of the hexon was expected to improve the potency of preexisting immune evasion and targeting, but in many cases, viral packaging is prevented by the inability of the chimeric hexon to assemble correctly. So far, few studies have examined the mechanisms of hexon trimer assembly. Here, we show how the chaperone protein L4-100K contributes to the assembly of the adenovirus capsid protein hexon, and these data will provide a guide for novel adenovirus vector design and development, as we desired.

Neuromyelitis optica spectrum disorder (NMOSD) is a relapsing autoimmune disease that can cause permanent neurological disabilities. However, the interleukin-6 (IL-6) signaling pathway is a promising therapeutic target for relapse prevention. Therefore, this study evaluated the long-term effectiveness of tocilizumab, a humanized anti-IL-6 receptor antibody, for NMOSD. We enrolled 65 patients with NMOSD who received regular intravenous administration of tocilizumab (8 mg/kg) between October 2017 and January 2022. Then, we retrospectively collected data on the clinical characteristics and baseline glial fibrillary acidic protein (GFAP) and neurofilament light chain levels. The primary outcome was the annualized relapse rate (ARR). Risk factors were assessed using a multivariable logistic regression model. During the median follow-up of 34.1 (interquartile range: 25.5-39.3) months, 23% (15/65) of patients relapsed during tocilizumab treatment, but the median ARR decreased from 1.9 (range 0.12-6.29) to 0.1 (range 0-1.43, p < 0.0001). A prolonged infusion interval (> 4 weeks, odds ratio [OR]: 10.7, 95% confidence interval [CI]: 1.6-71.4, p = 0.014) and a baseline plasma GFAP level of > 220 pg/mL (OR: 20.6, 95% CI 3.3-129.4, p  = 0.001) were risk factors for future relapses. During treatment, the median Expanded Disability Status Scale score significantly decreased in aquaporin-4 antibody-positive and -negative patients, but the pain did not considerably improve. There were no severe safety concerns. Tocilizumab treatment significantly reduced the relapse rate in patients with NMOSD. However, prolonged infusion intervals and high baseline plasma GFAP levels may increase the relapse risk during tocilizumab therapy., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

As a common abiotic stress, drought severely impairs the growth, development, and even survival of plants. Here we report a transcription factor, Caragana korshinskii REVOLUTA(CkREV), which can bidirectionally regulate the expression of the critical enzyme gene CkYUC5 in auxin synthesis according to external environment changes, so as to control the biosynthesis of auxin and further enhance the drought resistance of plants. Quantitative analysis reveals that the expression level of both CkYUC5 and AtYUC5 is down-regulated after C. korshinskii and Arabidopsis thaliana are exposed to drought. Functional verification of CkREV reveals that CkREV up-regulates the expression of AtYUC5 in transgenic A. thaliana under common conditions, while down-regulating it under drought conditions. Meanwhile, the expression of CkYUC5 is also down-regulated in C. korshinskii leaves instantaneously overexpressing CkREV. We apply a dual-luciferase reporter system to discover that CkREV can bind to the promoter of CkYUC5 to regulate its expression, which is further proved by EMSA and Y1H esxperiments. Functional verification of CkREV in C. korshinskii and transgenic A. thaliana shows that CkREV can regulate the expression of CkYUC5 and AtYUC5 in a contrary way, maintaining the equilibrium of plants between growth and drought resisting. CkREV can positively regulate the expression of CkYUC5 to promote auxin synthesis in favor of growth under normal development. However, CkREV can also respond to external signals and negatively regulate the expression of CkYUC5 , which inhibits auxin synthesis in order to reduce growth rate, lower water demands, and eventually improve the drought resistance of plants.

Well-preserved molecular cargo in circulating extracellular vesicles (EVs) offers an ideal material for detecting oncogenic gene alterations in cancer patients, providing a noninvasive diagnostic solution for detection of disease status and monitoring treatment response. Therefore, technologies that conveniently isolate EVs with sufficient efficiency are desperately needed. Here, a lipid labeling and click chemistry-based EV capture platform ("Click Beads"), which is ideal for EV message ribonucleic acid (mRNA) assays due to its efficient, convenient, and rapid purification of EVs, enabling downstream molecular quantification using reverse transcription digital polymerase chain reaction (RT-dPCR) is described and demonstrated. Ewing sarcoma protein (EWS) gene rearrangements and kirsten rat sarcoma viral oncogene homolog (KRAS) gene mutation status are detected and quantified using EVs isolated by Click Beads and matched with those identified in biopsy specimens from Ewing sarcoma or pancreatic cancer patients. Moreover, the quantification of gene alterations can be used for monitoring treatment responses and disease progression., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Circulating tumor cell (CTC) clusters are present in cancer patients with severe metastasis, resulting in poor clinical outcomes. However, CTC clusters have not been studied as extensively as single CTCs, and the clinical utility of CTC clusters remains largely unknown. In this study, we aim sought to explore the feasibility of NanoVelcro Chips to simultaneously detect both single CTCs and CTC clusters with negligible perturbation to their intrinsic properties in neuroendocrine tumors (NETs). We discovered frequent CTC clusters in patients with advanced NETs and examined their potential roles, together with single NET CTCs, as novel biomarkers of patient response following peptide receptor radionuclide therapy (PRRT). We observed dynamic changes in both total NET CTCs and NET CTC cluster counts in NET patients undergoing PRRT which correlated with clinical outcome. These preliminary findings suggest that CTC clusters, along with single CTCs, offer a potential non-invasive option to monitor the treatment response in NET patients undergoing PRRT., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Pain is a common experience for inpatients, and intensive care unit (ICU) patients undergo more pain than other departmental patients, with an incidence of 50% at rest and up to 80% during common care procedures. At present, the management of persistent pain in ICU patients has attracted considerable attention, and there are many related clinical studies and guidelines. However, the management of transient pain caused by certain ICU procedures has not received sufficient attention. We reviewed the different management strategies for procedural pain in the ICU and reached a conclusion. Pain management is a process of continuous quality improvement that requires multidisciplinary team cooperation, pain-related training of all relevant personnel, effective relief of all kinds of pain, and improvement of patients' quality of life. In clinical work, which involves complex and diverse patients, we should pay attention to the following points for procedural pain: (1) Consider not only the patient's persistent pain but also his or her procedural pain; (2) Conduct multimodal pain management; (3) Provide combined sedation on the basis of pain management; and (4) Perform individualized pain management. Until now, the pain management of procedural pain in the ICU has not attracted extensive attention. Therefore, we expect additional studies to solve the existing problems of procedural pain management in the ICU., Competing Interests: Conflict-of-interest statement: Authors declare no conflict of interests for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Photothermal agents (PTAs) based on organic small-molecule dyes emerge as promising theranostic strategy in imaging and photothermal therapy (PTT). However, hydrophobicity, photodegradation, and low signal-to-noise ratio impede their transformation from bench to bedside. In this study, a novel supramolecular PTT formulation by a stimuli-responsive macrocyclic host is prepared to overcome these obstacles of organic small-molecule PTAs. Methods: Sulfonated azocalix[4]arene (SAC4A) was synthesized as a hypoxia-responsive macrocyclic host. Taking IR780 as an example, the supramolecular nanoformulation IR780@SAC4A was constructed by grinding method, and its solubility, photostability, and photothermal conversion were evaluated. The hypoxia tumor-selective imaging and supramolecular PTT of IR780@SAC4A were further evaluated in vitro and in vivo . Results: IR780@SAC4A is capable of enhancing the solubility, photostability, and photothermal conversion of IR780 significantly, which achieve this supramolecular formulation with good imaging-guided PTT efficacy in vitro and in vivo . Conclusions: This study demonstrates that the supramolecular PTT strategy is a promising cancer theranostic method. Moreover, this supramolecular approach is applicative to construct kinds of supramolecular PTAs, opening a general avenue for extending smart PTT formulations., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Neurofilament light chain (NfL) and glial fibrilliary acidic protein (GFAP) have been suggested to be biomarkers of the pathophysiological process of neuromyelitis optica spectrum disorders (NMOSD), but the relationship between the plasma levels of these molecules with disease activity and treatment is incompletely understood., Objective: To investigate the treatment effects of disease-modifying drugs on plasma neurofilament light chain (pNfL) and plasma glial fibrillary acidic protein (pGFAP) and explore the predictive value of pNfL and pGFAP in the activity of NMOSD., Methods: pNfL and pGFAP levels were measured using single-molecule arrays in 72 patients with NMOSD and 38 healthy controls (HCs). Patients with NMOSD received tocilizumab ( n  = 29), rituximab ( n  = 23), oral prednisone ( n  = 16), and oral azathioprine or mycophenolate mofetil ( n  = 4)., Results: NMOSD patients had significantly higher pNfL and pGFAP levels than HCs (pNfL, 18.3 (11.2-39.3) versus 11.5 (7.0-23.3) pg/mL; p  = 0.001; pGFAP, 149.7 (88.6-406.5) versus 68.7 (59.4-80.8) pg/mL; p  < 0.001). Multivariable regression analyses indicated that baseline pNfL concentration was associated with age ( p  = 0.017), Expanded Disability Status Scale (EDSS) score ( p  = 0.002), and recent relapses ( p  < 0.001). Baseline pGFAP concentration was also associated with EDSS ( p  < 0.001) and recent relapses ( p  < 0.001). Compared with prednisone, tocilizumab and rituximab significantly reduced pNfL [tocilizumab, exp(β), 0.65; 95% confidence interval (CI), 0.56-0.75; p  < 0.001; rituximab, exp(β), 0.79; 95% CI = 0.68-0.93; p  = 0.005] and pGFAP levels [tocilizumab, exp(β), 0.64; 95% CI, 0.51-0.80; p  < 0.001; rituximab, exp(β), 0.77; 95% CI, 0.61-0.98; p  = 0.041] at the end of the study. The pNfL levels in the tocilizumab and rituximab groups were reduced to those of HCs [tocilizumab, 8.5 (7.06-17.90) pg/mL; p  = 0.426; rituximab, 14.0 (9.94-21.80) pg/mL; p  = 0.216]. However, the pGFAP levels did not decrease to those of HCs in NMOSD patients at the end of study [tocilizumab, 88.9 (63.4-131.8) pg/mL; p  = 0.012; rituximab, 141.7 (90.8-192.7) pg/mL; p  < 0.001]., Conclusion: pNfL and pGFAP may serve as biomarkers for NMOSD disease activity and treatment effects., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2021.)

Background: Interleukin-6 receptor blockade is effective in reducing the risk of relapses in neuromyelitis optica spectrum disorder (NMOSD). However, its efficacy during acute attacks of NMOSD remains elusive., Objective: We investigated the effects of tocilizumab on disability during acute attacks, as well as its maintenance, in patients with moderate-to-severe myelitis., Methods: Nineteen patients with NMOSD received tocilizumab treatment as add-on to high-dose methylprednisolone (HDMP) in acute myelitis and twenty-two patients who only received HDMP were compared. Disease disability was assessed using a multi-level scaling system that included the expanded disability status scale (EDSS), Hauser ambulation index (HAI), modified Rankin scale (mRS), pain numerical rating scale (NRS), functional assessment of chronic illness therapy-fatigue scale (FACIT-F), activity of daily living (ADL), EuroQol five-dimensions-three-level questionnaire (EQ-5D-3L), and sensory function score and bowel and bladder function score in Kurtzke functional systems scores (FSS)., Results: Improved EDSS, HAI, and mRS, as well as increased ADL and EQ-5D-3L were significant in patients on tocilizumab compared with those on steroids as monotherapy at 3 months ( p < 0.05). Both groups of patients showed improved pain, fatigue, sensory function, and autonomic function at follow-ups, compared with baseline respectively. The changes in NRS, FACIT-F, and sensory and autonomic FSS showed no significant differences between the two groups. Tocilizumab significantly lowered the risk of relapses (HR = 0.21, 95% CI 0.06-0.76, p = 0.017) and reduced the annualized relapse rate compared with those by steroids (0.1 ± 0.2 vs 0.5 ± 0.6, p = 0.013)., Conclusion: Early initiation of tocilizumab provided a safe and effective add-on alternative during attacks, and its maintenance contributed to a significant reduction of relapse rate in NMOSD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Du, Zeng, Han, Zhang, Jia, Shi and Zhang.)

Objective: The skin is the second most affected organ after articular involvement in systemic lupus erythematosus (SLE) patients. Cutaneous involvement occurs in approximately 80% of patients during the course of SLE. Interaction between the host and skin microorganism is a complex process. There are few studies on the diversity of skin microbes in SLE patients. Therefore, this study aims to explore the relationship between skin microorganisms and SLE., Methods: A total of 20 SLE patients, 20 controls with rosacea and 20 healthy controls were selected as study subjects. Both the skin microbiota of rash region and non-rash region for each SLE patient were collected.16S rRNA gene sequencing was used to detected skin microbiota from 80 specimens. α-Diversity and β-diversity of skin microbiota were analyzed based on operational taxonomic units (OTUs) and minimal entropy decomposition (MED). Using Wilcoxon test and Linear Discriminate Analysis Effect Size (LEfSe), skin microbial diversity and composition were analyzed. Functional capabilities of microbiota were estimated through Kyoto Encyclopedia of Genes and Genomes database., Results: Compared to rash region of SLE, diversity and richness were increased in healthy controls, and decreased in non-rash region of SLE and rash region of controls with rosacea. Additionally, changes of skin microbial composition were found at different taxonomic levels between four groups. For example, genus Halomonas was increased and genera Pelagibacterium , Novosphingobium , and Curvibacter were decreased in rash region compared to non-rash region of SLE based on OTUs and MED. Based on OTUs, metabolic pathways were also found differences in SLE patients, such as Xenobiotics Biodegradation and Metabolism., Conclusion: Compositions and diversity of skin microbiota in SLE patients are changed. This pilot study provides some suggestive evidence for further exploration of skin microbiota in SLE patients with cutaneous involvement.

Background and Objectives: To assess the molecular landscape of B-cell subpopulations across different compartments in patients with neuromyelitis optica spectrum disorder (NMOSD)., Methods: We performed B-cell transcriptomic profiles via single-cell RNA sequencing across CSF, blood, and bone marrow in patients with NMOSD., Results: Across the tissue types tested, 4 major subpopulations of B cells with distinct signatures were identified: naive B cells, memory B cells, age-associated B cells, and antibody-secreting cells (ASCs). NMOSD B cells show proinflammatory activity and increased expression of chemokine receptor genes ( CXCR3 and CXCR4 ). Circulating B cells display an increase of antigen presentation markers ( CD40 and CD83 ), as well as activation signatures ( FOS , CD69 , and JUN ). In contrast, the bone marrow B-cell population contains a large ASC fraction with increased oxidative and metabolic activity reflected by COX genes and ATP synthase genes. Typically, NMOSD B cells become hyperresponsive to type I interferon, which facilitates B-cell maturation and anti-aquaporin-4 autoantibody production. The pool of ASCs in blood and CSF were significantly elevated in NMOSD. Both CD19 - and CD19 + ASCs could be ablated by tocilizumab, but not rituximab treatment in NMOSD., Discussion: B cells are compartmentally fine tuned toward autoreactivity in NMOSD and become hyperreactive to type I interferon. Inhibition of type I interferon pathway may provide a new therapeutic avenue for NMOSD., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Placenta accreta spectrum (PAS) is a high-risk obstetrical condition associated with significant morbidity and mortality. Current clinical screening modalities for PAS are not always conclusive. Here, we report a nanostructure-embedded microchip that efficiently enriches both single and clustered circulating trophoblasts (cTBs) from maternal blood for detecting PAS. We discover a uniquely high prevalence of cTB-clusters in PAS and subsequently optimize the device to preserve the intactness of these clusters. Our feasibility study on the enumeration of cTBs and cTB-clusters from 168 pregnant women demonstrates excellent diagnostic performance for distinguishing PAS from non-PAS. A logistic regression model is constructed using a training cohort and then cross-validated and tested using an independent cohort. The combined cTB assay achieves an Area Under ROC Curve of 0.942 (throughout gestation) and 0.924 (early gestation) for distinguishing PAS from non-PAS. Our assay holds the potential to improve current diagnostic modalities for the early detection of PAS., (© 2021. The Author(s).)

Tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody, showed its therapeutic efficacy on neuromyelitis optica spectrum disorder (NMOSD). To assess the immunological effects of this drug on B cells, follicular T helper (Tfh) cells, and peripheral T helper (Tph) cells in patients with NMOSD, peripheral B cell and Tfh cell phenotypes were evaluated in 26 patients with NMOSD before and after tocilizumab treatment by nine-color flow cytometry, as well as the expression of costimulatory and co-inhibitory molecules on B cells. Results showed that the frequency of CD27 + IgD - switched memory B cells, CD27 - IgD - double-negative B cells, and CD27 high CD38 high antibody-secreting cells was increased in patients with NMOSD. Tocilizumab treatment led to a significant shift of B cells to naïve B cells from memory B cells after 3 months. Three markers on B cells associated with T-cell activation (i.e., CD86 CD69, and HLA-DR) were downregulated after tocilizumab treatment. The frequencies of total Tfh and Tph cells were decreased, whereas that of follicular regulatory T cells tended to increase. Intrinsic increased PD-L1 and PD-L2 expression was characteristic of B cells in patients with NMOSD. Tocilizumab selectively restored PD-L1 on B-cell subsets. These results provided evidence that tocilizumab enhanced B- and T-cell homoeostasis by regulating B-cell differentiation and inhibiting lymphocyte activation in patients with NMOSD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Zhang, Zhang, Yuan, Du, Zeng, Huang, Jia, Yang, Shi and Zhang.)

Fullerene has attracted much attention in biomedical research due to its unique physical and chemical properties. However, the hydrophobic nature of fullerene is limited to deploy in the body, given that the biofluids are mainly water. In this study, a water-soluble supramolecular nanoformulation based on a deep cavitand calixarene (SAC4A) and fullerene is developed to overcome the hydrophobicity of fullerene and is used as a potential photodynamic agent. SAC4A solubilizes fullerene very well with a simple grinding method. The significantly increased water solubility of fullerene enables efficient activation of reactive oxygen species. The host-guest strategy to solubilize fullerene can not only provide a new method to achieve water solubility but also expand the biomedical applications of fullerene., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Li, Li and Guo.)

Objective: The aim of this study is to analyze the effect of the artificial tear drop administration time on the regularity of the corneal surface in patients with dry eye., Methods: Patients with cataract who were admitted to the hospital from January 2018 to December 2018 were divided into four groups (A, B, C, and D) based on their grade of noninvasive tear break-up time (NIBUT) and the concentration of the eye drops used. Groups A and C were classified as NIBUT grade 1 (NIBUTf of 6-9 s and NIBUTav of 8-13 s), and groups B and D were classified as NIBUT grade 2 (NIBUTf of <5 s and NIBUTav of ≤7 s). Groups A and B received 0.1% sodium hyaluronate eye drops, and groups C and D received 0.3% sodium hyaluronate eye drops., Results: In group A, there was a significant increase (p < 0.05) in the surface regularity index (SRI) and the surface asymmetry index (SAI) measured 1 s after eye drop administration. In group B, there was a significant decrease (p < 0.05) in the SRI and the SAI measured 1 s and 5 and 10 min after eye drop administration. In group C, there was a significant increase (p < 0.05) in the astigmatism degree, SRI, SAI, and irregular astigmatism index (IAI) measured 1 s after eye drop administration. There was a significant decrease (p < 0.05) in potential visual acuity (PVA). In group D, there was a significant increase in the IAI and Q value (parameters of aspheric characteristics of cornea, corneal Q value) measured 1 s after eye drop administration as well as a significant decrease in PVA (p < 0.05)., Conclusion: The use of 0.1% sodium hyaluronate eye drops in patients with dry eye aid the temporary recovery of corneal surface regularity and the stability of tear film. The 0.1% sodium hyaluronate had a significant effect for the first 10 min after treatment., Competing Interests: The authors declare that they have no competing interests., (© 2021 Chen et al.)

The clinical features, imaging features, treatment methods and pathological features of 27 patients with metanephric adenoma were analyzed. It was found that the clinical features and imaging features of metanephric adenoma were difficult to differentiate from renal malignantology. Pathology can be clearly diagnosed and some can be combined with malignant components. Nephron sparing surgery is the first choice, and the prognosis is good, but still need regular follow-up.

Purpose: The increasing number of deaths due to road traffic accidents (RTAs) has attracted global attention. However, the influence of road types is rarely considered in the study of RTAs. This study evaluates the influence of different road types in RTAs in northern Guizhou to provide a basis for the formulation of evidence-based policies and measures., Methods: We obtained the data from the Zunyi Traffic Management Data Platform for the years 2009-2018. The mortality rates of RTAs were calculated. Descriptive methods and Chi-square tests were used to analyze the characteristics of road traffic collisions on different road types. We also examined the associations between the mortality rate per 10,000 vehicles and the growth of per capital gross domestic product (GDP) with Spearman's rank correlation analysis. According to the passing volume and the infrastructure, we defined different types of roads, like administrative road, functional road, general urban road and urban expressway., Results: In 2012, the traffic mortality rate of administrative roads was 8.9 per 100,000 people, and the mortality rate of functional roads was 7.4 per 100,000 people, which decreased in 2018 to 6.1 deaths per 100,000 people and 5.2 deaths per 100,000 people, respectively. The mortality rate per 10,000 vehicles reached the highest level in 2011 (28.8 per 10,000 vehicles and 22.5 per 10,000 vehicles on administrative and functional roads, respectively). The death rate of county roads was the highest among administrative roads (χ 2  = 17.389, p < 0.05) and that of fourth-class roads was the highest among functional roads (χ 2  = 21.785, p < 0.05). The mortality rate per 10,000 vehicles was negatively correlated with per capital GDP., Conclusion: Although our research shows that RTAs in northern Guizhou have steadily declined in recent years, the range of decline is relatively small. Many measures and sustainable efforts are needed to control road traffic death and accelerate the progress in road traffic safety in northern Guizhou., Competing Interests: Declaration of competing interest There was no conflict of interest declared., (Copyright © 2020 Chinese Medical Association. Production and hosting by Elsevier B.V. All rights reserved.)

Combination therapy based on molecular drugs and therapeutic genes provides an effective strategy for malignant tumor treatment. However, effective gene and drug combinations for cancer treatment are limited by the widespread antagonism between therapeutic genes and molecular drugs. Herein, a calixarene-embedded nanoparticle (CENP) is developed to co-deliver molecular drugs and therapeutic genes without compromising their biological functions, thereby achieving interference-free gene-drug combination cancer therapy. CENP is composed of a cationic polyplex core and an acid-responsive polymer shell, allowing CENP loading and delivering therapeutic genes with improved circulation stability and enhanced tumor accumulation. Moreover, the introduction of carboxylated azocalix[4]arene, which is a hypoxia-responsive calixarene derivatives, in the polyplex core endows CENP with the capability to load molecular drugs through the host-guest complexation as well as inhibit the interference between the drugs and genes by encapsulating the drugs into its cavity. By loading doxorubicin and a plasmid DNA-based CRISPR interference system that targets miR-21, CENP exhibits the significantly enhanced anti-tumor effects in mice. Considering the wide variety of calixarene derivatives, CENP can be adapted to deliver almost any combination of drugs and genes, providing the potential as a universal platform for the development of interference-free gene-drug combination cancer therapy., (© 2021 Wiley-VCH GmbH.)

A field-scale dry grass swale with impermeable bottom and shallow substrate layer was built in Shanghai, where the groundwater table is very high, to avoid groundwater pollution caused by runoff infiltration. The underdrain pipe of the facility was up bended to avoid outside water flowing backward because local ground elevation is very low. Performance of the facility under the actual precipitation conditions was evaluated in the rainy season of 2019. The average runoff volume reduction is 39.4%, and the peak flow is reduced effectively when rain intensity is lower than 8.0 mm ·h -1 . Influent mass load reduction of TSS, COD, TP, and TN are 95.4%, 83.1%, 90.0%, and 57.7%, respectively. Wood chips in the substrate layer and the saturated zone are effective for denitrification during the wet and dry periods, respectively. Hydraulic loading rate and antecedent drying period are the main factors affecting denitrification. Improved influent quality combined with the storage volume supplied by the local urban river network could meet the goal of annual runoff volume reduction and annual pollution load removal in districts with high groundwater levels.

In this paper, the development of a five-stage solid-state linear transformer driver (LTD) is described. Each stage consists of eight compact pulse generating modules and a magnetic core. The pulse generating modules contain a multilayer-ceramic-capacitor-based pulse-forming network (PFN) and an insulated-gate bipolar transistor (IGBT) switch array, as well as magnetic switches, which are used to speed up the pulse front. To prevent damage from the reverse voltage to the IGBT switch, a reverse voltage absorption circuit was added to the PFN. For this study, a larger cross-sectional core with improved output characteristics was adopted. The developed five-stage LTD has the advantages of long life, low jitter, fast rising edge, and so on. The device can provide a 35 kV, 119 ns, 4.3 kA square pulse train with a maximum frequency of 50 Hz. On this basis, a 50-stage LTD of output 500 kV, which would serve as a high-power microwave driver source, is under development.

Enhanced drug delivery can improve the therapeutic efficacy of drugs and help overcome side effects. However, many reported drug-delivery systems are too complex and irreproducible for practical use. In this work, the design of a hypoxia-responsive molecular container based on calixarene, called CAC4A, which presents a significant advance in practical, hypoxia-targeted drug-delivery, is reported. CAC4A enables a wide variety of clinical drugs to be quantitatively loaded to improve their solubility and stability, as well as enable the administration of reduced doses. Furthermore, as a result of its azo functional groups, which are sensitive to reduction within a hypoxic environment, it is possible to achieve tumor-targeted drug-release with reduced side effects. CAC4A fulfils all essential requirements for a drug-delivery system in addition to multiple advantages, including facile preparation, well-defined molecular weight, and structure, and universal applicability. Such features collectively enable supramolecular prodrugs to be formulated simply and reproducibly, with potential for bench-to-bedside translation. Moreover, CAC4A is amenable to other therapy modalities and can be facilely decorated with functional groups and hybridized with nanomaterials, providing ample possibilities for its role in future drug-delivery systems., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: The aim of this study was to investigate the effects of propofol on intestinal ischemia-reperfusion injury in rats through the nuclear factor-kappa B (NF-κB) pathway., Materials and Methods: A total of 24 Sprague-Dawley rats were selected and randomly divided into three groups, including sham operation group, ischemia group and propofol group. Rats in sham operation group were only treated with isolation of superior mesenteric artery, which was clipped for 1 h and reperfused for 2 h in ischemia group. Meanwhile, propofol (60 mg/kg) was injected into the femoral vein 1 h before ischemia in propofol group. TUNEL assay was performed to detect cell apoptosis of intestinal tissues. Real-time quantitative polymerase chain reaction (RT-qPCR) was conducted to measure the expression levels of malondialdehyde (MDA), superoxide dismutase (SOD), myeloperoxidase (MPO), caspase-3 and B-cell lymphoma-2 (Bcl-2) in rats of each group. Western blotting was utilized to detect the protein expression levels of NF-κB pathway related molecules, such as myeloid differential protein-88 (MyD88), v-rel avian reticuloendotheliosis viral oncogene homolog A (RelA) and NF-κB. Furthermore, changes in plasma cytokine levels were determined via enzyme-linked immunosorbent assay (ELISA)., Results: The number of apoptotic cells in ischemia group was remarkably higher than that in sham operation group (p<0.05). However, it decreased notably in propofol group compared with ischemia group (p<0.05). In comparison with sham operation group, significantly up-regulated expression of caspase-3 and down-regulated expression of Bcl-2 were observed in the intestinal tissues of rats in ischemia group (p<0.05). Caspase-3 was lowly expressed, while Bcl-2 was highly expressed in the intestinal tissues of rats in propofol group compared with ischemia group (p<0.05). In addition, no statistically significant differences were observed in the expression level of SOD among sham operation group, ischemia group and propofol group (p>0.05). The expression levels of MDA and MPO were overtly higher in the intestinal tissues of rats in ischemia group than those in sham operation group and propofol group (p<0.05). Besides, the protein expression levels of MyD88, RelA and NF-κB in the intestinal tissues of rats in ischemia group were remarkably higher than those in sham operation group and propofol group (p<0.05). The activity of the NF-κB pathway in the intestinal tissues of rats in propofol group significantly declined compared with ischemia group (p<0.05). Moreover, compared with sham operation group, plasma levels of TNF-α, interleukin (IL)-2, IL-6 and IL-4 increased significantly in rats of ischemia group (p<0.05). However, they were markedly lower in propofol group than those in ischemia group (p<0.05)., Conclusions: Propofol protects rats from intestinal ischemia-reperfusion injury through the NF-κB pathway.

Full tensor gravity gradiometers based on accelerometer pair combination are widely employed in earth resource explorations using gravity gradient measurements. However, the extremely high requirements of accelerometer dynamic range and the scale factor consistency of accelerometer pairs are the two main limitations to further improve their performances. In order to overcome these two extreme challenges, the torque type gravity gradiometer based on the Etövös torsion balance pendulum is re-considered. In this paper, an improved torque type full tensor gravity gradiometer with a flexure-strip suspension is proposed, which balances the mechanical sensitivity and the response time. The proposed gradiometer can be used to measure the full tensor gravity gradient by observing angle variations at three azimuths. The principle and feasibility of the torque type full tensor gravity gradiometer based on a flexure-strip suspension are introduced, and the main noise sources including mechanical thermal noise, position sensing noise, and readout noise are analyzed. A prototype gravity gradiometer with a designed resolution of 2 E/Hz 1/2 at 0.1 Hz is constructed (1 E = 10 -9 /s 2 ), and the experimental results indicate that its resolution comes to 3 E/Hz 1/2 at 0.1 Hz, which is mainly limited by the seismic noise. This type of gravity gradiometer can be further improved due to its high potential resolution and independence of matching combination requirement, which allows it to be applied in next generation gravity resource exploration.

Background: Azathioprine is used as a first-line treatment to prevent relapses of neuromyelitis optica spectrum disorder (NMOSD). Tocilizumab has been reported to reduce NMOSD disease activity in retrospective case reports. We aimed to compare the safety and efficacy of tocilizumab and azathioprine in patients with highly relapsing NMOSD., Methods: We did an open-label, multicentre, randomised, phase 2 trial at six hospitals in China. We recruited adult patients (aged ≥18 years) with highly relapsing NMOSD diagnosed according to 2015 International Panel for Neuromyelitis Optica Diagnosis criteria, who had an Expanded Disability Status Scale (EDSS) score of 7·5 or lower, and had a history of at least two clinical relapses during the previous 12 months or three relapses during the previous 24 months with at least one relapse within the previous 12 months. Patients were randomly assigned (1:1) to intravenous tocilizumab (8 mg/kg every 4 weeks) or oral azathioprine (2-3 mg/kg per day) by an independent statistician using computer-generated randomisation software with permuted blocks of four. The central review committee, EDSS raters, laboratory personnel, and radiologists were masked to the treatment assignment, but investigators and patients were aware of treatment allocation. The minimum planned duration of treatment was 60 weeks following randomisation. The primary outcome was time to first relapse in the full analysis set, which included all randomly assigned patients who received at least one dose of study drug, and the per-protocol population, which included all patients who used azathioprine or tocilizumab as monotherapy. For the analyses of the primary outcome, the patients were prespecified into two subgroups according to concomitant autoimmune disease status. Safety was assessed in the full analysis set. This study is registered with ClinicalTrials.gov, NCT03350633., Findings: Between Nov 1, 2017, and Aug 3, 2018, we enrolled 118 patients, of whom 59 were randomly assigned to tocilizumab and 59 were randomly assigned to azathioprine. All 118 patients received one dose of study drug and were included in the full analysis set. 108 participants were included in the per-protocol analysis (56 in the tocilizumab group and 52 in the azathioprine group). In the full analysis set, median time to the first relapse was longer in the tocilizumab group than the azathioprine group (78·9 weeks [IQR 58·3-90·6] vs 56·7 [32·9-81·7] weeks; p=0·0026). Eight (14%) of 59 patients in the tocilizumab group and 28 (47%) of 59 patients in the azathioprine group had a relapse at the end of the study (hazard ratio [HR] 0·236 [95% CI 0·107-0·518]; p<0·0001). In the per-protocol analysis, 50 (89%) of 56 patients in the tocilizumab group were relapse-free compared with 29 (56%) of 52 patients in the azathioprine group at the end of the study (HR 0·188 [95% CI 0·076-0·463]; p<0·0001); the median time to first relapse was also longer in the tocilizumab group than the azathioprine group (67·2 weeks [IQR 47·9-77·9] vs 38·0 [23·6-64·9]; p<0·0001). In the prespecified subgroup analysis of the full analysis set stratified by concomitant autoimmune diseases, among patients without concomitant autoimmune diseases, three (9%) of 34 patients in the tocilizumab group and 13 (35%) of 37 patients in the azathioprine group had relapsed by the end of the study. Among patients with concomitant autoimmune diseases, a lower proportion of patients in the tocilizumab group had a relapse than in the azathioprine group (five [20%] of 25 patients vs 15 [68%] of 22 patients; HR 0·192 [95% CI 0·070-0·531]; p=0·0004). 57 (97%) of 59 patients in the tocilizumab group and 56 (95%) of 59 patients in the azathioprine group had adverse events. Treatment-associated adverse events occurred in 36 (61%) of 59 tocilizumab-treated patients and 49 (83%) of 59 azathioprine-treated patients. One death (2%) occurred in the tocilizumab group and one (2%) in the azathioprine group, but neither of the deaths were treatment-related., Interpretation: Tocilizumab significantly reduced the risk of a subsequent NMOSD relapse compared with azathioprine. Tocilizumab might therefore be another safe and effective treatment to prevent relapses in patients with NMOSD., Funding: Tianjin Medical University, Advanced Innovation Center for Human Brain Protection, National Key Research and Development Program of China, National Science Foundation of China., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A solid-state pulse-forming network (PFN) module was designed using multilayer ceramic capacitors (MLCCs). In addition, an all-solid-state pulse generator was fabricated with a Blumlein line that consisted of two PFN single lines and an insulated gate bipolar transistor (IGBT) switch array. This generator was integrated on printed circuit boards (PCBs). The stage capacitors of the PFN were composed of MLCCs connected in series and parallel. To obtain a compact structure, folded, copper-clad wires were used as interstage inductors. The copper-clad wires were structurally optimized to reduce coupling between adjacent interstage inductors. A relatively fast rising waveform edge was obtained using an IGBT gate-boosting circuit and magnetic switch technology. A square-wave pulse with a rise time of 27 ns, a voltage of 5 kV, a width of 120 ns, a maximum repetition rate of 100 Hz, and an evaluated lifetime of 10 9 pulses was obtained on a load of 6.6 Ω. With its compact size, fast rise time, and long lifetime, the fabricated pulse generator can be used as a component in linear transformer drivers or Marx generators.

The fate of intravenously injected nanoparticles (NPs) is significantly affected by nano-protein interaction and corona formation. However, such an interaction between NPs and digestive enzymes occurring in the gastrointestinal tract (GIT) and its impacts on epithelial cell uptake are little known. We synthesized the poly(3-hydroxybutyrate- co-3-hydroxyhexanoate)-based cationic NPs (CNPs) and investigated the CNP-digestive enzyme interaction and its effect on the cellular uptake. The formation of enzyme corona was confirmed by size/zeta potential analysis, morphology, sodium dodecyl sulfate polyacrylamide gel electrophoresis, and enzyme quantification. The cellular uptake of CNPs by Caco-2 cells was significantly reduced upon the formation of enzyme corona. Our findings demonstrate the digestive enzyme corona formation and its inhibited effect on the epithelial cell uptake of CNPs for the first time. Understanding the enzyme corona could offer a new insight into the fate of nanomedicines in the GIT, and this understanding would be highly beneficial for guiding future nanomedicine designs.

Objectives: In this meta-analysis, we conducted a pooled analysis of clinical studies comparing the efficacy of a volume threshold of 300 ml/day before removing a chest tube (CT) versus 100 ml/day after a lobectomy., Methods: According to the recommendations of the Cochrane Collaboration, we established a rigorous study protocol. We performed a systematic electronic search of PubMed, Embase, Cochrane Library, Web of Science databases, CNKI, the Wanfang database, CBMdisc and Google Scholar to identify articles to include in our meta-analysis. A literature search was performed using relevant keywords. A meta-analysis was performed using RevMan© software., Results: Five studies, published between 2014 and 2015, including 615 patients (314 patients who had the CT removed when daily drainage was <300 ml and 301 patients who had the CT removed when daily drainage was <100 ml) met the selection criteria. From the available data, the patients using the volume threshold of 300 ml/day had a significantly decreased duration of drainage [MD = -44.07; 95% confidence interval (CI) -64.45 to -23.68; P < 0.0001] and hospital stay after operation (MD = -2.25; 95% CI -3.52 to -0.97; P = 0.0006) compared with patients using a volume threshold of 100 ml/day after a pulmonary lobectomy. However, no significant differences were observed in postoperative complications, such as pleural fluid reaccumulation [Odds ratio (OR) = 1.73; 95% CI = 0.74-4.07; P = 0.21] and atelectasis (OR = 0.97; 95% CI = 0.52-1.81; P = 0.93). Thoracentesis rates after removing the CT also showed no significant difference (OR = 1.53; 95% CI 0.55-4.22; P = 0.41)., Conclusions: Our results showed that a higher volume threshold, up to 300 ml/day, is effective in reducing hospitalization times and duration of drainage in patients who undergo a lobectomy. Moreover, the volume threshold of 300 ml/day does not increase the occurrence of postoperative atelectasis, pleural fluid reaccumulation and thoracentesis rates. However, this review is limited by the methodological quality of the included trials, and additional studies according to the recommendations of Cochrane Library are appreciated.

Polydatin (PD), a natural precursor of resveratrol, has been used to treat several diseases, such as cardiovascular diseases, hepatic diseases and various cancers. In this study, we aimed to investigate the protective effects and underlying mechanisms of PD on non-alcoholic fatty liver disease (NAFLD) using a high fat induced obese mice model. The studied subjects were randomly divided into a lean group, a high fat diet (HFD) group, and a high fat diet with PD (HFD + PD) group. The results showed that PD reduced the body weights in HFD mice. PD also downregulated the serum levels of triglyceride (TG), low density lipoprotein (LDL), aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and upregulated high density lipoprotein (HDL). Moreover, PD significantly alleviated hepatocyte steatosis and reduced Gr-1 + cells in the liver tissues of HFD mice. The mRNA levels of pro-inflammatory factors, such as monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), S100A8 and S100A9 were significantly decreased in the liver tissues of HFD mice with PD treatment, and the downregulation of MCP-1 and S100A9 protein expressions was also observed. In conclusion, PD had beneficial roles in suppressing lipid accumulation in hepatocytes and anti-inflammatory responses in the liver tissue of obese associated NAFLD., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

Aim: Recently, nano-bio interactions and their biomedical impacts have drawn much attention, but nano-bacteria interaction and its function are unknown. Herein, we aim to synthesize drug-free and cationic nanoparticles (CNPs) and investigate CNP-bacteria interaction and its antibiofilm effect., Materials & Methods: The bioactivity of CNPs against Streptococcus mutans was examined by colony-forming units counting and scanning electron microscopy. CNP-bacteria interaction force was measured by atomic force microscopy., Results: CNPs (217.7 nm, 14.7 mv) showed a concentration-dependent activity against bacteria. Particularly, CNPs at 200 μg/ml completely inhibited planktonic bacterial growth and biofilm formation, and disrupted ∼70% mature biofilm. CNP-bacteria interaction force was up to 184 nN., Conclusion: CNPs have great potentials for convenient local use for prevention and treatment of bacteria-related oral diseases.