Bruton's tyrosine kinase-bearing B cells and microglia in neuromyelitis optica spectrum disorder.

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.

tPA Mobilizes Immune Cells That Exacerbate Hemorrhagic Transformation in Stroke.

RATIONALE: Hemorrhagic complications represent a major limitation of intravenous thrombolysis using tPA (tissue-type plasminogen activator) in patients with ischemic stroke. The expression of tPA receptors on immune cells raises the question of what effects tPA exerts on these cells and whether these effects contribute to thrombolysis-related hemorrhagic transformation. OBJECTIVE: We aim to determine the impact of tPA on immune cells and investigate the association between observed immune alteration with hemorrhagic transformation in ischemic stroke patients and in a rat model of embolic stroke. METHODS AND RESULTS: Paired blood samples were collected before and 1 hour after tPA infusion from 71 patients with ischemic stroke. Control blood samples were collected from 27 ischemic stroke patients without tPA treatment. A rat embolic middle cerebral artery occlusion model was adopted to investigate the underlying mechanisms of hemorrhagic transformation. We report that tPA induces a swift surge of circulating neutrophils and T cells with profoundly altered molecular features in ischemic stroke patients and a rat model of focal embolic stroke. tPA exacerbates endothelial injury, increases adhesion and migration of neutrophils and T cells, which are associated with brain hemorrhage in rats subjected to embolic stroke. Genetic ablation of annexin A2 in neutrophils and T cells diminishes the effect of tPA on these cells. Decoupling the interaction between mobilized neutrophils/T cells and the neurovascular unit, achieved via a S1PR (sphingosine-1-phosphate receptor) 1 modulator RP101075 and a CCL2 (C-C motif chemokine ligand 2) synthesis inhibitor bindarit, which block lymphocyte egress and myeloid cell recruitment, respectively, attenuates hemorrhagic transformation and improves neurological function after tPA thrombolysis. CONCLUSIONS: Our findings suggest that immune invasion of the neurovascular unit represents a previously unrecognized mechanism underlying tPA-mediated brain hemorrhage, which can be overcome by precise immune modulation during thrombolytic therapy.

Batoclimab as an add-on therapy in neuromyelitis optica spectrum disorder patients with acute attacks.

BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorder (NMOSD) is a severe neurological inflammatory disease mainly caused by pathogenic aquaporin-4 antibodies (AQP4-IgG). The safety and efficacy of the neonatal Fc receptor antagonist batoclimab addition to conventional intravenous methylprednisolone pulse (IVMP) therapy in patients with NMOSD acute attacks was assessed. METHODS: In an open-label, dose-escalation phase 1b study, NMOSD patients with acute myelitis and/or optic neuritis received four doses of weekly subcutaneous injections of either 340 mg or 680 mg batoclimab with concurrent IVMP and were followed up for 27 weeks. The primary end-points were safety and tolerability. Secondary end-points included pharmacodynamics and efficacy, with key efficacy assessment at week 4. RESULTS: In total nine NMOSD patients were enrolled, including two and seven in the 340 and 680 mg groups. Five patients had acute myelitis, while the remaining four had unilateral optic neuritis. Batoclimab add-on therapy had an overall good safety profile without serious adverse events. In the 680 mg group, mean immunoglobulin G (IgG) reached its maximum reduction at the last dose (day 22). In the meantime, AQP4-IgG was undetectable in six of seven subjects whose baseline AQP4-IgG titers ranged from 1:32 to 1:320. Expanded Disability Status Scale score was reduced by 1.3 ± 0.4 at week 4 (2.7 ± 1.3) compared with baseline (4.0 ± 1.0). CONCLUSIONS: Batoclimab add-on therapy to IVMP is safe and tolerated in patients with NMOSD. Preliminary evidence suggests a beneficial neurological effect. A randomized controlled trial would be needed to prove the efficacy.

Highly Soluble and Stable, High Release Rate Nanocellulose Codrug Delivery System of Curcumin and AuNPs for Dual Chemo-Photothermal Therapy.

As a natural antitumor drug, curcumin (CUR) has received increasing attention from researchers and patients due to its various medicinal properties. However, currently CUR is still restricted due to its low and stand-alone therapeutic effects that seriously limit its clinical application. Here, by using cellulose nanocrystals (CNCs) as a nanocarrier to load CUR and AuNPs simultaneously, we developed a hybrid nanoparticle as a codrug delivery system to enhance the low and stand-alone therapeutic effects of CUR. Aided with the encapsulation of ß-cyclodextrin (ßCD), both the solubility and the stability of CUR are greatly enhanced (solubility increased from 0.89 to 131.7 µg/mL). Owing to the unique rod-like morphology of CNCs, the system exhibits an outstanding loading capacity of 31.4 µg/mg. Under the heat effects of coloaded AuNPs, the system demonstrates a high release rate of 77.63%. Finally, with CNC as a bridge nanocarrier, all aforementioned functions were integrated into one hybrid nanoparticle. The all-in-one integration ensures CUR to have enhanced therapeutic effects and enables the delivery system to exhibit combined chemo-photothermal therapy outcomes. This work presents a significant step toward CUR's clinical application and provides a new strategy for effective and integrative treatment of tumor disease.

The incidence and prevalence, diagnosis, and treatment of multiple sclerosis in China: a narrative review.

In 2018, the first list of rare diseases was published by the National Health Council of China, and multiple sclerosis (MS) was included in this list. Since then, the Chinese government and neurologists have made efforts to improve the clinical outcomes of patients with MS. During last few years, the incidence of MS in China was also investigated. The early and accurate diagnosis of MS was improved due to the application and promotion of magnetic resonance imaging and new diagnosis criteria. The market for and medical insurance access to disease-modifying therapies (DMTs) has been greatly accelerated, which has provided more treatment options and improved clinical outcomes for patients with MS, as well as reduced treatment cost. The pattern of MS in China is gradually changing, from delayed to early diagnosis, and from no treatment to treatment with DMTs during remission. This narrative review aimed to summarize an update to the status of MS in China, including incidence and prevalence, diagnosis, and available treatments. This would help to better understand the diagnosis and treatment gap between mainland China and other Asian regions, demonstrating the necessity of accurate diagnosis and optimized treatment of MS in China.

Multiple intestinal hemangioma concurrent with low-grade appendiceal mucinous neoplasm presenting as intussusception-a case report and literature review.

BACKGROUND: Cases with intussusception caused by either intestinal hemangiomas or appendiceal mucinous neoplasms are extremely rare. CASE PRESENTATION: In this study, we reported a 47-year-old male presented with paroxysmal abdominal pain and postprandial bloating for 3 days. CT results indicated a high possibility of secondary intussusception in ascending colon. Histopathology indicated a mixed type of cavernous and capillary hemangioma, combined with low-grade appendiceal mucinous neoplasms (LAMNs) and intestinal obstruction. The patient underwent laparotomy and right hemicolectomy. Finally, the patient was followed up for 4 months with no disease progression. CONCLUSIONS: Rare studies reported the intestine hemangiomas coincided with appendix low-grade mucinous tumor. Its manifestations are not specific, which is a challenge in the preoperative diagnosis. For cases with intussusception that was not observed in time, it may lead to intestinal necrosis and diffuse peritonitis. Additionally, the ruptured mucinous tumor in the appendix may lead to pathogenesis of pseudomyxoma peritonei. Therefore, accurate diagnosis and appropriate surgery-based treatment contribute to the improvement of prognosis and severe outcomes among these patients.

Preparation and Evaluation of a Xanthan Gum-Containing Linezolid Ophthalmic Solution for Topical Treatment of Experimental Bacterial Keratitis.

PURPOSE: To formulate a xanthan gum-containing linezolid ophthalmic solution (LZD-XG) as a new antibiotic treatment against ocular bacterial infection. METHODS: LZD-XG was prepared and evaluated for its in vitro/in vivo ocular tolerance, in vitro/in vivo antibacterial activity, and in vivo ocular penetration. RESULTS: The optimized LZD-XG exhibited good in vitro/in vivo eye tolerance. A prolonged ocular surface residence time of LZD-XG was observed after topical instillation, and the ocular permeation was significantly better for LZD-XG than fora linezolid (LZD) ophthalmic solution. The in vitro antimicrobial activity was significantly better with LZD-XG than with LZD. In vivo evaluation also confirmed a strong therapeutic treatment effect of LZD-XG, as it significantly improved the clinical symptoms, ameliorated the damage of Staphylococcus aureus to ocular tissues, lowered the colony forming unit counts in the cornea, and decreased the myeloperoxidase activity in the cornea. CONCLUSION: LZD-XG was deemed a viable ophthalmic solution against ocular bacterial infection due to its excellent in vitro and in vivo characterizations.

Exploring polypharmacy burden among elderly patients with chronic diseases in Chinese community: a cross-sectional study.

BACKGROUND: In the long-term use of multiple medications for elderly patients diagnosed with chronic diseases, medication problems are prominent, which seriously reduces their quality of life. The burden of medications of patients critically affects their medication beliefs, behaviors and disease outcomes. It may be a solution to stress the burden of medications of patients. Its medication issues develops a novel perspective. The present study aimed to exploit the Chinese version of Living with Medicines Questionnaire-3(C-LMQ-3) to quantify the medicines burden of elderly patients diagnosed with chronic diseases in China, and evaluate the relevant demographic characteristics of sub-populations with high medicines burden. METHODS: The survey was distributed to elderly patients aged ≥ 60 years with chronic disease by using ≥ 5 medicines, C-LMQ-3 scores and domain scores were compared by the characteristics of elderly patients by employing descriptive statistics and performing statistical tests. RESULTS: On the whole, 430 responses were analyzed, and the participants were aged between 60 and 91 years, with the average age of 73.57 years (SD: 7.87). Most of the responses were female (61.7 %) with middle school education (38.5 %). Moreover, 54.1 % of the participants lived with spouse only, 16.2 % had both spouse and children, and 10.0 % lived alone. As indicated from regression analysis, higher C-LMQ-3 scores were associated with those who were with low education level, 60-69 years-old, using ≥ 11 medicines, using medicines ≥ 3 times a day, income per month (RMB) ≤ 3000, and who having higher monthly self-paid medication (RMB) ≥ 300 (p < 0.01). Burden was mainly driven by cost-related burden, concerns about medicines, and the lack of autonomy over medicine regimens. CONCLUSIONS: This study presents the preliminary evidence to elderly patients diagnosed with chronic diseases in mainland China that pay attention to multiple medications burden may help reduce the Drug Related Problems, whereas some elderly patients have a higher burden of medication. Chinese health care providers are required to primarily evaluate and highlight such patients, and formulate relevant intervention strategies to ensure medication adherence and daily medication management of elderly patients with polypharmacy.

Highly Thermally Stable, Green Solvent Disintegrable, and Recyclable Polymer Substrates for Flexible Electronics.

Flexible electronics require its substrate to have adequate thermal stability, but current thermally stable polymer substrates are difficult to be disintegrated and recycled; hence, generate enormous electronic solid waste. Here, a thermally stable and green solvent-disintegrable polymer substrate is developed for flexible electronics to promote their recyclability and reduce solid waste generation. Thanks to the proper design of rigid backbones and rational adjustments of polar and bulky side groups, the polymer substrate exhibits excellent thermal and mechanical properties with thermal decomposition temperature (Td,5% ) of 430 °C, upper operating temperature of over 300 °C, coefficient of thermal expansion of 48 ppm K-1 , tensile strength of 103 MPa, and elastic modulus of 2.49 GPa. Furthermore, the substrate illustrates outstanding optical and dielectric properties with high transmittance of 91% and a low dielectric constant of 2.30. Additionally, it demonstrates remarkable chemical and flame resistance. A proof-of-concept flexible printed circuit device is fabricated with this substrate, which demonstrates outstanding mechanical-electrical stability. Most importantly, the substrate can be quickly disintegrated and recycled with alcohol. With outstanding thermally stable properties, accompanied by excellent recyclability, the substrate is particularly attractive for a wide range of electronics to reduce solid waste generation, and head toward flexible and "green" electronics.

A facile one-pot preparation of Bi2O2CO3/g-C3N4 composites with enhanced photocatalytic activity.

Bi2O2CO3 modified graphitic carbon nitride (g-C3N4) nanosheets were prepared by a simple one-pot synthetic strategy. In the presence of ammonium nitrate, different mass ratios of bismuth nitrate/melamine were used to fabricate these catalysts, which were characterized by X-ray diffraction (XRD), N2-physisorption, Fourier transform infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), UV-vis analysis, and photoluminescence (PL). The catalytic properties of composites were evaluated by photodegrading tetracycline hydrochloride (TC) under visible light irradiation. Among these catalysts, Bi2O2CO3(1.5)/g-C3N4 showed the highest catalytic activity, which was more than 16 times greater than the pristine g-C3N4 material. The improved photocatalytic properties of Bi2O2CO3/g-C3N4 may be due to the formation of a heterojunction between Bi2O2CO3 and g-C3N4, leading to the effective separation of photo-induced carriers and the enhanced absorption of visible light. Furthermore, the Bi2O2CO3/g-C3N4 composites had considerable catalytic stability, which was a key element for their potential applications.

Infiltration and persistence of lymphocytes during late-stage cerebral ischemia in middle cerebral artery occlusion and photothrombotic stroke models.

BACKGROUND: Evidence suggests that brain infiltration of lymphocytes contributes to acute neural injury after cerebral ischemia. However, the spatio-temporal dynamics of brain-infiltrating lymphocytes during the late stage after cerebral ischemia remains unclear. METHODS: C57BL/6 (B6) mice were subjected to sham, photothrombosis, or 60-min transient middle cerebral artery occlusion (MCAO) procedures. Infarct volume, neurodeficits, production of reactive oxygen species (ROS) and inflammatory factors, brain-infiltrating lymphocytes, and their activation as well as pro-inflammatory cytokine IFN-γ production were assessed. Brain-infiltrating lymphocytes were also measured in tissue sections from post-mortem patients after ischemic stroke by immunostaining. RESULTS: In mice subjected to transient MCAO or photothrombotic stroke, we found that lymphocyte infiltration persists in the ischemic brain until at least day 14 after surgery, during which brain infarct volume significantly diminished. These brain-infiltrating lymphocytes express activation marker CD69 and produce proinflammatory cytokines such as IFN-γ, accompanied with a sustained increase of reactive oxygen species (ROS) and inflammatory cytokines release in the brain. In addition, brain-infiltrating lymphocytes were observed in post-mortem brain sections from patients during the late stage of ischemic stroke. CONCLUSION: Our results demonstrate that brain-infiltration of lymphocytes persists after the acute stage of cerebral ischemia, facilitating future advanced studies to reveal the precise role of lymphocytes during late stage of stroke.

Potential Metabolic Biomarkers to Identify Interstitial Lung Abnormalities.

Determining sensitive biomarkers in the peripheral blood to identify interstitial lung abnormalities (ILAs) is essential for the simple early diagnosis of ILAs. This study aimed to determine serum metabolic biomarkers of ILAs and the corresponding pathogenesis. Three groups of subjects undergoing health screening, including healthy subjects, subjects with ILAs, and subjects who were healthy initially and with ILAs one year later (Healthy→ILAs), were recruited for this study. The metabolic profiles of all of the subjects' serum were analyzed by liquid chromatography quadruple time-of-flight mass spectrometry. The metabolic characteristics of the ILAs subjects were discovered, and the corresponding biomarkers were predicted. The metabolomic data from the Healthy→ILAs subjects were collected for further verification. The results indicated that five serum metabolite alterations (up-regulated phosphatidylcholine, phosphatidic acid, betaine aldehyde and phosphatidylethanolamine, as well as down-regulated 1-acylglycerophosphocholine) were sensitive and reliable biomarkers for identifying ILAs. Perturbation of the corresponding biological pathways (RhoA signaling, mTOR/P70S6K signaling and phospholipase C signaling) might be at least partially responsible for the pathogenesis of ILAs. This study may provide a good template for determining the early diagnostic markers of subclinical disease status and for obtaining a better understanding of their pathogenesis.

Responsiveness to Tocilizumab in Anti-Acetylcholine Receptor-Positive Generalized Myasthenia Gravis.

Tocilizumab, a humanized IL-6R monoclonal antibody, has been used in autoimmune diseases closely related to humoral immunity. This report aims to evaluate the efficacy and safety in patients with anti-acetylcholine receptor-positive (AChR+) generalized myasthenia gravis (gMG). We performed a prospective, open-label, single-arm study in patients with gMG in a 48-week follow-up. All patients were AChR+ and were given tocilizumab by intravenous infusion at a dose of 8 mg/kg at intervals of 4 weeks. The primary endpoint was mean change from baseline in quantitative MG (QMG) score at week 12. The secondary endpoints were mean changes from baseline in MG activities of daily living (MG-ADL) score, AChR-ab titers, and the dosage of oral prednisone at week 12. At week 48, QMG, MG-ADL, and the use of prednisone were also evaluated. Fourteen gMG patients were enrolled and all of them completed the study. Tocilizumab treatment started 8 (4-192) months after the onset of gMG. During tocilizumab treatment, the QMG score was significantly decreased from 15.5 (interqualile range, 9-26) at baseline to 4 (0-9) at week 12 (p < 0.001). The change of ADL was decreased from 14.5(11-19) at baseline to 4 (0-19) at week 12 (p < 0.001) and the change of AChR-ab titers from 15 (7.5-19) at baseline to 6.8 (11.6-4.3) at week 12 (p < 0.001). The dosage of prednisone decreased from baseline 60 (20-65) mg/d to 30 (30-50) mg/d at week 12 (p < 0.001). By the end of the study, the QMG score was 2 (0-7) and MG-ADL score was 1.5 (0-6). 12 (85.7%) patients achieved minimal manifestations. 4 (28.6%) patients were able to discontinue prednisone. No patients experienced exacerbation at the end of the study. No serious adverse events were observed during follow-up. Tocilizumab treatment was associated with a good clinical response and safety over a 48-week observation period, as evidenced by significant improvements in QMG and MG-ADL.

Relationship between stigma and infertility-related stress among couples undergoing AID: The mediating role of communication patterns.

Infertility can be stressful for infertile couples. This study aims to examine the intra-dyadic associations between stigma, communication patterns, and infertility-related stress in couples undergoing artificial insemination by donor semen (AID). This cross-sectional study was conducted from January to April 2021. Two hundred and three couples undergoing AID were recruited from a reproductive centre in China. All of the couples completed a two-item stigma questionnaire, Communication Pattern Questionnaire, and Fertility Problem Inventory. The actor-partner interdependence mediation analysis was performed using AMOS 23.0. The analysis demonstrated significant actor-actor effects for couples undergoing AID. More specifically, higher levels of stigma among wives and husbands were associated with more negative communication patterns, thereby increasing their own infertility-related stress. Simultaneously, there was a significant partner-actor effect among infertile wives, demonstrating that the husband's stigma can affect his wife's infertility-related stress by influencing her communication patterns. Couples undergoing AID experience increased infertility-related stress when they have high levels of stigma and negative communication patterns, and husbands' stigma is correlated to wives' communication patterns. Therefore, dyadic interventions aiming to improving stigma and enhancing positive communication may be conducive to reducing infertility-related stress.

The change of intimate relationship between people with Alzheimer's disease and their adult child caregivers: An interpretative phenomenological analysis.

This study aims to explore the change of intimate relationship between people with Alzheimer's disease and their adult child caregivers as the disease progresses. Twelve adult child caregivers were recruited through purposive sampling. Explanatory phenomenological analysis was conducted to analyse data collected by semi-structured in-depth interviews. This study found a dynamically changing relationship between adult child caregivers and their parents with Alzheimer's disease during care giving that evolved with the progress of the disease. The relationship was the most intimate in the middle stage of the disease for most caregivers and a new reciprocal relationship developed due to caregiving. Caregivers experienced different degrees of self-growth when providing care, though caregiver burdens were common. The positive experience and perception of caregivers were important for improving the quality of life for adult child caregivers of people with Alzheimer's disease.

CYP2C19 polymorphisms and antiplatelet effects of clopidogrel in acute ischemic stroke in China.

BACKGROUND AND PURPOSE: Little research regarding genotypes and clopidogrel response related to acute ischemic stroke has been published. This study was conducted to investigate whether the polymorphisms of receptors or enzymes involved in the metabolic process of clopidogrel affect clopidogrel response and prognosis related to acute stroke. METHODS: A total of 259 patients with acute ischemic stroke were enrolled in this study; all received follow-up evaluations 3 and 6 months after clopidogrel treatment. CYP2C19, CYP3A4, and P2Y12 were screened. The adenosine diphosphate-induced platelet aggregation test, the National Institutes of Health Stroke Scale (NIHSS), and the modified Rankin Scale (mRS) were used, and blood vascular events were evaluated. RESULTS: The difference before and after clopidogrel treatment on adenosine diphosphate-induced platelet aggregation was significantly smaller in patients carrying 1 or 2 CYP2C19 loss-of-function alleles (*2, *3) compared with patients carrying none. Patients with none had better outcomes than patients with CYP2C19 loss-of-function alleles, as demonstrated by NIHSS and mRS scores at 3 and 6 months after treatment. Regression analysis showed that CYP2C19 was an independent predictor of clopidogrel resistance. CONCLUSIONS: CYP2C19 genotypes had significant impact on clopidogrel response and prognosis of patients with stroke. Clinical Trial Registration Information- URL: http://www.chictr.org/. Unique Identifier: ChiCTR-OCH-12002681.

Experimental and theoretic mechanism of successive adsorption of oppositely charged Cu(II) and Cr(VI) onto amine-rich cellulose adsorbent.

A novel layer-by-layer adsorption was proposed and used for adsorption of Cu(II) and Cr(VI) on the pre-bleached sawdust cellulose coated with polyethylenimine (PSC-PEI). It was found that PSC-PEI loaded with Cu(II) cations was favorable for Cr(VI) anions adsorption. The maximum adsorption capacities estimated by Langmuir model for Cu(II) and Cr(VI) were 80.0 and 93.5 mg/g, respectively. The kinetic regression results, as fitted by the pseudo-second order model, revealed that the rate constant (k2) for Cr(VI) at 0.07 g/mg/min is significantly greater than that observed for Cu(II) at 0.02 g/mg/min, indicating that PSC-PEI exhibited a stronger affinity towards Cr(VI). The first-layer adsorption mechanism for Cu(II) involved the formation of copper-amine complex. Zeta potential and XPS results revealed that the second-layer adsorption of Cr(VI) mainly involved electrostatic attraction and redox reaction. The simulated results for dynamic column test showed good agreement between the theoretical values and the experimental values. The mass transfer mechanism indicated that Cu(II) adsorption was dependent on external mass transfer process, while the internal mass transfer is the rate-determining step for Cr(VI) adsorption. The saturated adsorbent was regenerated by washing with 5% NaOH and 5% H2SO4 solutions and the adsorption ability of more than 70% was sustained after three cycles of regeneration. This study demonstrated that the oppositely charged Cu(II) cations and Cr(VI) anions could be effectively removed by amine-rich cellulose adsorbent from wastewater through layer-by-layer adsorption.

A real-world study of interleukin-6 receptor blockade in patients with neuromyelitis optica spectrum disorder.

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.

A boronization-induced amorphous-crystalline interface on a Prussian blue analogue for efficient and stable seawater splitting.

A promising electrocatalyst with an amorphous-crystalline structure was designed through a NaBH4 reduction strategy. Such a surface-defective heterophase structure remarkably prevents the catalyst from corroding by hindering the transport of Cl-, resulting in efficient and stable overall seawater splitting.

The SsAtg1 Activating Autophagy Is Required for Sclerotia Formation and Pathogenicity in Sclerotinia sclerotiorum.

Sclerotinia sclerotiorum is a necrotrophic phytopathogenic fungus that produces sclerotia. Sclerotia are essential components of the survival and disease cycle of this devastating pathogen. In this study, we analyzed comparative transcriptomics of hyphae and sclerotia. A total of 1959 differentially expressed genes, 919 down-regulated and 1040 up-regulated, were identified. Transcriptomes data provide the possibility to precisely comprehend the sclerotia development. We further analyzed the differentially expressed genes (DEGs) in sclerotia to explore the molecular mechanism of sclerotia development, which include ribosome biogenesis and translation, melanin biosynthesis, autophagy and reactivate oxygen metabolism. Among these, the autophagy-related gene SsAtg1 was up-regulated in sclerotia. Atg1 homologs play critical roles in autophagy, a ubiquitous and evolutionarily highly conserved cellular mechanism for turnover of intracellular materials in eukaryotes. Therefore, we investigated the function of SsAtg1 to explore the function of the autophagy pathway in S. sclerotiorum. Deficiency of SsAtg1 inhibited autophagosome accumulation in the vacuoles of nitrogen-starved cells. Notably, ΔSsAtg1 was unable to form sclerotia and displayed defects in vegetative growth under conditions of nutrient restriction. Furthermore, the development and penetration of the compound appressoria in ΔSsAtg1 was abnormal. Pathogenicity analysis showed that SsAtg1 was required for full virulence of S. sclerotiorum. Taken together, these results indicate that SsAtg1 is a core autophagy-related gene that has vital functions in nutrient utilization, sclerotia development and pathogenicity in S. sclerotiorum.