Single-cell analysis of refractory anti-SRP necrotizing myopathy treated with anti-BCMA CAR-T cell therapy.

Immune-mediated necrotizing myopathy (IMNM) is an autoimmune disorder associated with the presence of autoantibodies, characterized by severe clinical presentation with rapidly progressive muscular weakness and elevated levels of creatine kinase, while traditional pharmacological approaches possess varying and often limited effects. Considering the pathogenic role of autoantibodies, chimeric antigen receptor (CAR)-T cells targeting B cell maturation antigen (BCMA) have emerged as a promising therapeutic strategy. We reported here a patient with anti-signal recognition particle IMNM refractory to multiple available therapies, who was treated with BCMA-targeting CAR-T cells, exhibited favorable safety profiles, sustained reduction in pathogenic autoantibodies, and persistent clinical improvements over 18 mo. Longitudinal single-cell RNA, B cell receptor, T cell receptor sequencing analysis presented the normalization of immune microenvironment after CAR-T cell infusion, including reconstitution of B cell lineages, replacement of T cell subclusters, and suppression of overactivated immune cells. Analysis on characteristics of CAR-T cells in IMNM demonstrated a more active expansion of CD8+ CAR-T cells, with a dynamic phenotype shifting pattern similar in CD4+ and CD8+ CAR-T cells. A comparison of CD8+ CAR-T cells in patients with IMNM and those with malignancies collected at different timepoints revealed a more NK-like phenotype with enhanced tendency of cell death and neuroinflammation and inhibited proliferating ability of CD8+ CAR-T cells in IMNM while neuroinflammation might be the distinct characteristics. Further studies are warranted to define the molecular features of CAR-T cells in autoimmunity and to seek higher efficiency and longer persistence of CAR-T cells in treating autoimmune disorders.

Macrophage-Expressed Coagulation Factor VII Promotes Adverse Cardiac Remodeling.

BACKGROUND: Excess fibrotic remodeling causes cardiac dysfunction in ischemic heart disease, driven by MAP (mitogen-activated protein) kinase-dependent TGF-ß1 (transforming growth factor-ß1) activation by coagulation signaling of myeloid cells. How coagulation-inflammatory circuits can be specifically targeted to achieve beneficial macrophage reprogramming after myocardial infarction (MI) is not completely understood. METHODS: Mice with permanent ligation of the left anterior descending artery were used to model nonreperfused MI and analyzed by single-cell RNA sequencing, protein expression changes, confocal microscopy, and longitudinal monitoring of recovery. We probed the role of the tissue factor (TF)-FVIIa (activated factor VII)-integrin ß1-PAR2 (protease-activated receptor 2) signaling complex by utilizing genetic mouse models and pharmacological intervention. RESULTS: Cleavage-insensitive PAR2R38E and myeloid cell integrin ß1-deficient mice had improved cardiac function after MI compared with controls. Proximity ligation assays of monocytic cells demonstrated that colocalization of FVIIa with integrin ß1 was diminished in monocyte/macrophage FVII-deficient mice after MI. Compared with controls, F7fl/fl CX3CR1 (CX3C motif chemokine receptor 1)Cre mice showed reduced TGF-ß1 and MAP kinase activation, as well as cardiac dysfunction after MI, despite unaltered overall recruitment of myeloid cells. Single-cell mRNA sequencing of CD45 (cluster of differentiation 45)+ cells 3 and 7 days after MI uncovered a trajectory from recruited monocytes to inflammatory TF+/TREM (triggered receptor expressed on myeloid cells) 1+ macrophages requiring F7. As early as 7 days after MI, macrophage F7 deletion led to an expansion of reparative Olfml 3 (olfactomedin-like protein 3)+ macrophages and, conversely, to a reduction of TF+/TREM1+ macrophages, which were also reduced in PAR2R38E mice. Short-term treatment from days 1 to 5 after nonreperfused MI with a monoclonal antibody inhibiting the macrophage TF-FVIIa-PAR2 signaling complex without anticoagulant activity improved cardiac dysfunction, decreased excess fibrosis, attenuated vascular endothelial dysfunction, and increased survival 28 days after MI. CONCLUSIONS: Extravascular TF-FVIIa-PAR2 complex signaling drives inflammatory macrophage polarization in ischemic heart disease. Targeting this signaling complex for specific therapeutic macrophage reprogramming following MI attenuates cardiac fibrosis and improves cardiovascular function.

Staged suppression of microglial autophagy facilitates regeneration in CNS demyelination by enhancing the production of linoleic acid.

Microglia play a critical role in the clearance of myelin debris, thereby ensuring functional recovery from neural injury. Here, using mouse model of demyelination following two-point LPC injection, we show that the microglial autophagic-lysosomal pathway becomes overactivated in response to severe demyelination, leading to lipid droplet accumulation and a dysfunctional and pro-inflammatory microglial state, and finally failed myelin debris clearance and spatial learning deficits. Data from genetic approaches and pharmacological modulations, via microglial Atg5 deficient mice and intraventricular BAF A1 administration, respectively, demonstrate that staged suppression of excessive autophagic-lysosomal activation in microglia, but not sustained inhibition, results in better myelin debris degradation and exerts protective effects against demyelination. Combined multi-omics results in vitro further showed that enhanced lipid metabolism, especially the activation of the linoleic acid pathway, underlies this protective effect. Supplementation with conjugated linoleic acid (CLA), both in vivo and in vitro, could mimic these effects, including attenuating inflammation and restoring microglial pro-regenerative properties, finally resulting in better recovery from demyelination injuries and improved spatial learning function, by activating the peroxisome proliferator-activated receptor (PPAR-γ) pathway. Therefore, we propose that pharmacological inhibition targeting microglial autophagic-lysosomal overactivation or supplementation with CLA could represent a potential therapeutic strategy in demyelinated disorders.

Soluble TREM2 triggers microglial dysfunction in neuromyelitis optica spectrum disorders.

Microglia-mediated neuroinflammation contributes to acute demyelination in neuromyelitis optica spectrum disorders (NMOSD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the CSF has been associated with microglial activation in several neurodegenerative diseases. However, the basis for this immune-mediated attack and the pathophysiological role of sTREM2 in NMOSD remain to be elucidated. Here, we performed Mendelian randomization analysis and identified a genetic association between increased CSF sTREM2 and NMOSD risk. CSF sTREM2 was elevated in patients with NMOSD and was positively correlated with neural injury and other neuroinflammation markers. Single-cell RNA sequencing of human macrophage/microglia-like cells in CSF, a proxy for microglia, showed that increased CSF sTREM2 was positively associated with microglial dysfunction in patients with NMOSD. Furthermore, we demonstrated that sTREM2 is a reliable biomarker of microglial activation in a mouse model of NMOSD. Using unbiased transcriptomic and lipidomic screens, we identified that excessive activation, overwhelmed phagocytosis of myelin debris, suppressed lipid metabolism and enhanced glycolysis underlie sTREM2-mediated microglial dysfunction, possibly through the nuclear factor kappa B (NF-κB) signalling pathway. These molecular and cellular findings provide a mechanistic explanation for the genetic association between CSF sTREM2 and NMOSD risk and indicate that sTREM2 could be a potential biomarker of NMOSD progression and a therapeutic target for microglia-mediated neuroinflammation.

Recent advances in the involvement of epigenetics in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a typical systemic autoimmune disease that manifests as skin rash, arthritis, lymphadenopathy, and multiple organ lesions. Epigenetics, including DNA methylation, histone modification, and non-coding RNA regulation, mainly affect the function and characteristics of cells through the regulation of gene transcription or translation. Increasing evidence indicates that there are a variety of complex epigenetic effects in patients with SLE, which interfere with the differentiation and function of T, and B lymphocytes, monocytes, and neutrophils, and enhance the expression of SLE-associated pathogenic genes. This paper summarizes our currently knowledge regarding pathogenesis of SLE, and introduces current advances in the epigenetic regulation of SLE from three aspects: immune function, inflammatory response, and lupus complications. We propose that epigenetic changes could be used as potential biomarkers and therapeutic targets of SLE.

Bruton's tyrosine kinase inhibition ameliorated neuroinflammation during chronic white matter ischemia.

Chronic cerebral hypoperfusion (CCH), a disease afflicting numerous individuals worldwide, is a primary cause of cognitive deficits, the pathogenesis of which remains poorly understood. Bruton's tyrosine kinase inhibition (BTKi) is considered a promising strategy to regulate inflammatory responses within the brain, a crucial process that is assumed to drive ischemic demyelination progression. However, the potential role of BTKi in CCH has not been investigated so far. In the present study, we elucidated potential therapeutic roles of BTK in both in vitro hypoxia and in vivo ischemic demyelination model. We found that cerebral hypoperfusion induced white matter injury, cognitive impairments, microglial BTK activation, along with a series of microglia responses associated with inflammation, oxidative stress, mitochondrial dysfunction, and ferroptosis. Tolebrutinib treatment suppressed both the activation of microglia and microglial BTK expression. Meanwhile, microglia-related inflammation and ferroptosis processes were attenuated evidently, contributing to lower levels of disease severity. Taken together, BTKi ameliorated white matter injury and cognitive impairments induced by CCH, possibly via skewing microglia polarization towards anti-inflammatory and homeostatic phenotypes, as well as decreasing microglial oxidative stress damage and ferroptosis, which exhibits promising therapeutic potential in chronic cerebral hypoperfusion-induced demyelination.

DOMAS: a data management software framework for advanced light sources.

In recent years, China's advanced light sources have entered a period of rapid construction and development. As modern X-ray detectors and data acquisition technologies advance, these facilities are expected to generate massive volumes of data annually, presenting significant challenges in data management and utilization. These challenges encompass data storage, metadata handling, data transfer and user data access. In response, the Data Organization Management Access Software (DOMAS) has been designed as a framework to address these issues. DOMAS encapsulates four fundamental modules of data management software, including metadata catalogue, metadata acquisition, data transfer and data service. For light source facilities, building a data management system only requires parameter configuration and minimal code development within DOMAS. This paper firstly discusses the development of advanced light sources in China and the associated demands and challenges in data management, prompting a reconsideration of data management software framework design. It then outlines the architecture of the framework, detailing its components and functions. Lastly, it highlights the application progress and effectiveness of DOMAS when deployed for the High Energy Photon Source (HEPS) and Beijing Synchrotron Radiation Facility (BSRF).

Blended BA.5 infection within 8 days after a boosted bivalent mRNA vaccination strengthens and lengthens the host immunity.

The impact of SARS-CoV-2 infection shortly after vaccination on vaccine-induced immunity is unknown, which is also one of the concerns for some vaccinees during the pandemic. Here, based on a cohort of individuals who encountered BA.5 infection within 8 days after receiving the fourth dose of a bivalent mRNA vaccine, preceded by three doses of inactivated vaccines, we show that booster mRNA vaccination provided 48% protection efficacy against symptomatic infections. At Day 7 postvaccination, the level of neutralizing antibodies (Nabs) against WT and BA.5 strains in the uninfected group trended higher than those in the symptomatic infection group. Moreover, there were greater variations in Nabs levels and a significant decrease in virus-specific CD4+ T cell response observed in the symptomatic infection group. However, symptomatic BA.5 infection significantly increased Nab levels against XBB.1.9.1 and BA.5 (symptomatic > asymptomatic > uninfected group) at Day 10 and resulted in a more gradual decrease in Nabs against BA.5 compared to the uninfected group at Day 90. Our data suggest that BA.5 infection might hinder the early generation of Nabs and the recall of the CD4+ T cell response but strengthens the Nab and virus-specific T cell response in the later phase. Our data confirmed that infection can enhance host immunity regardless of the short interval between vaccination and infection and alleviate concerns about infections shortly after vaccination, which provides valuable guidance for developing future vaccine administration strategies.

E3 ligase MaNIP1 degradation of NON-YELLOW COLORING1 at high temperature inhibits banana degreening.

Banana (Musa acuminata) fruit ripening under high temperatures (>24 °C) undergoes green ripening due to failure of chlorophyll degradation, which greatly reduces marketability. However, the mechanism underlying high temperature-repressed chlorophyll catabolism in banana fruit is not yet well understood. Here, using quantitative proteomic analysis, 375 differentially expressed proteins were identified in normal yellow and green ripening in banana. Among these, one of the key enzymes involved in chlorophyll degradation, NON-YELLOW COLORING 1 (MaNYC1), exhibited reduced protein levels when banana fruit ripened under high temperature. Transient overexpression of MaNYC1 in banana peels resulted in chlorophyll degradation under high temperature, which weakens the green ripening phenotype. Importantly, high temperature induced MaNYC1 protein degradation via the proteasome pathway. A banana RING E3 ligase, NYC1-interacting protein 1 (MaNIP1), was found to interact with and ubiquitinate MaNYC1, leading to its proteasomal degradation. Furthermore, transient overexpression of MaNIP1 attenuated MaNYC1-induced chlorophyll degradation in banana fruits, indicating that MaNIP1 negatively regulates chlorophyll catabolism by affecting MaNYC1 degradation. Taken together, the findings establish a post-translational regulatory module of MaNIP1-MaNYC1 that mediates high temperature-induced green ripening in bananas.

E3 ubiquitin ligase MaRZF1 modulates high temperature-induced green ripening of banana by degrading MaSGR1.

High temperatures (>24°C) prevent the development of a yellow peel on bananas called green ripening, owing to the inhibition of chlorophyll degradation. This phenomenon greatly reduces the marketability of banana fruit, but the mechanisms underlining high temperature-repressed chlorophyll catabolism need to be elucidated. Herein, we found that the protein accumulation of chlorophyll catabolic enzyme MaSGR1 (STAY-GREEN 1) was reduced when bananas ripened at high temperature. Transiently expressing MaSGR1 in banana peel showed its positive involvement in promoting chlorophyll degradation under high temperature, thereby weakening green ripening phenotype. Using yeast two-hybrid screening, we identified a RING-type E3 ubiquitin ligase, MaRZF1 (RING Zinc Finger 1), as a putative MaSGR1-interacting protein. MaRZF1 interacts with and targets MaSGR1 for ubiquitination and degradation via the proteasome pathway. Moreover, upregulating MaRZF1 inhibited chlorophyll degradation, and attenuated MaSGR1-promoted chlorophyll degradation in bananas during green ripening, indicating that MaRZF1 negatively regulates chlorophyll catabolism via the degradation of MaSGR1. Taken together, MaRZF1 and MaSGR1 form a regulatory module to mediate chlorophyll degradation associated with high temperature-induced green ripening in bananas. Therefore, our findings expand the understanding of posttranslational regulatory mechanisms of temperature stress-caused fruit quality deterioration.

Radial IR-GRIN lens prepared by multi-temperature fields manipulated gradient crystallization within chalcogenide glass.

Chalcogenide glass has achieved great success in manufacturing axial-type infrared gradient refractive index (IR-GRIN) lenses. However, studies on radial-type IR-GRIN lenses, which are more ideal for optical design, remain rare. The present study introduces what we believe to be a new method for preparing radial IR-GRIN lens by creating high refractive index (n) In2S3 nanocrystals within a 65GeS2-25In2S3-10CsCl (GIC, in molar percentage) glass matrix. Upon introduction of multi-temperature field manipulation, we have successfully achieved central crystallization and simultaneous gradient attenuation spreading toward the edge within GIC glass, providing a radial GRIN profile with Δn over 0.1 while maintaining excellent IR transparency. In addition, the optical and structural properties of the GIC GRIN samples were characterized. The relationship between Raman intensity and the n of glass ceramics at different heat treatment temperatures was investigated, thereby enabling the indirect confirmation of the presence of radial gradient crystallization within the prepared GIC GRIN samples through Raman intensity. Multiple experimental results have shown that this approach has excellent reproducibility and potential for large-scale productions.

The targeting of DAPK1 with miR-190a-3p promotes autophagy in trophoblast cells.

Pre-eclampsia (PE) is a dangerous pathological status that occurs during pregnancy and is a leading reason for both maternal and fetal death. Autophagy is necessary for cellular survival in the face of environmental stress as well as cellular homeostasis and energy management. Aberrant microRNA (miRNA) expression is crucial in the pathophysiology of PE. Although studies have shown that miRNA (miR)-190a-3p function is tissue-specific, the precise involvement of miR-190a-3p in PE has yet to be determined. We discovered that miR-190a-3p was significantly lower and death-associated protein kinase 1 (DAPK1) was significantly higher in PE placental tissues compared to normal tissues, which is consistent with the results in cells. The luciferase analyses demonstrated the target-regulatory relationship between miR-190a-3p and DAPK1. The inhibitory effect of miR-190a-3p on autophagy was reversed by co-transfection of si-DAPK1 and miR-190a-3p inhibitors. Thus, our data indicate that the hypoxia-dependent miR-190a-3p/DAPK1 regulatory pathway is implicated in the development and progression of PE by promoting autophagy in trophoblast cells.

Nuclear imaging of PD-L1 expression promotes the synergistic antitumor efficacy of targeted radionuclide therapy and immune checkpoint blockade.

PURPOSE: In order to maximize synergistic effect of targeted radionuclide therapy (TRT) and immune checkpoint blockade (ICB) as well as reduce the toxicity, we pioneered a strategy guided by PD-L1-targeted nuclear medicine imaging for the combination of TRT and ICB towards precision cancer therapy. METHODS: As a novel targeted radiotherapeutic agent, 177Lu-AB-3PRGD2 targeting integrin αvß3 was developed to achieve sustained antitumor effect by introducing an albumin binder (AB) into the structure of 3PRGD2. The 177Lu-AB-3PRGD2 TRT as well as different types of combination therapies of 177Lu-AB-3PRGD2 TRT and anti-PD-L1 ICB were performed in animal models. The changes of PD-L1 expression in tumors after TRT were evaluated in vitro and in vivo by PD-L1-specific SPECT/CT imaging of 99mTc-MY1523. RESULTS: 177Lu-AB-3PRGD2 showed improved tumor uptake and prolonged tumor retention, leading to significantly enhanced tumor growth suppression. Moreover, 177Lu-AB-3PRGD2 TRT remodeled the tumor immune microenvironment by upregulating PD-L1 expression and increasing tumor-infiltrating CD8+ T cells, facilitating immunotherapy. We found that the anti-PD-L1 treatment was more effective during the upregulation of tumor PD-L1 expression, and the time window could be determined by 99mTc-MY1523 SPECT/CT. CONCLUSION: We developed a novel and long-acting radiotherapeutic agent 177Lu-AB-3PRGD2, and pioneered a strategy guided by PD-L1-targeted nuclear medicine imaging for the combination of TRT and ICB towards precision cancer therapy, optimizing the therapeutic efficacy and reducing the cost and potential toxicity risks. This strategy could also be adapted for clinical practice, combining conventional radiotherapy or chemotherapy with ICB to enhance therapeutic efficacy.

Ldl-stimulated microglial activation exacerbates ischemic white matter damage.

The role of microglia in triggering the blood-brain barrier (BBB) impairment and white matter damage after chronic cerebral hypoperfusion is unclear. Here we demonstrated that the vessel-adjacent microglia were specifically activated by the leakage of plasma low-density lipoprotein (LDL), which led to BBB breakdown and ischemic demyelination. Interestingly, we found that LDL stimulation enhanced microglial phagocytosis, causing excessive engulfment of myelin debris and resulting in an overwhelming lipid burden in microglia. Surprisingly, these lipid-laden microglia exhibited a suppressed profile of inflammatory response and compromised pro-regenerative properties. Microglia-specific knockdown of LDLR or systematic medication lowering circulating LDL-C showed protective effects against ischemic demyelination. Overall, our findings demonstrated that LDL-stimulated vessel-adjacent microglia possess a disease-specific molecular signature, characterized by suppressed regenerative properties, which is associated with the propagation of demyelination during ischemic white matter damage.

Clinical outcomes of endoscopic submucosal dissection for superficial esophageal neoplasia in close proximity to esophageal varices: a multicenter international experience.

BACKGROUND : There are limited data on the feasibility of endoscopic submucosal dissection (ESD) for superficial esophageal neoplasia (SEN) located at or adjacent to esophageal varices. We aimed to evaluate the outcomes of ESD in these patients. METHODS: This multicenter retrospective study included cirrhotic patients with a history of esophageal varices with SEN located at or adjacent to the esophageal varices who underwent ESD. RESULTS: 23 patients with SEN (median lesion size 30 mm; 16 squamous cell neoplasia and seven Barrett's esophagus-related neoplasia) were included. The majority were Child-Pugh B (57 %) and had small esophageal varices (87 %). En bloc, R0, and curative resections were achieved in 22 (96 %), 21 (91 %), and 19 (83 %) of patients, respectively. Severe intraprocedural bleeding (n = 1) and delayed bleeding (n = 1) were successfully treated endoscopically. No delayed perforation, hepatic decompensation, or deaths were observed. During a median (interquartile range) follow-up of 36 (22-55) months, one case of local recurrence occurred after noncurative resection. CONCLUSION: ESD is feasible and effective for SEN located at or adjacent to esophageal varices in cirrhotic patients. Albeit, the majority of the esophageal varices in our study were small in size, when expertise is available, ESD should be considered as a viable option for such patients.

U-fiber diffusion kurtosis and susceptibility characteristics in relapsing-remitting multiple sclerosis may be related to cognitive deficits and neurodegeneration.

OBJECTIVES: To evaluate the diffusion kurtosis and susceptibility change in the U-fiber region of patients with relapsing-remitting multiple sclerosis (pwRRMS) and their correlations with cognitive status and degeneration. MATERIALS AND METHODS: Mean kurtosis (MK), axial kurtosis (AK), radial kurtosis (RK), kurtosis fractional anisotropy (KFA), and the mean relative quantitative susceptibility mapping (mrQSM) values in the U-fiber region were compared between 49 pwRRMS and 48 healthy controls (HCs). The U-fiber were divided into upper and deeper groups based on the location. The whole brain volume, gray and white matter volume, and cortical thickness were obtained. The correlations between the mrQSM values, DKI-derived metrics in the U-fiber region and clinical scale scores, brain morphologic parameters were further investigated. RESULTS: The decreased MK, AK, RK, KFA, and increased mrQSM values in U-fiber lesions (p < 0.001, FDR corrected), decreased RK, KFA, and increased mrQSM values in U-fiber non-lesions (p = 0.034, p < 0.001, p < 0.001, FDR corrected) were found in pwRRMS. There were differences in DKI-derived metrics and susceptibility values between the upper U-fiber region and the deeper one for U-fiber non-lesion areas of pwRRMS and HCs (p < 0.05), but not for U-fiber lesions in DKI-derived metrics. The DKI-derived metrics and susceptibility values were widely related with cognitive tests and brain atrophy. CONCLUSION: RRMS patients show abnormal diffusion kurtosis and susceptibility characteristics in the U-fiber region, and these underlying tissue abnormalities are correlated with cognitive deficits and degeneration. CLINICAL RELEVANCE STATEMENT: The macroscopic and microscopic tissue damages of U-fiber help to identify cognitive impairment and brain atrophy in multiple sclerosis and provide underlying pathophysiological mechanism. KEY POINTS: • Diffusion kurtosis and susceptibility changes are present in the U-fiber region of multiple sclerosis. • There are gradients in diffusion kurtosis and susceptibility characteristics in the U-fiber region. • Tissue damages in the U-fiber region are correlated with cognitive impairment and brain atrophy.

Comparison of diffusion tensor imaging (DTI) tissue characterization parameters in white matter tracts of patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD).

OBJECTIVE: To investigate the microstructural properties of T2 lesion and normal-appearing white matter (NAWM) in 20 white matter tracts between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) and correlations between the tissue damage and clinical variables. METHODS: The white matter (WM) compartment of the brain was segmented for 56 healthy controls (HC), 48 patients with MS, and 38 patients with NMOSD, and for the patients further subdivided into T2 lesion and NAWM. Subsequently, the diffusion tensor imaging (DTI) tissue characterization parameters of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were compared for 20 principal white matter tracts. The correlation between tissue damage and clinical variables was also investigated. RESULTS: The higher T2 lesion volumes of 14 fibers were shown in MS compared to NMOSD. MS showed more microstructure damage in 13 fibers of T2 lesion, but similar microstructure in seven fibers compared to NMOSD. MS and NMOSD had microstructure damage of NAWM in 20 fibers compared to WM in HC, with more damage in 20 fibers in MS compared to NMOSD. MS patients showed higher correlation between the microstructure of T2 lesion areas and NAWM. The T2 lesion microstructure damage was correlated with duration and impaired cognition in MS. CONCLUSIONS: Patients with MS and NMOSD show different patterns of microstructural damage in T2 lesion and NAWM areas. The prolonged disease course of MS may aggravate the microstructural damage, and the degree of microstructural damage is further related to cognitive impairment. CLINICAL RELEVANCE STATEMENT: Microstructure differences between T2 lesion areas and normal-appearing white matter help distinguish multiple sclerosis and neuromyelitis optica spectrum disorder. In multiple sclerosis, lesions rather than normal-appearing white matter should be a concern, because the degree of lesion severity correlated both with normal-appearing white matter damage and cognitive impairment. KEY POINTS: • Multiple sclerosis and neuromyelitis optica spectrum disorder have different damage patterns in T2 lesion and normal-appearing white matter areas. • The microstructure damage of normal-appearing white matter is correlated with the microstructure of T2 lesion in multiple sclerosis and neuromyelitis optica spectrum disorder. • The microstructure damage of T2 lesion in multiple sclerosis is correlated with duration and cognitive impairment.

Association between social capital and utilization of essential public health services among elderly migrants: a multilevel logistic study based on the 2017 China migrant dynamic survey (CMDS).

BACKGROUND: As the number of elderly migrants in China continues to grow, it is necessary to pay closer attention to their health and health services. Some studies have confirmed that social capital plays a significant role in the utilization of health services. Therefore, an in-depth exploration of the relationship between social capital and the utilization of essential public health services (EPHS) by elderly migrants will not only contribute to improving their overall health but also facilitate a more balanced development of public health service system in China. METHODS: Based on the cross-sectional data from the 2017 China Migrants Dynamic Survey (CMDS), this study examined the impact of social capital on the utilization of EPHS among elderly migrants. We evaluated social capital at two distinct levels: the individual and the community, and considered two dimensions of social capital: structural social capital (SSC) and cognitive social capital (CSC). The study aimed to delve into the impact of these forms of social capital on the utilization of EPHS among elderly migrants, and whether the migration range moderates this impact by multilevel logistic regression analysis. RESULTS: A total of 5,728 migrant elderly individuals were selected. The health records establishment rate and health education acceptance rate were approximately 33.0% and 58.6%, respectively. Social capital influenceed the utilization of EPHS among elderly migrants. Specifically, individual-level SSC and CSC have impacts on both the establishment of health records (OR = 1.598, 95%CI 1.366-1.869; OR = 1.705, 95%CI 1.433-2.028) and the acceptance of health education (OR = 1.345, 95%CI 1.154-1.567; OR = 2.297, 95%CI 1.906-2.768) among elderly migrants, while community-level SSC only affected the acceptance of health education (OR = 3.838, 95%CI 1.328-11.097). There were significant differences in individual-level SSC, health records, and health education among different migration range subgroups among elderly migrants. Migration range moderated the effect of social capital on the utilization of EPHS, crossing provinces could weaken the relationship between SSC and health education. CONCLUSIONS: Social capital is associated with a higher utilization rate of EPHS among elderly migrants. It is necessary to encourage them to actively participate in social activities, strengthen public services and infrastructure construction in the area, and improve their sense of belonging and identity.

Effects of Integrating Nursing Early Warning Systems with Doula-Assisted Childbirth on Natural Childbirth Rates and Neonatal Outcomes: A Single Center Prospective Study.

Objective: This study aims to evaluate the efficacy of integrating nursing early warning systems with doula-assisted childbirth nursing on natural childbirth rates and associated outcomes. Methods: A total of 150 women who underwent childbirth in the obstetrics and gynecology department of our hospital between September 2021 and March 2023 were enrolled as participants. They were randomly allocated into either the observation group or the control group, each comprising 75 individuals. The control group received standard nursing care, while the observation group received nursing early warning systems combined with doula-assisted childbirth nursing. Comparison between the two groups included modes of childbirth, the intensity of childbirth pain, neonatal Apgar scores, the incidence of postpartum hemorrhage, duration of the first and second stages of labor, and maternal satisfaction with nursing care. Results: Our findings indicated a higher natural childbirth rate in the observation group compared to the control group (P < .05). Furthermore, the SAS score of the observation group post-nursing was significantly lower than that of the control group. Additionally, neonates in the observation group exhibited higher Apgar scores compared to those in the control group. Moreover, mothers who underwent natural childbirth in the observation group experienced lower childbirth pain scores and reduced postpartum hemorrhage incidence (P < .05). The duration of both the first and second stages of childbirth was shorter in the observation group than in the control group. Furthermore, overall satisfaction with care was significantly higher in the observation group than in the control group, with a statistically significant difference (P < .05). Conclusions: This study underscores the effectiveness of implementing nursing early warning systems combined with doula-assisted nursing in enhancing maternal satisfaction, reducing postpartum hemorrhage, and improving maternal well-being and neonatal outcomes. The findings advocate for the widespread adoption of this intervention in clinical practice.

Mrlac1, an extracellular laccase, is required for conidial morphogenesis as well as the well adaptability in field of Metarhizium rileyi.

Acting as an extremely promising fungal pesticide, Metarhizium rileyi exhibits robust insecticidal activity against Lepidoptera pests, particularly the larvae. Though there is a slight delay in efficacy, biopesticides offer salient advantages over traditional chemical pesticide especially in environmental safety, cyclic infection and resistant inhibition. In this study, an exterior T-DNA was randomly inserted into the genome of M. rileyi, resulting in the acquisition of a mutant strain that displayed a colour transition from green to yellow within its conidia. The disruption of Mrlac1, a laccase, has been confirmed to attribute to the epigenetic alterations. Mrlac1 is a secreted protein harboring an N-terminal signaling peptide that undergoes in vivo synthesis and accumulates on the cell wall of M. rileyi. Targeted knock-out mutant exhibited alterations not just in conidia coloration, but significantly diminished capacity to withstand external stressors, particularly non-biological factors such as high humidity, Congo red exposure, and UV radiation. The disruptant suffered a constraint on hyphal polar growth, alteration in conidial surface structure, as well as noticeable increase in adhesion forces between conidia, the core infection factors. There is a remarkable diminution in virulence of Mrlac1 deletion variant against larvae of Spodoptera litura by topical inoculation, but not hemolymph injection. Our findings suggest that Mrlac1 acts as a positive regulator in the normal morphogenesis of fungal conidia, encompassing pigment production, inter-conidia adhesion, and conidial cell wall integrity, while the preservation of these structures holds paramount importance for the survival and infection of M. rileyi in the field.