Impact of glucocorticoids and rapamycin on autophagy in Candida glabrata-infected macrophages from BALB/c mice.

Objective: In the defense against microorganisms like Candida albicans, macrophages recruit LC3(Microtubule-associated protein 1A/1B-light chain 3) to the periplasm, engaging in the elimination process through the formation of a single-membrane phagosome known as LC3-associated phagocytosis (LAP). Building on this, we propose the hypothesis that glucocorticoids may hinder macrophage phagocytosis of Candida glabrata by suppressing LAP, and rapamycin could potentially reverse this inhibitory effect. Methods: RAW264.7 cells were employed for investigating the immune response to Candida glabrata infection. Various reagents, including dexamethasone, rapamycin, and specific antibodies, were utilized in experimental setups. Assays, such as fluorescence microscopy, flow cytometry, ELISA (Enzyme-Linked Immunosorbent Assay), Western blot, and confocal microscopy, were conducted to assess phagocytosis, cytokine levels, protein expression, viability, and autophagy dynamics. Results: Glucocorticoids significantly inhibited macrophage autophagy, impairing the cells' ability to combat Candida glabrata. Conversely, rapamycin exhibited a dual role, initially inhibiting and subsequently promoting phagocytosis of Candida glabrata by macrophages. Glucocorticoids hinder macrophage autophagy in Candida glabrata infection by suppressing the MTOR pathway(mammalian target of rapamycin pathway), while the activation of MTOR pathway by Candida glabrata diminishes over time. Conclusion: Our study elucidates the intricate interplay between glucocorticoids, rapamycin, and macrophage autophagy during Candida glabrata infection. Understanding the implications of these interactions not only sheds light on the host immune response dynamics but also unveils potential therapeutic avenues for managing fungal infections.

A study of the impact of the new digital divide on the ICT competences of rural and urban secondary school teachers in China.

Teachers' competence in information and communication technology (ICT) applications can lead to a deeper integration of technology into the curriculum and improve the quality of education. However, its application and distribution issues could result in resource inequality and social injustice. Based on the ICT competency framework for teachers, the study investigates the variables influencing teachers' ICT competency. A prediction model of teachers' ICT competency is built using empirical data from secondary school teachers in Hebei Province, China, both in urban and rural settings. The study results show that a new digital divide does exist between urban and rural teachers and that differences in digital environment and digital literacy reflecting the new digital divide have different degrees of impact on teachers' ICT competence. Age and subject also affect teachers' ICT competence. In the new era, we can start with knowledge acquisition, knowledge deepening and knowledge creation to improve teachers' ICT competence.

Bismuth Telluride Supported Sub-1 nm Polyoxometalate Cluster for High-Efficiency Thermoelectric Energy Conversion.

Size plays a crucial role in chemistry and material science. Subnanometer polyoxometalate (POM) clusters have gained attention in various fields, but their use in thermoelectrics is still limited. To address this issue, we propose the POM clusters as an effective second phase to enhance the thermoelectric properties of Bi0.4Sb1.6Te3. Thanks to their subnanometer size, POM clusters improve electrical transport behavior through the superposition of atomic orbitals and the interfacial scattering effect. Furthermore, their ultrasmall size strongly reduces thermal conductivity. Consequently, the introduction of a mere 0.1 mol % of POM into the Bi0.4Sb1.6Te3 matrix realizes a state-of-the-art zT value of 1.46 at 348 K, a 45% enhancement over Bi0.4Sb1.6Te3 (1.01), along with a maximum thermoelectric-conversion efficiency of the integrated module of 6.0%. The enhancement of carrier mobility and the suppression of thermal conduction achieved by introducing the subnanometer clusters hold promise for various applications, such as electronic devices and thermal management.

Stratum affects the distribution of soil selenium bioavailability by modulating the soil physicochemical properties: A case study in a Se-enriched area, China.

The soil selenium (Se) content and bioavailability are important for human health. In this regard, knowing the factors driving the concentration of total Se and bioavailable Se in soils is essential to map Se, enhance foodstuffs' Se content, and improve the Se nutritional status of humans. In this study, total Se and Se bioavailability (i.e., phosphate extracted Se) in surface soils (0-20 cm) developed on different strata were analyzed in a Se-enriched region of Southwest China. Furthermore, the interaction between the stratum and soil properties was assessed and how did the stratum effect on the concentration and spatial distribution of Se bioavailability in soils was investigated. Results showed that the median concentration of total Se in soils was 0.308 mg/kg, which is higher than China's soil background. The mean proportion of phosphate extracted Se in total Se was 12.2 %. The values of total Se, phosphate extracted Se, and soil organic matter (SOM) in soils increased with the increasing stratum age. In contrast, the coefficient of weathering and eluviation (BA) values decreased. The analysis of statistics and Geodetector revealed that the SOM, stratum, and BA were the dominant controlling factors for the contents and distributions of soil total Se and phosphate extracted Se. This study provided strong evidence that the soil properties that affected the total Se and Se bioavailability were modulated by the local geological background, and had important practical implications for addressing Se malnutrition and developing the Se-rich resource in the study region and similar geological settings in different parts of the globe.

Metabolism of Inulin via Difructose Anhydride I Pathway in Microbacterium flavum.

Difructose anhydride I (DFA-I) can be produced from inulin, with DFA-I-forming inulin fructotransferase (IFTase-I). However, the metabolism of inulin through DFA-I remains unclear. To clarify this pathway, several genes of enzymes related to this pathway in the genome of Microbacterium flavum DSM 18909 were synthesized, and the corresponding enzymes were encoded, purified, and investigated in vitro. After inulin is decomposed to DFA-I by IFTase-I, DFA-I is hydrolyzed to inulobiose by DFA-I hydrolase. Inulobiose is then hydrolyzed by ß-fructofuranosidase to form fructose. Finally, fructose enters glycolysis through fructokinase. A ß-fructofuranosidase (MfFFase1) clears the byproducts (sucrose and fructo-oligosaccharides), which might be partially hydrolyzed by fructan ß-(2,1)-fructosidase/1-exohydrolase and another fructofuranosidase (MfFFase2). Exploring the DFA-I pathway of inulin and well-studied enzymes in vitro extends our basic scientific knowledge of the energy-providing way of inulin, thereby paving the way for further investigations in vivo and offering a reference for further nutritional investigation of inulin and DFA-I in the future.

In Situ Synthesis of Self-Assembly Supramolecular Crystal Seeds within Continuous Carbon Nanofibers for Improved Fiber Graphitic Structure.

The utilization of carbon-based fibers as a fundamental constituent holds strong appeal for diverse materials and devices. However, the poor fiber graphitic structure resulting from the heat treatment of atactic polyacrylonitrile (PAN) precursors often leads to a modest performance of carbon-based fibers. This paper takes electrospun carbon nanofibers (CNFs) as the research object and provides a seed-assisted graphitization strategy to improve the fiber graphitic structures. The typical melamine/cyanuric acid self-assembly precursor of graphitic carbon nitride is applied as supramolecular seeds in CNFs and demonstrates significant promotion of fiber graphitization, while it decomposes at elevated temperatures. Further studies show that the higher carbon content contributes to the better heat resistance of seeds; thus, nanoscale 2,6-diaminopyridine/cyanuric acid and 2,4,6-triaminopyrimidine/barbituric acid supramolecular seeds are developed. Both systems can be uniformly distributed in PAN precursors through in situ self-assembly and withstand high-temperature carbonization without severe pyrolysis. The dispersed seeds contribute to the formation of fibrillar PAN crystals and promote their conversion to ordered graphitic domains through nucleation and templating roles. The obtained CNFs exhibit increased crystallinity and graphitization degree with improved orientation and refined size of fiber crystals. As a result, the strength, modulus, and elongation at break of CNFs are comprehensively enhanced.

'Only to reconcile with it'. The coping experience amongst middle-aged and older cancer survivors: A qualitative study.

BACKGROUND: Cancer threat is relevant to age, and the threat of a foreshortened life coupled with a lengthy treatment process negatively affects middle-aged and older adults. Understanding the coping throughout the cancer experience in middle-aged and older cancer survivors will help develop supportive care to promote their physiological and psychological coping effects. OBJECTIVES: To explore the cancer coping experiences of middle-aged adults aged 40-59 and older adults over 60. DESIGN: A descriptive phenomenological study was employed. METHODS: Face-to-face, in-depth, semistructured interviews were conducted with 22 oncology patients in a tertiary university hospital aged 40 or above from August to October 2023. The interview data were analyzed using thematic analysis procedures. RESULTS: Five themes and 13 subthemes were formed through analysis: acceptance of cancer (considering cancer as chronic, believing in fate and attributing cancer to karma); having different information needs (desired to be truthfully informed, information-seeking behaviour, information avoidance behaviour); getting families involved (developing dependent behaviours, feeling emotional support, family members suffering worse); striving to maintain positive psychological state (positive thinking, seeking peer support) and negative experience (undesirable, low self-esteem). CONCLUSION: Our study reveals that cancer survivors' attitudes towards having cancer have changed from a death sentence to a more positive perception of a chronic disease. Supportive programmes for developing coping strategies should consider the cultural traditions and religious beliefs, different information needs, involvement of family and promoting a positive psychological state while avoiding negative factors. PATIENT OR PUBLIC CONTRIBUTION: Participants with experience of coping with cancer were involved in the semistructured interview.

The changing health effects of air pollution exposure for respiratory diseases: a multicity study during 2017-2022.

BACKGROUND: Multifaceted SARS-CoV-2 interventions have modified exposure to air pollution and dynamics of respiratory diseases. Identifying the most vulnerable individuals requires effort to build a complete picture of the dynamic health effects of air pollution exposure, accounting for disparities across population subgroups. METHODS: We use generalized additive model to assess the likely changes in the hospitalisation and mortality rate as a result of exposure to PM2.5 and O3 over the course of COVID-19 pandemic. We further disaggregate the population into detailed age categories and illustrate a shifting age profile of high-risk population groups. Additionally, we apply multivariable logistic regression to integrate demographic, socioeconomic and climatic characteristics with the pollution-related excess risk. RESULTS: Overall, a total of 1,051,893 hospital admissions and 34,954 mortality for respiratory disease are recorded. The findings demonstrate a transition in the association between air pollutants and hospitalisation rates over time. For every 10 µg/m3 increase of PM2.5, the rate of hospital admission increased by 0.2% (95% CI: 0.1-0.7%) and 1.4% (1.0-1.7%) in the pre-pandemic and dynamic zero-COVID stage, respectively. Conversely, O3-related hospitalization rate would be increased by 0.7% (0.5-0.9%) in the pre-pandemic stage but lowered to 1.7% (1.5-1.9%) in the dynamic zero-COVID stage. Further assessment indicates a shift of high-risk people from children and young adolescents to the old, primarily the elevated hospitalization rates among the old people in Lianyungang (RR: 1.53, 95%CI: 1.46, 1.60) and Nantong (RR: 1.65, 95%CI: 1.57, 1.72) relative to those for children and young adolescents. Over the course of our study period, people with underlying diseases would have 26.5% (22.8-30.3%) and 12.7% (10.8-14.6%) higher odds of having longer hospitalisation and over 6 times higher odds of deaths after hospitalisation. CONCLUSIONS: Our estimates provide the first comprehensive evidence on the dynamic pollution-health associations throughout the pandemic. The results suggest that age and underlying diseases collectively determines the disparities of pollution-related health effect across population subgroups, underscoring the urgency to identifying the most vulnerable individuals to air pollution.

Distinct Prostate Cancer Survival Outcomes in Firefighters: A Population-Based Study.

Introduction: Survival outcomes for prostate cancer among specific occupational groups prone to regular medical check-ups vis-à-vis the general population have been understudied. For firefighters, a demographic subject to rigorous medical evaluations, possessing above-average medical expertise, and exposed to specific carcinogens of interest, prostate cancer survival in the US has never been studied. Methods: We conducted a retrospective study, utilizing data from the Florida Cancer Data System spanning 2004 to 2014, coupled with firefighter certification records from the Florida State Fire Marshal's Office. Our study cohort consisted of 1058 prostate cancer cases among firefighters as well as prostate cases for the Florida general population (n = 150,623). We compared cause-specific survival between the two using Cox regression models adjusted for demographics and clinical characteristics, including PSA levels, Gleason scores, and treatment modalities. Results: Firefighters demonstrated a higher five-year cause-specific survival rate (96.1%, 95% CI: 94.7-97.1%) than the general population (94.2%, 95%CI: 94.1-94.3%). Overall, firefighters' diagnoses were established at younger ages (median age 63 vs. 67 in the general population), exhibited a higher proportion of localized stage cancers (84.7% vs. 81.1%), and had a greater utilization of surgery (46.4% vs. 37.6%), a treatment modality with a high success rate but potential side effects. In multivariable analysis, firefighters displayed a survival advantage for localized stage (adjusted hazard ratio [aHR] = 0.53; 95%CI: 0.34-0.82). However, for regional or distant stages, firefighters aged 65 and above exhibited a higher risk of death (aHR = 1.84; 95% CI: 1.18-2.86) than the general population. Conclusion: Firefighters experience enhanced prostate cancer survival, primarily in cases diagnosed at localized stages, likely due to increased PSA testing. Nonetheless, for regional or distant stage, survival among older firefighters' lags behind that of the general population. Further investigations are warranted to unravel factors influencing the development of aggressive disease beyond PSA and Gleason scores in this population, as well as to assess the impact of a higher rate of surgical treatment on firefighters' quality of life.

Peripheral Control of the Assembly and Chirality of Anion-Based Octanuclear Cubes by Cation-π Networks.

Self-assembly of sophisticated polyhedral cages has drawn much attention because of their elaborate structures and potential applications. Herein, we report the anion-coordination-driven assembly of the first A8L12 (A = anion, L = ligand) octanuclear cubic structures from phosphate anion and p-xylylene-spaced bis-bis(urea) ligands via peripheral templating of countercations (TEA+ or TPA+). By attaching terminal aryl rings (phenyl or naphthyl) to the ligand through a flexible (methylene) linker, these aryls actively participate in the formation of plenty of "aromatic pockets" for guest cation binding. As a result, multiple peripheral guests (up to 22) of suitable size are bound on the faces and vertices of the cube, forming a network of cation-π interactions to stabilize the cube structure. More interestingly, when chiral ligands were used, either diastereomers of mixed Λ- and Δ-configurations (with TEA+ countercation) for the phosphate coordination centers or enantiopure cubes (with TPA+) were formed. Thus, the assembly and chirality of the cube can be modulated by remote terminal groups and peripheral templating tetraalkylammonium cations.

Unveiling the Dynamic Electrocatalytic Activity of Online Synthesized Bimetallic Nanocatalysts via Electrochemiluminescence Microscopy.

Effective bimetallic nanoelectrocatalysis demands precise control of composition, structure, and understanding catalytic mechanisms. To address these challenges, we employ a two-in-one approach, integrating online synthesis with real-time imaging of bimetallic Au@Metal core-shell nanoparticles (Au@M NPs) via electrochemiluminescence microscopy (ECLM). Within 120 s, online electrodeposition and in situ catalytic activity screening alternate. ECLM captures transient faradaic processes during potential switches, visualizes electrochemical processes in real-time, and tracks catalytic activity dynamics at the single-particle level. Analysis using ECL photon flux density eliminates size effects and yields quantitative electrocatalytic activity results. Notably, a nonlinear activity trend corresponding to the shell metal to Au surface atomic ratio is discerned, quantifying the optimal surface component ratio of Au@M NPs. This approach offers a comprehensive understanding of catalytic behavior during the deposition process with high spatiotemporal resolution, which is crucial for tailoring efficient bimetallic nanocatalysts for diverse applications.

Synthesis of Organopolysilazane Nanoparticles as Lithium-Ion Battery Anodes with Superior Electrochemical Performance via the Two-Step Stöber Method.

The Stöber method, a widely utilized sol-gel technique, stands as a green and reliable approach for preparing nanostructures on a large scale. In this study, we employed an enhanced Stöber method to synthesize organopolysilazane nanoparticles (OPSZ NPs), utilizing polysilazane oligomers as the primary precursor material and ammonia as the catalytic agent. By implementing a two-step addition process, control over crucial parameters facilitated the regulation of the nanoparticle size. Generally, maintaining relatively low concentrations of organopolysilazane and catalyst while adjusting the water/acetonitrile ratio can effectively enhance the surface energy of the organopolysilazane, resulting in the uniform formation of small spherical particles. The average particle size of the synthesized OPSZ NPs is about 140 nm, which were monodispersed and characterized by scanning electron microscopy, transmission electron microscopy, and dynamic light scattering. Furthermore, the composition of OPSZ NPs after pyrolysis was confirmed as SiC2.054N0.206O1.631 with 5.44 wt % free carbon structure by X-ray diffraction and energy-dispersive X-ray spectroscopy. Notably, the electrochemical performance assessment of SiCNO NPs as potential electrode materials for lithium-ion batteries exhibited promising outcomes. Specifically, at 1 A g-1 current density, the specific capacity is 585.45 mA h g-1 after 400 cycles, and the minimum capacity attenuation per cycle is only 0.1076 mA h g-1 (0.0172% of the original capacity), which indicates excellent energy storage capacity and cycle stability. In summary, this research contributes to the development of advanced anode materials for next-generation energy storage systems, marking a stride toward sustainable energy solutions.

Methylation patterns associated with C-reactive protein in racially and ethnically diverse populations.

Systemic low-grade inflammation is a feature of chronic disease. C-reactive protein (CRP) is a common biomarker of inflammation and used as an indicator of disease risk; however, the role of inflammation in disease is not completely understood. Methylation is an epigenetic modification in the DNA which plays a pivotal role in gene expression. In this study we evaluated differential DNA methylation patterns associated with blood CRP level to elucidate biological pathways and genetic regulatory mechanisms to improve the understanding of chronic inflammation. The racially and ethnically diverse participants in this study were included as 50% White, 41% Black or African American, 7% Hispanic or Latino/a, and 2% Native Hawaiian, Asian American, American Indian, or Alaska Native (total n = 13,433) individuals. We replicated 113 CpG sites from 87 unique loci, of which five were novel (CADM3, NALCN, NLRC5, ZNF792, and cg03282312), across a discovery set of 1,150 CpG sites associated with CRP level (p < 1.2E-7). The downstream pathways affected by DNA methylation included the identification of IFI16 and IRF7 CpG-gene transcript pairs which contributed to the innate immune response gene enrichment pathway along with NLRC5, NOD2, and AIM2. Gene enrichment analysis also identified the nuclear factor-kappaB transcription pathway. Using two-sample Mendelian randomization (MR) we inferred methylation at three CpG sites as causal for CRP levels using both White and Black or African American MR instrument variables. Overall, we identified novel CpG sites and gene transcripts that could be valuable in understanding the specific cellular processes and pathogenic mechanisms involved in inflammation.

Design and rationale of the Comprehensive intelligent Hypertension managEment SyStem (CHESS) evaluation study: a cluster randomized controlled trial for hypertension management in primary care.

BACKGROUND: Hypertension management in China is suboptimal with high prevalence and low control rate due to various barriers, including lack of self-management awareness of patients and inadequate capacity of physicians. Digital therapeutic interventions including mobile health and computational device algorithms such as clinical decision support systems (CDSS) are scalable with the potential to improve blood pressure (BP) management and strengthen the healthcare system in resource-constrained areas, yet their effectiveness remains to be tested. The aim of this report is to describe the protocol of the Comprehensive intelligent Hypertension managEment SyStem (CHESS) evaluation study assessing the effect of a multi-faceted hypertension management system for supporting patients and physicians on BP lowering in primary care settings. MATERIALS AND METHODS: The CHESS evaluation study is a parallel-group, cluster-randomized controlled trial conducted in primary care settings in China. 41 primary care sites from 3 counties of China are randomly assigned to either the usual care or the intervention group with the implementation of the CHESS system, more than 1600 patients aged 35-80 years with uncontrolled hypertension and access to a smartphone by themselves or relatives are recruited into the study and followed up for 12 months. In the intervention group, participants receive patient-tailored reminders and alerts via messages or intelligent voice calls triggered by uploaded home blood pressure monitoring data and participants' characteristics, while physicians receive guideline-based prescription instructions according to updated individual data from each visit, and administrators receive auto-renewed feedback of hypertension management performance from the data analysis platform. The multiple components of the CHESS system can work synergistically and have undergone rigorous development and pilot evaluation using a theory-informed approach. The primary outcome is the mean change in 24-hour ambulatory systolic BP from baseline to 12-month. DISCUSSION: The CHESS trial will provide evidence and novel insight into the effectiveness and feasibility of an implementation strategy using a comprehensive digital BP management system for reducing hypertension burden in primary care settings. TRIAL REGISTRATION: https://www. CLINICALTRIALS: gov, NCT05605418.

An observational prospective study based on a large cohort of HIV-negative neurosyphilis patients with particular reference to the Jarisch-Herxheimer reaction.

PURPOSE: The purpose of this study is to outline a complete picture of Jarisch-Herxheimer reaction (JHR) in the central nervous system among HIV-negative neurosyphilis patients. METHODS: A prospective study cohort of 772 cases with almost all stages of neurosyphilis depicted the features of JHR including occurrence rate, risk profiles, clinical manifestations, medical management and prognosis. RESULTS: The total occurrence rate of JHR was 9.3% (95% CI, 7.3-11.4%), including 4.1% (95% CI, 2.7-5.6%) with severe JHR. The reaction started 5 h after treatment initiation, peaked after 8 h, and subsided after 18 h. Patients with severe JHR experienced a longer recovery time (26 h). Patients with general paresis (OR = 6.825), ocular syphilis (OR = 3.974), pleocytosis (OR = 2.426), or a high CSF-VDRL titre (per log2 titre increase, OR = 2.235) were more likely to experience JHR. Patients with general paresis had an 11.759-fold increased risk of severe JHR. Worsening symptoms included cognitive impairment, mania, nonsense speech, and dysphoria, while symptoms of hallucination, urination disorder, seizures, myoclonus, or aphasia appeared as new-onset symptoms. Neurosyphilis treatment did not need to be interrupted in most patients with JHR and could be reinstated in patients with seizures under supportive medication when JHR subsided. CONCLUSION: Severe JHR displayed a 4.1% occurrence rate and clinicians should pay particular attention to patients at a higher risk of JHR. The neurosyphilis treatment regime can be restarted under intensive observation for patients with severe JHR and, if necessary, supportive medication should be initiated and continued until the end of therapy.

Rakicidin J and K, two cytotoxic and antibacterial cyclic depsipeptides from the marine bacterium Micromonospora chalcea.

Rakicidin J (1) and rakicidin K (2), two new cyclic depsipeptides, were isolated from culture broth of Micromonospora chalcea FIM-R150103. Their structures were elucidated by extensive analysis of NMR, HR-ESI-MS, and electronic circular dichroism (ECD) data. The two compounds showed strong cytotoxic activity against human colon carcinoma HCT-8 and human pancreatic cancer PANC-1 cells under normoxic and hypoxic conditions in the range of IC50 values from 0.024 to 0.79 µg/mL. Moreover, compounds 1 and 2 also showed moderate antibacterial activity against ten Gram-positive bacterial strains with MIC values ranging from 4 to more than 32 µg/mL. Structure-activity relationship of these two compounds with a close analogue, rakicidin B1, is also discussed.

Complement C1q-mediated microglial synaptic elimination by enhancing desialylation underlies sevoflurane-induced developmental neurotoxicity.

BACKGROUND: Repeated neonatal sevoflurane exposures led to neurocognitive disorders in young mice. We aimed to assess the role of microglia and complement C1q in sevoflurane-induced neurotoxicity and explore the underlying mechanisms. METHODS: Neonatal mice were treated with sevoflurane on postnatal days 6, 8, and 10, and the Morris water maze was performed to assess cognitive functions. For mechanistic explorations, mice were treated with minocycline, C1q-antibody ANX005, and sialidase-inhibitor N-acetyl-2,3-dehydro-2-deoxyneuraminic acid (NADNA) before sevoflurane exposures. Western blotting, RT-qPCR, Golgi staining, 3D reconstruction and engulfment analysis, immunofluorescence, and microglial morphology analysis were performed. In vitro experiments were conducted in microglial cell line BV2 cells. RESULTS: Repeated neonatal sevoflurane exposures resulted in deficiencies in learning and cognition of young mice, accompanied by microglial activation and synapse loss. Sevoflurane enhanced microglia-mediated synapse elimination through C1q binding to synapses. Inhibition of microglial activation and phagocytosis with minocycline significantly reduced the loss of synapses. We further revealed the involvement of neuronal sialic acids in this process. The enhanced activity of sialidase by sevoflurane led to the loss of sialic acids, which facilitated C1q binding to synapses. Inhibition of C1q with ANX005 or inhibition of sialidase with NADNA significantly rescued microglia-mediated synapse loss and improved neurocognitive function. Sevoflurane enhanced the engulfment of BV2 cells, which was reversed by ANX005. CONCLUSIONS: Our findings demonstrated that C1q-mediated microglial synaptic elimination by enhancing desialylation contributed to sevoflurane-induced developmental neurotoxicity. Inhibition of C1q or sialidase may be a potential therapeutic strategy for this neurotoxicity.

OTUD5 promotes the inflammatory immune response by enhancing MyD88 oligomerization and Myddosome formation.

Myddosome is an oligomeric complex required for the transmission of inflammatory signals from TLR/IL1Rs and consists of MyD88 and IRAK family kinases. However, the molecular basis for the self-assemble of Myddosome proteins and regulation of intracellular signaling remains poorly understood. Here, we identify OTUD5 acts as an essential regulator for MyD88 oligomerization and Myddosome formation. OTUD5 directly interacts with MyD88 and cleaves its K11-linked polyubiquitin chains at Lys95, Lys231 and Lys250. This polyubiquitin cleavage enhances MyD88 oligomerization after LPS stimulation, which subsequently promotes the recruitment of downstream IRAK4 and IRAK2 to form Myddosome and the activation of NF-κB and MAPK signaling and production of inflammatory cytokines. Consistently, Otud5-deficient mice are less susceptible to LPS- and CLP-induced sepsis. Taken together, our findings reveal a positive regulatory role of OTUD5 in MyD88 oligomerization and Myddosome formation, which provides new sights into the treatment of inflammatory diseases.