Isobavachalcone: a redox antifungal agent impairs the mitochondria protein of Cryptococcus neoformans.

Isobavachalcone (IBC) is a natural small-molecule with various biological activities; however, its inhibitory effects on Cryptococcus neoformans remain unclear. In our study, IBC showed a good antifungal effect. Through in vitro experiments, its minimum inhibitory concentration (MIC) was 0.5-1 µg/mL. It exhibited the same antifungal effect as Amphotericin B in brain and lung infections in in vivo experiments. IBC also showed a synergistic antifungal effect with emodin with lower toxicity, and C. neoformans did not develop drug resistance to IBC. In the mechanistic study, significantly damaged mitochondria of C. neoformans, a significant reduction in mitochondrial membrane potential and adenosine triphosphate (ATP) production, and an increase in hydrogen peroxide [H2O2] caused by IBC were observed using transmission electron microscopy. Through drug affinity-responsive target stability combined with phenotype detection, riboflavin synthases of aconitase and succinate dehydrogenase were screened. Molecular docking, quantitative polymerase chain reaction experiments, target inhibitor and agonist intervention, molecular interaction measurements, and MIC detection of the constructed expression strains revealed that IBC targeted the activity of these two enzymes, interfered by the tricarboxylic acid cycle, inhibited the production of ATP, blocked electron transport, reduced mitochondrial membrane potential, and induced antioxidation imbalance and reactive oxygen species accumulation, thus producing an antifungal effect. Therefore, IBC is a promising lead drug and redox antifungal agent for C. neoformans.

Alternative splicing of a potato disease resistance gene maintains homeostasis between growth and immunity.

Plants possess a robust and sophisticated innate immune system against pathogens and must balance growth with rapid pathogen detection and defense. The intracellular receptors with nucleotide-binding leucine-rich repeat (NLR) motifs recognize pathogen-derived effector proteins and thereby trigger the immune response. The expression of genes encoding NLR receptors is precisely controlled in multifaceted ways. The alternative splicing (AS) of introns in response to infection is recurrently observed but poorly understood. Here we report that the potato (Solanum tuberosum) NLR gene RB undergoes AS of its intron, resulting in two transcriptional isoforms, which coordinately regulate plant immunity and growth homeostasis. During normal growth, RB predominantly exists as intron-retained isoform RB_IR, encoding a truncated protein containing only the N-terminus of the NLR. Upon late blight infection, the pathogen induces intron splicing of RB, increasing the abundance of RB_CDS, which encodes a full-length and active R protein. By deploying the RB splicing isoforms fused with a luciferase reporter system, we identified IPI-O1 (also known as Avrblb1), the RB cognate effector, as a facilitator of RB AS. IPI-O1 directly interacts with potato splicing factor StCWC15, resulting in altered localization of StCWC15 from the nucleoplasm to the nucleolus and nuclear speckles. Mutations in IPI-O1 that eliminate StCWC15 binding also disrupt StCWC15 re-localization and RB intron splicing. Thus, our study reveals that StCWC15 serves as a surveillance facilitator that senses the pathogen-secreted effector and regulates the trade-off between RB-mediated plant immunity and growth, expanding our understanding of molecular plant-microbe interactions.

The fungal secretory peptide micasin induces itch by activating MRGPRX1/C11/A1 on peripheral neurons.

Pruritus is the leading symptom of dermatophytosis. Microsporium canis is one of the predominant dermatophytes causing dermatophytosis. However, the pruritogenic agents and the related molecular mechanisms of the dermatophyte M. canis remain poorly understood. Here, the secretion of the dermatophyte M. canis was found to dose-dependently evoke itch in mice. The fungal peptide micasin secreted from M. canis was then identified to elicit mouse significant scratching and itching responses. The peptide micasin was further revealed to directly activate mouse dorsal root ganglia (DRG) neurons to mediate the non-histaminergic itch. Knockout and antagonistic experiments demonstrated that MRGPRX1/C11/A1 rather than MRGPRX2/b2 activated by micasin contributed to pruritus. The chimera and mutation of MRGPRX1 showed that three domains (ECL3, TMH3 and TMH6) and four hydrophobic residues (Y99, F237, L240 and W241) of MRGPRX1 played the key role in micasin-triggered MRGPRX1 activation. Our study sheds light on the dermatophytosis-associated pruritus and may provide potential therapeutic targets and strategies against pruritus caused by dermatophytes.

Radiomics in esophagogastric junction cancer: A scoping review of current status and advances.

PURPOSE: This scoping review aimed to understand the advances in radiomics in esophagogastric junction (EGJ) cancer and assess the current status of radiomics in EGJ cancer. METHODS: We conducted systematic searches of PubMed, Embase, and Web of Science databases from January 18, 2012, to January 15, 2023, to identify radiomics articles related to EGJ cancer. Two researchers independently screened the literature, extracted data, and assessed the quality of the studies using the Radiomics Quality Score (RQS) and the METhodological RadiomICs Score (METRICS) tool, respectively. RESULTS: A total of 120 articles were retrieved from the three databases, and after screening, only six papers met the inclusion criteria. These studies investigated the role of radiomics in differentiating adenocarcinoma from squamous carcinoma, diagnosing T-stage, evaluating HER2 overexpression, predicting response to neoadjuvant therapy, and prognosis in EGJ cancer. The median score percentage of RQS was 34.7% (range from 22.2% to 38.9%). The median score percentage of METRICS was 71.2% (range from 58.2% to 84.9%). CONCLUSION: Although there is a considerable difference between the RQS and METRICS scores of the included literature, we believe that the research value of radiomics in EGJ cancer has been revealed. In the future, while actively exploring more diagnostic, prognostic, and biological correlation studies in EGJ cancer, greater emphasis should be placed on the standardization and clinical application of radiomics.

Berberine alleviates ovarian tissue damage in mice with hepatolenticular degeneration by suppressing ferroptosis and endoplasmic reticulum stress.

OBJECTIVE: Hepatolenticular degeneration (HLD) is an autosomal recessive disorder that manifests as multiorgan damage due to impaired copper (Cu) metabolism. Female patients with HLD often experience reproductive impairments. This study investigated the protective effect of berberine against ovarian damage in toxic-milk (TX) mice, a murine model for HLD. METHODS: Mice were categorized into control group, HLD TX group (HLD group), penicillamine (Cu chelator)-treated TX group and berberine-treated TX group. Body weight, ovary weight and the number of ovulated eggs were recorded. Follicular morphology and cellular ultrastructure were examined. Total iron, ferrous iron (Fe2+) and trivalent iron (Fe3+) levels, as well as malondialdehyde (MDA), glutathione (GSH) and oxidized glutathione (GSSG), were measured in the ovaries. Western blot analysis was used to analyze the expression of proteins related to ferroptosis and endoplasmic reticulum (ER) stress. RESULTS: Ovarian tissue damage was evident in the HLD group, with a significant increase in ferroptosis and ER stress compared to the control group. This damage was inhibited by treatment with penicillamine, a Cu chelator. Compared with the HLD group, berberine increased the number of ovulations, and improved ovarian morphology and ultrastructure. Further, we found that berberine reduced total iron, Fe2+, MDA and GSSG levels, elevated GSH levels, decreased the expression of the ferroptosis marker protein prostaglandin-endoperoxide synthase 2 (PTGS2), and increased glutathione peroxidase 4 (GPX4) expression. Furthermore, berberine inhibited the expression of ER stress-associated proteins mediated by the protein kinase RNA-like ER kinase (PERK) pathway. CONCLUSION: Ferroptosis and ER stress are involved in Cu-induced ovarian damage in TX mice. Berberine ameliorates ovarian damage in HLD TX mice by inhibiting ferroptosis and ER stress. Please cite this article as: Liu QZ, Han H, Fang XR, Wang LY, Zhao D, Yin MZ, Zhang N, Jiang PY, Ji ZH, Wu LM. Berberine alleviates ovarian tissue damage in mice with hepatolenticular degeneration by suppressing ferroptosis and endoplasmic reticulum stress. J Integr Med. 2024; Epub ahead of print.

Green infrastructure layout based on a dynamic operation feature of drainage systems.

Increasingly frequent urban floods strain the traditional grey infrastructure, overwhelming the capacity of drainage networks and causing challenges in managing stormwater. The heavy precipitation leads to flooding and damage to drainage systems. Consequently, efficient mitigation strategies for flooding have been researched deeply. Green infrastructure (GI) has proved to be effective in responding the increasing risk of flood and alleviate pressure on drainage systems. However, as the primary infrastructure of stormwater management, there is still a lack of attention to the dynamic operation feature of urban sewer systems during precipitation events. To fill this gap, we proposed a novel approach that integrates hydraulic characteristics and the topological structure of a sewer network system. This approach aims to identify influential nodes, which contribute to the connectivity of the sewer network amidst dynamic changes in inflow during precipitation events. Furthermore, we adopted rain barrels to serve as exemplars of GI, and 14 GI layout schemes are produced based on the different ranks of influential nodes. Implementing GI measures on both poorly performing and well-performing nodes can yield distinct benefits in mitigating node flooding. This approach provides a new perspective for stormwater management, establishing effective synergy between GI and the drainage system.

Long-term spatial distribution and implication of black and brown carbon in the Tibetan Plateau.

Black carbon (BC) and brown carbon (BrC) over the high-altitude Tibetan Plateau (TP) can significantly influence regional and global climate change as well as glacial melting. However, obtaining plateau-scale in situ observations is challenging due to its high altitude. By integrating reanalysis data with on-site measurements, the spatial distribution of BC and BrC can be accurately estimated using the random forest algorithm (RF). In our study, the on-site observations of BC and BrC were successively conducted at four sites from 2018 to 2021. Ground-level BC and BrC concentrations were then obtained at a spatial resolution of 0.25° × 0.25° for three periods (including Periods-1980, 2000, and 2020) using RF and multi-source data. The highest annual concentrations of BC (1363.9 ± 338.7 ng/m3) and BrC (372.1 ± 96.2 ng/m3) were observed during Period-2000. BC contributed a dominant proportion of carbonaceous aerosol, with concentrations 3-4 times higher than those of BrC across the three periods. The ratios of BrC to BC decreased from Period-1980 to Period-2020, indicating the increasing importance of BC over the TP. Spatial distributions of plateau-scale BC and BrC concentrations showed heightened levels in the southeastern TP, particularly during Period-2000. These findings significantly enhance our understanding of the spatio-temporal distribution of light-absorbing carbonaceous aerosol over the TP.

Self-Rolled-Up WSe2 One-Dimensional/Two-Dimensional Homojunctions: Enabling High-Performance Self-Powered Polarization-Sensitive Photodetectors.

Mixed-dimensional heterostructures integrate materials of diverse dimensions with unique electronic functionalities, providing a new platform for research in electron transport and optoelectronic detection. Here, we report a novel covalently bonded one-dimensional/two-dimensional (1D/2D) homojunction structure with robust junction contacts, which exhibits wide-spectrum (from the visible to near-infrared regions), self-driven photodetection, and polarization-sensitive photodetection capabilities. Benefiting from the ultralow dark current at zero bias voltage, the on/off ratio and detectivity of the device reach 1.5 × 103 and 3.24 × 109 Jones, respectively. Furthermore, the pronounced anisotropy of the WSe2 1D/2D homojunction is attributed to its low symmetry, enabling polarization-sensitive detection. In the absence of any external bias voltage, the device exhibits strong linear dichroism for wavelengths of 638 and 808 nm, with anisotropy ratios of 2.06 and 1.96, respectively. These results indicate that such mixed-dimensional structures can serve as attractive building blocks for novel optoelectronic detectors.

Erratum: Author correction to 'FGF4 protects the liver from immune-mediated injury by activating CaMKKß-PINK1 signal pathway to inhibit hepatocellular apoptosis' [Acta Pharm Sin B 14 (2024) 1605-1623].

[This corrects the article DOI: 10.1016/j.apsb.2023.12.012.].

Tau Protein Accumulation Trajectory-Based Brain Age Prediction in the Alzheimer's Disease Continuum.

Clinical cognitive advancement within the Alzheimer's disease (AD) continuum is intimately connected with sustained accumulation of tau protein pathology. The biological brain age and its gap show great potential for pathological risk and disease severity. In the present study, we applied multivariable linear support vector regression to train a normative brain age prediction model using tau brain images. We further assessed the predicted biological brain age and its gap for patients within the AD continuum. In the AD continuum, evaluated pathologic tau binding was found in the inferior temporal, parietal-temporal junction, precuneus/posterior cingulate, dorsal frontal, occipital, and inferior-medial temporal cortices. The biological brain age gaps of patients within the AD continuum were notably higher than those of the normal controls (p < 0.0001). Significant positive correlations were observed between the brain age gap and global tau protein accumulation levels for mild cognitive impairment (r = 0.726, p < 0.001), AD (r = 0.845, p < 0.001), and AD continuum (r = 0.797, p < 0.001). The pathologic tau-based age gap was significantly linked to neuropsychological scores. The proposed pathologic tau-based biological brain age model could track the tau protein accumulation trajectory of cognitive impairment and further provide a comprehensive quantification index for the tau accumulation risk.

Copper exposure induces inflammation and PANoptosis through the TLR4/NF-κB signaling pathway, leading to testicular damage and impaired spermatogenesis in Wilson disease.

Copper is a toxic heavy metal that causes various damage when it accumulates in the body beyond the physiological threshold. Wilson disease (WD) is an inherited disorder characterized by impaired copper metabolism. Reproductive damage in male patients with WD is gradually attracting attention. However, the underlying mechanisms of copper toxicity are unclear. In this study, we investigated the role of inflammation and PANoptosis in testicular damage and impaired spermatogenesis caused by copper deposition using the WD model toxic milk (TX) mice. Copper chelator-penicillamine and toll-like receptor 4 (TLR4) inhibitor-eritoran were used to intervene in TX mice in our animal experiment methods. Testis samples were collected from mice for further analysis. The results showed that the morphology and ultrastructure of the testis and epididymis in TX mice were damaged, and the sperm counts decreased significantly. The TLR4/nuclear factor kappa-B (NF-κB) signaling pathway was activated by copper deposition, which led to the upregulation of serum and testicular inflammatory factors in TX mice. Meanwhile, pyroptosis, apoptosis, and necroptosis were significant in the testis of TX mice. Both chelated copper or inhibited TLR4 expression markedly suppressed the TLR4/NF-κB signaling pathway, thereby reducing the expression of inflammatory factors. PANoptosis in the testis of TX mice was also reversed. Our study indicated that pathological copper exposure induces inflammation and PANoptosis through the TLR4/NF-κB signaling pathway, leading to toxic testicular damage and impaired spermatogenesis in WD.

Multifunctional Integrated Organic-Inorganic-Metal Hybrid Aerogel for Excellent Thermal Insulation and Electromagnetic Shielding Performance.

Vehicles operating in space need to withstand extreme thermal and electromagnetic environments in light of the burgeoning of space science and technology. It is imperatively desired to high insulation materials with lightweight and extensive mechanical properties. Herein, a boron-silica-tantalum ternary hybrid phenolic aerogel (BSiTa-PA) with exceptional thermal stability, extensive mechanical strength, low thermal conductivity (49.6 mW m-1 K-1), and heightened ablative resistance is prepared by an expeditious method. After extremely thermal erosion, the obtained carbon aerogel demonstrates noteworthy electromagnetic interference (EMI) shielding performance with an efficiency of 31.6 dB, accompanied by notable loading property with specific modulus of 272.8 kN·m kg-1. This novel design concept has laid the foundation for the development of insulation materials in more complex extreme environments.

Genome-Wide Analysis of MYB Gene Family in Chrysanthemum ×morifolium Provides Insights into Flower Color Regulation.

MYBs constitute the second largest transcription factor (TF) superfamily in flowering plants with substantial structural and functional diversity, which have been brought into focus because they affect flower colors by regulating anthocyanin biosynthesis. Up to now, the genomic data of several Chrysanthemum species have been released, which provides us with abundant genomic resources for revealing the evolution of the MYB gene family in Chrysanthemum species. In the present study, comparative analyses of the MYB gene family in six representative species, including C. lavandulifolium, C. seticuspe, C. ×morifolium, Helianthus annuus, Lactuca sativa, and Arabidopsis thaliana, were performed. A total of 1104 MYBs, which were classified into four subfamilies and 35 lineages, were identified in the three Chrysanthemum species (C. lavandulifolium, C. seticuspe, and C. ×morifolium). We found that whole-genome duplication and tandem duplication are the main duplication mechanisms that drove the occurrence of duplicates in CmMYBs (particularly in the R2R3-MYB subfamily) during the evolution of the cultivated chrysanthemums. Sequence structure and selective pressure analyses of the MYB gene family revealed that some of R2R3-MYBs were subjected to positive selection, which are mostly located on the distal telomere segments of the chromosomes and contain motifs 7 and 8. In addition, the gene expression analysis of CmMYBs in different organs and at various capitulum developmental stages of C. ×morifolium indicated that CmMYBS2, CmMYB96, and CmMYB109 might be the negative regulators for anthocyanin biosynthesis. Our results provide the phylogenetic context for research on the genetic and functional evolution of the MYB gene family in Chrysanthemum species and deepen our understanding of the regulatory mechanism of MYB TFs on the flower color of C. ×morifolium.

Characterization of tau propagation pattern and cascading hypometabolism from functional connectivity in Alzheimer's disease.

Tau pathology and its spatial propagation in Alzheimer's disease (AD) play crucial roles in the neurodegenerative cascade leading to dementia. However, the underlying mechanisms linking tau spreading to glucose metabolism remain elusive. To address this, we aimed to examine the association between pathologic tau aggregation, functional connectivity, and cascading glucose metabolism and further explore the underlying interplay mechanisms. In this prospective cohort study, we enrolled 79 participants with 18F-Florzolotau positron emission tomography (PET), 18F-fluorodeoxyglucose PET, resting-state functional, and anatomical magnetic resonance imaging (MRI) images in the hospital-based Shanghai Memory Study. We employed generalized linear regression and correlation analyses to assess the associations between Florzolotau accumulation, functional connectivity, and glucose metabolism in whole-brain and network-specific manners. Causal mediation analysis was used to evaluate whether functional connectivity mediates the association between pathologic tau and cascading glucose metabolism. We examined 22 normal controls and 57 patients with AD. In the AD group, functional connectivity was associated with Florzolotau covariance (ß = .837, r = 0.472, p < .001) and glucose covariance (ß = 1.01, r = 0.499, p < .001). Brain regions with higher tau accumulation tend to be connected to other regions with high tau accumulation through functional connectivity or metabolic connectivity. Mediation analyses further suggest that functional connectivity partially modulates the influence of tau accumulation on downstream glucose metabolism (mediation proportion: 49.9%). Pathologic tau may affect functionally connected neurons directly, triggering downstream glucose metabolism changes. This study sheds light on the intricate relationship between tau pathology, functional connectivity, and downstream glucose metabolism, providing critical insights into AD pathophysiology and potential therapeutic targets.

Cross-talk of Three Molecular Subtypes of Telomere Maintenance Defines Clinical Characteristics and Tumor Microenvironment in Gastric Cancer.

Background: Telomere maintenance takes part in the regulation of gastric cancer (GC) pathogenesis and is essential for patients' clinical features. Though the correlation between a single telomere maintenance-related gene and GC has previously been published, comprehensive exploration and systematic analysis remain to be studied. Our study is aimed at determining telomere maintenance-related molecular subtypes and examining their role in GC. Methods: By analyzing the transcriptome data, we identified three telomere maintenance-associated clusters (TMCs) with heterogeneity in clinical features and tumor microenvironment (TME). Then, we screened five prognostic telomere maintenance-related genes and established corresponding TM scores. Additionally, the expression level and biological function of tubulin beta 6 class V (TUBB6) were validated in GC tissues and cells. Results: TMC1 was correlated with EMT and TGF-beta pathway and predicted low tumor mutation burden (TMB) as well as bad prognostic outcomes. TMC3 was associated with cell cycle and DNA repair. In terms of TMB and overall survival, TMC3 exhibited opposite results against TMC1. Significant heterogeneity was observed between TMCs. TUBB6 was upregulated and could promote GC proliferation, migration, and invasion. Conclusion: Altogether, combining bioinformatics and functional experiments, we identified three molecular subtypes based on telomere maintenance-associated genes in GC, which could bring new ideas and novel biomarkers to the clinic.

Comparative transcriptomic analysis provides insights into the genetic networks regulating oil differential production in oil crops.

BACKGROUND: Plants differ more than threefold in seed oil contents (SOCs). Soybean (Glycine max), cotton (Gossypium hirsutum), rapeseed (Brassica napus), and sesame (Sesamum indicum) are four important oil crops with markedly different SOCs and fatty acid compositions. RESULTS: Compared to grain crops like maize and rice, expanded acyl-lipid metabolism genes and relatively higher expression levels of genes involved in seed oil synthesis (SOS) in the oil crops contributed to the oil accumulation in seeds. Here, we conducted comparative transcriptomics on oil crops with two different SOC materials. In common, DIHYDROLIPOAMIDE DEHYDROGENASE, STEAROYL-ACYL CARRIER PROTEIN DESATURASE, PHOSPHOLIPID:DIACYLGLYCEROL ACYLTRANSFERASE, and oil-body protein genes were both differentially expressed between the high- and low-oil materials of each crop. By comparing functional components of SOS networks, we found that the strong correlations between genes in "glycolysis/gluconeogenesis" and "fatty acid synthesis" were conserved in both grain and oil crops, with PYRUVATE KINASE being the common factor affecting starch and lipid accumulation. Network alignment also found a conserved clique among oil crops affecting seed oil accumulation, which has been validated in Arabidopsis. Differently, secondary and protein metabolism affected oil synthesis to different degrees in different crops, and high SOC was due to less competition of the same precursors. The comparison of Arabidopsis mutants and wild type showed that CINNAMYL ALCOHOL DEHYDROGENASE 9, the conserved regulator we identified, was a factor resulting in different relative contents of lignins to oil in seeds. The interconnection of lipids and proteins was common but in different ways among crops, which partly led to differential oil production. CONCLUSIONS: This study goes beyond the observations made in studies of individual species to provide new insights into which genes and networks may be fundamental to seed oil accumulation from a multispecies perspective.

Recent drug development of dorzagliatin, a new glucokinase activator, with the potential to treat Type 2 diabetes: A review study.

Type 2 diabetes mellitus (T2DM) is a complicated disease related to metabolism that results from resistance to insulin and sustained hyperglycemia. Traditional antidiabetic drugs cannot meet the demand of different diabetes patients for reaching the glycemic targets; thus, the identification of new antidiabetic drugs is urgently needed for the treatment of T2DM to enhance glycemic control and the prognosis of patients suffering from T2DM. Recently, glucokinase (GK) has attracted much attention and is considered to be an effective antidiabetic agent. Glucokinase activators (GKA) represented by dorzagliatin could activate GK and mimic its function that triggers a counter-regulatory response to blood glucose changes. Dorzagliatin has shown great potential for glycemic control in diabetic patients in a randomized, double-blind, placebo-controlled Phase 3 trial (SEED study) and had a favorable safety profile and was well tolerated (DAWN study). In the SEED study, dorzagliatin significantly reduced glycosylated hemoglobin (HbA1c) by 1.07% and postprandial blood glucose by 2.83 mol/L, showing the great potential of this drug to control blood glucose in diabetic patients, with good safety and good tolerance. An extension of the SEED study, the DREAM study, confirmed that dorzagliatin monotherapy significantly improved 24-h glucose variability and increased time in range (TIR) to 83.7% over 46 weeks. Finally, the clinical study of dorzagliatin combined with metformin (DAWN study) confirmed that dorzagliatin could significantly reduce HbA1c by 1.02% and postprandial blood glucose by 5.45 mol/L. The current review summarizes the development of GK and GKA, as well as the prospects, trends, applications, and shortcomings of these treatments, especially future directions of clinical studies of dorzagliatin.

The Tick Saliva Peptide HIDfsin2 TLR4-Dependently Inhibits the Tick-Borne Severe Fever with Thrombocytopenia Syndrome Virus in Mouse Macrophages.

Ticks transmit a variety of pathogens to their hosts by feeding on blood. The interactions and struggle between tick pathogens and hosts have evolved bilaterally. The components of tick saliva can directly or indirectly trigger host biological responses in a manner that promotes pathogen transmission; however, host cells continuously develop strategies to combat pathogen infection and transmission. Moreover, it is still unknown how host cells develop their defense strategies against tick-borne viruses during tick sucking. Here, we found that the tick saliva peptide HIDfsin2 enhanced the antiviral innate immunity of mouse macrophages by activating the Toll-like receptor 4 (TLR4) signaling pathway, thereby restricting tick-borne severe fever with thrombocytopenia syndrome virus (SFTSV) replication. HIDfsin2 was identified to interact with lipopolysaccharide (LPS), a ligand of TLR4, and then depolymerize LPS micelles into smaller particles, effectively enhancing the activation of the nuclear factor kappa-B (NF-κB) and type I interferon (IFN-I) signaling pathways, which are downstream of TLR4. Expectedly, TLR4 knockout completely eliminated the promotion effect of HIDfsin2 on NF-κB and type I interferon activation. Moreover, HIDfsin2 enhanced SFTSV replication in TLR4-knockout mouse macrophages, which is consistent with our recent report that HIDfsin2 hijacked p38 mitogen-activated protein kinase (MAPK) to promote the replication of tick-borne SFTSV in A549 and Huh7 cells (human cell lines) with low expression of TLR4. Together, these results provide new insights into the innate immune mechanism of host cells following tick bites. Our study also shows a rare molecular event relating to the mutual antagonism between tick-borne SFTSV and host cells mediated by the tick saliva peptide HIDfsin2 at the tick-host-virus interface.

Novel insights into intrinsic mechanisms of magnetic field on long-term performance of anaerobic ammonium oxidation process.

The performance of an anaerobic ammonium oxidation (anammox) reactor with the magnetic field of 40 mT was systematically investigated. The total nitrogen removal rate was enhanced by 16% compared with that of the control group. The enhancing mechanism was elucidated from the improved mass transfer efficiency, the complicated symbiotic interspecific relationship and the improved levels of functional genes. The magnetic field promoted formation of the loose anammox granular sludge and the homogeneous and well-connected porous structure to enhance the mass transfer. Consequently, Candidatus Brocadia predominated in the sludge with an increase in abundance of 13%. Network analysis showed that the positive interactions between Candidatus Brocadia and heterotrophic bacteria were strengthened, which established a more complicated stable microbial community. Moreover, the magnetic field increased the levels of hdh by 26% and hzs by 35% to promote the nitrogen metabolic process. These results provided novel insights into the magnetic field-enhanced anammox process.

The causal relationship between major depression disorder and thyroid diseases: A Mendelian randomization study and mediation analysis.

BACKGROUND: Studies have been conducted on the relationship between depression and thyroid diseases and function, its causal relationship remains unclear. METHODS: Using summary statistics of genome-wide association studies of European and East Asian ancestry, we conducted 2-sample bidirectional Mendelian randomization to estimate the association between MDD and thyroid function (European: normal range TSH, T4, T3, fT4, TPOAb levels and TPOAb-positives; East Asian: T4) and thyroid diseases (hypothyroidism, hyperthyroidism, and Hashimoto's thyroiditis), and used Mediation analysis to evaluate potential mediators (alcohol intake, antidepressant) of the association and calculate the mediated proportions. RESULTS: It was observed a significant causal association between MDD on hypothyroidism (P = 8.94 × 10-5), hyperthyroidism (P = 8.68 × 10-3), and hashimoto's thyroiditis (P = 3.97 × 10-5) among European ancestry, which was mediated by Alcohol intake (alcohol intake versus 10 years previously for hypothyroidism (P = 0.026), hashimoto's thyroiditis (P = 0.042), and alcohol intake frequency for hypothyroidism (P = 0.015)) and antidepressant (for hypothyroidism (P = 0.008), hashimoto's thyroiditis (P = 0.010)), but not among East Asian ancestry (PMDD-hypothyroidism = 0.016, but ß direction was different; PMDD-hyperthyroidism = 0.438; PMDD-hashimoto's thyroiditis = 0.496). There was no evidence for bidirectional causal association between thyroid function mentioned above and MDD among both ancestry (all P > 0.05). CONCLUSION: We importantly observed a significant causal association between MDD on risk of hypothyroidism, hyperthyroidism, and hashimoto's thyroiditis among European ancestry, and Alcohol intake and antidepressant as mediators for prevention of hypothyroidism, hashimoto's thyroiditis attributable to MDD.