Polyamine metabolism controls B-to-Z DNA transition to orchestrate DNA sensor cGAS activity.

Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) synthase (cGAS) is a universal double-stranded DNA (dsDNA) sensor that recognizes foreign and self-DNA in the cytoplasm and initiates innate immune responses and has been implicated in various infectious and non-infectious contexts. cGAS binds to the backbone of dsDNA and generates the second messenger, cGAMP, which activates the stimulator of interferon genes (STING). Here, we show that the endogenous polyamines spermine and spermidine attenuated cGAS activity and innate immune responses. Mechanistically, spermine and spermidine induced the transition of B-form DNA to Z-form DNA (Z-DNA), thereby decreasing its binding affinity with cGAS. Spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme in polyamine catabolism that decreases the cellular concentrations of spermine and spermidine, enhanced cGAS activation by inhibiting cellular Z-DNA accumulation; SAT1 deficiency promoted herpes simplex virus 1 (HSV-1) replication in vivo. The results indicate that spermine and spermidine induce dsDNA to adopt the Z-form conformation and that SAT1-mediated polyamine metabolism orchestrates cGAS activity.

Regulation of intestinal immunity and tissue repair by enteric glia.

Tissue maintenance and repair depend on the integrated activity of multiple cell types1. Whereas the contributions of epithelial2,3, immune4,5 and stromal cells6,7 in intestinal tissue integrity are well understood, the role of intrinsic neuroglia networks remains largely unknown. Here we uncover important roles of enteric glial cells (EGCs) in intestinal homeostasis, immunity and tissue repair. We demonstrate that infection of mice with Heligmosomoides polygyrus leads to enteric gliosis and the upregulation of an interferon gamma (IFNγ) gene signature. IFNγ-dependent gene modules were also induced in EGCs from patients with inflammatory bowel disease8. Single-cell transcriptomics analysis of the tunica muscularis showed that glia-specific abrogation of IFNγ signalling leads to tissue-wide activation of pro-inflammatory transcriptional programs. Furthermore, disruption of the IFNγ-EGC signalling axis enhanced the inflammatory and granulomatous response of the tunica muscularis to helminths. Mechanistically, we show that the upregulation of Cxcl10 is an early immediate response of EGCs to IFNγ signalling and provide evidence that this chemokine and the downstream amplification of IFNγ signalling in the tunica muscularis are required for a measured inflammatory response to helminths and resolution of the granulomatous pathology. Our study demonstrates that IFNγ signalling in enteric glia is central to intestinal homeostasis and reveals critical roles of the IFNγ-EGC-CXCL10 axis in immune response and tissue repair after infectious challenge.

Classical swine fever virus non-structural protein 5B hijacks host METTL14-mediated m6A modification to counteract host antiviral immune response.

Classical Swine Fever (CSF), caused by the Classical Swine Fever Virus (CSFV), inflicts significant economic losses on the global pig industry. A key factor in the challenge of eradicating this virus is its ability to evade the host's innate immune response, leading to persistent infections. In our study, we elucidate the molecular mechanism through which CSFV exploits m6A modifications to circumvent host immune surveillance, thus facilitating its proliferation. We initially discovered that m6A modifications were elevated both in vivo and in vitro upon CSFV infection, particularly noting an increase in the expression of the methyltransferase METTL14. CSFV non-structural protein 5B was found to hijack HRD1, the E3 ubiquitin ligase for METTL14, preventing METTL14 degradation. MeRIP-seq analysis further revealed that METTL14 specifically targeted and methylated TLRs, notably TLR4. METTL14-mediated regulation of TLR4 degradation, facilitated by YTHDF2, led to the accelerated mRNA decay of TLR4. Consequently, TLR4-mediated NF-κB signaling, a crucial component of the innate immune response, is suppressed by CSFV. Collectively, these data effectively highlight the viral evasion tactics, shedding light on potential antiviral strategies targeting METTL14 to curb CSFV infection.

Astaxanthin Inhibits STING Carbonylation and Enhances Antiviral Responses.

STING-mediated DNA sensing pathway plays a crucial role in the innate antiviral immune responses. Clarifying its regulatory mechanism and searching STING agonists has potential clinical implications. Although multiple STING agonists have been developed to target cancer, there are few for the treatment of infectious diseases. Astaxanthin, a natural and powerful antioxidant, serves many biological functions and as a potential candidate drug for many diseases. However, how astaxanthin combats viruses and whether astaxanthin regulates the cyclic GMP-AMP synthase-STING pathway remains unclear. In this study, we showed that astaxanthin markedly inhibited HSV-1-induced lipid peroxidation and inflammatory responses and enhanced the induction of type I IFN in C57BL/6J mice and mouse primary peritoneal macrophages. Mechanistically, astaxanthin inhibited HSV-1 infection and oxidative stress-induced STING carbonylation and consequently promoted STING translocation to the Golgi apparatus and oligomerization, which activated STING-dependent host defenses. Thus, our study reveals that astaxanthin displays a strong antiviral activity by targeting STING, suggesting that astaxanthin might be a promising STING agonist and a therapeutic target for viral infectious diseases.

The UAF1-USP1 Deubiquitinase Complex Stabilizes cGAS and Facilitates Antiviral Responses.

Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) detects cytoplasmic microbial DNA and self-DNA from genomic instability, initiates innate immunity, and plays fundamental roles in defense against viruses and the development of various diseases. The cellular cGAS level determines the magnitude of the response to DNA. However, the underlying mechanisms of the control of cGAS stability, especially its feedback regulation during viral infection, remain largely unknown. In this study, we show that viral infection induces the expression of the UAF1-USP1 deubiquitinase complex in primary peritoneal macrophages (PMs) of C57BL/6J mice. UAF1-USP interacts with cGAS, selectively cleaves its K48-linked polyubiquitination, and thus stabilizes its protein expression in PMs and HEK293T cells. Concordantly, the UAF1-USP1 deubiquitinase complex enhances cGAS-dependent type I IFN responses in PMs. Uaf1 deficiency and ML323 (a specific inhibitor of UAF1-USP1 deubiquitinase complex) attenuates cGAS-triggered antiviral responses and facilitates viral replication both in vitro and in vivo. Thus, our study uncovers a positive feedback mechanism of cGAS-dependent antiviral responses and suggests the UAF1-USP1 complex as a potential target for the treatment of diseases caused by aberrant cGAS activation.

Selenoprotein K enhances STING oligomerization to facilitate antiviral response.

Stimulator-of-interferon gene (STING) is a vital element of the innate immune system against DNA viruses. Optimal activation of STING is crucial for maintaining immune homeostasis and eliminating invading viruses, and the oligomerization of STING is an essential prerequisite for STING activation. However, the mechanism of cGAMP-induced STING oligomerization in ER remains unclear. Selenoproteins are crucial for various physiological processes. Here, we identified that the endoplasmic reticulum (ER)-located transmembrane selenoprotein K (SELENOK) was induced during virus infection and facilitated innate immune responses against herpes simplex virus-1 (HSV-1). Mechanistically, SELENOK interacts with STING in the ER and promotes STING oligomerization, which in turn promotes its translocation from the ER to the Golgi. Consequently, Selenok deficiency suppresses STING-dependent innate responses and facilitates viral replication in vivo. Thus, the control of STING activation by selenium-mediated SELENOK expression will be a priming therapeutic strategy for the treatment of STING-associated diseases.

Bioremediation of mercury-polluted soil and water by the plant symbiotic fungus Metarhizium robertsii.

Fungi are central to every terrestrial and many aquatic ecosystems, but the mechanisms underlying fungal tolerance to mercury, a global pollutant, remain unknown. Here, we show that the plant symbiotic fungus Metarhizium robertsii degrades methylmercury and reduces divalent mercury, decreasing mercury accumulation in plants and greatly increasing their growth in contaminated soils. M. robertsii does this by demethylating methylmercury via a methylmercury demethylase (MMD) and using a mercury ion reductase (MIR) to reduce divalent mercury to volatile elemental mercury. M. robertsii can also remove methylmercury and divalent mercury from fresh and sea water even in the absence of added nutrients. Overexpression of MMD and MIR significantly improved the ability of M. robertsii to bioremediate soil and water contaminated with methylmercury and divalent mercury. MIR homologs, and thereby divalent mercury tolerance, are widespread in fungi. In contrast, MMD homologs were patchily distributed among the few plant associates and soil fungi that were also able to demethylate methylmercury. Phylogenetic analysis suggests that fungi could have acquired methylmercury demethylase genes from bacteria via two independent horizontal gene transfer events. Heterologous expression of MMD in fungi that lack MMD homologs enabled them to demethylate methylmercury. Our work reveals the mechanisms underlying mercury tolerance in fungi, and may provide a cheap and environmentally friendly means of cleaning up mercury pollution.

The transcription factor MYC1 interacts with FIT to negatively regulate iron homeostasis in Arabidopsis thaliana.

Iron (Fe) is an indispensable trace mineral element for the normal growth of plants, and it is involved in different biological processes; Fe shortage in plants can induce chlorosis and yield loss. The objective of this research is to identify novel genes that participated in the regulation of Fe-deficiency stress in Arabidopsis thaliana. A basic helix-loop-helix (bHLH) transcription factor (MYC1) was identified to be interacting with the FER-LIKE IRON DEFICIENCY-INDUCED TRANSCRIPTION FACTOR (FIT) using a yeast-two-hybrid assay. Transcript-level analysis showed that there was a decrease in MYC1 expression in Arabidopsis to cope with Fe-deficiency stress. Functional deficiency of MYC1 in Arabidopsis leads to an increase in Fe-deficiency tolerance and Fe-accumulation, whereas MYC1-overexpressing plants have an enhanced sensitivity to Fe-deficiency stress. Additionally, MYC1 inhibited the formation of FIT and bHLH38/39 heterodimers, which suppressed the expressed level for Fe acquisition genes FRO2 and IRT1 during Fe-deficiency stress. These results showed that MYC1 functions as a negative modulator of the Fe-deficiency stress response by inhibiting the formation of FIT and bHLH38/39 heterodimers, thereby suppressing the binding of FIT and bHLH38/39 heterodimers to the promoters of FRO2 and IRT1 to modulate Fe intake during Fe-deficiency stress. Overall, the findings of this study elucidated the role of MYC1 in coping with Fe-deficiency stress, and provided potential targets for the developing of crop varieties resistant to Fe-deficiency stress.

A novel starch-active lytic polysaccharide monooxygenase discovered with bioinformatics screening and its application in textile desizing.

BACKGROUND: Lytic polysaccharide monooxygenases (LPMOs) catalyzing the oxidative cleavage of different types of polysaccharides have potential to be used in various industries. However, AA13 family LPMOs which specifically catalyze starch substrates have relatively less members than AA9 and AA10 families to limit their application range. Amylase has been used in enzymatic desizing treatment of cotton fabric for semicentury which urgently need for new assistant enzymes to improve reaction efficiency and reduce cost so as to promote their application in the textile industry. RESULTS: A total of 380 unannotated new genes which probably encode AA13 family LPMOs were discovered by the Hidden Markov model scanning in this study. Ten of them have been successfully heterologous overexpressed. AlLPMO13 with the highest activity has been purified and determined its optimum pH and temperature as pH 5.0 and 50 °C. It also showed various oxidative activities on different substrates (modified corn starch > amylose > amylopectin > corn starch). The results of enzymatic textile desizing application showed that the best combination of amylase (5 g/L), AlLPMO13 (5 mg/L), and H2O2 (3 g/L) made the desizing level and the capillary effects increased by 3 grades and more than 20%, respectively, compared with the results treated by only amylase. CONCLUSION: The Hidden Markov model constructed basing on 34 AA13 family LPMOs was proved to be a valid bioinformatics tool for discovering novel starch-active LPMOs. The novel enzyme AlLPMO13 has strong development potential in the enzymatic textile industry both concerning on economy and on application effect.

WRKY transcription factors modulate flowering time in four Arachis species: a bioinformatics analysis.

BACKGROUND: WRKY proteins are important transcription factors (TFs) in plants, involved in growth and development and responses to environmental changes. Although WRKY TFs have been studied at the genome level in Arachis genus, including oil crop and turfgrass, their regulatory networks in controlling flowering time remain unclear. The aim of this study was to predict the molecular mechanisms of WRKY TFs regulation flowering time in Arachis genus at the genome level using bioinformatics approaches. RESULTS: The flowering-time genes of Arachis genus were retrieved from the flowering-time gene database. The regulatory networks between WRKY TFs and downstream genes in Arachis genus were predicted using bioinformatics tools. The results showed that WRKY TFs were involved in aging, autonomous, circadian clock, hormone, photoperiod, sugar, temperature, and vernalization pathways to modulate flowering time in Arachis duranensis, Arachis ipaensis, Arachis monticola, and Arachis hypogaea cv. Tifrunner. The WRKY TF binding sites in homologous flowering-time genes exhibited asymmetric evolutionary pattern, indicating that the WRKY TFs interact with other transcription factors to modulate flowering time in the four Arachis species. Protein interaction network analysis showed that WRKY TFs interacted with FRUITFULL and APETALA2 to modulate flowering time in the four Arachis species. WRKY TFs implicated in regulating flowering time had low expression levels, whereas their interaction proteins had varying expression patterns in 22 tissues of A. hypogaea cv. Tifrunner. These results indicate that WRKY TFs exhibit antagonistic or synergistic interactions with the associated proteins. CONCLUSIONS: This study reveals complex regulatory networks through which WRKY TFs modulate flowering time in the four Arachis species using bioinformatics approaches.

The transcription factor bZIP44 cooperates with MYB10 and MYB72 to regulate the response of Arabidopsis thaliana to iron deficiency stress.

Nicotianamine (NA) plays a crucial role in transporting metal ions, including iron (Fe), in plants; therefore, NICOTIANAMINE SYNTHASE (NAS) genes, which control NA synthesis, are tightly regulated at the transcriptional level. However, the transcriptional regulatory mechanisms of NAS genes require further investigations. In this study, we determined the role of bZIP44 in mediating plant response to Fe deficiency stress by conducting transformation experiments and assays. bZIP44 positively regulated the response of Arabidopsis to Fe deficiency stress by interacting with MYB10 and MYB72 to enhance their abilities to bind at NAS2 and NAS4 promoters, thereby increasing NAS2 and NAS4 transcriptional levels and promote NA synthesis. In summary, the transcription activities of bZIP44, MYB10, and MYB72 were induced in response to Fe deficiency stress, which enhanced the interaction between bZIP44 and MYB10 or MYB72 proteins, synergistically activated the transcriptional activity of NAS2 and NAS4, promoted NA synthesis, and improved Fe transport, thereby enhancing plant tolerance to Fe deficiency stress.

Mechanism of Autocatalytic Reduction of CO2 over MgCO3 to High Value-Added Chemicals: A DFT & AIMD Study.

Calcination of MgCO3 is an important industrial reaction, but it causes significant and unfavorable CO2 production. Calcination in a reducing green hydrogen atmosphere can substantially reduce CO2 release and produce high value-added products such as CO or hydrocarbons, but the mechanism is still unclear. Here, the in situ transformation process of MgCO3 interacting with hydrogen and the specific formation mechanism of the high value-added products are thoroughly investigated based on reaction thermodynamic, ab initio molecular dynamics (AIMD) simulations, and density functional theory (DFT) calculations. The reaction thermodynamic parameters of MgCO3 coupled with hydrogen to produce CO or methane are calculated, revealing that increasing and decreasing the thermal reductive decomposition temperature favors the production of CO and methane, respectively. Kinetically, the energy barriers of each possible production pathway for the dominant products CO and methane are further calculated in conjunction with the AIMD simulation results of the transformation process. The results suggest that CO is produced via the MgO catalytic-carboxyl pathway (CO2*→ COOH*trans→ COOH*cis→ CO*→ CO), which is autocatalyzed by MgO derived from the thermal reductive decomposition of MgCO3. For the mechanism of methane formation, it prefers to be produced by the stepwise interaction of carbonates in the MgCO3 laminates with hydrogen adsorbed on their surfaces (direct conversion pathway: sur-O-CO → sur-O-HCO → sur-O-HCOH → sur-O-HC → sur-O-CH2 → sur-O-CH3 → sur-O + CH4*).

YTHDF3 Regulates the Degradation and Stability of m6A-Enriched Transcripts to Facilitate the Progression of Castration-Resistant Prostate Cancer.

RNA N6-methyladenosine (m6A) readers mediate cancer progression. However, the functional role and potential mechanisms of the m6A readers in prostate cancer tumorigenicity remain to be elucidated. In this study, we demonstrate that YTHDF3 expression is elevated in castration-resistant prostate cancer (CRPC) and positively correlated to high grade, bone metastasis and poor survival. YTHDF3 expression promoted CRPC cell proliferation, epithelial to mesenchymal transition (EMT) and tumour progression. Mechanistically, YTHDF3 promoted the RNA degradation of SPOP and NXK3.1 but stabilized RNA expressions of TWIST1 and SNAI2 dependent on m6A to facilitate cell proliferation and EMT. Additionally, YTHDF3 expression enhanced AKT activity via degrading SPOP in an m6A-dependent manner. Importantly, we found that melatonin can compete with m6A to occupy the m6A-binding cage of YTHDF3, leading to inhibition of YTHFD3 and its target expressions as well as CRPC tumour growth. Our findings uncover an essential role of YTHDF3 in the progression of CRPC and highlight the role of melatonin in anti-CRPC activity.

Relationships among anxiety, depression, and health-related quality of life in adult epilepsy: A network analysis.

OBJECTIVE: Comorbid depression and anxiety in patients with epilepsy (PWE) are common and frequently under-treated, thus, causing poor health-related quality of life (HRQoL). However, little is known regarding the interconnections between anxious/depressive symptoms and the dimensions of HRQoL. Therefore, we conducted a network analysis to explore these relationships in detail among Chinese adult PWE. METHODS: A cohort of adult PWE was consecutively recruited from the First Affiliated Hospital of Chongqing Medical University. HRQoL, depression, and anxiety were measured with Quality of Life in Epilepsy Inventory-31, Neurological Disorders Depression Inventory for Epilepsy, and Generalized Anxiety Disorder 7-Item Scale, respectively. A regularized partial correlation network was constructed to investigate the interconnections between symptoms of anxiety/depression and the dimensions of HRQoL. We calculated expected influence (EI) and bridge expected influence (BEI) values to identify the most influential nodes. RESULTS: A total of 396 PWE were enrolled in this study, 78.1% of whom had focal onset epilepsy. The prevalence of anxiety and depression was 30.3% and 28.8%, respectively. The symptoms "frustrated" and "uncontrollable worry" had the highest EI values, whereas "emotional well-being", "seizure worry", "difficulty finding pleasure", and "nervousness or anxiety" had the highest BEI values. CONCLUSION: This study provides new insights into the relationships among anxiety, depression, and HRQoL. Critical central symptoms and bridge symptoms identified in the network might help to quickly identify PWE comorbid anxiety and depression in busy outpatient settings, thereby enabling early intervention and enhancing quality of life.

Theoretical study on electrocatalytic carbon dioxide reduction over copper with copper-based layered double hydroxides.

The conversion of CO2 into valuable fuels and multi-carbon chemical substances by electrical energy is an effective strategy to solve environmental problems by using renewable energy sources. In this work, the density functional theory (DFT) method is used to reveal the electrocatalytic mechanism of CO2 reduction reaction (CO2RR) over the surface of CuAl-Cl-layered double hydroxides (LDHs) with Cu monoatoms (Cu@CuAl-Cl-LDH), Cu2 diatoms (Cu2@CuAl-Cl-LDH), orthotetrahedral Cu4 clusters (Td-Cu4@CuAl-Cl-LDH) and planar Cu4 clusters (Pl-Cu4@CuAl-Cl-LDH). The active sites, density of states, adsorption energy, charge density difference and free energy are calculated. The results show that CO2RR over all the above five catalysts can generate C2 products. Pl-Cu4@CuAl-Cl-LDH tends to generate C2H5OH, while the remaining four structures all tend to produce C2H4. Cuδ+ favors CO2RR, and Td-Cu4@CuAl-Cl-LDH with a larger positively charged area at the active site has the better electrocatalytic performance among the calculated systems with a maximum step height of 0.78 eV. The selectivity of the products C2H4 and C2H5OH depends on the dehydration of the intermediate *C2H2O to *C2H3O or *CCH; if the dehydration produces *CCH intermediate, the final product is C2H4, and if no dehydration occurs, C2H5OH is produced. This work provides theoretical information and guidance for further rational design of efficient CO2RR catalysts for energy saving and emission reduction.

AKR1C2 genetic variants mediate tobacco carcinogens metabolism involving bladder cancer susceptibility.

Tobacco carcinogens metabolism-related genes (TCMGs) could generate reactive metabolites of tobacco carcinogens, which subsequently contributed to multiple diseases. However, the association between genetic variants in TCMGs and bladder cancer susceptibility remains unclear. In this study, we derived TCMGs from metabolic pathways of polycyclic aromatic hydrocarbons and tobacco-specific nitrosamines, and then explored genetic associations between TCMGs and bladder cancer risk in two populations: a Chinese population of 580 cases and 1101 controls, and a European population of 5930 cases and 5468 controls, along with interaction and joint analyses. Expression patterns of TCMGs were sourced from Nanjing Bladder Cancer (NJBC) study and publicly available datasets. Among 43 TCMGs, we observed that rs7087341 T > A in AKR1C2 was associated with a reduced risk of bladder cancer in the Chinese population [odds ratio (OR) = 0.84, 95% confidence interval (CI) = 0.72-0.97, P = 1.86 × 10-2]. Notably, AKR1C2 rs7087341 showed an interaction effect with cigarette smoking on bladder cancer risk (Pinteraction = 5.04 × 10-3), with smokers carrying the T allele increasing the risk up to an OR of 3.96 (Ptrend < 0.001). Genetically, rs7087341 showed an allele-specific transcriptional regulation as located at DNA-sensitive regions of AKR1C2 highlighted by histone markers. Mechanistically, rs7087341 A allele decreased AKR1C2 expression, which was highly expressed in bladder tumors that enhanced metabolism of tobacco carcinogens, and thereby increased DNA adducts and reactive oxygen species formation during bladder tumorigenesis. These findings provided new insights into the genetic mechanisms underlying bladder cancer.

Evaluation of the in vitro human skin percutaneous absorption of ketoprofen in topical anhydrous and aqueous gels.

BACKGROUND: Ketoprofen is a nonsteroidal anti-inflammatory drug used for the treatment of acute and chronic pain associated with inflammatory conditions. This study aims to evaluate the in vitro percutaneous absorption of ketoprofen 10% formulated in proprietary anhydrous and aqueous gels using the Franz skin finite dose model. MATERIALS AND METHODS: The anhydrous gel was initially characterized for cytotoxicity using EpiDerm skin tissue model by cell proliferation assay and Western blot analysis. The Ultra Performance Liquid Chromatography method for measuring ketoprofen was validated and the stability of ketoprofen 10% in the anhydrous gel formulation was evaluated at 5°C and 25°C for 181 days. The percutaneous absorption of ketoprofen was determined using donated human skin. The tissue sections were mounted within Franz diffusion cells. A variable finite dose of each ketoprofen formulation in either anhydrous or aqueous gel was applied to the skin sections and receptor solutions were collected at various time points. RESULTS: Cell proliferation assay showed minimal cell death when EpiDerm skin tissue was exposed to the anhydrous gel for 24 h; the levels of protein markers of cell proliferation were not affected after 17-h exposure. Ketoprofen was stable in the anhydrous gel when stored at 5°C and 25°C. When compounded in the anhydrous and aqueous gels, ketoprofen had mean flux rate of 2.22 and 2.50 µg/cm2 /h, respectively, after 48 h. The drug was distributed to the epidermis and dermis sections of the skin. Both the anhydrous and aqueous gels facilitated the percutaneous absorption of ketoprofen without statistically significant differences. CONCLUSION: The anhydrous gel can be used as a base to facilitate the transdermal delivery of ketoprofen. Although the anhydrous and aqueous gels can deliver a similar amount of ketoprofen, the anhydrous gel (water activity below 0.6) allows for extended default beyond-use-date of compounding preparations.

A MYB4-MAN3-Mannose-MNB1 signaling cascade regulates cadmium tolerance in Arabidopsis.

Our previous studies showed that MAN3-mediated mannose plays an important role in plant responses to cadmium (Cd) stress. However, the underlying mechanisms and signaling pathways involved are poorly understood. In this study, we showed that an Arabidopsis MYB4-MAN3-Mannose-MNB1 signaling cascade is involved in the regulation of plant Cd tolerance. Loss-of-function of MNB1 (mannose-binding-lectin 1) led to decreased Cd accumulation and tolerance, whereas overexpression of MNB1 significantly enhanced Cd accumulation and tolerance. Consistently, expression of the genes involved in the GSH-dependent phytochelatin (PC) synthesis pathway (such as GSH1, GSH2, PCS1, and PCS2) was significantly reduced in the mnb1 mutants but markedly increased in the MNB1-OE lines in the absence or presence of Cd stress, which was positively correlated with Cd-activated PC synthesis. Moreover, we found that mannose is able to bind to the GNA-related domain of MNB1, and that mannose binding to the GNA-related domain of MNB1 is required for MAN3-mediated Cd tolerance in Arabidopsis. Further analysis showed that MYB4 directly binds to the promoter of MAN3 to positively regulate the transcript of MAN3 and thus Cd tolerance via the GSH-dependent PC synthesis pathway. Consistent with these findings, overexpression of MAN3 rescued the Cd-sensitive phenotype of the myb4 mutant but not the mnb1 mutant, whereas overexpression of MNB1 rescued the Cd-sensitive phenotype of the myb4 mutant. Taken together, our results provide compelling evidence that a MYB4-MAN3-Mannose-MNB1 signaling cascade regulates cadmium tolerance in Arabidopsis through the GSH-dependent PC synthesis pathway.

UPLC/Q-TOF-MS-based metabolomics and molecular docking analysis of Bifidobacterium adolescentis exposure to levofloxacin.

Antibiotic-associated diarrhea is a common adverse reaction caused by the widespread use of antibiotics. The decrease in probiotics is one of the reasons why antibiotics cause drug-induced diarrhea. However, few studies have addressed the intrinsic mechanism of antibiotics inhibiting probiotics. To investigate the underlying mechanism of levofloxacin against Bifidobacterium adolescentis, we used a metabolomics mass spectrometry-based approach and molecular docking analysis for a levofloxacin-induced B. adolescentis injury model. The results showed that levofloxacin reduced the survival rate of B. adolescentis and decreased the number of B. adolescentis. The untargeted metabolomics analysis identified 27 potential biomarkers, and many of these metabolites are involved in energy metabolism, amino acid metabolism and the lipid metabolism pathway. Molecular docking showed that levofloxacin can bind with aminoacyl-tRNA synthetase and lactic acid dehydrogenase. This result provides a novel insight into the mechanism of the adverse reactions of levofloxacin.

Altered temporal lobe connectivity is associated with psychotic symptoms in drug-naïve adolescent patients with first-episode schizophrenia.

Research on individuals with a younger onset age of schizophrenia is important for identifying neurobiological processes derived from the interaction of genes and the environment that lead to the manifestation of schizophrenia. Schizophrenia has long been recognized as a disorder of dysconnectivity, but it is largely unknown how brain connectivity changes are associated with psychotic symptoms. Twenty-one adolescent-onset schizophrenia (AOS) patients and 21 matched healthy controls (HCs) were recruited and underwent resting-state functional magnetic resonance imaging. Regional homogeneity (ReHo) was used to investigate local brain connectivity alterations in AOS. Regions with significant ReHo changes in patients were selected as "seeds" for further functional connectivity (FC) analysis and Granger causality analysis (GCA), and associations of the obtained functional brain measures with psychotic symptoms in patients with AOS were examined. Compared with HCs, AOS patients showed significantly increased ReHo in the right middle temporal gyrus (MTG), which was positively correlated with PANSS-positive scores, PSYRATS-delusion scores and auditory hallucination scores. With the MTG as the seed, lower connectivity with the bilateral postcentral gyrus (PCG) and higher connectivity with the right precuneus were observed in patients. The reduced FC between the right MTG and bilateral PCG was significantly and positively correlated with hallucination scores. GCA indicated decreased Granger causality from the right MTG to the left middle frontal gyrus (MFG) and from the right MFG to the right MTG in AOS patients, but such effects did not significantly associate with psychotic symptoms. Abnormalities in the connectivity within the MTG and its connectivity with other networks were identified and were significantly correlated with hallucination and delusion ratings. This region may be a key neural substrate of psychotic symptoms in AOS.