Human Neonatal Fc Receptor Is the Cellular Uncoating Receptor for Enterovirus B.

Enterovirus B (EV-B), a major proportion of the genus Enterovirus in the family Picornaviridae, is the causative agent of severe human infectious diseases. Although cellular receptors for coxsackievirus B in EV-B have been identified, receptors mediating virus entry, especially the uncoating process of echovirus and other EV-B remain obscure. Here, we found that human neonatal Fc receptor (FcRn) is the uncoating receptor for major EV-B. FcRn binds to the virus particles in the "canyon" through its FCGRT subunit. By obtaining multiple cryo-electron microscopy structures at different stages of virus entry at atomic or near-atomic resolution, we deciphered the underlying mechanisms of enterovirus attachment and uncoating. These structures revealed that different from the attachment receptor CD55, binding of FcRn to the virions induces efficient release of "pocket factor" under acidic conditions and initiates the conformational changes in viral particle, providing a structural basis for understanding the mechanisms of enterovirus entry.

Structures of the SARS-CoV-2 nucleocapsid and their perspectives for drug design.

COVID-19, caused by SARS-CoV-2, has resulted in severe and unprecedented economic and social disruptions in the world. Nucleocapsid (N) protein, which is the major structural component of the virion and is involved in viral replication, assembly and immune regulation, plays key roles in the viral life cycle. Here, we solved the crystal structures of the N- and C-terminal domains (N-NTD and N-CTD) of SARS-CoV-2 N protein, at 1.8 and 1.5 Å resolution, respectively. Both structures show conserved features from other CoV N proteins. The binding sites targeted by small molecules against HCoV-OC43 and MERS-CoV, which inhibit viral infection by blocking the RNA-binding activity or normal oligomerization of N protein, are relatively conserved in our structure, indicating N protein is a promising drug target. In addition, certain areas of N-NTD and N-CTD display distinct charge distribution patterns in SARS-CoV-2, which may alter the RNA-binding modes. The specific antigenic characteristics are critical for developing specific immune-based rapid diagnostic tests. Our structural information can aid in the discovery and development of antiviral inhibitors against SARS-CoV-2 in the future.

Two pairs of bioactive cyclohexene alkaloid enantiomers from the roots of Piper nigrum.

Two pairs of cyclohexene amide alkaloid enantiomers were obtained from the root of Piper nigrum. Their plane structures were established by NMR and HRESIMS spectra. The absolute configurations of 1a/1b and 2a/2b were determined by the comparison between the experimental and calculated electronic circular dichroism (ECD) spectra. All identified compounds were tested for inhibitory effects on acetylcholinesterase (AChE) in vitro. Notably, compounds 1b and 2b showed strong inhibitory effects on AChE and the interaction between proteins and compounds was discussed by molecular docking studies.

[pMBRT: Principles and Design of Advanced Proton Radiotherapy Techniques].

The development history of pMBRT, the biological role of minibeam, the mechanism of minibeam protection of tissues, the generation of minibeam (collimator method and magnetic focusing method), and the analysis of advantages and disadvantages of proton minibeam matrix arrays is introduced with advanced proton minibeam arrays (pMBRT). It is proposed that the combination of proton minibeam arrays and magnetic resonance fields can help to exploit the normal tissue protective function of pMBRT, and improve the precision of proton therapy.

[Proposal and Analysis of "Ternary" Model of Sensitization for Proton Therapy].

In order to improve the biological effect of proton therapy, the authors first propose a new method of boron-based proton-enhanced radiotherapy in a " ternary " radiotherapy mode, based on the existing sensitizing effect of proton radiotherapy: i.e, Boron-based mediators (11B and 10B) induce the proton-hydrogen-boron fusion reaction of the low-energy protons arriving at the Bragg peak region of the tumor target area (p+11B→3α) and thermal neutron capture (10B+n→7Li3+(0.84 MeV)+4He2+(1.47 MeV)+γ(0.477 MeV)), which release low-energy α-particles with high LETs to enhance the biological effect of proton dose in the target area, thus improve the clinical effect of proton therapy. Then, the advantages and disadvantages of the "ternary" model were analyzed from the theoretical basis and current research status, and finally, the "ternary" model is summarized and prospected.

Enhancement of TKI sensitivity in lung adenocarcinoma through m6A-dependent translational repression of Wnt signaling by circ-FBXW7.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) that specifically target mutational points in the EGFR gene have significantly reduced suffering and provided greater relief to patients with lung adenocarcinoma (LUAD). The third-generation EGFR-TKI, Osimertinib, has been successfully employed in clinical treatments to overcome resistance to both original and acquired T790M and L858R mutational points. Nevertheless, the issue of treatment failure response has emerged as an insurmountable problem. METHODS: By employing a combination of multiple and integrated approaches, we successfully identified a distinct population within the tumor group that plays a significant role in carcinogenesis, resistance, and recurrence. Our research suggests that addressing TKI resistance may involve targeting the renewal and repopulation of stem-like cells. To investigate the underlying mechanisms, we conducted RNA Microarray and m6A Epi-Transcriptomic Microarray analyses, followed by assessment of transcription factors. Additionally, we specifically designed a tag to detect the polypeptide circRNA-AA, and its expression was confirmed through m6A regulations. RESULTS: We initially identified unique molecular signatures present in cancer stem cells that contributed to poor therapeutic responses. Activation of the alternative Wnt pathway was found to sustain the renewal and resistant status of these cells. Through bioinformatics analysis and array studies, we observed a significant decrease in the expression of circFBXW7 in Osimertinib-resistant cell lines. Notably, the abnormal expression pattern of circFBXW7 determined the cellular response to Osimertinib. Functional investigations revealed that circFBXW7 inhibits the renewal of cancer stem cells and resensitizes both resistant LUAD cells and stem cells to Osimertinib. In terms of the underlying mechanism, we discovered that circFBXW7 can be translated into short polypeptides known as circFBXW7-185AA. These polypeptides interact with ß-catenin in an m6A-dependent manner. This interaction leads to reduced stability of ß-catenin by inducing subsequent ubiquitination, thereby suppressing the activation of canonical Wnt signaling. Additionally, we predicted that the m6A reader, YTHDF3, shares common binding sites with hsa-Let-7d-5p. Enforced expression of Let-7d post-transcriptionally decreases the levels of YTHDF3. The repression of Let-7d by Wnt signaling releases the stimulation of m6A modification by YTHDF3, promoting the translation of circFBXW7-185AA. This creates a positive feedback loop contributing to the cascade of cancer initiation and promotion. CONCLUSIONS: Our bench study, in vivo experiments, and clinical validation have unequivocally shown that circFBXW7 effectively inhibits the abilities of LUAD stem cells and reverses resistance to TKIs by modulating Wnt pathway functions through the action of circFBXW7-185AA on ß-catenin ubiquitination and inhibition. The regulatory role of circRNA in Osimertinib treatment has been rarely reported, and our findings reveal that this process operates under the influence of m6A modification. These results highlight the tremendous potential of this approach in enhancing therapeutic strategies and overcoming resistance to multiple TKI treatments.

Improved Interfacial Interactions of Dip Coatings by In Situ Introducing Silica to Enhance Corrosion Resistance and Metal Bonding Strength.

Corrosion is an irreversible phenomenon in nature that has been a major source of metal degradation. We herein provide a unique approach for embedding nanoparticles into epoxy resins via hydrogen bonding adsorption of in situ hydrophilic silica. Based on this adsorption action, a super-anticorrosive epoxy-based Teflon (MEP-PTFE) coating for usage on metals such as aluminum alloys was developed utilizing one-step dip coating, with promising engineering and public applications. It should be noted that the binding strength between the resultant MEP-PTFE coating and the substrate was 13.5 N. This coating had an impedance modulus of over 8 × 109 Ω·cm2 at 0.01 Hz and an impressive corrosion inhibition efficiency of 99.999%. The anticorrosion barrier from the diffusion control to the charge transfer control was revealed for the future good design of resin matrix coatings with excellent corrosion resistance.

The role of extreme high humidex in depression in chongqing, China: A time series-analysis.

As global climate change intensifies, people are paying increasing attention to the impact of temperature changes on adverse mental health outcomes, especially depression. While increasing attention has been paid to the effect of temperature, there is little research on the effect of humidity. We aimed to investigate the association between humidex, an index combining temperature and humidity to reflect perceived temperature, and outpatient visits for depression from 2014 to 2019 in Chongqing, the largest and one of the most hot and humid cities of China. We also aimed to further identify susceptible subgroups. A distributed lag non-linear model (DLNM) was used to explore the concentration-response relationship between humidex and depression outpatient visits. Hierarchical analysis was carried out by age and gender. A total of 155,436 visits for depression were collected from 2014 to 2019 (2191 days). We found that depression outpatient visits were significantly associated with extremely high humidex (≥40). The significant positive single-lag day effect existed at lag 0 (RR = 1.029, 95%CI: 1.000-1.059) to lag 2 (RR = 1.01, 95%CI: 1.004-1.028), and lag 12 (RR = 1.013, 95%CI: 1.002-1.024). The significant cumulative adverse effects lasted from lag 01 to lag 014. Hierarchical analyses showed that females and the elderly (≥60 years) appeared to be more susceptible to extremely high humidex. The attributable numbers (AN) and fraction (AF) of extremely high humidex on depression outpatients were 1709 and 1.10%, respectively. Extremely high humidex can potentially increase the risk of depression, especially in females and the elderly. More protective measures should be taken in vulnerable populations.

Lactate dehydrogenase inhibition synergizes with IL-21 to promote CD8+ T cell stemness and antitumor immunity.

Interleukin (IL)-2 and IL-21 dichotomously shape CD8+ T cell differentiation. IL-2 drives terminal differentiation, generating cells that are poorly effective against tumors, whereas IL-21 promotes stem cell memory T cells (TSCM) and antitumor responses. Here we investigated the role of metabolic programming in the developmental differences induced by these cytokines. IL-2 promoted effector-like metabolism and aerobic glycolysis, robustly inducing lactate dehydrogenase (LDH) and lactate production, whereas IL-21 maintained a metabolically quiescent state dependent on oxidative phosphorylation. LDH inhibition rewired IL-2-induced effects, promoting pyruvate entry into the tricarboxylic acid cycle and inhibiting terminal effector and exhaustion programs, including mRNA expression of members of the NR4A family of nuclear receptors, as well as Prdm1 and Xbp1 While deletion of Ldha prevented development of cells with antitumor effector function, transient LDH inhibition enhanced the generation of memory cells capable of triggering robust antitumor responses after adoptive transfer. LDH inhibition did not significantly affect IL-21-induced metabolism but caused major transcriptomic changes, including the suppression of IL-21-induced exhaustion markers LAG3, PD1, 2B4, and TIM3. LDH inhibition combined with IL-21 increased the formation of TSCM cells, resulting in more profound antitumor responses and prolonged host survival. These findings indicate a pivotal role for LDH in modulating cytokine-mediated T cell differentiation and underscore the therapeutic potential of transiently inhibiting LDH during adoptive T cell-based immunotherapy, with an unanticipated cooperative antitumor effect of LDH inhibition and IL-21.

A distributed-order fractional stochastic differential equation driven by Lévy noise: Existence, uniqueness, and a fast EM scheme.

In this paper, we consider a distributed-order fractional stochastic differential equation driven by Lévy noise. We, first, prove the existence and uniqueness of the solution. A Euler-Maruyama (EM) scheme is constructed for the equation, and its strong convergence order is shown to be min{1-α∗,0.5}, where α∗ depends upon the weight function. Besides, we present a fast EM method and also the error analysis of the fast scheme. In addition, several numerical experiments are carried out to substantiate the mathematical analysis.

Ratiometric fluorescent probe based on non-conjugated polymer dots for pH measurements in ordinary Portland cement-based materials.

An organic fluorescent probe, citric acid-1,3-Propanediamine-Rhodamine B (CPR) was synthesized to determine pH of ordinary Portland cement requiring only a small sample size (less than 500 µL cement leachate). The SEM, XRD, and FTIR investigations demonstrate that citric acid-1,3-Propanediamine are polymer dots with a fusiform structure. Ratio pH probe is constructed by rhodamine B with polymer dots, which exhibits a linear response in high alkaline range. A 6-fold increase in fluorescence intensity (455 nm) is achieved at pH from 12.00 to 13.25. Combined with measurements of the isothermal calorimeter, mineral composition, and microscopic morphology, variation of pH is used to evaluate the changes of components during hydration. Furthermore, CPR can be applied to measure pH of high-dose pulverized fuel ash blending systems, the non-pure cement with slightly lower alkalinity.

Salivary microbiome and metabolome analysis of severe early childhood caries.

BACKGROUND: Severe early childhood caries (SECC) is an inflammatory disease with complex pathology. Although changes in the oral microbiota and metabolic profile of patients with SECC have been identified, the salivary metabolites and the relationship between oral bacteria and biochemical metabolism remains unclear. We aimed to analyse alterations in the salivary microbiome and metabolome of children with SECC as well as their correlations. Accordingly, we aimed to explore potential salivary biomarkers in order to gain further insight into the pathophysiology of dental caries. METHODS: We collected 120 saliva samples from 30 children with SECC and 30 children without caries. The microbial community was identified through 16S ribosomal RNA (rRNA) gene high-throughput sequencing. Additionally, we conducted non-targeted metabolomic analysis through ultra-high-performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry to determine the relative metabolite levels and their correlation with the clinical caries status. RESULTS: There was a significant between-group difference in 8 phyla and 32 genera in the microbiome. Further, metabolomic and enrichment analyses revealed significantly altered 32 salivary metabolites in children with dental caries, which involved pathways such as amino acid metabolism, pyrimidine metabolism, purine metabolism, ATP-binding cassette transporters, and cyclic adenosine monophosphate signalling pathway. Moreover, four in vivo differential metabolites (2-benzylmalate, epinephrine, 2-formaminobenzoylacetate, and 3-Indoleacrylic acid) might be jointly applied as biomarkers (area under the curve = 0.734). Furthermore, the caries status was correlated with microorganisms and metabolites. Additionally, Spearman's correlation analysis of differential microorganisms and metabolites revealed that Veillonella, Staphylococcus, Neisseria, and Porphyromonas were closely associated with differential metabolites. CONCLUSION: This study identified different microbial communities and metabolic profiles in saliva, which may be closely related to caries status. Our findings could inform future strategies for personalized caries prevention, detection, and treatment.

Anisodamine Enhances Macrophage M2 Polarization through Suppressing G9a-Mediated Interferon Regulatory Factor 4 Silencing to Alleviate Lipopolysaccharide-Induced Acute Lung Injury.

Acute lung injury (ALI) is a serious inflammatory lung disease. Imbalances in the polarization of classically activated (M1) and alternatively activated (M2) macrophages are closely related to ALI. Anisodamine has a promising therapeutic effect for septic shock. Nevertheless, the role of anisodamine in progression of ALI remains to be investigated. Our results showed that anisodamine significantly reduced lung damage, myeloperoxidase (MPO) activity, lung wet/dry ratio, total cell number, and protein concentrations in bronchoalveolar lavage fluid and decreased interleukin (IL)-6 level and the levels of M1 phenotypic markers, whereas it increased IL-10 level and the levels of M2 phenotypic markers in mice with a nasal instillation of lipopolysaccharide (LPS). Bone marrow-derived macrophages (BMDMs) were stimulated or transfected with LPS plus anisodamine or LPS plus G9a short hairpin RNA. Anisodamine and downregulation of G9a both promoted BMDM M2 polarization caused by IL-4 treatment and inhibited M1 polarization resulting from LPS treatment. Chromatin immunoprecipitation assay revealed that anisodamine inhibited G9a-mediated methylation and expression suppression on interferon regulatory factory 4 (IRF4). Overexpression of G9a or silence of IRF4 reversed the improvement effect of anisodamine on lung tissue injury, evidenced by an increase of MPO activity and the restoration of LPS-induced alterations of M1 and M2 polarization. In conclusion, anisodamine protected against LPS-induced ALI, during which anisodamine suppressed the LPS-stimulated alterations of macrophage M1 and M2 polarization through inhibiting G9a-mediated methylation of IRF4, suggesting that anisodamine was a potential therapeutic drug to alleviate ALI. SIGNIFICANCE STATEMENT: Anisodamine treatment was able to attenuate lung injury and pulmonary edema caused by lipopolysaccharide (LPS) stimulation, and the specific mechanism was that anisodamine reversed the LPS-induced alterations of M1 and M2 polarization by inhibiting G9a-mediated methylation and expression suppression of interferon regulatory factor 4, which suggests that anisodamine has the potential to alleviate acute lung injury.

Fluorescent silicon nanoparticle-based quantitative hemin assay.

Hemin with functions such as oxygen carrying, oxygen storing, promoting redox, and performing electron transfer is important for the health of organisms. In this paper, green synthetic silicon nanoparticles (Si-NPs) were synthesized and used for free hemin detection in serum (a low limit of detection (LOD), 29.5 nM). The quenching mechanism was investigated by UV-vis absorption spectra, time-resolved luminescence decay curve, and circular dichroism (CD) spectra. It was confirmed that multiple redox centers of hemin led to intensified effective collision and increased the electron transfer rate, therefore enhancing the dynamic quenching, and it was undeniable that the inner filter effect (IFE) also played a role in the quenching.

Highly Oxidized Germacranolides from Elephantopus tomentosus and the Configurational Revision of Some Previously Reported Analogues.

Highly oxidized germacranolides are mainly found in the genus Elephantopus, contain a characteristic ten-membered molecular core that is highly flexible, and exhibit potential cytotoxic properties. However, their configurations were assigned ambiguously in previous reports due to spectroscopic observation of macrocyclic systems. Herein, 17 highly oxidized germacranolides, including 12 new germacranolides (1-12), were isolated from Elephantopus tomentosus. Their structures were characterized by spectroscopic data analysis combined with X-ray crystallography and ECD calculations, and it was possible to propose configurational revisions of five previously reported analogues (13-17). Cytotoxic activities for 1-17 against two hepatocellular carcinoma cell lines (HepG2 and Hep3B) were tested, and compounds 1-10 and 13-16 generated IC50 values of 2.2-9.8 µM. Furthermore, the observed cytotoxic activity of 1 was determined as being mediated by inducing the apoptosis of HepG2 and Hep3B cells via mitochondrial dysfunction.

Green rust (GR) and glucose oxidase (GOX) based Fenton-like reaction: Capacity of sustainable release, promoted conversion of glucose through GOX-iron and pH self-adjustment.

The Fenton reaction is regarded as highly efficient for the degradation of organic contaminants. However, the traditional Fenton reaction is still flawed in a narrow pH working range and low utilization efficiency of the reagents. Based on two striking features, a sustained release of H2O2 in-situ under the catalysis of glucose oxidase (GOX) and the rapid electron donation & transferability from green rust (GR), an adaptable biological Fenton-like system (GGGMFs) was established. The coupling roles of glucose, GOX and GR in the degradation of 3,4-dimethylaniline (3,4-DMA) and the types of reactive species were deduced by electron spin resonance (ESR), etc.. Results demonstrated that the suitable pH range of the system was optimized from acidic to circumneutral, which was favorable for practical application, owing to the heterogeneous formation of GR and the pH self-adjustable capacity of GOX-Glucose. Meanwhile, hydroxyl radical (·OH), superoxide radical (·O2-) and Fe (IV) were identified to be the main oxidizing reactive species. Taking different selectivity of the reactive species to certain pollutant functional groups into consideration, the degradation pathways of 3,4-DMA were proposed. Moreover, it was shown that GR not only acted as the activating substance of the Fenton-like reaction, but also enhanced the activity of GOX, resulting in the promotion of glucose conversion in GGGMFs. This study shed light on the enhancement mechanism consisting of two aspects: (i) the elimination of product inhibition (ii) the formation of a 2Fe(III)-FAD complex with FAD, the active center of GOX, which prompted the electronic transfer in the enzyme catalytic reaction.

Association between short-term ambient nitrogen dioxide and type 2 diabetes outpatient visits: A large hospital-based study.

Type 2 diabetes (T2DM) as a non-communicable disease imposes heavy disease burdens on society. Limited studies have been conducted to assess the effects of short-term air pollution exposure on T2DM, especially in Asian regions. Our research aimed to determine the association between short-term exposure to ambient nitrogen dioxide (NO2) and outpatient visits for T2DM in Chongqing, the largest city in western China, based on the data collected from November 28, 2013 to December 31, 2019. A generalized additive model (GAM) was applied, and stratified analyses were performed to investigate the potential modifying effects by age, gender, and season. Meanwhile, the disease burden was revealed from attributable risk. Positive associations between short-term NO2 and daily T2DM outpatient visits were observed. The strongest association was observed at lag 04, with per 10 µg/m3 increase of NO2 corresponded to increased T2DM outpatient visits at 1.57% [95% confidence interval (CI): 0.48%, 2.65%]. Stronger associations were presented in middle-aged group (35-64 years old), male group, and cool seasons (October to March). Moreover, there were 1.553% (8664.535 cases) of T2DM outpatient visits attributable to NO2. Middle-aged adults, males, and patients who visited in cool seasons suffered heavier burdens. Conclusively, short-term exposure to NO2 was associated with increased outpatient visits for T2DM. Attention should be paid to the impact of NO2 on the burden of T2DM, especially for those vulnerable groups.

YdiV regulates Escherichia coli ferric uptake by manipulating the DNA-binding ability of Fur in a SlyD-dependent manner.

Iron is essential for all bacteria. In most bacteria, intracellular iron homeostasis is tightly regulated by the ferric uptake regulator Fur. However, how Fur activates the iron-uptake system during iron deficiency is not fully elucidated. In this study, we found that YdiV, the flagella gene inhibitor, is involved in iron homeostasis in Escherichia coli. Iron deficiency triggers overexpression of YdiV. High levels of YdiV then transforms Fur into a novel form which does not bind DNA in a peptidyl-prolyl cis-trans isomerase SlyD dependent manner. Thus, the cooperation of YdiV, SlyD and Fur activates the gene expression of iron-uptake systems under conditions of iron deficiency. Bacterial invasion assays also demonstrated that both ydiV and slyD are necessary for the survival and growth of uropathogenic E. coli in bladder epithelial cells. This reveals a mechanism where YdiV not only represses flagella expression to make E. coli invisible to the host immune system, but it also promotes iron acquisition to help E. coli overcome host nutritional immunity.

LINC00891 regulated by miR-128-3p/GATA2 axis impedes lung cancer cell proliferation, invasion and EMT by inhibiting RhoA pathway.

Long non-coding RNA (lncRNA) LINC00891 knockdown is associated with poor prognosis of lung adenocarcinoma, but the underlying mechanism remains to be further explored. Here, we found that LINC00891 expression is downregulated in lung cancer tissues and cell lines compared with that in adjacent normal tissues and normal lung epithelial cells. LINC00891 overexpression impedes cell proliferation, invasion, migration and epithelial-to-mesenchymal transition (EMT) process in lung cancer cells. Mechanistic research showed that GATA2 directly binds to LINC00891 promoter and transcriptionally regulates LINC00891 expression. Meanwhile, GATA2 was identified as a target of miR-128-3p, and it is negatively regulated by miR-128-3p. Moreover, overexpression of GATA2 suppresses lung cancer cell proliferation, invasion, migration, and EMT process. Furthermore, LINC00891 restrains the RhoA pathway activity, and treatment with CCG-1423 (a specific RhoA pathway inhibitor) antagonizes the promoting effect of LINC00891 knockdown on cell malignant behaviors. Additionally, silencing of LINC00891 promotes xenograft tumor growth, which can be reversed by administration with CCG-1423. In summary, LINC00891 regulated by the miR-128-3p/GATA2 axis restrains lung cancer cell malignant progression and hinders xenograft tumor growth by suppressing the RhoA pathway.

Coumarins from Sarcandra glabra (Thunb.) Nakai and Acetylcholinesterase Inhibiting Activity.

Nine coumarins including a pair of new enantiomers (1a/1b) and seven known compounds (2-8) were isolated from Sarcandra glabra (Thunb.) Nakai. Among them, compounds 1a and 1b were naturally occurring coumarin-phenylpropanoid conjugate enantiomers. Their structures were identified by NMR and ECD calculations. Compounds 1-8 were tested for acetylcholinesterase (AchE) inhibiting activity. The results of the enzymology experiment showed that compound 3 demonstrated obvious AchE inhibitory activity which showed the IC50 value of 1.982±0.003 µM, and the binding sites were predicted by molecular docking.