Evaluation of serum Epstein-Barr virus envelope glycoproteins antibodies and their association with systemic autoimmune diseases.

Systemic autoimmune diseases (SADs) are a growing spectrum of autoimmune disorders that commonly affect multiple organs. The role of Epstein-Barr virus (EBV) infection or reactivation as a trigger for the initiation and progression of SADs has been established, while the relationship between EBV envelope glycoproteins and SADs remains unclear. Here, we assessed the levels of IgG, IgA, and IgM against EBV glycoproteins (including gp350, gp42, gHgL, and gB) in serum samples obtained from patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), and found that RA and SLE patients exhibited a statistically significant increase in the levels of 8 and 11 glycoprotein antibodies, respectively, compared to healthy controls (p < 0.05). The LASSO model identified four factors as significant diagnostic markers for RA: gp350 IgG, gp350 IgA, gHgL IgM, and gp42 IgA; whereas for SLE it included gp350 IgG, gp350 IgA, gHgL IgA, and gp42 IgM. Combining these selected biomarkers yielded an area under the curve (AUC) of 0.749 for RA and 0.843 for SLE. We subsequently quantified the levels of autoantibodies associated with SADs in mouse sera following immunization with gp350. Remarkably, none of the tested autoantibody levels exhibited statistically significant alterations. Elevation of glycoprotein antibody concentration suggests that Epstein-Barr virus reactivation and replication occurred in SADs patients, potentially serving as a promising biomarker for diagnosing SADs. Moreover, the absence of cross-reactivity between gp350 antibodies and SADs-associated autoantigens indicates the safety profile of a vaccine based on gp350 antigen.

Surface Engineering and Programmed Self-Assembly of Silica Nanoparticles with Controllable Polystyrene/Poly(4-vinybenzyl azide) Patches.

The programmed self-assembly of patchy nanoparticles (NPs) through a bottom-up approach is an efficient strategy for producing highly organized materials with a predetermined architecture. Herein, we report the preparation of di- and trivalent silica NPs with polystyrene (PS)/poly(4-vinylbenzyl azide) (PVBA) patches and assemble them in a THF mixture by lowering the solvent quality. Silica-PS/PVBA colloidal hybrid clusters were synthesized through the seeded growth emulsion copolymerization of styrene and 4-vinylbenzyl azide (VBA) in varying ratios. Subsequently, macromolecules on silica NPs originating from the copolymerization of growing PS or PVBA chains with the surface-grafted MMS compatibilizer are engineered by fine-tuning of polymer compositions or adjustment of solvent qualities. Moreover, multistage silica regrowth of tripod and tetrapod allowed a fine control of the patch-to-particle size ratio ranging from 0.69 to 1.54. Intriguingly, patchy silica NPs (1-, 2-, 3-PSNs) rather than hybrid clusters are successfully used as templates for multistep regrowth experiments, leading to the formation of silica NPs with a new morphology and size controllable PVBA/PS patches. Last but not least, combined with mesoscale dynamics simulations, the self-assembly kinetics of 2-PSN and 3-PSN into linear colloidal polymers and honeycomb-like lattices are studied. This work paves a new avenue for constructing colloidal polymers with a well-defined sequence and colloidal crystals with a predetermined architecture.

Hepatic kynurenic acid mediates phosphorylation of Nogo-A in the medial prefrontal cortex to regulate chronic stress-induced anxiety-like behaviors in mice.

Exercise training effectively relieves anxiety disorders via modulating specific brain networks. The role of post-translational modification of proteins in this process, however, has been underappreciated. Here we performed a mouse study in which chronic restraint stress-induced anxiety-like behaviors can be attenuated by 14-day persistent treadmill exercise, in association with dramatic changes of protein phosphorylation patterns in the medial prefrontal cortex (mPFC). In particular, exercise was proposed to modulate the phosphorylation of Nogo-A protein, which drives the ras homolog family member A (RhoA)/ Rho-associated coiled-coil-containing protein kinases 1(ROCK1) signaling cascade. Further mechanistic studies found that liver-derived kynurenic acid (KYNA) can affect the kynurenine metabolism within the mPFC, to modulate this RhoA/ROCK1 pathway for conferring stress resilience. In sum, we proposed that circulating KYNA might mediate stress-induced anxiety-like behaviors via protein phosphorylation modification within the mPFC, and these findings shed more insights for the liver-brain communications in responding to both stress and physical exercise.

A Benzothiadiazole-Based Zn(II) Metal-Organic Framework with Visual Turn-On Sensing for Anthrax Biomarker and Theoretical Calculation.

2,6-pyridine dicarboxylic acid (DPA) is an exceptional biomarker of notorious anthrax spores. Therefore, the rapid, sensitive, and selective quantitative detection of DPA is extremely significant and urgent. This paper reports a Zn(II) metal-organic framework with the formula of {[Zn6(NDA)6(DPBT)3] 2H2O·3DMF}n (MOF-1), which consists of 2,6-naphthalenedicarboxylic acid (2,6-NDA), 4,7-di(4-pyridyl)-2,1,3-benzothiadiazole (DPBT), and Zn(II) ions. Structural analysis indicated that MOF-1 is a three-dimensional (3D) network which crystallized in the monoclinic system with the C2/c space group, revealing high pH, solvent, and thermal stability. Luminescence sensing studies demonstrated that MOF-1 had the potential to be a highly selective, sensitive, and recyclable fluorescence sensor for the identification of DPA. Furthermore, fluorescent test paper was made to detect DPA promptly with color changes. The enhancement mechanism was established by the hydrogen-bonding interaction and photoinduced electron transfer transition between MOF-1 and DPA molecules.

Design, Synthesis, Application and Research Progress of Fluorescent Probes.

Fluorescent probes are sensitive, selective, nontoxic in detection and thus provided a new solution in biomedical, environmental monitoring, and food safety. In order to expand the application of fluorescent probes in various fields, the paper discusses the design, synthesis, and characterization of fluorescent probes, explores new design and development trends of fluorescent probes in various fields, and improves the performance and applicability of fluorescent probes by using new materials and technologies to meet the evolving demands of molecular detection in various fields.

Natural Enfumafungin Analogues from Hormonema carpetanum and Their Antifungal Activities.

Ibrexafungerp, an inhibitor of fungal ß-(1,3)-d-glucan synthase, represents the first new class of antifungals to be approved in the last 20 years. Ibrexafungerp is a semisynthetic derivative of the naturally occurring triterpene glycoside enfumafungin. In order to search for new analogues of enfumafungin and to probe its biosynthesis, we undertook a reinvestigation of Hormonema carpetanum, which led to the isolation of two new analogues, enfumafungins B and C, together with enfumafungin. Due to the presence of a hemiacetal moiety in the structure, the enfumafungins appear as a mixture of two interconverting epimers during both the purification process and NMR data acquisition. The structure elucidation, including the differentiation of 25S* and 25R* epimers, was completed by combined analyses of NMR and MS spectroscopic data. The discovery of enfumafungins B and C may have implications for enfumafungin biosynthesis. The antifungal activity of enfumafungins B and C was significantly lower than that of enfumafungin, suggesting that the C-2 substituents and the C-19 carboxy acid are important for activity. Molecular docking simulations revealed significant hydrogen bond interactions between enfumafungins and ß-(1,3)-d-glucan synthase, which may be useful for developing new antifungal agents.

Discovery of novel triazoles containing benzyloxy phenyl isoxazole side chain with potent and broad-spectrum antifungal activity.

As a continuation study, 29 novel triazoles containing benzyloxy phenyl isoxazole side chain were designed and synthesized based on our previous work. The majority of the compounds exhibited high potency in vitro antifungal activities against eight pathogenic fungi. The most active compounds 13, 20 and 27 displayed outstanding antifungal activity with MIC values ranging from <0.008 µg/mL to 1 µg/mL, and showed potent activity against six drug-resistant Candida auris isolates. Growth curve assays further confirmed the high potency of these compounds. Moreover, compounds 13, 20 and 27 showed a potent inhibitory activity on biofilm formation of C. albicans SC5314 and C. neoformans H99. Notably, compound 13 showed no inhibition of human CYP1A2 and low inhibitory activity against CYP2D6 and CYP3A4, suggesting a low risk of drug-drug interactions. With high potency in vitro and in vivo and good safety profiles, compound 13 will be further investigated as a promising candidate.

Novel biosynthesis of gold nanoparticles for multifunctional applications: Electrochemical detection of hydrazine and treatment of gastric cancer.

In this work, an environmentally friendly strategy was used to synthesize gold nanoparticles (Au NPs) using Olea europaea (olive) fruit. Transmission electron microscopy (TEM), UV-Vis spectroscopy, X-ray diffraction (XRD) and energy-dispersive X-ray (EDX) were used to characterize the physicochemical properties of the synthesized NPs. An Au NPs modified glassy carbon electrode was used to investigate the direct electrochemical oxidation of hydrazine. The suggested hydrazine sensor has good performance, such as a wide linear range (2.5-275 µM), low limit of detection (0.09 µM), notable selectivity and excellent reproducibility (RSD = 2.2%). The in-vitro cytotoxicity of three human cancer cell lines (KATOIII, NCI-N87, and SNU-16) was also explored with various concentrations of Au NPs prepared from olive fruit extract. Bio-synthesized Au NPs were found to have cytotoxic properties against gastric cancer in humans based on MTT assay protocol. The obtained results show that green synthesized Au NPs can be successfully employed in electrochemical sensing and cancer treatment applications.

Design, synthesis and in vitro biological studies of novel triazoles with potent and broad-spectrum antifungal activity.

A series of novel triazole derivatives containing aryl-propanamide side chains was designed and synthesised. In vitro antifungal activity studies demonstrated that most of the compounds inhibited the growth of six human pathogenic fungi. In particular, parts of phenyl-propionamide-containing compounds had excellent, broad-spectrum antifungal activity against Candida albicans SC5314, Cryptococcus neoformans 22-21, Candida glabrata 537 and Candida parapsilosis 22-20 with MIC values in the range of ≤0.125 µg/mL-4.0 µg/mL. In addition, compounds A1, A2, A6, A12 and A15 showed inhibitory activities against fluconazole-resistant Candida albicans and Candida auris. Preliminary structure-activity relationships (SARs) are also summarised. Moreover, GC-MS analysis demonstrated that A1, A3, and A9 interfered with the C. albicans ergosterol biosynthesis pathway by inhibiting Cyp51. Molecular docking studies elucidated the binding modes of A3 and A9 with Cyp51. These compounds with low haemolytic activity and favourable ADME/T properties are promising for the development of novel antifungal agents.

Design, Synthesis and Structure-Activity Relationship Studies of Nicotinamide Derivatives as Potent Antifungal Agents by Disrupting Cell Wall.

Fungal infections pose a serious challenge to human health due to the limited paucity of antifungal treatments. Starting as a hit compound screened from our compound library, a series of nicotinamide derivatives have been successfully synthesized via a facile one-step coupling reaction of aromatic carboxylic acid and amine. The synthesized compounds were evaluated for their antifungal activity against Candida albicans SC5314. Among the 37 nicotinamide derivatives screened, compound 16g was found to be the most active against C. albicans SC5314, with an MIC value of 0.25 µg/mL and without significant cytotoxicity. The rudimentary structure-activity relationships study revealed that the position of the amino and isopropyl groups of 16g was critical for its antifungal activity. In particular, compound 16g showed potent activity against six fluconazole-resistant C. albicans strains with MIC values ranging from 0.125-1 µg/mL and showed moderate activity against the other seven species of Candida, three strains of Cryptococcus neoformans, and three strains of Trichophyton. Furthermore, compound 16g showed fungicidal, anti-hyphal, and anti-biofilm activities in vitro, which were related to its ability to disrupt the cell wall of C. albicans. Taken together, 16g is a promising compound that is fungal-specific by targeting the cell wall and could be used as a lead compound for further investigation.

Exploration of Baicalein-Core Derivatives as Potent Antifungal Agents: SAR and Mechanism Insights.

Baicalein (BE), the major component of Scutellaria Baicalensis, exhibited potently antifungal activity against drug-resistant Candida albicans, and strong inhibition on biofilm formation. Therefore, a series of baicalein-core derivatives were designed and synthesized to find more potent compounds and investigate structure-activity relationship (SAR) and mode of action (MoA). Results demonstrate that A4 and B5 exert a more potent antifungal effect (MIC80 = 0.125 µg/mL) than BE (MIC80 = 4 µg/mL) when used in combination with fluconazole (FLC), while the MIC80 of FLC dropped from 128 µg/mL to 1 µg/mL. SAR analysis indicates that the presence of 5-OH is crucial for synergistic antifungal activities, while o-dihydroxyls and vic-trihydroxyls are an essential pharmacophore, whether they are located on the A ring or the B ring of flavonoids. The MoA demonstrated that these compounds exhibited potent antifungal effects by inhibiting hypha formation of C. albicans. However, sterol composition assay and enzymatic assay conducted in vitro indicated minimal impact of these compounds on sterol biosynthesis and Eno1. These findings were further confirmed by the results of the in-silico assay, which assessed the stability of the complexes. Moreover, the inhibition of hypha of this kind of compound could be attributed to their effect on the catalytic subunit of 1,3-ß-d-glucan synthase, 1,3-ß-d-glucan-UDP glucosyltransferase and glycosyl-phosphatidylinositol protein, rather than inhibiting ergosterol biosynthesis and Eno1 activity by Induced-Fit Docking and Molecular Dynamics Simulations. This study presents potential antifungal agents with synergistic effects that can effectively inhibit hypha formation. It also provides new insights into the MoA.

Passivation Effect of the Chlorinated Paraffin Added in the Cutting Fluid on the Surface Corrosion Resistance of the Stainless Steel.

Cutting fluids are the most effective method to lower the cutting temperature and decrease the cutting tool wear. At the same time, the cutting fluids influence the corrosion resistance property of the machined surface. In this study, chlorinated paraffin (CP), which is a common additive in the cutting fluid, was selected as the research objective to study its corrosion resistance property. The passivation effect of CP with different concentrations on the machined surface of stainless steel was studied. Electrochemical measurements and surface morphology investigation were used to characterize the passivation effect of CP with different concentrations. The test results showed that the corrosion resistance of stainless steel in the cutting fluid was enhanced with the increase in CP additive. This reason is that the charge transfer resistance increases and the corrosion current density decreases with the increase in CP additive. The X-ray photoelectron spectroscopy (XPS) results show that the proportion of metal oxides on the processed surface of the stainless steel sample was increased from 20.4% to 22.0%, 32.9%, 26.6%, and 31.1% after adding 1 mL, 2 mL, 4 mL and 6 mL CP in the cutting fluid with a total volume of 500 mL, respectively. The oxidation reaction between CP and the stainless steel sample resulted in an increase in metal oxides proportion, which prevented the stainless steel sample from corrosion in cutting fluid.

Physical exercise rescues cocaine-evoked synaptic deficits in motor cortex.

Drug exposure impairs cortical plasticity and motor learning, which underlies the reduced behavioral flexibility in drug addiction. Physical exercise has been used to prevent relapse in drug rehabilitation program. However, the potential benefits and molecular mechanisms of physical exercise on drug-evoked motor-cortical dysfunctions are unknown. Here we report that 1-week treadmill training restores cocaine-induced synaptic deficits, in the form of improved in vivo spine formation, synaptic transmission, and spontaneous activities of cortical pyramidal neurons, as well as motor-learning ability. The synaptic and behavioral benefits relied on de novo protein synthesis, which are directed by the activation of the mechanistic target of rapamycin (mTOR)-ribosomal protein S6 pathway. These findings establish synaptic functional restoration and mTOR signaling as the critical mechanism supporting physical exercise training in rehabilitating the addicted brain.

Visible-Light-Induced Difunctionalization of Alkenyl Ketones with α-Carbonyl Alkyl Bromide: Concomitant Installation of C-C Bonds.

The visible-light-promoted difunctionalization of alkenyl ketones has been developed for easy access of various tetralones, cyclopropane, or alkenyl migration compounds. With fac-[Ir(ppy)3] as the photocatalyst, alkenyl ketones captured the α-carbonyl alkyl radical and evolved through intramolecular cyclization and the elimination of a proton to give the difunctionalized products. This strategy is characterized by good yields, mild reaction conditions, and outstanding functional group tolerance.

iTRAQ-based proteomics revealed baicalein enhanced oxidative stress of Candida albicans by upregulating CPD2 expression.

Baicalein could inhibit the growth and biofilm formation of Candida albicans, the most common clinical fungal pathogen. However, the antifungal mechanism of baicalein has not been elucidated. In this study, isobaric tags for relative and absolute quantification (iTRAQ) was used to verify the mechanism of antifungal fluconazole and baicalein. A total of 58 common proteins were detected in cells treated with fluconazole. These proteins encompassed fluconazole-targeted sterol synthesis pathway, including Erg11p, Erg6p, Erg3p, Erg25p, Erg5p, Erg10p, and Ncp1p. Next, iTRAQ was applied to the comparison of baicalein-treated C. albicans proteins, which detected 16 common proteins. The putative NADH dehydrogenase Cpd2p and the ATP-binding cassette transporter Snq2p were the most upregulated proteins with the treatment of baicalein. Our results showed that CPD2 disruption elevated C. albicans resistance to baicalein significantly both in vitro and in vivo. Further in-depth studies revealed that CPD2 disruption reduced the activation of C. albicans metacaspase and partially restored the mitochondrial membrane potential reduction caused by the treatment of baicalein, which indicated that CPD2 was involved in the apoptosis induced by baicalein. Consistently, under the treatment of baicalein, CPD2Δ/Δ mutant produced lower reactive oxygen species that was critical in causing oxidative damage and apoptosis in C. albicans. These results indicated that baicalein could increase intracellular oxidative damage by upregulating the expression of Cpd2p so as to inhibit the growth of C. albicans, which provides new insights for investigating the antifungal target of baicalein.

In our study, isobaric tags for relative and absolute quantification (iTRAQ) was used to study the antifungal mechanisms of fluconazole and baicalein. Baicalein could enhance the oxidative stress of Candida albicans by upregulating CPD2 expression.

Proton-Conductive Polyoxometalate Architectures Constructed from Lanthanide-Incorporated Polyoxoniobate Cages.

Two new extended polyoxometalate (POM) architectures based on lanthanide-incorporated polyoxoniobate (Ln-incorporated PONb) cages, namely, H4[CuII(en)2]4{K4(H2O)2[CuII(en)2]5[CuII5(trz)2(en)4(OH)2][Dy2CuII2(en)2(CO3)3(H2O)2(OH)3][Dy(H2O)4][DyNb23O68(H2O)4]2}·60H2O (1, en = ethylenediamine) and H20[CuII(en)2]4{[CuII(en)2]4[Dy2(C2O4)(H2O)4]2[(Nb32(OH)4(H2O)3O89]2}·54H2O (2), have been successfully synthesized and structurally characterized, demonstrating a feasible strategy to develop functional POM materials. In addition, the proton conductivity and magnetic behaviors of both 1 and 2 were studied.

The stereoselective conversion of epimerized alkoxyl phosphine-borane to P,C, axial-stereogenic tertiary phosphine via cleavage of P-O bond.

The P-O bond of epimerized alkoxyl phosphine-borane was cleaved by naphthalene-lithium, to form two diastereomers of P-anions in a ratio of 86 : 14, which was then converted to secondary phosphine-borane via acidification, and to tertiary phosphines with alkyl halides with enhanced 96 : 4 dr. The isolated tertiary phosphine containing hydroxyl (in >99 : 1 dr) was converted to multi-stereogenic tertiary phosphines via O-alkylation with alkylene dihalides.

Design, synthesis, and in vitro evaluation of novel antifungal triazoles containing substituted 1,2,3-triazole-methoxyl side chains.

In order to develop new triazole derivatives, we optimized the lead compound a6 by structural modifications to obtain a series of (2R,3R)-3-((1-substituted-1H-1,2,3-triazol-4-yl) methoxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol, compounds 5-36. Most of the target compounds exhibited excellent in vitro antifungal activity against Candida albicans 10231 and Candida glabrata 537 with MIC ≤ 0.125 µg/mL. Of particular note, compounds 6, 22, 28, 30 and 36 were highly active against Candida neoformans 32609 with MIC ≤ 0.125 µg/mL and showed broad-spectrum antifungal activity including against fluconazole-resistant Candida auris 891. In addition, compounds 6 and 22 demonstrated inhibitory effects on filamentation in the azole-resistant C. albicans isolate. Moreover, compounds 6 and 22 were minimally toxic to HUVECs and possessed weak inhibitory effects on the human CYP3A4 and CYP2D6. SARs and docking study further indicated that ortho-substituted groups in the terminal phenyl ring can promote the compounds to improve their antifungal activity.

Molecular Studies of Relationships and Identifications Among Insects of the Subfamily Panchaetothripinae (Thysanoptera, Thripidae).

The Panchaetothripinae comprises 42 genera and 146 species of leaf-feeding thrips, some of which are horticultural pests. We examined representatives of the 18 genera that include most of these pests. For species delimitation, we used DNA barcoding to produce171 sequences for 40 morphospecies. Most species were found to be monophyletic, although cryptic diversity was evident in 8 presumptive species. A multilocus molecular phylogenetic assessment was based on one mitochondrial (COI) and three nuclear loci (EF-1α, ITS2, and 28S) from 132 specimens (18 genera and 33 species), representing all genera and ~82% of species in China. Maximum likelihood (ML) and Bayesian inference (BI) confirmed monophyly of each genus with strong support. Monophyly of tribes Panchaetothripini and Monilothripini were refuted, but the well supported tribe Tryphactothripini was confirmed. Rhipiphorothrips was recovered as a sister to the remainder of the genera of Panchaetothripinae combined. Both analyses revealed two major clades. Clade A comprised the majority of the genera, including tribe Tryphactothripini. Clade B included only four genera of which two, Helionothrips and Caliothrips, are particularly species rich. The relationships of some genera remain unresolved.

Application of the Mutant Libraries for Candida albicans Functional Genomics.

Candida albicans is a typical opportunistic pathogen in humans that causes serious health risks in clinical fungal infections. The construction of mutant libraries has made remarkable developments in the study of C. albicans molecular and cellular biology with the ongoing advancements of gene editing, which include the application of CRISPR-Cas9 and novel high-efficient transposon. Large-scale genetic screens and genome-wide functional analysis accelerated the investigation of new genetic regulatory mechanisms associated with the pathogenicity and resistance to environmental stress in C. albicans. More importantly, sensitivity screening based on C. albicans mutant libraries is critical for the target identification of novel antifungal compounds, which leads to the discovery of Sec7p, Tfp1p, Gwt1p, Gln4p, and Erg11p. This review summarizes the main types of C. albicans mutant libraries and interprets their applications in morphogenesis, biofilm formation, fungus-host interactions, antifungal drug resistance, and target identification.