Toxoplasma Gondii infection and cardiovascular mortality: sex-specific differences in a United States population-based cohort study.

BACKGROUND: Although Toxoplasma gondii (T. gondii) infection has been linked to cardiac injury, the extent to which it increases the risk of cardiovascular disease (CVD) mortality remains unclear. We aimed to assess the association between T. gondii infection and CVD mortality in the United States population. METHODS: This study used data from the National Health and Nutrition Examination Survey (NHANES) conducted between 2009 and 2014 to investigate the association between T. gondii infection and CVD mortality. The T. gondii infection status was determined by measuring serum T. gondii IgG antibody levels. CVD mortality outcomes were ascertained through linkage with the national mortality index records. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and the corresponding 95% confidence intervals (CIs) of T. gondii infection on CVD mortality. RESULTS: A total of 10,237 (Male, n = 5010; Female, n = 5227) individuals aged ≥ 20 years were included in the analysis, of which 1,632 were positive for T. gondii serum IgG antibodies. After a median follow-up of eight years, there were 312 deaths due to CVD. In multivariable-adjusted analyses, the risk of death from CVD was 40% higher in T. gondii-seropositive men compared with seronegative men (HR: 1.40; 95%CI: 1.02-1.93), but not in women (HR: 0.87; 95% CI: 0.57-1.34). These results remained consistent in further stratified and sensitivity analyses. CONCLUSION: In this large population-based cohort study, T. gondii infection was associated with an increased risk of CVD mortality in men, but not in women. Further studies are required to elucidate the underlying mechanisms and potential sex-specific differences in the effects of T. gondii infection on CVD mortality. Future investigations should focus on validating these results and exploring the potential implications for cardiovascular risk assessment and management.

Production of Polyhalogenated Carbazoles in Marine Red Alga Corallina officinalis: A Possible Natural Source.

Polyhalogenated carbazoles (PHCZs) have been increasingly detected in the environment as a result of anthropogenic and natural origin. However, it is unclear how PHCZs are naturally produced. In this study, the formation of PHCZs from bromoperoxidase (BPO)-mediated halogenation of carbazole was investigated. A total of six PHCZs were identified in reactions under different incubation conditions. The presence of Br- significantly influenced the formation of PHCZs. The products were first dominated by 3-bromocarbazole and then 3,6-dibromocarbazole as the reactions proceeded. Both bromo- and chlorocarbazoles were identified in the incubations with trace Br-, suggesting the co-occurrence of BPO-catalyzed bromination and chlorination. However, BPO-catalyzed chlorination of carbazole was much weaker than that of bromination. The formation of PHCZs could be attributable to the halogenation of carbazole by reactive halogen species generated from BPO-catalyzed oxidation of Br- and Cl- by H2O2. The halogenation was found to follow a successive substitution order of C-3, C-6, and C-1 on the carbazole ring, forming 3-, 3,6-, and 1,3,6-isomers. Similar to the incubation experiments, six PHCZs were for the first time detected in red algal samples collected from the South China Sea, China, suggesting the biogenesis of PHCZs in marine red algae. Given the widespread distribution of red algae in the marine environment, BPO-catalyzed halogenation of carbazole may be a natural origin for PHCZs.

Improvement of Seed Germination under Salt Stress via Overexpressing Caffeic Acid O-methyltransferase 1 (SlCOMT1) in Solanum lycopersicum L.

Melatonin (MT) is a phytohormone-like substance and is profoundly involved in modulating nearly all aspects of plant development and acclimation to environmental stressors. However, there remain no studies about the effects of MT on tomato seed germination under salt stress. Here we reported that the overexpression of caffeic acid O-methyltransferase 1 (SlCOMT1) significantly increased both MT content and salt tolerance in the germinated seeds of a transgenic tomato relative to wild type (WT) samples. Physiological investigation showed higher amylase activity in the stressed overexpression seeds than WT, leading to the promoted starch decomposition and enhanced soluble sugar content. The stimulated production of osmolytes and enhanced activities of SOD, POD, and CAT, together with the significant reduction in H2O2 and O2·- accumulation, were revealed in the stressed overexpression seeds relative to WT, largely accounting for their lower membrane lipid peroxidation. qPCR assay showed that, upon salt stress, the transcript abundance of hub genes related to germination (SlCYP707A1, SlABA1, SlGA3ox2 and SlGA2ox4) and stress tolerance (SlCDPK1, SlWRKY33 and SlMAPK1) were distinctly altered in the overexpression samples when compared to WT, providing a molecular basis for MT-mediated improvement of seed salt tolerance. Altogether, our observations shed new insights into biological functions of SlCOMT1 and could expand its utilization in genetic improvement of tomato salt tolerance in future.

Revealing the Mechanisms for Linalool Antifungal Activity against Fusarium oxysporum and Its Efficient Control of Fusarium Wilt in Tomato Plants.

Fusarium oxysporum f. sp. radicis-lycopersici (Forl) is a destructive soil-borne phytopathogenic fungus that causes Fusarium crown and root rot (FCRR) of tomato, leading to considerable field yield losses. In this study, we explored the antifungal capability of linalool, a natural plant volatile organic component, against Forl and its role in controlling FCRR symptoms in tomatoes. Our results showed that Forl mycelial growth was inhibited by the linalool treatment and that the linalool treatment damaged cell membrane integrity, enhanced reactive oxygen species levels, depleted glutathione, and reduced the activities of many antioxidant enzymes in Forl. Transcriptomic and proteomic analyses demonstrated that linalool also downregulated metabolic biosynthetic pathways at the transcript and protein levels, including redox, transporter activity, and carbohydrate metabolism in Forl. Moreover, linalool significantly decreased the expression of many Forl pathogenic genes, such as cell wall degrading enzymes (CWDEs) and G proteins, which is likely how a Forl infection was prevented. Importantly, exogenously applied linalool activated the salicylic acid (SA) and jasmonic acid (JA) defensive pathways to improve disease resistance and relieved the negative effects of Forl on plant growth. Taken together, we report that linalool is an effective fungicide against Forl and will be a promising green chemical agent for controlling FCRR.

Evaluation about wettability, water absorption or swelling of excipients through various methods and the correlation between these parameters and tablet disintegration.

OBJECTIVE: To evaluate parameters about wettability, water absorption or swelling of excipients in forms of powders or dosage through various methods systematically and explore its correlation with tablet disintegration. MATERIAL AND METHODS: The water penetration and swelling of powders with different proportions of excipients including microcrystalline cellulose (MCC), mannitol, low-substituted hydroxypropyl cellulose (L-HPC), crospolyvinylpyrrolidone (PVPP), carboxymethyl starch sodium (CMS-Na), croscarmellose sodium (CCMC-Na) and magnesium stearate (MgSt) were determined by Washburn capillary rise. Both contact angle of water on the excipient compacts and surface swelling volume were measured by sessile drop technique. Moreover, the test about water absorption and swelling of compacts was fulfilled by a modified method. Eventually, the disintegration of tablets with or without loratadine was performed according to the method described in USP. RESULTS AND DISCUSSION: These parameters were successfully identified by the methods above, which proved that excipient wettability or swelling properties varied with the structure of excipients. For example, MgSt could improve the water uptake, while impeded tablet swelling. Furthermore, in the present study it is verified that tablet disintegration was closely related to these parameters, especially wetting rate and initial water absorption rate. The higher wetting rate of water on tablet or initial water absorption rate, the faster swelling it be, resulting in the shorter tablet disintegration time. CONCLUSION: The methods utilized in the present study were feasible and effective. The disintegration of tablets did relate to these parameters, especially wetting rate and initial water absorption rate.

Titanium cis-1,2-diaminocyclohexane (cis-DACH) salalen catalysts for the asymmetric epoxidation of terminal non-conjugated olefins with hydrogen peroxide.

Chiral Ti salalen complexes catalyze the asymmetric epoxidation of terminal non-conjugated olefins with hydrogen peroxide. Modular ligands based on cis-1,2-diamino-cyclohexane (cis-DACH) were developed, giving high yields and enantiomeric excesses (ee, up to 96 %) at catalyst loadings as low as 0.1-0.5 mol %, and even under solvent-free conditions.

Biological artificial fluid-induced non-lamellar phases in glyceryl monooleate: the kinetics pathway and its digestive process by bile salts.

BACKGROUND: The cubic (Q(II)) phase is a promising sustained-release system. However, its rigid gel-like propensity is highly viscous, which makes it difficult to handle in pharmaceutical applications. To circumvent this problem, a less viscous lamellar (L(α)) phase that could spontaneously transform to Q(II) phase by the introduction of water or biological artificial fluid can be used. However, the kinetics pathway of phase transition, susceptibility to digestive processes and impact of the transition on drug release are not yet well understood. METHOD: We investigated various biological artificial fluid-induced L(α) to inverse Q(II) phase transition over time in glyceryl monooleate (GMO) by water penetration scan and light polarizing microscopy. To reveal the structure stability, fluorescence spectroscopy studies were conducted using pyrene as a probe. Furthermore, the release mechanism of pyrene as a lipophilic drug model in the spontaneously formed Q(II) was investigated. RESULT: Although hexagonal (H(II)) mesophases occurred when phosphate buffered saline (PBS) 7.4, 0.1 M HCl or sodium taurocholate (NaTC) solutions were introduced to GMO at room temperature, they disappear with the exception of 0.1 M HCl at 37 °C. Compared with 25 °C, L(α) to Q(II) phase transition was in a faster rate as almost completely transforms were observed after 2 h post-immersion. The spontaneously formed mesophases were stable over 24 h immersions in PBS or pancreatic lipase solutions as proven by the extremely low fluorescence signal, however they were digestible by bile salts. This result indicated that digestion by bile salts was the major pathway instead of digestion by lipases. Moreover, pyrene fluorescence spectroscopy confirmed that the digestion by bile salts induced the formation of GMO-bile salt mixed micelles whose performance depended on the bile salt concentrations. This dependence influenced the drug release from the spontaneously formed Q(II) phase. CONCLUSION: All the results concluded that temperature, pH and ionic strength tendencies for the formation of non-lamellar structures greatly influenced the self-assembly process, thereby affecting the final mesophase structure. The results of this study are important to understand the lamellar to non-lamellar lipid-phase transitions and their possible pharmaceutical applications.

[The rheology properties of common hydrophilic gel excipients].

To investigate theological properties of common hydrophilic gel excipients such as Carbopol based on viscosity, the viscosity was determined by rotation method and falling-ball method. Linear regression was made between ln(eta) and concentration, the slope of which was used to explore the relation between viscosity and concentration of different excipients. The viscosity flow active energy (E(eta)) was calculated according to Arrhenius equation and was used to investigate the relation between viscosity and temperature of different excipients. The results showed that viscosities measured by two methods were consistent. Concentration of guargum (GG) and hydroxypropylmethyl cellulose (HPMC) solution had a great influence on the viscosity, k > 5; while concentration of polyvinylpyrrolidone-K30 (PVP-K30) and polyethylene glycol 6000 (PEG6000) exerted a less effect on viscosity, k < 0.2; viscosity flow active energy of different excipients were close, which ranged from 30 to 40 kJ x mol(-1). Therefore, theological properties study could provide the basis for application of excipients and establish a foundation for the research of relation between excipients structure, property and function.

Impact of Nutrient Enrichment on Community Structure and Co-Occurrence Networks of Coral Symbiotic Microbiota in Duncanopsammia peltata: Zooxanthellae, Bacteria, and Archaea.

Symbiotic microorganisms in reef-building corals, including algae, bacteria, archaea, fungi, and viruses, play critical roles in the adaptation of coral hosts to adverse environmental conditions. However, their adaptation and functional relationships in nutrient-rich environments have yet to be fully explored. This study investigated Duncanopsammia peltata and the surrounding seawater and sediments from protected and non-protected areas in the summer and winter in Dongshan Bay. High-throughput sequencing was used to characterize community changes, co-occurrence patterns, and factors influencing symbiotic coral microorganisms (zooxanthellae, bacteria, and archaea) in different environments. The results showed that nutrient enrichment in the protected and non-protected areas was the greatest in December, followed by the non-protected area in August. In contrast, the August protected area had the lowest nutrient enrichment. Significant differences were found in the composition of the bacterial and archaeal communities in seawater and sediments from different regions. Among the coral symbiotic microorganisms, the main dominant species of zooxanthellae is the C1 subspecies (42.22-56.35%). The dominant phyla of bacteria were Proteobacteria, Cyanobacteria, Firmicutes, and Bacteroidota. Only in the August protected area did a large number (41.98%) of SAR324_cladeMarine_group_B exist. The August protected and non-protected areas and December protected and non-protected areas contained beneficial bacteria as biomarkers. They were Nisaea, Spiroplasma, Endozoicomonas, and Bacillus. No pathogenic bacteria appeared in the protected area in August. The dominant phylum in Archaea was Crenarchaeota. These symbiotic coral microorganisms' relative abundances and compositions vary with environmental changes. The enrichment of dissolved inorganic nitrogen in environmental media is a key factor affecting the composition of coral microbial communities. Co-occurrence analysis showed that nutrient enrichment under anthropogenic disturbances enhanced the interactions between coral symbiotic microorganisms. These findings improve our understanding of the adaptations of coral holobionts to various nutritional environments.

A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome.

Rett syndrome (RTT) results from loss-of-function mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2) and is characterized by abnormal motor, respiratory and autonomic control, cognitive impairment, autistic-like behaviors and increased risk of seizures. RTT patients and Mecp2-null mice exhibit reduced expression of brain-derived neurotrophic factor (BDNF), which has been linked in mice to increased respiratory frequency, a hallmark of RTT. The present study was undertaken to test the hypotheses that BDNF deficits in Mecp2 mutants are associated with reduced activation of the BDNF receptor, TrkB, and that pharmacologic activation of TrkB would improve respiratory function. We characterized BDNF protein expression, TrkB activation and respiration in heterozygous female Mecp2 mutant mice (Het), a model that recapitulates the somatic mosaicism for mutant MECP2 found in typical RTT patients, and evaluated the ability of a small molecule TrkB agonist, LM22A-4, to ameliorate biochemical and functional abnormalities in these animals. We found that Het mice exhibit (1) reduced BDNF expression and TrkB activation in the medulla and pons and (2) breathing dysfunction, characterized by increased frequency due to periods of tachypnea, and increased apneas, as in RTT patients. Treatment of Het mice with LM22A-4 for 4 weeks rescued wild-type levels of TrkB phosphorylation in the medulla and pons and restored wild-type breathing frequency. These data provide new insight into the role of BDNF signaling deficits in the pathophysiology of RTT and highlight TrkB as a possible therapeutic target in this disease.

Ibuprofen ion-exchange fiber complex: improved dissolution and gastric tolerance based on ion exchange.

The purpose of the present study is to develop a novel method to improve the dissolution of water-insoluble drug ibuprofen and the gastric tolerance of this non-steroidal anti-inflammatory drug which has potentially serious gastrointestinal side effects. This method is based on ion exchange of ion-exchange fibers. Water-insoluble drug ibuprofen was dispersed in deionized water, and then the ion-exchange fibers in OH(-) type was immersed in it. Ibuprofen and the active groups of the ion-exchange fibers combined into ion pairs based on the acid-base reaction. This drug carrier did not release drugs in deionized water, but in water solution containing other ions it would release the drugs into the solution by ion exchange. Confirmed by the X-ray diffraction and the scanning electron microscopy, the ibuprofen combined onto the ion-exchange fibers was in a highly molecular level dispersed state. The improved dissolution of ibuprofen ion-exchange fiber complexes is likely to originate from this ibuprofen's highly dispersed state. Due to this, ibuprofen's highly dispersed state, ibuprofen ion-exchange fiber complexes significantly decreases the gastrointestinal side effects of ibuprofen by avoiding the solid ibuprofen's educing. The present study showed that ibuprofen ion-exchange fiber complexes have the two-fold advantages. One is to improve the dissolution of ibuprofen. The other is to decrease the ibuprofen's gastrointestinal toxicity.

Effects of linalool on Botrytis cinerea growth and control of tomato gray mold.

We examined the antifungal characteristics of linalool against Botrytis cinerea using plate inhibition assay and spore germination assay, and assessed the capacity of linalool in controlling tomato gray mold disease via tomato pot inoculation assay. The results showed that linalool exhibited strong inhibitive effects on mycelial growth of B. cinerea, with an EC50 value of 0.581 mL·L-1. In the spore germination test, linalool treatment inhibited spore germination in a dose-dependent manner. The electric conductivity and the malondialdehyde (MDA) contents were significantly increased in linalool-treated B. cinerea than that of the control, indicating that linalool induced oxidative damage and destroyed the cell membrane integrity in B. cinerea. The activities of the superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) in the linalool-treated B. cinerea were decreased significantly by 27.4%, 68.9% and 26.0%, respectively, suggesting that linalool inhibited the antioxidant activity of B. cinerea. In the pot experiment, the diameter of lesions in linalool-treated tomatoes was significantly smaller than that of the control. The activities of SOD, POD, CAT, polyphenol oxidase, and phenylalnine ammonialyase in the linalool-treated tomatoes increased, while the MDA content decreased, suggesting that linalool could alleviate the oxidative damage caused by B. cinerea and promote plant disease resistance. In summary, linalool had inhibitory effect on the growth of B. cinerea and could control gray mold disease in tomatoes. These findings could lay the foundation for developing bota-nical antifungal agents for management of tomato gray mold disease.

High-fidelity Cas13 variants for targeted RNA degradation with minimal collateral effects.

CRISPR-Cas13 systems have recently been used for targeted RNA degradation in various organisms. However, collateral degradation of bystander RNAs has limited their in vivo applications. Here, we design a dual-fluorescence reporter system for detecting collateral effects and screening Cas13 variants in mammalian cells. Among over 200 engineered variants, several Cas13 variants including Cas13d and Cas13X exhibit efficient on-target activity but markedly reduced collateral activity. Furthermore, transcriptome-wide off-targets and cell growth arrest induced by Cas13 are absent for these variants. High-fidelity Cas13 variants show similar RNA knockdown activity to wild-type Cas13 but no detectable collateral damage in transgenic mice or adeno-associated-virus-mediated somatic cell targeting. Thus, high-fidelity Cas13 variants with minimal collateral effects are now available for targeted degradation of RNAs in basic research and therapeutic applications.

Improved initial burst of estradiol organogel as long-term in situ drug delivery implant: formulation, in vitro and in vivo characterization.

OBJECTIVE: The present investigation was aimed at optimizing of estradiol (E2) loaded l-amino acid derivatives organogel formulations resulting in improved the high initial release problems and sustained release of E2. METHODS: The visco-elastic properties of blank organogels were measured by rheometer. The E2 organogel formulations were optimized using a central composite design. Also, the effect of gelator structure and composition of the gel formulations on release behavior (in vitro and in vivo) had been studied. RESULTS: The change of the gelator structure could affect significantly the stiffness of the implants. The release behavior of gel without N-Methyl-2-pyrrolidinone (NMP) was controlled by gel corrosion only. While the drug release of the gel with NMP was controlled by both corrosion and diffusion. The high initial release problems of the organogels were improved by optimizing the formulations. The system consisting by N-Lauroyl L-lysine methyl ester (LLM) derivative in the oil indicated the lowest initial drug release, showed a much lower blood drug level and maintained a steady state for nearly 1 month. CONCLUSION: Organogels based on L-lysine methyl ester derivative were ideal carriers for long-term parenteral administration of E2.

[The preparation and kinetic study on enzymatically-controlled drug release of isotretinoin/amylose inclusion complex].

The inclusion complex of isotretinoin was prepared by sealed-control temperature method and amylose was used as carrier. The formation of inclusion complex was confirmed by powder X-ray diffraction and DSC. The equation of enzymatically-controlled drug release was established by kinetic theory, and the release characteristic of drug was confirmed by using the kinetic equation. The results show that the drug release was attributed to first order reaction without alpha-amylase. However, with alpha-amylase, the drug release was an acceleration process by the effect of both dissociation and enzymatic hydrolysis simultaneously. The research indicates that drug release from the inclusion complex was modulated by the addition of alpha-amylase.

Develop an efficient and specific AAV-based labeling system for Muller glia in mice.

Reprogramming Müller glia (MG) into functional cells is considered a promising therapeutic strategy to treat ocular diseases and vision loss. However, current AAV-based system for MG-tracing was reported to have high leakage in recent studies. Here, we focused on reducing the leakage of AAV-based labeling systems and found that different AAV serotypes showed a range of efficiency and specificity in labeling MG, leading us to optimize a human GFAP-Cre reporter system packaged in the AAV9 serotype with the woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) removed. The leakage ratio of the AAV9-hGFAP-Cre-ΔWPRE decreased by an approximate 40-fold compared with the AAV9-hGFAP-Cre-WPRE labeling system. In addition, we validated the specificity of the AAV-ΔWPRE system for tracing MG reprogramming under Ptbp1-suppression and observed strict non-MG-conversion, similar to previous studies using genetic lineage tracking mouse models. Thus, the AAV9-hGFAP-Cre-ΔWPRE system showed high efficiency and specificity for MG labeling, providing a promising tool for tracing cell fate in vivo.

Identification of the metabolites of baicalein in human plasma.

The metabolites of baicalein in human plasma were investigated after taking baicalein, which is one of the main bioactive flavones in Scutellaria baicalensis Georgi. Five metabolites (M1-M5) together with the parent drug baicalein (P) were detected and identified by the HPLC-diode-array detector (DAD) and LC-MS/MS methods. Among them, 7-methoxybaicalein 6-O-glucuronide (M5) is a new metabolite. Based on the results, the proposed metabolic pathway of baicalein in humans was inferred.

Modulating drug loading and release profile of beta-cyclodextrin polymers by means of cross-linked degree.

The purpose of the present study is to use beta-cyclodextrin polymers (beta-CDP) with different cross-linked degree (CLD) to form inclusion complexes with ibuprofen and examine the effects of structural and compositional factors of beta-CDP on its drug loading and release behaviors. A series of beta-CDP with different CLD were synthesized and characterized by Fourier Transform Infrared Spectroscopy (FT-IR) and 13C NMR spectrum. The beta-CDP was systemically characterized for the relation between the CLD of beta-CDP and the drug loading and release as well. The results of FT-IR and 13C NMR showed that similar peak-shaped vibration of beta-CDP and beta-CD implies that the polymer keeps the original characteristic structure of beta-CD. The CLD of the beta-CDP played a critical role in the drug loading and release, increasing the CLD resulted in reduction of drug loading, but increase in drug release.

A metal-free salalen ligand with anti-tumor and synergistic activity in resistant leukemia and solid tumor cells via mitochondrial pathway.

PURPOSE: Since the discovery of the well-known cis-platin, transition metal complexes are highly recognized as cytostatic agents. However, toxic side effects of the metal ions present in the complexes may pose significant problems for their future development. Therefore, we investigated the metal-free salalen ligand WQF 044. METHODS: DNA fragmentations in leukemia (Nalm6) and solid tumor cells (BJAB, MelHO, MCF-7, RM82) proved the apoptotic effects of WQF 044, its overcoming of resistances and the cellular pathways that are affected by the substance. The apoptotic mechanisms finding were supported by western blot analysis, measurement of the mitochondrial membrane potential and polymerase chain reactions. RESULTS: A complex intervention in the mitochondrial pathway of apoptosis with a Bcl-2 and caspase dependence was observed. Additionally, a wide range of tumors were affected by the ligand in a low micromolar range in-vitro. The compound overcame multidrug resistances in P-gp over-expressed acute lymphoblastic leukemia and CD95-downregulated Ewing's sarcoma cells. Quite remarkable synergistic effects with vincristine were observed in Burkitt-like lymphoma cells. CONCLUSION: The investigation of a metal-free salalen ligand as a potential anti-cancer drug revealed in promising results for a future clinical use.

Synthesis of zwitterionic salts of pyridinium-Meldrum acid and barbiturate through unique four-component reactions.

An efficient synthetic procedure for the preparation of the unusual charge-separated pyridinium-Meldrum acid and N,N-dimethylbarbiturate acid zwitterionic salts was developed though a unique one-pot four-component reaction involving pyridine, aromatic aldehyde, Meldrum acid or N,N-dimethylbarbituric acid, and p-nitrobenzyl bromide in acetonitrile. By varying combinations of four components involving nitrogen-containing heterocycles, we conveniently established reactive alpha-halomethylene compounds, aldehydes and beta-dicarbonyl compounds a library of zwitterionic salts.