Approaches for posaconazole therapeutic drug monitoring and their clinical benefits.

OBJECTIVE: This review examines the progress of research on posaconazole therapeutic drug monitoring (TDM) that has focused on differences in the TDM of posaconazole after clinical application in different formulations and in different populations, the factors that affect posaconazole concentrations, the advantages of posaconazole TDM in terms of clinical efficacy and cost savings, and measurement methods. METHODS: A literature search (2006 to 2024) was performed in PubMed and Embase with the following search terms: noxafil, posaconazole hydrate, posaconazole, drug monitoring, therapeutic drug monitoring, and TDM. Abstracts of review articles, prospective studies, and retrospective studies were reviewed. RESULTS: TDM should be implemented earlier for posaconazole tablets and injections than for oral posaconazole suspensions. Posaconazole TDM is beneficial for improving clinical efficacy, and the incidence of breakthrough invasive fungal infections (IFIs) can be significantly reduced by gradually adjusting the posaconazole dose in response to TDM in patients with inadequate trough concentrations. Early TDM allows more patients to achieve target therapeutic posaconazole concentrations. TDM can also facilitate dose adjustments, which reduce the cost of this expensive drug. Different assay techniques, including chromatography, microbiological detection, chemofluorimetry, paper spray mass spectrometry, and capillary electrophoresis, can be used for posaconazole TDM. CONCLUSIONS: Posaconazole TDM has potential clinical utility and cost-saving benefits and could improve the outcomes of IFI treatment.

Synthesis, Structural Characterization, and Biological Activities of 1,3,4- Thiadiazole Derivatives Containing Sulfonylpiperazine Structures.

To develop novel bacterial biofilm inhibiting agents, a series of 1,3,4-thiadiazole derivatives containing sulfonylpiperazine structures were designed, synthesized, and characterized using 1H nuclear magnetic resonance (1H NMR), 13C nuclear magnetic resonance (13C NMR), and high-resolution mass spectrometry. Meanwhile, their biological activities were evaluated, and the ensuing structure-activity relationships were discussed. The bioassay results showed the substantial antimicrobial efficacy exhibited by most of the compounds. Among them, compound A24 demonstrated a strong efficacy with an EC50 value of 7.8 µg/mL in vitro against the Xanthomonas oryzae pv. oryzicola (Xoc) pathogen, surpassing commercial agents thiodiazole copper (31.8 µg/mL) and bismerthiazol (43.3 µg/mL). Mechanistic investigations into its anti-Xoc properties revealed that compound A24 operates by increasing the permeability of bacterial cell membranes, inhibiting biofilm formation and cell motility, and inducing morphological changes in bacterial cells. Importantly, in vivo tests showed its excellent protective and curative effects on rice bacterial leaf streak. Besides, molecular docking showed that the hydrophobic effect and hydrogen-bond interactions are key factors between the binding of A24 and AvrRxo1-ORF1. Therefore, these results suggest the utilization of 1,3,4-thiadiazole derivatives containing sulfonylpiperazine structures as a bacterial biofilm inhibiting agent, warranting further exploration in the realm of agrochemical development.

Regio- and Enantioselective Allylic Cyanomethylation by Synergistic Rhodium and Silane Catalysis.

Rh/silane-cocatalyzed regio- and enantioselctive allylic cyanomethylation with inert acetonitrile directly has been developed. Addition of a catalytic amount neutral silane reagent as an acetonitrile anion carrier is essential for the success of this reaction. The synthesis of mono- and bis-allylation products can be switched by adjusting the size of substituents on the silane, ligands, and temperature. Chiral homoallylic nitriles could be synthesized in above 20:1 branch/linear ratio, up to 98% yield and >99% ee.

Characteristics of hypertension in the last 16 years in high prevalence region of China and the attribute ratios for cardiovascular mortality.

BACKGROUND: Tianjin is one of the cities with the highest prevalence of hypertension in China and one of the first regions to develop community management of hypertension. Our aim was to analyze the characteristics of hypertension in the last 16 years, and estimate the population attributable fraction for cardiovascular mortality in Tianjin, China. METHODS: We compared the epidemiological characteristics of hypertension between 2002 and 2018 by analyzing data from the National Nutrition and Chronic Disease Risk Factor Survey. Subsequently, we obtained the cause-specific mortality in the same year from the Tianjin All Cause of Death Registration System (CDRS), and the population attributable fraction was used to estimate the annual cardiovascular disease (CVD) deaths caused by hypertension. RESULTS: In 2002 and 2018, the crude prevalence, awareness, treatment rate in diagnosed, control rate in treated, and overall control rate of hypertension were 36.6% and 39.8%, 36.0% and 51.9%, 76.0% and 90.1%, 17.4% and 38.3%, 4.8% and 17.9%, respectively (P < 0.05). The mean SBP for males between the ages of 25 and 50 was significantly higher in 2018 than in 2002. The number of CVD deaths attributed to hypertension was 13.8 thousand in 2002 (account for 59.1% of total CVD deaths), and increased to 21.7 thousand in 2018 (account for 58.8% of total CVD deaths). The population attributable fraction have increased in the age groups of 25-44 and 75 and above, and decreased in the age group of 45-74 from 2002 to 2018. CONCLUSIONS: Compare to 2002, the proportion of CVD deaths attributed to hypertension remains high, particularly among younger and older people, despite a very significant increase in treatment and control rates for hypertension in 2018.

Design, Synthesis and Bioactivity of Novel Pyrimidine Sulfonate Esters Containing Thioether Moiety.

Pesticides play an important role in crop disease and pest control. However, their irrational use leads to the emergence of drug resistance. Therefore, it is necessary to search for new pesticide-lead compounds with new structures. We designed and synthesized 33 novel pyrimidine derivatives containing sulfonate groups and evaluated their antibacterial and insecticidal activities. Results: Most of the synthesized compounds showed good antibacterial activity against Xanthomonas oryzae pv. Oryzae (Xoo), Xanthomonas axonopodis pv. Citri (Xac), Pseudomonas syringae pv. actinidiae (Psa) and Ralstonia solanacearum (Rs), and certain insecticidal activity. A5, A31 and A33 showed strong antibacterial activity against Xoo, with EC50 values of 4.24, 6.77 and 9.35 µg/mL, respectively. Compounds A1, A3, A5 and A33 showed remarkable activity against Xac (EC50 was 79.02, 82.28, 70.80 and 44.11 µg/mL, respectively). In addition, A5 could significantly improve the defense enzyme (superoxide dismutase, peroxidase, phenylalanine ammonia-lyase and catalase) activity of plants against pathogens and thus improve the disease resistance of plants. Moreover, a few compounds also showed good insecticidal activity against Plutella xylostella and Myzus persicae. The results of this study provide insight into the development of new broad-spectrum pesticides.

Rh-Catalyzed Regio- and Enantioselective Allylic Phosphinylation.

Transition-metal-catalyzed branched and enantioselective allylic substitution of monosubstituted precursors with carbon, nitrogen, oxygen, sulfur, and fluoride nucleophiles has been well-established. However, such a selective carbon-phosphorus bond formation has not been realized probably due to the catalyst deactivation by the strong coordinating nature of phosphinylating reagents. Herein, we report a Rh-catalyzed highly regio- and enantioselective synthesis of allylic phosphine oxides in the presence of a chiral bisoxazoline-phosphine ligand. The application of α-hydroxylalkylphosphine oxides to keep the low concentration of the secondary phosphine oxides is essential for the high yields. The addition of diphenyl phosphoric acid was found to not only activate allylic alcohols but also accelerate the carbon-phosphorus bond formation.

Facile Benzylic Alkylation of Arenes with Alcohols by Catalysis with Spirocyclic NHC IrIII Pincer Complex.

A facile benzylic alkylation of indenes and other arenes was developed from readily available primary and secondary alcohols using our newly investigated CCC pincer IrIII catalyst (SNIr-H). Excellent regioselectivity and yield (89 %) of the C3-alkylated indenes were obtained. Additionally, the challenging sp2 C-alkylation was readily accomplished. This method could be utilized for the synthesis of the analogs of a histamine H1 receptor antagonist and the functional material template molecule, indeno[2,1-a]indene. A hemilabile IrIII -dihydride intermediate was proposed based on control experiments and previous density functional theory (DFT) calculations for the borrowing hydrogen mechanism and is key to the success of this IrIII catalyst in the reduction of unactivated multi-substituted olefin intermediates.

Rhodium-Catalyzed Regio- and Enantioselective Allylic Amination of Racemic 1,2-Disubstituted Allylic Phosphates.

Alkynylphosphines are rarely used as ligands in asymmetric metal catalysis. We synthesized a series of chiral bis(oxazoline)alkynylphosphine ligands and used them in Rh-catalyzed highly regio- and enantioselective allylic amination reactions of 1,2-disubstituted allylic phosphates. Chiral 1,2-disubstituted allylic amines were synthesized in up to 95% yield with >20:1 branched/linear (b/l) ratio and 99% ee from racemic 1,2-disubstituted allylic precursors. The sterically smaller linear alkynyl group on the P atom in the bis(oxazoline)alkynylphosphine ligands was the key to fit the new requirements of the introduction of bulky 2-R' groups.

Rhodium-Catalyzed Chemodivergent Regio- and Enantioselective Allylic Alkylation of Indoles.

The control of C3/N1 chemoselectivity in indole alkylation with the same electrophiles is still challenging. An Rh/bisoxazolinephosphane-catalyzed chemodivergent regio- and enantioselective allylic alkylation of indoles was developed. Chiral C3- and N1-allylindoles can be selectively obtained with high branched/linear ratio and up to 99 % ee by changing the counteranion of Rh, the allylic carbonate, the reaction temperature, and the ligand.

Simultaneous determination of capsid proteins in nine-valent human papilloma virus vaccines by liquid chromatography tandem mass spectrometry.

A liquid chromatography-tandem mass spectrometry method was developed to determine nine types of capsid proteins simultaneously in nine-valent human papillomavirus vaccines. Signature peptides were optimized in terms of specificity, repeatability, determination accuracy and sensitivity. As a result, three signature peptides per capsid protein were obtained. The linear calibration curves were achieved in the range of 11.6-373.6 nmol/L (R2  > 0.998). Compared to our previous liquid chromatography-tandem mass spectrometry method, the current method was more sensitive (3.18-fold) and it can be used for quality evaluation of nine-valent human papillomavirus vaccines, unlike the previous method, which could only be used for bivalent human papillomavirus vaccines. Then, they were utilized to determine nine types of capsid proteins in nine-valent human papillomavirus vaccines from four different manufactures. Intraday and interday precision values for the determination of capsid proteins in nine-valent human papillomavirus vaccines were less than 6.8 and 9.1%, respectively. Recovery rates of all capsid proteins investigated were in the range of 80-120%. In addition, the current assay was used for determination of free capsid protein in nine-valent human papilloma virus vaccines, and the results were used to evaluate the adsorption rate of the adjuvant.

Angular micro-vibration of the Micius satellite measured by an optical sensor and the method for its suppression.

Satellite angular micro-vibration has an important impact on the efficiency of space quantum communication links. We measured the micro-vibrations on the Micius satellite in orbit using a high-precision optical sensor mounted on the satellite and analyzed the power spectral density. We designed a compound axis acquisition, tracking, and pointing (ATP) system based on a two-axis turntable and tested its suppressive effect on the micro-vibration through in-orbit experiments. The tracking error caused by the angular micro-vibration was found to be 9.3 µrad, with the energy concentrated primarily in the frequencies below 30 Hz; after suppression by the ATP system, the error was 0.47 µrad.

Rapid determination of 20 bile acids in human serum by ultra performance liquid chromatography-tandem mass spectrometry.

A method was established for the simultaneous determination of 20 kinds of bile acids in human serum employing ultraperformance liquid chromatography-tandem mass spectrometry. Chromatographic conditions and sample preparation were optimized to achieve good separation and maximum sensitivity for these analytes. The linearity, accuracy and repeatability of the development method were validated with a series of experiments. Under the optimum conditions, good linearities were achieved in the quantitative range for each bile acid with the correlation coefficients (r2 ) >0.9901. The limit of detections (signal-noise ratio 3) of the method were in a range from 0.02 to 0.57 nmol/L. The recoveries were in the range of 88.1-109.9%, RSD < 6.12%. This method was successfully applied for the determination of bile acids in a human serum sample with simple operation, high sensitivity and good accuracy, and provides a reference for the clinical determination of bile acid content.

Enantioselective Synthesis of Pyridines with All-Carbon Quaternary Carbon Centers via Cobalt-Catalyzed Desymmetric [2+2+2] Cycloaddition.

A Co-catalyzed enantioselective desymmetric [2+2+2] cycloaddition for synthesis of pyridines with all-carbon quaternary carbon centers has been developed. The regio- and enantioselectivities are controlled by the inherent nature of terminal alkynes and the substituents on the bisoxazolinephosphine ligands. Pyridines with 5-substitutents could be obtained with >20:1 regioselectivity and up to 94 % ee when terminal alkyl, alkenyl or silyl alkynes and DTBM/Ph-based NPN* ligand L6 were used. Terminal aryl alkynes and Ph/Bn-based ligand L4 leads to formation of pyridines with 6-substitutents in up to 99 % ee.

Regio- and Enantioselective Allylic Alkylation of Terminal Alkynes by Synergistic Rh/Cu Catalysis.

A highly branch- and enantioselective 1,4-enynes synthesis from readily available terminal alkynes and racemic allylic carbonates by Sonogashira type synergistic Rh and Cu catalysis under neutral conditions has been developed. Aliphatic and aromatic terminal alkynes with various functional groups could be used directly. An inner-sphere reductive elimination C(sp)-C(sp3) bond formation mechanism is supported by the stoichiometric reaction.

Design and in-orbit test of a high accuracy pointing method in satellite-to-ground quantum communication.

To meet the requirement of high-accuracy pointing of quantum signals in satellite-to-ground quantum communication, this paper proposes a flexible satellite-based pointing method that changes the fine tracking point to solve the problem from point-ahead angle and ground beacon laser offset. This method does not require the use of a point-ahead mechanism and can detect the pointing angle in real time. Detailed algorithms and analysis are given. The method has been verified in orbit on the quantum science satellite Micius. The satellite-to-ground test results show that the quantum signal pointing accuracy is between 0.5∼1.0 µrad, which meets the efficiency requirements of satellite-to-ground quantum communication.

Comprehensive analysis of key genes associated with ceRNA networks in nasopharyngeal carcinoma based on bioinformatics analysis.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with high morbidity rates in the east and southeast Asia. The molecular mechanisms of NPC remain largely unknown. We explored the pathogenesis, potential biomarkers, and prognostic indicators of NPC. METHODS: We analyzed mRNAs, long non-coding RNAs (lncRNAs), and microRNAs (miRNAs) in the whole transcriptome sequencing dataset of our hospital (five normal tissues vs. five NPC tissues) and six microarray datasets (62 normal tissues vs. 334 NPC tissues) downloaded from the Gene Expression Omnibus (GSE12452, GSE13597, GSE95166, GSE126683, and GSE70970, GSE43039). Differential expression analyses, gene ontology (GO) enrichment, kyoto encyclopedia of genes and genomes (KEGG) analysis, and gene set enrichment analysis (GSEA) were conducted. The lncRNA-miRNA-mRNA competing endogenous RNA (ceRNA) networks were constructed using the miRanda and TargetScan database, and a protein-protein interaction (PPI) network of differentially expressed genes (DEGs) was built using Search Tool for the Retrieval of Interacting Genes (STRING) software. Hub genes were identified using Molecular Complex Detection (MCODE), NetworkAnalyzer, and CytoHubba. RESULTS: We identified 61 mRNAs, 14miRNAs, and 10 lncRNAs as shared DEGs related to NPC in seven datasets. Changes in NPC were enriched in the chromosomal region, sister chromatid segregation, and nuclear chromosome segregation. GSEA indicated that the mitogen-activated protein kinase (MAPK) pathway, phosphatidylinositol-3 OH kinase/protein kinase B (PI3K-Akt) pathway, apoptotic pathway, and tumor necrosis factor (TNF) were involved in the initiation and development of NPC. Finally, 20 hub genes were screened out via the PPI network. CONCLUSIONS: Several DEGs and their biological processes, pathways, and interrelations were found in our current study by bioinformatics analyses. Our findings may offer insights into the biological mechanisms underlying NPC and identify potential therapeutic targets for NPC.

Determination of glycosylation degree for glycoconjugate vaccines using a solid-phase extraction combined with liquid chromatography and tandem mass spectrometry method.

In this study, a solid-phase extraction with liquid chromatography and tandem mass spectrometry method was developed to determine the degree of glycosylation of glycosylation sites and the ratio of free carrier protein to total carrier protein for glycoconjugate vaccines. To remove and enrich the glycosylated peptides, a solid-phase extraction method was developed, optimized, and hyphenated to liquid chromatography-tandem mass spectrometry. The developed solid-phase extraction with liquid chromatography-tandem mass spectrometry method was shown to possess a wide linear dynamic range (0.03-100 µg/mL), a high sensitivity (0.03 µg/mL for CRM197), good interday and intra-day precision (relative standard deviation of peak area < 3.3%), and good recoveries from vaccine matrix (90-105%). Finally, the method was utilized to determine the degree of glycosylation and free carrier protein to total carrier protein ratio for pneumococcal conjugate vaccines and meningococcal vaccines. For quality evaluation of glycoconjugate vaccines, the method could provide more information than the traditional size exclusion chromatography method. Fourteen and twelve reported glycosylation sites for CRM197- and tetanus toxin-based vaccines can be detected, respectively.

Exogenous hydrogen sulfide alleviates surgery-induced neuroinflammatory cognitive impairment in adult mice by inhibiting NO signaling.

BACKGROUND: To investigate the effect and mechanisms of exogenous hydrogen sulfide in surgery-induced neuroinflammatory cognitive dysfunction. METHODS: C57BL/6 J male mice (n = 140) were used and randomly divided into seven groups: the sham group, surgery group, GYY4137 group, L-NAME group, surgery+GYY4137 group, surgery +L-NAME group, and surgery+GYY4137 + L-NAME group. After the interventions, open field tests (OFT) and the Morris water maze (MWM) test were conducted to evaluate learning and memory abilities in the mice. ELISAs, nitrate reductase assays, and Western blots (WB) were conducted to evaluate interleukin-1 beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), inducible nitric oxide synthase (iNOS), malondialdehyde (MDA), and antioxidant enzyme superoxide dismutase (SOD) levels. Furthermore, the expression level of microglial marker ionized calcium binding adaptor molecule 1 (IBA) in the hippocampal CA1 and CA3 areas was detected by an immunohistochemical (IHC) assay and apoptotic cells were observed using terminal deoxynucleotidyl transferase dUTP end-labeling (TUNEL) staining kits. RESULTS: We found that surgery induced neuroinflammatory cognitive dysfunction, oxidative stress, microglial activation, and cell apoptosis in the hippocampus. Moreover, following surgery, NO and iNOS levels were elevated in the hippocampus. Notably, all the effects caused by surgery were reversed by the H2S donor GYY4137 or the iNOS inhibitor N(gamma)-nitro-L-arginine methyl ester (L-NAME). However, the combined application of GYY4137 and L-NAME was not superior to treatment with either agent alone and the effect of GYY4137 was similar to that of L-NAME. CONCLUSION: The long-acting hydrogen sulfide donor GYY4137 had an ability to reversed the cognitive deficits and inflammation caused by carotid artery exposure surgery. This implies that NO signaling pathways might participate in this process. These results indicate that exogenous H2S may be a promising therapy for POCD.

Cobalt-Catalyzed Regio- and Enantioselective Allylic Amination.

The first earth-abundant cobalt-catalyzed highly branched- and enantioselective allylic amination of racemic branched allylic carbonates bearing alkyl groups with both aromatic and aliphatic amines has been developed. The process allows rapid access of allylic amines in high yields with exclusively branched selectivity and excellent enantioselectivities (normally 99% ee) under mild reaction conditions.

Effects of applying Lactobacillus helveticus H9 as adjunct starter culture in yogurt fermentation and storage.

Lactobacillus helveticus H9 is a probiotic bacterium originating from traditional Tibetan kurut. It has high angiotensin-converting enzyme-inhibitory (ACEI) and antihypertensive activities. We aimed to evaluate the effects of L. helveticus H9 supplementation in yogurt fermentation and storage. We monitored changes of multiple parameters over 28 d of storage at 4°C; namely, pH, titratable acidity, free amino groups, ACEI activity, physical properties, volatile flavor compounds, and sensory quality. Supplementation of L. helveticus H9 enhanced fermented milk acidification and proteolysis, resulting in a shorter fermentation time. The H9 treatment significantly increased the ACEI activity of the fermented milks. Fifteen key volatile flavors were detected by solid-phase microextraction-gas chromatography-mass spectrometry across all samples. More alcohols, aldehydes, and nitrogenous compounds, especially acetoin and benzaldehyde, were detected in the H9-supplemented fermented milks. The human sensory scores for flavor and texture, but not appearance, were lower for the H9-supplemented fermented milks, particularly beyond 2 wk of cold storage. Our results will be of interest to the dairy industry for developing novel functional dairy products.