Platelet Membrane-Camouflaged Silver Metal-Organic Framework Biomimetic Nanoparticles for the Treatment of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is characterized by high malignancy and limited treatment options. Given the pressing need for more effective treatments for TNBC, this study aimed to develop platelet membrane (PM)-camouflaged silver metal-organic framework nanoparticles (PM@MOF-Ag NPs), a biomimetic nanodrug. PM@MOF-Ag NP construction involved the utilization of 2-methylimidazole and silver nitrate to prepare silver metal-organic framework (MOF-Ag) NPs. The PM@MOF-Ag NPs, due to their camouflage, possess excellent blood compatibility, immune escape ability, and a strong affinity for 4T1 tumor cells. This enhances their circulation time in vivo and promotes the aggregation of PM@MOF-Ag NPs at the 4T1 tumor site. Importantly, PM@MOF-Ag NPs demonstrated promising antitumor activity in vitro and in vivo. We further revealed that PM@MOF-Ag NPs induced tumor cell death by overproducing reactive oxygen species and promoting cell apoptosis. Moreover, PM@MOF-Ag NPs enhanced apoptosis by upregulating the ratios of Bax/Bcl-2 and cleaved caspase3/pro-caspase3. Notably, PM@MOF-Ag NPs exhibited no significant organ toxicity, whereas the administration of MOF-Ag NPs resulted in liver inflammation compared to the control group.

Molecular characterization, expression analysis and function identification of Pf_IL-12p35, Pf_IL-23p19 and Pf_IL-12p40 genes in yellow catfish (Pelteobagrus fulvidraco).

The interleukin-12 (IL-12) family is a class of heterodimeric cytokines that play crucial roles in pro-inflammatory and pro-stimulatory responses. Although some IL-12 and IL-23 paralogues have been found in fish, their functional activity in fish remains poorly understood. In this study, Pf_IL-12p35a/b, Pf_IL-23p19 and Pf_IL-12p40a/b/c genes were cloned from yellow catfish (Pelteobagrus fulvidraco), four α-helices were found in Pf_IL-12p35a/b and Pf_IL-23p19. The transcripts of these six genes were relatively high in mucus and immune tissues of healthy individuals, and in gill leukocytes. Following Edwardsiella ictaluri infection, Pf_IL-12p35a/b and Pf_IL-23p19 mRNAs were induced in brain and kidney (or head kidney), Pf_IL-12p40a mRNA was induced in gill, and Pf_IL-12p40b/c mRNAs were induced in brain and liver (or skin). The mRNA expression of these genes in PBLs was induced by phytohaemagglutinin (PHA) and polyinosinic-polycytidylic acid (poly I:C), while lipopolysaccharides (LPS) induced the mRNA expression of Pf_IL-12p35a and Pf_IL-12p40b/c in PBLs. After stimulation with recombinant (r) Pf_IL-12 and rPf_IL-23 subunit proteins, either alone or in combination, mRNA expression patterns of genes related to T helper cell development exhibited distinct differences. The results suggest that Pf_IL-12 and Pf_IL-23 subunits may play important roles in regulating immune responses to pathogens and T helper cell development.

A combination of a TLR7/8 agonist and an epigenetic inhibitor suppresses triple-negative breast cancer through triggering anti-tumor immune.

BACKGROUND: Combination therapy involving immune checkpoint blockade (ICB) and other drugs is a potential strategy for converting immune-cold tumors into immune-hot tumors to benefit from immunotherapy. To achieve drug synergy, we developed a homologous cancer cell membrane vesicle (CM)-coated metal-organic framework (MOF) nanodelivery platform for the codelivery of a TLR7/8 agonist with an epigenetic inhibitor. METHODS: A novel biomimetic codelivery system (MCM@UN) was constructed by MOF nanoparticles UiO-66 loading with a bromodomain-containing protein 4 (BRD4) inhibitor and then coated with the membrane vesicles of homologous cancer cells that embedding the 18 C lipid tail of 3M-052 (M). The antitumor immune ability and tumor suppressive effect of MCM@UN were evaluated in a mouse model of triple-negative breast cancer (TNBC) and in vitro. The tumor immune microenvironment was analyzed by multicolor immunofluorescence staining. RESULTS: In vitro and in vivo data showed that MCM@UN specifically targeted to TNBC cells and was superior to the free drug in terms of tumor growth inhibition and antitumor immune activity. In terms of mechanism, MCM@UN blocked BRD4 and PD-L1 to prompt dying tumor cells to disintegrate and expose tumor antigens. The disintegrated tumor cells released damage-associated molecular patterns (DAMPs), recruited dendritic cells (DCs) to efficiently activate CD8+ T cells to mediate effective and long-lasting antitumor immunity. In addition, TLR7/8 agonist on MCM@UN enhanced lymphocytes infiltration and immunogenic cell death and decreased regulatory T-cells (Tregs). On clinical specimens, we found that mature DCs infiltrating tumor tissues of TNBC patients were negatively correlated with the expression of BRD4, which was consistent with the result in animal model. CONCLUSION: MCM@UN specifically targeted to TNBC cells and remodeled tumor immune microenvironment to inhibit malignant behaviors of TNBC.

Transcriptome sequencing analysis of bovine mammary epithelial cells induced by lipopolysaccharide.

Mastitis in cows is caused by the inflammation of the mammary glands due to an infection by external pathogenic bacteria. Mammary gland epithelial cells, which are in direct contact with the external environment, are responsible for the first line of defense of the mammary gland against pathogenic bacteria, playing an essential role in immune defense. To investigate the mechanism of bovine mammary epithelial cells in the inflammatory process, we treated the cells with LPS for 12 hours and analyzed the changes in mRNA by transcriptome sequencing. The results showed that compared to the control group, the LPS treatment group had 121 up-regulated genes and 18 down-regulated genes. GO and KEGG enrichment analysis revealed that these differential genes were mainly enriched in the IL-17 signaling pathway, Legionellosis, Cytokine-cytokine receptor interaction, NF-kappa B signaling pathway, and other signaling pathways. Furthermore, the expression of GRO1 and CXCL3 mRNAs increased significantly after LPS treatment. These findings provide new insights for the treatment of mastitis in cows in the future.

[In vitro expression and functional analyses of the mutants p.R243Q, p.R241C and p.Y356X of the human phenylalanine hydroxylase]. / äººè‹¯ä¸™æ°¨é ¸ç¾ŸåŒ–é ¶çªå˜ä½“p.R243Q、p.R241C和p.Y356Xçš„ä½“å¤–è¡¨è¾¾åŠåŠŸèƒ½ç ”ç©¶.

OBJECTIVES: To study the in vitro expression of three phenylalanine hydroxylase (PAH) mutants (p.R243Q, p.R241C, and p.Y356X) and determine their pathogenicity. METHODS: Bioinformatics techniques were used to predict the impact of PAH mutants on the structure and function of PAH protein. Corresponding mutant plasmids of PAH were constructed and expressed in HEK293T cells. Quantitative reverse transcription polymerase chain reaction was used to measure the mRNA expression levels of the three PAH mutants, and their protein levels were assessed using Western blot and enzyme-linked immunosorbent assay. RESULTS: Bioinformatics analysis predicted that all three mutants were pathogenic. The mRNA expression levels of the p.R243Q and p.R241C mutants in HEK293T cells were similar to the mRNA expression level of the wild-type control (P>0.05), while the mRNA expression level of the p.Y356X mutant significantly decreased (P<0.05). The PAH protein expression levels of all three mutants were significantly reduced compared to the wild-type control (P<0.05). The extracellular concentration of PAH protein was reduced in the p.R241C and p.Y356X mutants compared to the wild-type control (P<0.05), while there was no significant difference between the p.R243Q mutant and the wild type control (P>0.05). CONCLUSIONS: p.R243Q, p.R241C and p.Y356X mutants lead to reduced expression levels of PAH protein in eukaryotic cells, with p.R241C and p.Y356X mutants also affecting the function of PAH protein. These three PAH mutants are to be pathogenic.

High-dose amoxicillin-proton pump inhibitor dual therapy as first-line treatment for Helicobacter pylori infection in Northwest China: A prospective, randomised controlled trial.

AIMS: We aimed to assess the eradication efficacy and factors that influencing it of high-dose dual therapy (HDDT) in Gansu region, Northwest China. METHODS: A total of 216 treatment-naive patients with Helicobacter pylori infection were randomly assigned to two groups for the 14-day eradication treatment: the HDDT group (amoxicillin 750 mg q.i.d. and esomeprazole 40 mg t.i.d.) and the amoxicillin and clarithromycin-containing bismuth quadruple therapy group (ACBQT: esomeprazole 20 mg, bismuth potassium citrate 2 g, amoxicillin 1 g, and clarithromycin 500 mg; b.i.d.). The eradication rates, adverse effects and patient compliance of these two groups were compared. Eradication efficacy was determined by 13 C urea breath test (13 C UBT) 4-8 weeks after finishing treatment. Antibiotic resistance was determined by the Epsilometer testing (E-test) method. RESULTS: The eradication rates for the HDDT and ACBQT groups were 71.0% and 74.7% (P = .552) by per-protocol analysis, and 65.7% and 68.5% (P = .664) by intention-to-treat analysis. The overall adverse event rates in the HDDT and ACBQT groups were 2.0% and 43.4% (P < .001), respectively. The resistance rates to amoxicillin, clarithromycin, tetracycline, levofloxacin and metronidazole were 15.2%, 42.0%, 5.4%, 35.7% and 83.0%, respectively. Amoxicillin resistance and delta over baseline (DOB) of 13 C UBT ≥ 20 before treatment significantly reduced the eradication rate in 112 participants with H. pylori cultured. CONCLUSION: The HDDT as first-line treatment for H. pylori was unsatisfactory in Gansu. Amoxicillin resistance and DOB of 13 C UBT ≥ 20 before treatment were significantly correlated with H. pylori eradication failure.

Combination therapy based on dual-target biomimetic nano-delivery system for overcoming cisplatin resistance in hepatocellular carcinoma.

Strategies to overcome toxicity and drug resistance caused by chemotherapeutic drugs for targeted therapy against hepatocellular carcinoma (HCC) are urgently needed. Previous studies revealed that high oxidored-nitro domain-containing protein 1(NOR1) expression in HCC was associated with cisplatin (DDP) resistance. Herein, a novel dual-targeting nanocarrier system AR-NADR was generated for the treatment of DDP resistance in HCC. The core of the nanocarrier system is the metal-organic frameworks (MOF) modified with nuclear location sequence (NLS), which loading with DDP and NOR1 shRNA (R). The shell is an A54 peptide inserted into the erythrocyte membrane (AR). Our results show that AR-NADR efficiently internalized by tumor cells due to its specific binding to the A54 receptors that are abundantly expressed on the surface of HCC cells and NLS peptide-mediated nuclear entry. Additionally, DDP is more likely to be released due to the degradation of Ag-MOF in the acidic tumor microenvironment. Moreover, by acting as a vector for gene delivery, AR-NADR effectively inhibits tumor drug resistance by suppressing the expression of NOR1, which induces intracellular DDP accumulation and makes cells sensitive to DDP. Finally, the anti-HCC efficacy and mechanisms of AR-NADR were systematically elucidated by a HepG2/DDP cell model as well as a tumor model. Therefore, AR-NADR constitutes a key strategy to achieve excellent gene silencing and antitumor efficacy, which provides effective gene therapy and precise treatment strategies for cisplatin resistance in HCC.

Bioengineered stem cell membrane functionalized nanoparticles combine anti-inflammatory and antimicrobial properties for sepsis treatment.

BACKGROUND: Sepsis is a syndrome of physiological, pathological and biochemical abnormalities caused by infection. Although the mortality rate is lower than before, many survivors have persistent infection, which means sepsis calls for new treatment. After infection, inflammatory mediators were largely released into the blood, leading to multiple organ dysfunction. Therefore, anti-infection and anti-inflammation are critical issues in sepsis management. RESULTS: Here, we successfully constructed a novel nanometer drug loading system for sepsis management, FZ/MER-AgMOF@Bm. The nanoparticles were modified with LPS-treated bone marrow mesenchymal stem cell (BMSC) membrane, and silver metal organic framework (AgMOF) was used as the nanocore for loading FPS-ZM1 and meropenem which was delivery to the infectious microenvironments (IMEs) to exert dual anti-inflammatory and antibacterial effects. FZ/MER-AgMOF@Bm effectively alleviated excessive inflammatory response and eliminated bacteria. FZ/MER-AgMOF@Bm also played an anti-inflammatory role by promoting the polarization of macrophages to M2. When sepsis induced by cecal ligation and puncture (CLP) challenged mice was treated, FZ/MER-AgMOF@Bm could not only reduce the levels of pro-inflammatory factors and lung injury, but also help to improve hypothermia caused by septic shock and prolong survival time. CONCLUSIONS: Together, the nanoparticles played a role in combined anti-inflammatory and antimicrobial properties, alleviating cytokine storm and protecting vital organ functions, could be a potential new strategy for sepsis management.

Transcriptomic profiling of lipopolysaccharide-challenged bovine mammary epithelial cells treated with forsythoside A.

Mastitis is usually caused by a variety of pathogenic bacteria that seriously impact the health and milk-production ability of dairy cows, with consequent, economically detrimental effects on the dairy industry. Forsythoside A (FTA), isolated from the fruit and leaves of Forsythia suspensa (Thunb.) Vahl (Oleaceae), has been reported to have significant antioxidant, anti-inflammatory, and antibacterial effects. However, it is not clear whether FTA exerts a protective effect against lipopolysaccharide (LPS)-induced bovine mastitis and its potential gene signature. In this study, high-throughput sequencing technology was performed to analyze the differences between the mRNA and enrichment pathway of bovine mammary epithelial cells of the control, LPS, and LPS + FTA groups. The results showed that there were 139 differentially expressed genes (DEGs) (p-value < 0.05, |log2FoldChange| > 1, FPKM > 1) in the LPS group compared with the control group, including 121 up-regulated genes and 18 down-regulated genes, which were mainly enriched in the cellular response to lipopolysaccharide, cytokine activity, protein binding, and IL-17 signaling pathway based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, respectively. Compared with the control group and LPS + FTA group, there were 349 DEGs, including 322 up-regulated genes and 27 down-regulated genes. They were mainly enriched in protein localization to organelles, centrosomes, binding, and the IL-17 signaling pathway, based on GO and KEGG analysis. Compared to the LPS group, the LPS + FTA group had 272 DEGs, including 259 up-regulated genes and 13 down-regulated genes, which were mainly enriched in RNA processing, IL-6 receptor binding, and the lysosome pathway, based on GO and KEGG analyses. It can be seen that LPS stimulation induced the expression of inflammation-related genes, IL-17 and IL-6, whereas FTA treatment promoted the expression of the spliceosome-, lysosome-, and oxidative stress-related genes HSP70, HSPA8, and PARP2. The study utilized RNA-sequencing analysis of FTA against LPS-challenged bovine mammary epithelial cells to explore key mRNA findings that may be strongly associated with inflammation and oxidative stress, and provides a theoretical reference for further elucidation of molecular mechanisms of bovine mastitis and therapeutic effects of FTA against bovine mastitis.

Enterolactone and trabectedin suppress epithelial ovarian cancer synergistically via upregulating THBS1.

Epithelial ovarian cancer (EOC) is the most common and fatal subtype of ovarian malignancies, with no effective therapeutics available. Our previous studies have demonstrated extraordinary suppressive efficacy of enterolactone (ENL) on EOC. A chemotherapeutic agent, trabectedin (Trabe), is shown to be effective on ovarian cancer, especially when combined with other therapeutics, such as pegylated liposomal doxorubicin or oxaliplatin. Thrombospondin 1 (THBS1), a kind of matrix glycoprotein, plays important roles against cancer development through inhibiting angiogenesis but whether it is involved in the suppression of EOC by ENL or Trabe remains unknown. To test combined suppressive effects of ENL and Trabe on EOC and possible involvement of THBS1 in the anticancer activities of ENL and Trabe. The EOC cell line ES-2 was transfected with overexpressed THBS1 by lentivirus vector. We employed tube formation assay to evaluate the anti-angiogenesis activity of ENL and of its combined use with Trabe after THBS1 overexpression and established drug intervention and xenograft nude mouse cancer models to assess the in vivo effects of the hypothesized synergistic suppression between the agents and the involvement of THBS1. Mouse fecal samples were collected for 16S rDNA sequencing and microbiota analysis. We detected strong inhibitory activities of ENL and Trabe against the proliferation and migration of cancer cells and observed synergistic effects between ENL and Trabe in suppressing EOC. ENL and Trabe, given either separately or in combination, could suppress the tube formation capability of human microvascular endothelial cells, and this inhibitory effect became even stronger with THBS1 overexpression. In the ENL plus Trabe combination group, the expression of tissue inhibitor of metalloproteinases 3 and cluster of differentiation 36 was both upregulated, whereas matrix metalloproteinase 9, vascular endothelial growth factor, and cluster of differentiation 47 were all decreased. With the overexpression of THBS1, the results became even more pronounced. In animal experiments, combined use of ENL and Trabe showed superior inhibitory effects to either single agent and significantly suppressed tumor growth, and the overexpression of THBS1 further enhanced the anti-cancer activities of the drug combination group. ENL and Trabe synergistically suppress EOC and THBS1 could remarkably facilitate the synergistic anticancer effects of ENL and Trabe.

Prevalence and risk factors for subjective cognitive decline and the correlation with objective cognition among community-dwelling older adults in China: Results from the Hubei memory and aging cohort study.

INTRODUCTION: The prevalence and risk factors for subjective cognitive decline (SCD) and its correlation with objective cognition decline (OCD) among community-dwelling older adults is inconsistent. METHODS: Older adults underwent neuropsychological and clinical evaluations to reach a consensus on diagnoses. RESULTS: This study included 7486 adults without mild cognitive impairment and dementia (mean age: 71.35 years [standard deviation = 5.40]). The sex-, age-, and residence-adjusted SCD prevalence was 58.33% overall (95% confidence interval: 58.29% to 58.37%), with higher rates of 61.25% and 59.87% in rural and female subgroups, respectively. SCD global and OCD language, SCD memory and OCD global, SCD and OCD memory, and SCD and OCD language were negatively correlated in fully adjusted models. Seven health and lifestyle factors were associated with an increased risk for SCD. DISCUSSION: SCD affected 58.33% of older adults and may indicate concurrent OCD, which should prompt the initiation of preventative intervention for dementia. HIGHLIGHTS: SCD affects 58.33% of older adults in China. SCD may indicate concurrent objective cognitive decline. Difficulty finding words and memory impairments may indicate a risk for AD. The presence of SCD may prompt preventative treatment initiation of MCI or dementia. Social network factors may be initial targets for the early prevention of SCD.

Genome-Wide Analysis of the Odorant Receptor Gene Family in Solenopsis invicta, Ooceraea biroi, and Monomorium pharaonis (Hymenoptera: Formicidae).

Olfactory systems in eusocial insects play a vital role in the discrimination of various chemical cues. Odorant receptors (ORs) are critical for odorant detection, and this family has undergone extensive expansion in ants. In this study, we re-annotated the OR genes from the most destructive invasive ant species Solenopsis invicta and 2 other Formicidae species, Ooceraea biroi and Monomorium pharaonis, with the aim of systematically comparing and analyzing the evolution and the functions of the ORs in ant species, identifying 356, 298, and 306 potential functional ORs, respectively. The evolutionary analysis of these ORs showed that ants had undergone chromosomal rearrangements and that tandem duplication may be the main contributor to the expansion of the OR gene family in S. invicta. Our further analysis revealed that 9-exon ORs had biased chromosome localization patterns in all three ant species and that a 9-exon OR cluster (SinvOR4-8) in S. invicta was under strong positive selection (Ka/Ks = 1.32). Moreover, we identified 5 S. invicta OR genes, namely SinvOR89, SinvOR102, SinvOR352, SinvOR327, and SinvOR135, with high sequence similarity (>70%) to the orthologs in O. biroi and M. pharaonis. An RT-PCR analysis was used to verify the antennal expression levels of these ORs, which showed caste-specific expression. The subsequent analysis of the antennal expression profiles of the ORs of the S. invicta workers from the polygyne and monogyne social forms indicated that SinvOR35 and SinvOR252 were expressed at much higher levels in the monogyne workers than in the polygyne workers and that SinvOR21 was expressed at higher levels in polygyne workers. Our study has contributed to the identification and analysis of the OR gene family in ants and expanded the understanding of the evolution and functions of the ORs in Formicidae species.

Molecular Characterization of Nine TRAF Genes in Yellow Catfish (Pelteobagrus fulvidraco) and Their Expression Profiling in Response to Edwardsiella ictaluri Infection.

The yellow catfish (Pelteobagrus fulvidraco) is an economic fish with a large breeding scale, and diseases have led to huge economic losses. Tumor necrosis factor receptor-associated factors (TRAFs) are a class of intracellular signal transduction proteins that play an important role in innate and adaptive immune responses by mediating NF-κB, JNK and MAPK signaling pathways. However, there are few studies on the TRAF gene family in yellow catfish. In this study, the open reading frame (ORF) sequences of TRAF1, TRAF2a, TRAF2b, TRAF3, TRAF4a, TRAF4b, TRAF5, TRAF6 and TRAF7 genes were cloned and identified in yellow catfish. The ORF sequences of the nine TRAF genes of yellow catfish (Pf_TRAF1-7) were 1413-2025 bp in length and encoded 470-674 amino acids. The predicted protein structures of Pf_TRAFs have typically conserved domains compared to mammals. The phylogenetic relationships showed that TRAF genes are conserved during evolution. Gene structure, motifs and syntenic analyses of TRAF genes showed that the exon-intron structure and conserved motifs of TRAF genes are diverse among seven vertebrate species, and the TRAF gene family is relatively conserved evolutionarily. Among them, TRAF1 is more closely related to TRAF2a and TRAF2b, and they may have evolved from a common ancestor. TRAF7 is quite different and distantly related to other TRAFs. Real-time quantitative PCR (qRT-PCR) results showed that all nine Pf_TRAF genes were constitutively expressed in 12 tissues of healthy yellow catfish, with higher mRNA expression levels in the gonad, spleen, brain and gill. After infection with Edwardsiella ictaluri, the expression levels of nine Pf_TRAF mRNAs were significantly changed in the head kidney, spleen, gill and brain tissues of yellow catfish, of which four genes were down-regulated and one gene was up-regulated in the head kidney; four genes were up-regulated and four genes were down-regulated in the spleen; two genes were down-regulated, one gene was up-regulated, and one gene was up-regulated and then down-regulated in the gill; one gene was up-regulated, one gene was down-regulated, and four genes were down-regulated and then up-regulated in the brain. These results indicate that Pf_TRAF genes might be involved in the immune response against bacterial infection. Subcellular localization results showed that all nine Pf_TRAFs were found localized in the cytoplasm, and Pf_TRAF2a, Pf_TRAF3 and Pf_TRAF4a could also be localized in the nucleus, uncovering that the subcellular localization of TRAF protein may be closely related to its structure and function in cellular mechanism. The results of this study suggest that the Pf_TRAF gene family plays important roles in the immune response against pathogen invasion and will provide basic information to further understand the roles of TRAF gene against bacterial infection in yellow catfish.

Mutagenesis of Odorant Receptor Coreceptor Orco Reveals the Odorant-Detected Behavior of the Predator Eupeodes corollae.

The successful mating of the hoverfly and the search for prey aphids are of great significance for biological control and are usually mediated by chemical cues. The odorant receptor co-receptor (Orco) genes play a crucial role in the process of insect odor perception. However, the function of Orco in the mating and prey-seeking behaviors of the hoverfly remains relatively unexplored. In this study, we characterized the Orco gene from the hoverfly, Eupeodes corollae, a natural enemy insect. We used the CRISPR/Cas9 technique to knock out the Orco gene of E. corollae, and the EcorOrco-/- homozygous mutant was verified by the genotype analysis. Fluorescence in situ hybridization showed that the antennal ORN of EcorOrco-/- mutant lack Orco staining. Electroantennogram (EAG) results showed that the adult mutant almost lost the electrophysiological response to 15 odorants from three types. The two-way choice assay and the glass Y-tube olfactometer indicated that both the larvae and adults of hoverflies lost their behavioral preference to the aphid alarm pheromone (E)-ß-farnesene (EBF). In addition, the mating assay results showed a significant decrease in the mating rate of males following the knock out of the EcorOrco gene. Although the mating of females was not affected, the amount of eggs being laid and the hatching rate of the eggs were significantly reduced. These results indicated that the EcorOrco gene was not only involved in the detection of semiochemicals in hoverflies but also plays a pivotal role in the development of eggs. In conclusion, our results expand the comprehension of the chemoreceptive mechanisms in the hoverflies and offers valuable insights for the advancement of more sophisticated pest management strategies.

[Clinical Analysis of Voriconazole Concentrations in Cerebrospinal Fluid and Blood in Patients with Ryptococcal Meningitis].

Objective: To investigate the concentrations of voriconazole (VCZ) in the central nervous system (CNS) of patients with cryptococcal meningitis and the relationship thereof. Methods: We retrospectively analyzed the trough concentration of VCZ in the cerebrospinal fluid (CSF) and the blood of 25 adult patients who had cryptococcal meningitis, and who were not infected with HIV. We also examined patient-level characteristics that could contribute to the differences in CSF/plasma VCZ concentration ratio. Results: The trough concentration of VCZ in plasma ranged from 0.38 to 8.56 mg/L, and the median (P 25, P 75) was 1.81 (1.40, 3.84) mg/L. The trough concentration of VCZ in CSF ranged from 0.17 to 3.92 mg/L, and the median (P 25, P 75) was 1.02 (0.54, 1.84) mg/L. The CSF VCZ trough concentration showed a slight negative correlation with the nucleated cell counts in CSF, but the correlation was not statistically significant ( r=-0.377, P=0.063). There was a positive correlation between VCZ concentrations in CSF and that in the plasma ( r=0.736, P<0.001), and the median (P 25, P 75) CSF/plasma ratio was 0.43 (0.34, 0.68). The CSF/plasma ratio did not statistically correlate with age, body surface area (BSA), radiology changes (hydrocephalus), or intracranial pressure. Conclusion: There is a positive correlation between VCZ concentration in CSF and VCZ concentration in the plasma, and no influencing factors of CSF/plasma ratio were found.

[Carbohydrate-based quality consistency evaluation of Saposhnikoviae Radix].

This study aims to evaluate the quality consistency of Saposhnikoviae Radix based on carbohydrates, and explore the potential of carbohydrates as the internal quality control indicators of Saposhnikoviae Radix. The total polysaccharides were quantified by UV-Vis spectrophotometry and the molecular weight range of the polysaccharides was determined by high performance gel-permeation chromatography-evaporative light scattering detection(HPGPC-ELSD). The monosaccharides in polysaccharides and the free monosaccharides were quantified by high performance liquid chromatography-UV detection(HPLC-UV), and the oligosaccharides and fructose were quantified by high performance liquid chromatography-evaporative light scattering detection(HPLC-ELSD). The carbohydrate-based quality of Saposhnikoviae Radix was compared among 45 batches of commercial samples and 13 batches of self-collected samples. The results showed that the molecular weight distribution, monosaccharide composition, oligosaccharide, and free monosaccharide composition were similar in the 58 batches of samples. The average content of total polysaccharides, oligosaccharides, and total free monosaccharides in commercial samples were 39.66, 148.79, and 68.62 mg·g~(-1), respectively. The content showed significant differences among batches, with the highest differences of 3.51, 1.75, and 2.58 times, respectively. The RSD of the relative ratios of monosaccharides in the polysaccharides in commercial samples reached 28%-45%. The average content of total polysaccharides, oligosaccharides, and total free monosaccharides in self-collected samples were 68.07, 145.76, and 42.04 mg·g~(-1), respectively, with the inter-region differences of 2.88, 1.88, and 1.07 times, respectively. The RSD of the relative ratios of monosaccharides in polysaccharides in self-collected samples ranged from 8.2% to 59%. The total polysaccharides and total free monosaccharides in self-collected samples were 1.72 times higher and 1.63 times lower, respectively, than those in commercial samples. The content of oligosaccharides was similar between self-collected samples and commercial samples. To sum up, carbohydrates are one of the material bases for the internal quality consistency of Saposhnikoviae Radix. The qualitative characteristics of polysaccharides and the quantitative characteristics of polysaccharides and oligosaccharides are related to the origin of medicinal materials. Moreover, the quantitative characteristics of polysaccharides and free monosaccharides may be related to the storage conditions. Carbohydrates are potential indicators for the quality control of Saposhnikoviae Radix and deserve attention.

Substrate-Dependent Regioselectivity: Pd/PTC Cooperatively Catalyzed Domino Heck/Allylation of Allenamides with α-Carbon of Carbonyl Compounds.

A Pd/phase-transfer catalyst cooperatively catalyzed domino Heck/allylation reaction is first reported, which represents interesting substrate-dependent regioselectivity. Under the same conditions, Ts-protected N-(2-iodophenyl)allenamides produced only linear allylation products, while Cbz, Ac, or Boc-protected N-(2-iodophenyl)allenamides and N-(2-iodobenzoyl)allenamides with various compounds generated branch allylation products with an exocylic C═C bond and two vicinal stereocenters. Up-scale syntheses and diverse fused cyclization transformations of products were then carried out. The enantioselective version for the domino process was studied.

Facilitating Rh-Catalyzed C-H Alkylation of (Hetero)arenes and 6-Arylpurine Nucleosides (Nucleotides) with Electrochemistry.

An electrochemical approach to promote the ortho-C-H alkylation of (hetero)arenes via rhodium catalysis under mild conditions is described. This approach features mild conditions with high levels of regio- and monoselectivity that tolerate a variety of aromatic and heteroaromatic groups and offers a widely applicable method for late-stage diversification of complex molecular architectures including tryptophan, estrone, diazepam, nucleosides, and nucleotides. Alkyl boronic acids and esters and alkyl trifluoroborates are demonstrated as suitable coupling partners. The isolation of key rhodium intermediates and mechanistic studies provided strong support for a rhodium(III/IV or V) regime.

Associations of Postoperative Hemoglobin Level and Clinical Outcomes in Patients Undergoing Mitral Valve Surgery.

BACKGROUND: Postoperative hemoglobin could indicate useful information for transfusion practices. The aim of this study was to investigate the association of optimal hemoglobin level and clinical outcomes after mitral valve surgery (MVS). METHODS: This investigation was a multicenter observational cohort study including 1,518 patients undergoing mitral valve surgery from 2016 through 2018. Patients were separated into six predefined groups based on initial postoperative hemoglobin (< 7.5 g/dL, 7.5 - 8.4 g/dL, 8.5 - 9.4 g/dL, 9.5 - 10.4 g/dL, 10.5 - 11.4 g/dL, ≥ 11.5 g/dL). Multivariable regression analysis was used to adjust laboratory results and surgical features of patients to evaluate the relationships between initial hemoglobin after MVS and clinical outcomes. RESULTS: Patients with initial postoperative hemoglobin below 7.5 g/dL had longer length of stays [mean (95% confidence interval [CI]), 1.9 (1.093 - 1.367)] in comparison with the reference group of 9.5 - 10.4 g/dL. Similarly, for those with hemoglobin below 7.5 g/dL, the odds (95% CI) for secondary outcomes included myocardial infraction 11.801 (1.353 - 22.966) and thrombosis 5.113 (1.340 - 9.508). However, for clinical outcomes, there was no significant difference between the five groups with hemoglobin greater than 7.5 g/dL. CONCLUSIONS: In patients after MVS, initial postoperative hemoglobin values below 7.5 g/dL was associated with worse outcomes compared to other values. Given similar outcomes between hemoglobin more than 7.5 g/dL groups, targeting treatment to an initial postoperative hemoglobin value at the lower value may be more desirable.

Heart-targeting exosomes from human cardiosphere-derived cells improve the therapeutic effect on cardiac hypertrophy.

Exosomes of human cardiosphere-derived cells (CDCs) are very promising for treating cardiovascular disorders. However, the current challenge is inconvenient delivery methods of exosomes for clinical application. The present study aims to explore the potential to enhance the therapeutic effect of exosome (EXO) from human CDCs to myocardial hypertrophy. A heart homing peptide (HHP) was displayed on the surface of exosomes derived from CDCs that were forced to express the HHP fused on the N-terminus of the lysosomal-associated membrane protein 2b (LAMP2b). The cardiomyocyte-targeting capability of exosomes were analyzed and their therapeutic effects were evaluated in a mouse model of myocardial hypertrophy induced by transverse aorta constriction (TAC). The molecular mechanisms of the therapeutic effects were dissected in angiotensin II-induced neonatal rat cardiomyocyte (NRCMs) hypertrophy model using a combination of biochemistry, immunohistochemistry and molecular biology techniques. We found that HHP-exosomes (HHP-EXO) accumulated more in mouse hearts after intravenous delivery and in cultured NRCMs than control exosomes (CON-EXO). Cardiac function of TAC mice was significantly improved with intravenous HHP-EXO administration. Left ventricular hypertrophy was reduced more by HHP-EXO than CON-EXO via inhibition of ß-MHC, BNP, GP130, p-STAT3, p-ERK1/2, and p-AKT. Similar results were obtained in angiotensin II-induced hypertrophy of NRCMs, in which the beneficial effects of HHP-EXO were abolished by miRNA-148a inhibition. Our results indicate that HHP-EXO preferentially target the heart and improve the therapeutic effect of CDCs-exosomes on cardiac hypertrophy. The beneficial therapeutic effect is most likely attributed to miRNA-148a-mediated suppression of GP130, which in turn inhibits STAT3/ERK1/2/AKT signaling pathway, leading to improved cardiac function and remodeling.