Preoperative Quantitative Flow Ratio, Intraoperative Transit Time Flow Measurement Parameters, and Their Predictive Value for Short-Term Graft Failure After Coronary Artery Bypass Grafting.

BACKGROUND: Studies on the relationship between the preoperative quantitative flow ratio (QFR) and parameters of intraoperative transit time flow measurement (TTFM) are extremely rare. In addition, the predictive value of QFR and TTFM parameters for early internal mammary artery (IMA) failure after coronary artery bypass grafting still needs to be validated.Methods and Results: We retrospectively collected data from 510 patients who underwent in situ IMA grafting to the left anterior descending (LAD) artery at Fuwai Hospital. Spearman correlation coefficients between preoperative QFR of the LAD artery and intraoperative TTFM parameters of the IMA were -0.13 (P=0.004) for mean graft flow (Qm) and 0.14 (P=0.002) for the pulsatility index (PI). QFR and TTFM exhibited similar and good predictive value for early IMA failure (5.7% at 1 year), and they were better than percentage diameter stenosis (area under the curve 0.749 for QFR, 0.733 for Qm, 0.688 for PI, and 0.524 for percentage diameter stenosis). The optimal cut-off value of QFR was 0.765. Both univariate and multivariable regression analyses revealed that QFR >0.765, Qm ≤15 mL/min, and PI >3.0 independently contributed to early IMA failure. CONCLUSIONS: There were statistically significant correlations between preoperative QFR of the LAD artery and intraoperative TTFM parameters (Qm, PI) of the IMA. Preoperative QFR and intraoperative Qm and PI exhibited excellent predictive value for early IMA failure.

Parallel evolution of fluconazole resistance and tolerance in Candida glabrata.

Introduction: With the growing population of immunocompromised individuals, opportunistic fungal pathogens pose a global health threat. Candida species, particularly C. albicans and non-albicans Candida species such as C. glabrata, are the most prevalent pathogenic fungi. Azoles, especially fluconazole, are widely used therapeutic options. Objective: This study investigates how C. glabrata adapts to fluconazole, with a focus on understanding the factors regulating fluconazole tolerance and its relationship to resistance. Methods: This study compared the factors regulating fluconazole tolerance between C. albicans and C. glabrata. We analyzed the impact of temperature on fluconazole tolerance, and requirement of calcineurin and Hsp90 for maintenance of fluconazole tolerance. We isolated colonies from edge, inside and outside of inhibition zone in disk diffusion assays. And we exposed C. glabrata strain to high concentrations of fluconazole and investigated the mutants for development of fluconazole resistance and tolerance. Results: We found temperature modulated tolerance in the opposite way in C. albicans strain YJB-T1891 and C. glabrata strain CG4. Calcineurin and Hsp90 were required for maintenance of fluconazole tolerance in both species. Colonies from inside and outside of inhibition zones did not exhibited mutated phenotype, but colonies isolated from edge of inhibition zone exhibited diverse phenotype changes. Moreover, we discovered that high concentrations (16-128 µg/mL) of fluconazole induce the simultaneous but parallel development of tolerance and resistance in C. glabrata, unlike the sole development of tolerance in C. albicans. Conclusion: This study highlights that while tolerance to fluconazole is a common response in Candida species, the specific molecular mechanisms and evolutionary pathways that lead to this response vary between species. Our findings emphasize the importance of understanding the regulation of fluconazole tolerance in different Candida species to develop effective therapeutic strategies.

Miconazole induces aneuploidy-mediated tolerance in Candida albicans that is dependent on Hsp90 and calcineurin.

Antifungal resistance and antifungal tolerance are two distinct terms that describe different cellular responses to drugs. Antifungal resistance describes the ability of a fungus to grow above the minimal inhibitory concentration (MIC) of a drug. Antifungal tolerance describes the ability of drug susceptible strains to grow slowly at inhibitory drug concentrations. Recent studies indicate antifungal resistance and tolerance have distinct evolutionary trajectories. Superficial candidiasis bothers millions of people yearly. Miconazole has been used for topical treatment of yeast infections for over 40 years. Yet, fungal resistance to miconazole remains relatively low. Here we found different clinical isolates of Candida albicans had different profile of tolerance to miconazole, and the tolerance was modulated by physiological factors including temperature and medium composition. Exposure of non-tolerant strains with different genetic backgrounds to miconazole mainly induced development of tolerance, not resistance, and the tolerance was mainly due to whole chromosomal or segmental amplification of chromosome R. The efflux gene CDR1 was required for maintenance of tolerance in wild type strains but not required for gain of aneuploidy-mediated tolerance. Heat shock protein Hsp90 and calcineurin were essential for maintenance as well as gain of tolerance. Our study indicates development of aneuploidy-mediated tolerance, not resistance, is the predominant mechanism of rapid adaptation to miconazole in C. albicans, and the clinical relevance of tolerance deserves further investigations.

Weighted gene co-expression network analysis and single-cell sequence analysis uncover immune landscape and reveal hub genes of necroptosis in macrophages in myocardial ischaemia-reperfusion injury.

Myocardial ischaemia-reperfusion injury (MIRI) caused by the treatment of acute myocardial infarction (AMI) is the primary cause of severe ventricular remodelling, heart failure (HF), and high mortality. In recent studies, research on the role of necroptosis in MIRI has focused on cardiomyocytes, but new biomarkers and immunocyte mechanisms of necroptosis are rarely studied. In the present study, weighted gene co-expression network analysis (WGCNA) algorithms were used to establish a weighted gene co-expression network, and Casp1, Hpse, Myd88, Ripk1, and Tpm3 were identified as biological markers of necroptosis using least absolute shrinkage, selection operator (LASSO) regression and support vector machine (SVM) feature selection algorithms. The role and discriminatory power of these five genes in MIRI had never been studied. Single-cell and cell-talk analyses showed that hub genes of necroptosis were focused on macrophages, which mediate the functions of monocytes, fibroblasts, haematopoietic stem cells, and cardiomyocytes, primarily through the TNF/TNFRSF1A interaction. The polarisation and functional activation of macrophages were affected by the MIF signalling network (MIF CD74/CXCR4 and MIF CD74/CD44) of other cells. The results of the immune infiltration assay showed that the five genes involved in necroptosis were significantly related to the infiltration and functional activity of M2 macrophages. TWS-119 is predicted to be a molecular drug that targets key MIRI genes. A mouse model was established to confirm the expression of five hub genes, and ventricular remodelling increased with time after ischaemia-reperfusion injury (IRI). Therefore, Casp1, Hpse, Myd88, Ripk1, and Tpm3 may be key genes regulating necroptosis and polarisation in macrophages, and causing ventricular remodelling.

Reaction Mechanism of Nitrogen-Containing Heterocyclic Compounds Affecting Coal Spontaneous Combustion.

To uncover the reaction mechanism of nitrogen-containing heterocyclic compounds affecting coal self-heating, quantum chemical calculations and X-ray photoelectron spectroscopy (XPS) experiments were applied to elucidate the reaction pathways and thermodynamic characteristics of pyrrole, pyridine, indole, quinoline, and carbazole. Results show that in pyrrole, pyridine, indole, quinoline, and carbazole, the reaction with O2 captures the H atom and leads to the formation of ·OOH and pyrrolyl, pyridinyl, indolyl, quinolinyl, and carbazolyl radicals, respectively. The activation energies are 118.15, 86.642, 34.132, 21.004, and 47.259 kJ/mol, respectively. ROO· formed by spontaneous adsorption of O2 by nitrogen-containing radicals undergoes self-reaction, and the O-O bond is broken and dehydrogenated to generate ·OH. Subsequently, at room temperature, ·OH reacts with pyrrole, pyridine, indole, quinoline, and carbazole, resulting in the formation of H2O and pyrrolyl, pyridinyl, indolyl, quinolinyl, and carbazolyl radicals, respectively, thereby forming a cyclic chain reaction. The XPS analysis yielded the following findings: (i) when the temperature rises to 70 °C, the N-5 and N-6 content decrease, which is attributed to the activation energy; (ii) when the temperature reaches 200 °C, the N-5 content decreases, which can be attributed to the activation energy required for the oxidation of pyrrole (118.5 kJ/mol).

Susceptibility to caspofungin is regulated by temperature and is dependent on calcineurin in Candida albicans.

IMPORTANCE: Echinocandins are the newest antifungal drugs and are first-line treatment option for life-threatening systemic infections. Due to lack of consensus regarding what temperature should be used when evaluating susceptibility of yeasts to echinocandins, typically either 30°C, 35°C, or 37°C is used. However, the impact of temperature on antifungal efficacy of echinocandins is unexplored. In the current study, we demonstrated that Candida albicans laboratory strain SC5314 was more susceptible to caspofungin at 37°C than at 30°C. We also found that calcineurin was required for temperature-modulated caspofungin susceptibility. Surprisingly, the altered caspofungin susceptibility was not due to differential expression of some canonical genes such as FKS, CHS, or CHT genes. The molecular mechanism of temperature-modulated caspofungin susceptibility is undetermined and deserves further investigations.

Effects of herpes zoster vaccination and antiviral treatment on the risk of stroke: a systematic review and meta-analysis.

Background: Evidence suggests that there is an increased risk of stroke after herpes zoster (HZ). However, reports on the effects of HZ vaccination (HZV) and antiviral treatment on stroke risk are inconsistent. Thus, we examined these associations in a meta-analysis. Methods: To identify relevant studies, we searched three databases for articles published up to January 2023. Random-effect models were examined to determine overall pooled estimates and 95% confidence intervals (CIs). Results: This review included 12 observational studies (six on HZV and seven on antiviral treatment). When comparing vaccinated and unvaccinated patients, vaccination was found to be associated with a lower risk of stroke (OR, 0.78; 95% CI 0.68-0.9; P = 0.001). A meta-analysis of self-controlled case series (SCCS) revealed evidence of a reduced OR in individuals who received the vaccine (OR, 1.14; 95% CI 0.94-1.37; P = 0.181) compared with unvaccinated individuals (OR, 1.36; 95% CI 1.15-1.61; P < 0.001). Compared with untreated patients, antiviral therapy was not associated with a reduced risk of stroke (OR, 1.13; 95% CI 0.94-1.36; P = 0.201). The meta-analysis of the SCCS showed no evidence of a reduced OR in individuals who received antiviral therapy (OR, 1.33; 95% CI 1.17-1.51; P < 0.001) compared to untreated individuals (OR, 1.45; 95% CI 1.25-1.69; P < 0.001). Conclusions: This meta-analysis suggests that the HZV, but not antiviral treatment, decreases the odds of developing stroke.

Effects of pH and salinity on survival, growth, and enzyme activities in juveniles of the sunray surf clam (Mactra chinensis Philippi).

The study investigated the impact of salinity and pH changes on the survival, growth, and antioxidant enzyme activity in Mactra chinensis Philippi (1.00 ± 0.10 cm shell length, 0.75 ± 0.04 cm shell height), a marine clam species. Juveniles were exposed to various pH levels (5.4 - 9.6) and salinities (5 - 35 psu) for up to 20 days at 19 ± 0.5 ˚C. The individual effect of salinity and pH on juveniles were evaluated under pH 8.0 and salinity 30 psu, respectively. The results indicated that the highest survival rates were observed at pH 8.0 (85%, salinity = 30 psu) and salinity 30 psu (95%, pH = 8.0). The survival rates were significantly reduced at extreme pH (≤ 7.2; ≥ 8.4) and salinities (≤ 15; 35 psu). Additionally, oxidative stress was observed in clams exposed to low pH and salinity as indicated by the decreased activities of the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD). Notably, no significant difference in relative growth rates was observed between salinity 25 and 30 psu, between pH 7.8/8.4 and pH 8.0. Our results provide information on potential impact of pH and salinity changes on economically important bivalve species and may be used to optimize pH and salinity in aquaculture.

Chromosome 1 trisomy confers resistance to aureobasidin A in Candida albicans.

Introduction: Candida albicans is a prevalent opportunistic human fungal pathogen. However, there are currently very few antifungal treatments available. Inositol phosphoryl ceramide synthase is an essential and fungal-specific protein that also provides a novel and promising antifungal target. Aureobasidin A is a widely used inhibitor of inositol phosphoryl ceramide synthase, however the mechanism of resistance to aureobasidin A is largely unknown in pathogenic fungi. Methods: Here we investigated how C. albicans adapted to low and high concentrations of aureobasidin A. Results and discussions: We identified trisomy of chromosome 1 as the predominant mechanism of rapid adaptation. Resistance to aureobasidin A was unstable because of the inherent instability of aneuploids. Importantly, chromosome 1 trisomy simultaneously regulated genes which were associated with aureobasidin A resistance that are on this aneuploid chromosome as well as on other chromosomes. Furthermore, the pleiotropic effect of aneuploidy caused altered resistance not only to aureobasidin A but also to other antifungal drugs including caspofungin and 5-flucytosine. We posit aneuploidy provides a rapid and reversible mechanism of development of drug resistance and cross resistance in C. albicans.

Sesquiterpene Lactones and Cancer: New Insight into Antitumor and Anti-inflammatory Effects of Parthenolide-Derived Dimethylaminomicheliolide and Micheliolide.

Applied science nowadays works on the isolation and application of biological macromolecules (BMM). These BMM are isolates from plants using different techniques and used as anticancer, antimicrobial, and anti-inflammatory drugs. Parthenolide (PLT) is one of the most important biological macromolecules and a naturally occurring sesquiterpene lactone that is isolated from a plant species Tanacetum parthenium (T. parthenium). The anti-cancer and anti-inflammatory effects of PTL isolated from T. parthenium were previously reported and summarized in detail. These biological activities make it a vital candidate for further researches and drugs development. As per the previously obtained findings, the sesquiterpene is very much known for some biological activities; therefore, the anti-cancer and anti-inflammatory activities of the sesquiterpene were critically reviewed. During the research process, PTL was found to be unstable in both acidic and basic conditions with low solubility, so structurally related compounds micheliolide (MCL) and Dimethylaminomicheliolide (DMAMCL) (a prodrug of MCL) were developed. In this article, we briefly review the therapeutic effects of PTL and its derivative DMAPT on inflammatory diseases and tumors, focusing on the current application of PTL in targeted therapy and combination therapy, together with anti-inflammatory and anti-tumor functions of MCL and DMAMCL. The uniqueness of this biological macromolecule is not to harm the normal cell but target the cancerous cells. Therefore, the current literature review might be helpful and useful for prospects based on the effects of MCL and DMAMCL on cancer.

Generation of two ERF gene knockout human embryonic stem cell lines using CRISPR/Cas9 system.

Human ERF gene is a transcription factor involved in development, trophoblast differentiation, apoptosis, and cancer progress. To further understand the exact roles of ERF in these processes, here we report that establishment of two ERF knockout human embryonic stem cell (hESC) lines by CRISPR/Cas9 mediated gene targeting. These cell lines exhibited classical hESC morphology and normal karyotype, and highly expressed pluripotent markers, and had differentiation potential in vitro. These cell lines provide good materials to understand the roles of ERF in development, trophoblast differentiation and craniosynostosis for further studies.

11ß-Hydroxysteroid dehydrogenase 1 inhibition attenuates collagen-induced arthritis.

11ß-Hydroxysteroid dehydrogenase 1 (11ß-HSD1) plays an important role in inflammation. However, the role of 11ß-HSD1 in rheumatoid arthritis (RA) remains unknown. The purpose of this study was to evaluate the therapeutic effects of a selective 11ß-HSD1 inhibitor BVT-2733 in collagen-induced arthritis (CIA) and its underlying mechanisms. CIA mice were treated with BVT-2733 (100 mg/kg, orally) or vehicle twice daily for 2 weeks. Arthritis score and joint histology were investigated. The levels of pro-inflammatory cytokines as well as anti-type II collagen antibody (anti-CII) were detected by ELISA. Western blot analysis was used to assess the activation of NF-κB and NLRP1 inflammasome in joint tissues and in human RA synovial cells. BVT-2733 treatment attenuated the arthritis severity and anti-CII level in CIA mice. BVT-2733 also decreased the levels of serum TNF-α, IL-1ß, IL-6 and IL-17. BVT-2733 treatment also significantly reduced synovial inflammation and joint destruction. NF-κB activation and NLRP1 inflammasome assembly were also inhibited in arthritic joints and human RA synovial cells. In conclusion, BVT-2733 exhibits an anti-inflammatory effect on CIA. This protective effect is, at least partly, mediated by inhibition of the NF-κB and NLRP1 inflammasome signaling pathways. 11ß-HSD1 inhibition may represent a potential therapeutic target for RA patients.