Synchrotron X-Ray Analysis and Morphology Evidence for Stereo-Assemblies of Periodic Aggregates in Poly(3-hydroxybutyrate) with Unusual Photonic Iridescence.

3D morphology of poly(3-hydroxybutyrate) (PHB), crystallized in the presence of diluents of poly(1,3-trimethylene adipate) and poly(ethylene oxide), is probed using a novel approach coupled with selective etching. For interpreting the mechanisms of crystal periodic aggregation, various microscopic techniques and synchrotron microbeam X-ray analysis are used to observe the top surface in connection with the 3D crystal assemblies. Periodic grating architectures, with the cross-bar pitch exactly matching with the optical band spacing, are proved in banded PHB. The crystals under the ridge branch out to spawn finer crystals orienting/bending horizontally underneath the valley band, repeating till species drainage or impingement. The grating structure in the banded PHB resembles many nature's iridescence crystals and is further proved by photonic reflection results as a critical breakthrough novel finding.

A study on how using an interactive multimedia e-book improves teachers' ability to teach evidence-based medicine depending on their seniority.

BACKGROUND: Teaching evidence-based medicine (EBM) is not an easy task. The role of the electronic book (e-book) is a useful supplement to traditional methods for improving skills. Our aim is to use an interactive e-book or PowerPoint to evaluate instructors' teaching effects on EBM. METHODS: Our study group was introduced to learning EBM using an interactive e-book available on the Internet, while the control group used a PowerPoint presentation. We adopted the Modified Fresno test to assess EBM skills both before and after their learning. EBM teaching sessions via e-book or PowerPoint were 20-30 min long, followed by students' feedback. We adopted Student's t-test to compare teachers' evaluation of their EBM skills prior to the class and the students' assessment of the teachers' instruction. We also adopted repeated measures ANCOVA to compare teachers' evaluation of their EBM skills using the Fresno test both before and after the class. RESULTS: We observed no difference regarding EBM skills between the two groups prior to their experimental learning, which was assessed by the Modified Fresno test. After learning, physicians in the study group ranked higher in choosing a case to explain which kind of research design was used for the study type of the question and explaining their choice (P = 0.024) as assessed by the post-test to pre-test Fresno test. Teaching effect was better in the e-book group than in the control group for the items, "I am satisfied with this lesson," "The teaching was of high quality," "This was a good teaching method," and "It aroused my interest in EBM." However, no differences were observed between the two groups in physicians who had more than 10 years' experience. CONCLUSIONS: The use of interactive e-books in clinical teaching can enhance a teacher's EBM skills, though not in more senior physicians. This may suggest that teaching methodology and activities differ for teachers' varying years of experience.

Machine Learning Methods Applied to Predict Ventilator-Associated Pneumonia with Pseudomonas aeruginosa Infection via Sensor Array of Electronic Nose in Intensive Care Unit.

One concern to the patients is the off-line detection of pneumonia infection status after using the ventilator in the intensive care unit. Hence, machine learning methods for ventilator-associated pneumonia (VAP) rapid diagnose are proposed. A popular device, Cyranose 320 e-nose, is usually used in research on lung disease, which is a highly integrated system and sensor comprising 32 array using polymer and carbon black materials. In this study, a total of 24 subjects were involved, including 12 subjects who are infected with pneumonia, and the rest are non-infected. Three layers of back propagation artificial neural network and support vector machine (SVM) methods were applied to patients' data to predict whether they are infected with VAP with Pseudomonas aeruginosa infection. Furthermore, in order to improve the accuracy and the generalization of the prediction models, the ensemble neural networks (ENN) method was applied. In this study, ENN and SVM prediction models were trained and tested. In order to evaluate the models' performance, a fivefold cross-validation method was applied. The results showed that both ENN and SVM models have high recognition rates of VAP with Pseudomonas aeruginosa infection, with 0.9479 ± 0.0135 and 0.8686 ± 0.0422 accuracies, 0.9714 ± 0.0131, 0.9250 ± 0.0423 sensitivities, and 0.9288 ± 0.0306, 0.8639 ± 0.0276 positive predictive values, respectively. The ENN model showed better performance compared to SVM in the recognition of VAP with Pseudomonas aeruginosa infection. The areas under the receiver operating characteristic curve of the two models were 0.9842 ± 0.0058 and 0.9410 ± 0.0301, respectively, showing that both models are very stable and accurate classifiers. This study aims to assist the physician in providing a scientific and effective reference for performing early detection in Pseudomonas aeruginosa infection or other diseases.

Roles of transcriptional factor PsrA in the regulation of quorum sensing in Pseudomonas aeruginosa PAO1.

The transcription factor PsrA regulates fatty acid metabolism, the type III secretion system, and quinolone signaling quorum sensing system in Pseudomonas aeruginosa. To explore additional roles of PsrA in P. aeruginosa, this study engineered a P. aeruginosa PAO1 strain to carry a recombinant plasmid with the psrA gene (pMMBpsrA) and examined the impact of elevated psrA expression to the bacterium. Transcriptomic analysis revealed that PsrA significantly downregulated genes encoding the master quorum-sensing regulators, RhlR and LasR, and influenced many quorum-sensing-associated genes. The role of PsrA in quorum sensing was further corroborated by testing autoinducer synthesis in PAO1 [pMMBpsrA] using two reporter bacteria strains Chromobacterium violaceum CV026 and Escherichia coli [pSB1075], which respond to short- and long-chain acyl homoserine lactones, respectively. Phenotypic comparisons of isogenic ΔpsrA, ΔlasR, and ΔpsrAΔlasR mutants revealed that the reduced elastase, caseinase, and swarming activity in PAO1 [pMMBpsrA] were likely mediated through LasR. Additionally, electrophoretic mobility shift assays demonstrated that recombinant PsrA could bind to the lasR promoter at a 5'-AAACGTTTGCTT-3' sequence, which displays moderate similarity to the previously reported consensus PsrA binding motif. Furthermore, the PsrA effector molecule oleic acid inhibited PsrA binding to the lasR promoter and restored several quorum sensing-related phenotypes to wild-type levels. These findings suggest that PsrA regulates certain quorum-sensing phenotypes by negatively regulating lasR expression, with oleic acid acting as a crucial signaling molecule.

Antireflection of optical anisotropic dielectric metasurfaces.

We propose a hetero-nano-fin structure to further improve the efficiency of Pancharatnam-Berry phase metasurfaces. Two hetero-nano-fin types, MgF2/GaN and MgF2/Nb2O5, were investigated. The overall polarization conversion efficiency (PCE) improved from 52.7 to 54% for the MgF2/GaN nano-fin compared with the bare GaN nano-fin. The overall PCE of the Nb2O5 nano-fin was 1.7 times higher than that of the GaN nano-fin. The overall PCE improved from 92.4% up to 96% after the application of MgF2 antireflection. Moreover, the antireflection improves efficiency by an average of 4.3% in wavelengths from 450 to 700 nm. Although the increment of energy seems minimal, antireflection is crucial for a metasurface, not only enhancing efficiency but also reducing background signal of a meta-device.

The relationship between sovereign credit rating changes and firm risk.

Sovereign credit ratings, extensively studied for their influence on macroeconomics and country risk, have been less explored in the context of their impact on individual firms. This research delves into the effects of sovereign credit rating changes on firm risk. Our findings suggest that an upgrade in sovereign credit ratings decreases firm risk, while a downgrade amplifies it. Furthermore, the magnitude of a country's rating shift positively correlates with changes in firm risk. We also discern a contagion effect between trade-dependent countries: an elevated rating in one country diminishes the firm risk in its trading partner, and vice versa. When categorizing our data into developed and developing markets, we observe that firm risk in developed markets reacts more acutely to rating upgrades. Conversely, rating downgrades, whether domestic or in trade-associated countries, intensify firm risk in developing markets. A robustness check, which evaluates sovereign credit rating fluctuations outside of financial crises, corroborates our core findings.

Beneficial effect of probiotics on Pseudomonas aeruginosa-infected intestinal epithelial cells through inflammatory IL-8 and antimicrobial peptide human beta-defensin-2 modulation.

The human pathogen Pseudomonas aeruginosa can rapidly induce fatal sepsis, even in previously healthy infants or children treated with appropriate antibiotics. To reduce antibiotic overuse, exploring novel complementary therapies, such as probiotics that reportedly protect patients against P. aeruginosa infection, would be particularly beneficial. However, the major mechanism underlying the clinical effects is not completely understood. We thus aimed to investigate how probiotics affect IL-8 and human beta-defensin 2 (hBD-2) in P. aeruginosa-infected intestinal epithelial cells (IECs). We infected SW480 IECs with wild type PAO1 P. aeruginosa following probiotic treatment with Lactobacillus rhamnosus GG or Bifidobacterium longum spp. infantis S12, and analysed the mRNA expression and secreted protein of IL-8 and hBD-2, Akt signalling and NOD1 receptor protein expression. We observed that probiotics enhanced hBD-2 expression but suppressed IL-8 responses when administered before infection. They also enhanced P. aeruginosa-induced membranous NOD1 protein expression and Akt activation. The siRNA-mediated Akt or NOD1 knockdown counteracted P. aeruginosa-induced IL-8 or hBD-2 expression, indicating regulatory effects of these probiotics. In conclusion, these data suggest that probiotics exert reciprocal regulation of inflammation and antimicrobial peptides in P. aeruginosa-infected IECs and provide supporting evidence for applying probiotics to reduce antibiotic overuse.

Fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides as antitumor agents against CRC and NSCLC cancer cells.

A major cause of failure of therapy in patients with non-small cell lung cancer (NSCLC) is development of acquired drug resistance leading to tumor recurrence and disease progression. In addition to the development of new generations of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), different molecular targets may provide opportunities to improve the therapeutic outcomes. In this study, we utilized the core structure 5-fluorouracil (5-FU) or tegafur, a 5-FU prodrug combined through different linkers with resorcinol to generate a series of fluoropyrimidin-2,4-dihydroxy-5-isopropylbenzamides which inhibit potent Heat Shock Protein 90 (HSP90). These compounds were found to show significant antiproliferative activity in colorectal cancer (CRC) HCT116 and NSCLC A549, H460, and H1975 (EGFR L858R/T790 M double mutation) cells. Compound 12c, developed by molecular docking analysis and enzymatic assays exhibits promising inhibitory activity of HSP90. This compound, 12c shows the most potent HSP90 inhibitory activity with an IC50 value of 27.8 ± 4.4 nM, superior to that of reference compounds AUY-922 (Luminespib) and BIIB021 whose IC50 values are 43.0 ± 0.9 nM and 56.8 ± 4.0 nM respectively. This strong HSP90 inhibitory activity of 12c leads to rapid degradation of client proteins EGFR and Akt in NSCLC cells. In addition, 12c induces significant accumulation of a sub-G1 phase population in parallel with apoptosis by showing activated caspase-3, -8 and -9 and PARP induction. These results provide a new strategy for development of novel HSP90 inhibitors for cancer treatment.

Design, synthesis, and evaluation of N-phenyl-4-(2-phenylsulfonamido)-benzamides as microtubule-targeting agents in drug-resistant cancer cells, displaying HDAC inhibitory response.

Microtubule-targeting agents (MTA) have enjoyed significant clinical success for decades. However, several mechanisms may cause inactivation of such drugs, leading to acquired resistance in patients treated with them. Therefore, drugs containing a stilbene-like skeleton and possessing dual inhibitory activity may provide a new and differentiated treatment for patients to overcome challenging acquired resistance. A new compound (16c) displays promising anticancer activity with GI50 of 22 ± 2 and 12 ± 0.1 nM in vincristine-resistant nasopharyngeal (KB-Vin) cancer cells and etoposide-resistant nasopharyngeal (KB-7D) cancer cells and is better than vincristine, etoposide, ABT-751, and MS-275. A mechanistic study revealed that 16c interferes with the cell cycle distribution and induces cell cycle arrest at the G2/M phase and severe mitotic spindle defects followed by apoptosis. In addition, it produces much more significant cytotoxicity than vincristine and etoposide in the corresponding resistant cells, indicating that it may be a promising candidate to overcome drug resistance in cancer cells. Compound 16c also displays inhibitory activity against HDAC 1 and HDAC 2 with IC50 values of 1.07 µM, and 1.47 µM, respectively. These findings may lead to a new type of structural motif for future development of drugs that could overcome acquired resistance to MTAs.

MPT0G612, a Novel HDAC6 Inhibitor, Induces Apoptosis and Suppresses IFN-γ-Induced Programmed Death-Ligand 1 in Human Colorectal Carcinoma Cells.

Colorectal cancer (CRC) is the third most common cancer and the leading cause of cancer-associated death worldwide. Histone deacetylases (HDACs) have been implicated in regulating complex cellular mechanisms to influence tumor biology and immunogenicity in various types of cancer. The potential of selective inhibition of HDAC6 has been widely discussed for the treatment of hematologic malignancies. We previously identified that MPT0G612 is a novel HDAC6 inhibitor exhibiting a promising antitumor activity against several solid tumors. The purpose of the present study was to evaluate the feasibility and pharmacological mechanisms of MPT0G612 as a potential therapy for CRC patients. Results revealed that MPT0G612 significantly suppresses the proliferation and viability, as well as induces apoptosis in CRC cells. Autophagy activation with LC3B-II formation and p62 degradation was observed, and the inhibition of autophagy by pharmacological inhibitor or Atg5 knockdown enhances MPT0G612-induced cell death. In addition, HDAC6 knockdown reduces MPT0G612-mediated autophagy and further potentiates apoptotic cell death. Furthermore, MPT0G612 downregulates the expression of PD-L1 induced by IFN-γ in CRC cells. These results suggest that MPT0G612 is a potent cell death inducer through inhibiting HDAC6-associated pathway, and a potential agent for combination strategy with immune checkpoint inhibitors for the treatment of CRC.