Candida albicans
is the most common cause of fungal infection. The emergence of drug resistance leads to the need for novel antifungal agents. We aimed to design naphthofuranquinone analogs to treat ...drug-resistant
C. albicans
for topical application on cutaneous candidiasis. The time-killing response, agar diffusion, and live/dead assay of the antifungal activity were estimated against 5-fluorocytosine (5-FC)- or fluconazole-resistant strains. A total of 14 naphthofuranquinones were compared for their antifungal potency. The lead compounds with hydroxyimino (TCH-1140) or
O
-acetyl oxime (TCH-1142) moieties were the most active agents identified, showing a minimum inhibitory concentration (MIC) of 1.5 and 1.2 μM, respectively. Both compounds were superior to 5-FC and fluconazole for killing planktonic fungi. Naphthofuranquinones efficiently diminished the microbes inside and outside the biofilm. TCH-1140 and TCH-1142 were delivered into
C. albicans
-infected keratinocytes to eradicate intracellular fungi. The compounds did not reduce the
C. albicans
burden inside the macrophages, but the naphthofuranquinones promoted the transition of fungi from the virulent hypha form to the yeast form. In the
in vivo
skin mycosis mouse model, topically applied 5-FC and TCH-1140 reduced the
C. albicans
load from 1.5 × 10
6
to 5.4 × 10
5
and 1.4 × 10
5
CFU, respectively. The infected abscess diameter was significantly decreased by TCH-1140 (3-4 mm) as compared to the control (8 mm). The disintegrated skin-barrier function induced by the fungi was recovered to the baseline by the compound. The data support the potential of TCH-1140 as a topical agent for treating drug-resistant
C. albicans
infection without causing skin irritation.
Synthesis of type I LacNAc (Galβ1 → 3GlcNAc) oligosaccharides usually suffers from low yields. We herein report the efficient synthesis of type I LacNAc oligosaccharides by chemoselective ...glycosylation. With 16 relative reactivity values (RRVs) measured thiotoluenyl-linked disaccharide donors and acceptors, chemoselective glycosylations were investigated to obtain optimal conditions. In these reactions, the RRV difference between the donors and acceptors had to be more than 6311 to obtain type I LacNAc tetrasaccharides in 72–86% yields, with minimal occurrence of aglycon transfer. The threshold of RRV difference was further applied to plan the synthesis of longer glycans. Because it is challenging to measure the RRVs of tetrasaccharides, anomeric proton chemical shifts were utilized to predict the corresponding RRVs, which consequently explained the outcome of glycosylations for the synthesis of type I LacNAc hexasaccharides. The result supported the idea that elongation of glycan chains has to proceed from the reducing to the nonreducing end for a better yield.
In this work, two asymmetric non-fullerene acceptors (NFAs), BTP-EHBO-4F and BTP-PHD-4F, are designed to be applied in green-solvent-processable organic photovoltaics (OPVs). BTP-EHBO-4F and ...BTP-PHD-4F show good solubilities in green solvent o-xylene. As a result, PM6:BTP-EHBO-4F-based devices exhibit outstanding photovoltaic performances using o-xylene as a solvent. By comparison, due to the poor solubility of Y6 in o-xylene, PM6:Y6-based devices show poor performances. Owing to the favorable phase separation, molecule packing, and orientation observed from atomic force microscopy (AFM) and grazing-incidence wide-angle X-ray scattering (GIWAXS) measurements, PM6:BTP-PHD-4F-based devices demonstrate a PCE of 15.91% with a V OC of 0.87 V, a J SC of 25.64 mA/cm2, and an FF of 71.34%. Moreover, PM6:BTP-EHBO-4F-based devices exhibit an impressive PCE of 16.82% with a V OC of 0.85 V, a J SC of 26.12 mA/cm2, and an FF of 75.78%, which is outstanding for OPVs using o-xylene as a solvent.
OBJECTIVE:To investigate the risk and genetic association of oxcarbazepine-induced cutaneous adverse reactions (OXC-cADRs), including Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), in ...Asian populations (Chinese and Thai).
METHODS:We prospectively enrolled patients with OXC-cADRs in Taiwan and Thailand from 2006 to 2014, and analyzed the clinical course, latent period, drug dosage, organ involvement, complications, and mortality. We also investigated the carrier rate of HLA-B*15:02 and HLA-A*31:01 of patients with OXC-cADRs and compared to OXC-tolerant controls. The incidence of OXC-SJS/TEN was compared with carbamazepine (CBZ)–induced SJS/TEN according to the nationwide population dataset from the Taiwan National Health Insurance Research Database.
RESULTS:We enrolled 50 patients with OXC-cADRs, including 20 OXC-SJS/TEN and 6 drug reaction with eosinophilia and systemic symptoms, of Chinese patients from Taiwan and Thai patients from Thailand. OXC-cADRs presented with less clinical severity including limited skin detachment (all ≦5%) and no mortality. There was a significant association between HLA-B*15:02 and OXC-SJS (p = 1.87 × 10; odds ratio 27.90; 95% confidence interval CI 7.84–99.23) in Chinese and this significant association was also observed in Thai patients. The positive and negative predictive values of HLA-B*15:02 for OXC-SJS/TEN were 0.73% and 99.97%, respectively. HLA-A*31:01 was not associated with OXC-cADRs. The incidence and mortality of OXC-SJS/TEN was lower than CBZ-STS/TEN in new users (p = 0.003; relative risk 0.212; 95% CI 0.077–0.584).
CONCLUSIONS:Our findings suggest that HLA-B*15:02 is significantly associated with OXC-SJS in Asian populations (Chinese and Thai). However, the severity and incidence of OXC-SJS/TEN are less than that of CBZ-SJS/TEN. The need for preemptive HLA-B*15:02 screening should be evaluated further.
IκB kinase β (IKKβ) is involved in tumor development and progression through activation of the nuclear factor (NF)-κB pathway. However, the molecular mechanism that regulates IKKβ degradation remains ...largely unknown. Here, we show that a Cullin 3 (CUL3)-based ubiquitin ligase, Kelch-like ECH-associated protein 1 (KEAP1), is responsible for IKKβ ubiquitination. Depletion of KEAP1 led to the accumulation and stabilization of IKKβ and to upregulation of NF-κB-derived tumor angiogenic factors. A systematic analysis of the CUL3, KEAP1, and RBX1 genomic loci revealed a high percentage of genome loss and missense mutations in human cancers that failed to facilitate IKKβ degradation. Our results suggest that the dysregulation of KEAP1-mediated IKKβ ubiquitination may contribute to tumorigenesis.
Aneuploidy occurs within a significant proportion of childhood B-cell acute lymphoblastic leukemia (B-ALL). Some copy number variations (CNV), associated with novel subtypes of childhood B-ALL, have ...prognostic significance. A total of 233 childhood B-ALL patients were enrolled into this study. Focal copy number alterations of ERG, IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A/2B, and the Xp22.33/Yp11.31 region were assessed by Multiplex Ligation-dependent Probe Amplification (MLPA). The MLPA telomere kit was used to identify aneuploidy through detection of whole chromosome loss or gain. We carried out these procedures alongside measurement of DNA index in order to identify, aneuploidy status in our cohort. MLPA telomere data and DNA index correlated well with aneuploidy status at higher sensitivity than cytogenetic analysis. Three masked hypodiploid patients, undetected by cytogenetics, and their associated copy number neutral loss of heterozygosity (CN-LOH) were identified by STR and SNP arrays. Rearrangements of TCF3, located to 19p, were frequently associated with 19p deletions. Other genetic alterations including iAMP21, IKZF1 deletions, ERG deletions, PAX5
, which have clinical significance or are associated with novel subtypes of ALL, were identified. In conclusion, appropriate application of MLPA aids the identifications of CNV and aneuploidy in childhood B-ALL.
While considerable evidence supporting the positive influence of acute exercise on cognitive inhibition, little is known regarding the underlying cognitive processes. There is also little ...neuroelectric evidence regarding the effects on older adults of acute exercise-elicited cognitive benefits. Thus, our objective was to explore the possible neural markers underlying improved cognitive inhibition, with particular attention to the N450 and P3 components, following acute exercise. Another aim was to investigate whether cognitive gains seen in young adults are replicated in older adults. Twenty-four young males and 20 older males underwent either a single bout of aerobic exercise or video-watching in counterbalanced order. Afterwards, cognitive inhibition was assessed by the Stroop test. Results revealed that acute exercise resulted in shorter response time regardless of age or congruency. Regarding the neuroeletric data, acute exercise resulted in larger P3 amplitude and smaller N450 amplitude regardless of congruency or age. Further, following exercise, changes in response time interference were correlated with changes in incongruent N450 amplitude. Collectively, acute exercise-facilitated conflict monitoring and attention control, as signified by the N450 and P3 components, may be the underlying processes leading to better Stroop performance, with conflict monitoring having a stronger association with task performance. Further, cognitive gains resulting from acute exercise were found to the same extent in both young and older adults.
Purpose
There are few reports describing ventricular arrhythmias (VAs) from the crux and the corresponding endocardial site, i.e., the basal inferior segment of the interventricular septum (IVS). We ...aimed to investigate a distinct clinical group of VAs arising from the endocardium at this area in patients with structural heart diseases (SHD).
Methods
We included 17 patients with SHD and clinically documented VAs. Thirteen patients underwent endocardial mapping only. Three patients underwent both epicardial and endocardial approaches and one had only epicardial mapping. Eighteen VAs were identified, 14 focal and 4 reentrant VAs, confirmed by entrainment.
Results
There were 2 VAs from the crux, 5 VAs from the corresponding endocardial site in the right ventricle (RV), and 11 from the site in the left ventricle (LV). Compared with the VAs from RV endocardium, VAs from LV endocardium had a higher R wave in V3 than V2 (V2R/V3R ratio, 1.83 ± 0.84 vs. 0.86 ± 0.38,
P
= 0.008) and a higher V3 transition ratio percentage (2.16 ± 2.07 vs. 0.58 ± 0.62,
P
= 0.008). Combining all 16 patients with endocardial mapping, there were also lower bipolar voltages (1.21 ± 1.05 vs. 3.10 ± 2.65 mv,
P
< 0.0001), lower unipolar voltages (4.05 ± 1.92 vs. 5.75 ± 2.90 mv,
P
< 0.0001), and longer local electrocardiogram (EGM) lateness (157.6 ± 47.9 vs.140.3 ± 52.5 ms,
P
= 0.0001) in the dominant chambers.
Conclusions
In VAs from the crux and the corresponding endocardial site, the complete ECG V2R/V3R ratio and V3 transition ratio percentage could differentiate the VAs from the RV or LV endocardium. The lower unipolar, bipolar voltage mapping, and longer EGM lateness are helpful to identify the abnormal substrate in the endocardium in these patients.
This work fabricates a fishnet grating by exerting two one-dimensional (1D) holographic interference fields with mutually orthogonal grating vectors separately on the substrates of a dye-doped liquid ...crystal (DDLC) cell. The DDLC mixture in the cell includes a nematic LC, methyl red (MR) dye, and 4-methoxyazobenzene (4MAB) dye. The fishnet grating is formed because the periodical adsorption of the MR dye on the irradiated surfaces of the cell causes the anisotropic photoalignment of the LC. The fishnet grating can be erased (recovered) by the illumination of a UV (green) beam since the
trans
→
cis
(
cis
→
trans
) isomerization of the 4MAB dye causes the isothermal nematic → isotropic (isotropic → nematic) phase transition of the LC. Such a grating can be used to develop optically controllable photonic crystals. Simulated results depict that a photoresist-coated plastic substrate that is exposed to the fishnet pattern of a 2D grating can be used to develop terahertz fishnet metamaterials, and their resonance spectra can be passively tuned by moving the substrate and lens that forms the fishnet pattern during fabrication. Therefore, the mask-free photolithography can be used to fabricate passively tunable terahertz filters.
This work fabricates a fishnet grating by exerting two one-dimensional (1D) holographic interference fields with mutually orthogonal grating vectors separately on the substrates of a dye-doped liquid crystal (DDLC) cell.
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•BL21 harboring pdxY under the J23100 promoter resulted in highest yield of PLP.•pdxK plays a critical role in accumulation of PLP for biotransformation.•Lysine was 100 % converted to ...cadaverine in co-expressing pdxK and CadA.•Cadaverine biotransformation was enhanced for in vivo and in vitro applications.•Whole-cell biocatalyst achieved the highest cadaverine productivity of 121 g/L/h.
Cadaverine is a five-carbon diamine which serves as an important biochemical for the synthesis of bio-based nylon. It can be produced by the bioconversion of l-lysine with lysine decarboxylase (CadA; EC 4.1.1.18) and relies on cofactor pyridoxal 5′-phosphate (PLP), thus to recycle PLP from the super-salvage pathway by the genes of pdxH, pdxY, and pdxK in Escherichia coli is crucial and urgent. In this study, the optimal PLP production per gram dry cell weight (i.e., 7008 nmol/g-DCW) increased 30-fold in E. coli BL21 by overexpressing pdxY. Cadaverine production reached 34.7 g/L or 41.2 g/L by in vivo CadA co-expression with plasmids of pJY or pPK. The better conversion was obtained in APK strain (co-expressing CadA and pPK) via whole cell biotransformation, resulting in 97 % and 68 % conversion of 0.4 M and 1.2 M L-lysine to 39.6 g/L and 83.2 g/L cadaverine, respectively. Finally, cold shock treatment of whole-cell biocatalyst showed a significant increasing and achieved the highest cadaverine productivity of 121 g/L/h compared to the previous reports.
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