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Background Growing evidence has revealed abnormalities in the retinal structure of patients with alopecia areata (AA). However, the relationship between AA and retinopathy remains unclear. Objective To investigate the association between AA and retinal diseases. Method The study participants were recruited from the National Health Insurance Research Database in Taiwan. We included 9,909 patients with AA and 99,090 matched controls to assess the risk of retinal diseases. A Cox regression model was used for all analyses. Results Compared with the controls, patients with AA had an adjusted hazard ratio (aHR) of 2.96 (95% confidence interval [CI], 2.20–3.98) for retinal diseases. With respect to individual retinal disease, AA patients had a significantly higher risk of developing retinal detachment (aHR, 3.80; 95% CI, 1.97–7.31), retinal vascular occlusion (aHR, 2.14; 95% CI, 1.09–4.19), and retinopathy (aHR 3.18; 95% CI 2.21–4.57) than controls. Limitations This is a retrospective cohort study. Meanwhile, almost all the participating individuals were residents of Taiwan; therefore, the validity of our findings in other demographics remains unclear. Conclusion Patients with AA had a significantly higher risk of retinal disease than the controls. Further studies are needed to clarify the pathophysiology of AA and retinal diseases.

Aims: To investigate the efficacy and safety of Cerebrolysin and Cerebrolysin plus nootropics in the routine treatment of patients with acute ischemic stroke (AIS). Background: Acute ischemic stroke (AIS) is a leading cause of disability with unmet treatment needs lacking effective drug therapy. Multimodal drugs modulating stroke pathophysiology as Cerebrolysin constitute a good therapeutic option. Objective: In this study, we assessed the effects of Cerebrolysin and Cerebrolysin plus nootropics, in comparison with other nootropic drugs alone, on functional, neurological and cognitive recovery of patients with AIS in Vietnam. Methods.: This non-interventional, controlled, open-label, prospective and multicenter study included 398 AIS patients (234 males) treated with Cerebrolysin (n=190; 20 i.v. infusions of 10 ml), other nootropics (comparator group; n=86), or a combination of both (n=122). The study primary endpoint was the modified Ranking Scale (mRS) score on day 90. Secondary endpoints included study-period change in NIHSS score; percentage of well-recovered (mRS 0-2) patients, the proportion of good NIHSS response (≥6 points) cases, and MoCA scores at day 90; and safety indicators. Results: Compared with other nootropics, both Cerebrolysin and combined therapy induced significant improvements (p11) cases only. No drug-related adverse events were reported. Conclusion: Cerebrolysin alone or combined with other nootropics was effective and safe in routine AIS treatment, during both acute and recovery phases, which supports its use in daily clinical practice. Other: According to the results of this multicenter study, the importance of reducing differences in the treatment regimens of AIS in Vietnam should be further emphasized.

We have fabricated a new perylene bisimide (PBI) folda-dimer (BPBI-CB-1) by tethering two PBI moieties to the ortho-carbon positions of a carborane unit. The synthesized compound adopted distinct c...

In this study, waste glass was alkali-activated by activators with different amounts of sodium hydroxide and subjected to aging. The chemical reactions and resulting microstructures and properties of the alkali-activated glass inorganic binders (AAGIBs) were affected by the aging temperature and duration. An activation energy approach was used to evaluate the effects of aging temperature and duration on the 4-day compressive strengths of the AAGIB specimens. When the amount of sodium hydroxide in the activators was low, the activation energies for the dissolution and polycondensation reactions of the AAGIBs were 83.3 kJ/mol and 44.6 kJ/mol, respectively. As the weight fraction of sodium oxide (FSO) in the activators was increased, the microstructure of the hardened binder was destroyed because of vigorous stirring during aging. Consequently, the activation energy of the AAGIB polycondensation reaction increased to 76.2 kJ/mol when FSO > 5%.

We synthesized and developed 1,3-dihydro-2H-imidazo[4,5-b]phenazine-2-thione as a ratiometric chemosensor for Hg2+ recognition in a DMSO/H2O (v/v = 9:1) binary solution. We rationally introduced the phenazine imidazole group as the fluorophore and the thione moiety as the recognition site to bind Hg2+. Interestingly, the chemosensor showed an ultrasensitive response to Hg2+, and the lowest limit of detection was 0.167 nM. In addition, it can also separate Hg2+ from aqueous solutions with excellent ingestion capacity, with an adsorption ratio of up to 96%. Furthermore, ion test strips based on chemosensors were fabricated for convenient and efficient detection of Hg2+.

Isoflavones in soybean seed and root exudates are host-specific signal molecules for Phytophthora sojae to recognize its host, soybean. G protein and calcium signaling pathways are involved in the chemotaxis of zoospores in the recognition of isoflavones. The role played by non-host-specific signaling molecules (sugars and amino acids) found in seed and root exudates on zoospore chemotaxis and mycelial growth was studied. The transcriptome of P. sojae responding to aspartic acid (Asp) and glucose (Glc) was analyzed in parellel by the RNA-seq method. We found that the relative in situ concentrations of amino acids and sugars significantly promoted zoospore chemotaxis, as do isoflavones. Transcriptomics showed that both similarities and differences existed in response mechanisms of P. sojae to Asp and Glc. Asp and Glc activated mitogen-activated protein kinase signaling pathways and the phosphatidylinositol signaling system but not the G-protein signaling pathway, which have been reported to be responsible for zoospore chemotaxis. In addition, ubiquitin-mediated proteolysis and ATP binding cassette transporters were also activated by Asp and Glc. Meanwhile, the glutathione signaling pathway uniquely participated in the response of P. sojae to Asp but was not involved in the response process to Glc, which will be evaluated in another study. Our results provide new insights into the molecular mechanisms of zoospore response to Asp and Glc.

Background: Our previous comparative metabolomics research revealed that betaine (N,N,Ntrimethylglycine, a typically essential methyl-group donor for vitamin B12 biosynthesis) had powerful promoting effect on the generation of vitamin B12 precursors and intermediates in vitamin B12-producing Pseudomonas denitrificans. However, the integral effect of betaine on the vitamin B12 biosynthetic pathway is still unclear. Objective: Considering the vitamin B12 biosynthetic pathway of P. denitrificans as a whole, this work aimed to reveal the biological function of betaine on the vitamin B12 biosynthetic pathway in P. denitrificans, which would sharpen and expand understanding of betaine as the methyl-group donor for vitamin B12 biosynthesis. Materials and Methods: By using a proteomics method based on the iTRAQ technique, the present study compared and analyzed the differential expression of proteins involved in vitamin B12 biosynthetic pathway under 10 g/L betaine in addition to P. denitrificans fermentation medium. Results: The results showed that betaine could significantly up-regulate the expression of proteins related to the vitamin B12 biosynthetic pathway, which was mainly reflected in the following three aspects: 1) the δ-aminolevulinic acid (ALA) synthase and porphobilinogen synthase that were responsible for the formation of the committed precursors for tetrapyrrole-derived macrocycle in vitamin B12 molecule; 2) the C-methylation-related enzymes (such as precorrin-4 C(11)-methyltransferase, precorrin-2 C(20)- methyltransferase, precorrin-8X methylmutase, and precorrin-6Y C5,15-methyltransferase) and methionine synthase that were crucial to the C-methylation reactions for vitamin B12 biosynthesis; 3) the latestage key enzymes (Cobaltochelatase, and Cob(I)yrinic acid a,c-diamide adenosyltransferase) that were related to cobalt chelation of vitamin B12 molecule. Conclusions: The present study demonstrated clearly that betaine could significantly promote the expression of the integral enzymes involved in the vitamin B12 biosynthetic pathway of P. denitrificans, thus promoting vitamin B12 biosynthesis.

Phytophthora sojae does not infect nonhost maize (Zea mays) but infects nonhost common bean (Phaseolus vulgaris) under inoculation. Soybean seed exudates participate in mediating host resistance to P. sojae before infection. This study aims to elucidate the role of seed exudates in mediating the nonhost resistance of maize and common bean to P. sojae before infection. The behaviors of P. sojae zoospores in response to the seed exudates were determined using an assay chamber and a concave slide. The proteomes of P. sojae zoospores in response to the seed exudates were analyzed with the tandem mass tag method. The key proteins were quantitatively verified by parallel reaction monitoring. Maize seed exudates exerted a repellent effect on zoospores of P. sojae. This result explains why zoospores sense repelling signaling molecules in maize seed exudates that weaken and strongly inhibit chemotaxis signals in the phosphatidylinositol signaling pathway and arachidonic acid metabolism pathway. Common bean seed exudates did not exhibit any attraction to the zoospores because the guanine nucleotide-binding protein signaling pathway, which is responsible for transmitting chemotactic signals, had no significant change. The proteins protecting the cell membrane structure were significantly downregulated, and the early apoptosis signal glutathione was enhanced in zoospores responding to common bean seed exudates, which resulted in dissolution of the cysts. Maize and common bean seed exudates mediate part of the nonhost resistance to P. sojae via different mechanisms before infection. The immunity of maize to P. sojae is caused by the repellent effect of maize seed exudates on zoospores. Common bean seed exudates participate in mediating nonhost resistance by dissolving the cysts.

Aromatic L-amino acid decarboxylase deficiency results in decreased neurotransmitter levels and severe motor dysfunction. Twenty-six patients without head control received bilateral intraputaminal infusions of a recombinant adeno-associated virus type 2 vector containing the human aromatic L-amino acid decarboxylase gene (eladocagene exuparvovec) and have completed 1-year evaluations. Rapid improvements in motor and cognitive function occurred within 12 months after gene therapy and were sustained during follow-up for >5 years. An increase in dopamine production was demonstrated by positron emission tomography and neurotransmitter analysis. Patient symptoms (mood, sweating, temperature, and oculogyric crises), patient growth, and patient caretaker quality of life improved. Although improvements were observed in all treated participants, younger age was associated with greater improvement. There were no treatment-associated brain injuries, and most adverse events were related to underlying disease. Post-surgery complications such as cerebrospinal fluid leakage were managed with standard of care. Most patients experienced mild to moderate dyskinesia that resolved in a few months. These observations suggest that eladocagene exuparvovec treatment for aromatic L-amino acid decarboxylase deficiency provides durable and meaningful benefits with a favorable safety profile.

Based on the structural modification of regorafenib, 28 pyrazinyl–aryl urea derivatives were synthesized and their in vitro antiproliferative activities were evaluated. Six compounds (5-16, 5-17, 5-18, 5-19, 5-22, and 5-23) exhibited favorable inhibitory activity against the human bladder cancer T24 cell line, and 5-23 demonstrated the strongest inhibitory activity (IC(50) = 4.58 ± 0.24 μM) with high selectivity. Compound 5-23 induced apoptosis in the low concentration range (≤7.5 μM) combined with shorter incubation time (≤10 h) via the activation of caspases, while high concentrations and prolonged incubation times led to necroptotic cell death by activating the RIPK1/RIPK3/MLKL signaling pathway. Induced apoptosis and necroptosis were closely associated with intracellular reactive oxygen species generation and decreased mitochondrial membrane potential. Compared with regorafenib, 5-23 displayed improved pharmacokinetic profiles in an in vivo rat model. Molecular docking and structure–activity relationship analyses were in agreement with the biological data. Compound 5-23 may be a potent anti-bladder cancer agent and this small molecule can be considered as a promising structure for further optimization.

[Background and Aims] Multiple developments of squamous dysplasia and squamous cell carcinoma (SCC) in the upper aerodigestive tract have been explained by field cancerization phenomenon and were associated with alcohol and cigarette use. Second primary SCC development after curative treatment impairs patients’ quality of life and survival; however, how these consumption and cessation affect field cancerization is still unknown. [Methods] This is a multicenter cohort study including 331 patients with superficial esophageal SCC (ESCC) treated endoscopically and pooled data from 1022 healthy subjects for comparison. Physiological condition in the background esophageal mucosa was classified into 3 groups based on the number of Lugol-voiding lesions (LVLs) per endoscopic view: grade A, 0; grade B, 1–9; or grade C, ≥10 LVLs. Lifestyle surveys were conducted using a self-administered questionnaire. Patients were counseled on the need for alcohol and smoking cessation by physicians and were endoscopically surveyed every 6 months. [Results] LVL grades were positively associated with alcohol drinking intensity, flushing reactions, smoking, and high-temperature food and were negatively associated with eating green and yellow vegetables and fruit. Second primary ESCC and head/neck SCC were significantly more prevalent in the grade C LVL (cumulative 5-y incidences 47.1%, 95% confidence interval [CI] = 38.0–57.2 and 13.3%, 95% CI = 8.1–21.5, respectively). Alcohol and smoking cessation significantly reduced the development of second primary ESCC (adjusted hazard ratios 0.47, 95% = CI 0.26–0.85 and 0.49, 95% CI = 0.26–0.91, respectively). [Conclusion] Alcohol drinking, smoking, flushing reaction, and high-temperature food were closely associated with field cancerization, and cessation of alcohol and smoking significantly reduced the risk of development of second primary cancer. UMIN Clinical Trials Registry ID:UMIN000001676.

Summary Current industrial production of ammonia from the Haber-Bosch process and its transport concomitantly produces a large quantity of CO2. Herein, we successfully synthesize inorganic-structure-based catalysts with [Fe-S2-Mo] motifs with a connecting structure similar to that of FeMoco (a cofactor of nitrogenase) by placing iron atoms on a single molecular layer of MoS2 at various loadings. This type of new catalytic material functionally mimics the nitrogenase to convert N2 to ammonia and hydrogen in water without adding any sacrificial agent under visible-light illumination. Using the elevated temperature boosts the ammonia yield and the energy efficiency by one order of magnitude. The solar-to-NH3 energy-conversion efficiency can be up to 0.24% at 270°C, which is the highest efficiency among all reported photocatalytic systems. This method of ammonia production and the photocatalytic materials may open up an exciting possibility for the decentralization of ammonia production for fertilizer provision to local farmlands using solar illumination.

BACKGROUND A statistical model was developed in this study to describe lactic acid production through a fermentation process of carrot in a rice bran bed by Lactobacillus plantarum. METHODS Response surface methodology (RSM) based on Box-Behnken design was employed to statistically evaluate and optimize the conditions for maximum lactic acid production. RESULTS The significance and interaction of salt concentration, water and initial L. plantarum starter density on final lactic acid content were found. With the use of the developed quadratic model equation, a maximum achieved lactic acid content of 1.35% was obtained in a rice bran bed fermentation process at optimum operating conditions of approximately 2.95% salt, 48.24% water and 2.9 log cfu/g of L. plantarum. After fermentation, the amount of total polyphenol content, antioxidant activity and carbohydrate had increased while the β-carotene in carrot was significantly retained (92.84%). CONCLUSIONS The above results could provide a practical basis for the fermentation process in rice bran bed to produce a delicious and reliable product using L. plantarum strain XK 1.4 which could be a significant contribution to the food industry.

2-O-α- d- Glucopyranosyl-6-O-(2-propylpentanoyl)- l -ascorbic acid (6-bOcta-AA-2G) has shown a remarkable antitumor effect in an in vivo study. However, an efficient and low-cost process for synthesis of 6-bOcta-AA-2G has not been established yet. The process used for synthesis of 6-bOcta-AA-2G in this study consisted of three steps. The first step was acylation of l -ascorbic acid (AA) at the C-6 position with 2-propylpentanoic acid in concentrated H2SO4 at room temperature for 24 h to obtain 6-O-(2-propylpentanoyl)- l -ascorbic acid (6-bOcta-AA). Next, specific glycosylation of 6-bOcta-AA at the C-2 position by cyclodextrin glucanotransferase (CGTase) from Thermoanaerobacter sp. was carried out using soluble starch as a low-cost glycosyl donor in acetate buffer (pH 6.0) at 40 °C for 24 h. In this glycosylation reaction by CGTase, oligoglucosylated 6-bOcta-AAs seemed to be generated, and thus these oligoglucosides were further hydrolyzed by amyloglucosidase from Rhizopus sp. at 40 °C for 1 h in the reaction mixture containing CGTase to efficiently obtain 6-bOcta-AA-2G. The overall yield of 6-bOcta-AA-2G was 19.4 %. The presented synthetic process can be used for mass production of 6-bOcta-AA-2G as an antitumor agent.

Backgrounds: Metabolic syndrome is a subclinical status in promoting atherosclerotic cardiovascular disease and type 2 diabetes mellitus. The significance of metabolic syndrome and pathophysiology in chronic kidney disease is not investigated. Methods: We enrolled adult patients with CKD stages 3 to 5 from December 2006 to December 2007. Metabolic syndrome was defined by the US National Cholesterol Education Programme Adult Treatment Panel III guidelines. Plasma levels of angiogenic growth factors were measured. Univariate and multivariate logistic regression analyses were used. Results: Total 451 patients were analyzed with median estimated glomerular filtration rate of 27.0 ml/min per 1.73m2 (interquartile range 14.3–41.3). Patients with metabolic syndrome were older (P = 0.002), had higher percentage using diuretics (P = 0.002) but lower percentage using pentoxifylline (P = 0.017). Patients with metabolic syndrome had higher levels of high-sensitivity C-reactive protein (P < 0.0001), uric acid (P = 0.009) and angiopoietin-2 (P = 0.001). Multivariate logistic regression analyses revealed significant association between plasma levels of angiopoietin-2 and metabolic syndrome (P = 0.042). Conclusion: The prevalence of metabolic syndrome in advanced CKD was higher than general population. CKD patients with metabolic syndrome had higher levels of high-sensitivity C-reactive protein, uric acid and angiopoietin-2. Plasma levels of angiopoietin-2 were significantly associated with metabolic syndrome in patients with CKD. Metabolic syndrome in CKD may be not only a prognostic factor but also an interventional target, possibly through ameliorating inflammation. Prospective and interventional studies are necessary to establish the pathophysiology.

In fruit production, the application of the plant growth regulator 1-(2-chloro-4-pyridyl)-3-phenylurea (CPPU) dulls the fruit aroma. Gas chromatography–mass spectrometry and transcriptome analyses were performed on CPPU-treated and pollinated fruits to determine how CPPU affects the production of aroma in melon fruit. The results showed that the contents of two important esters (benzyl acetate and phenethyl acetate) in the CPPU-treated fruits were significantly lower than those in the pollinated fruits. Transcriptome sequencing data revealed that most differentially expressed genes were involved in “phenylalanine metabolism” pathway, and their expression was significantly decreased in the CPPU-treated fruits. Further analysis showed that the phenylalanine content in the CPPU-treated fruits was significantly higher than that in the pollinated fruits. In summary, CPPU application interferes with phenylalanine metabolism in melon fruits and affects the production of aromatic esters.

There have been no reports of outcome differences between distinctive subgroups in patients with unilateral primary aldosteronism with histopathologically classical adenomas. The characteristics and incidence of complete clinical success in the patients with unilateral primary aldosteronism could be associated with the concomitant existence of multiple aldosterone-producing micronodules/nodules. Altogether, 74 classical adenomas (mean, 52.9 years and 40 men [54.1%]) were identified among 98 operated patients with unilateral primary aldosteronism. Among them accompanying multiple aldosterone-producing micronodules/nodules (group A) were identified in 38 (51.3%) of the adrenal glands; these patients showed lower likelihood (42.1%) to achieve complete clinical success than that (80.6%) of those with aldosterone-producing adenoma/nodules alone (group B, P =0.001). Additionally, group A adenomas were associated with less complete clinical success (odds ratio, 5.53, P =0.005) in the multivariable regression analysis. Group A patients also had higher baseline aldosterone production (absolute aldosterone ratio) from the contralateral adrenal gland ( P =0.039). Based on the patterns of genes with highly differential expressions as uncovered by RNA-seq analysis, Group A adenomas showed distinct transcriptomic profiles in comparison to the gene expressions from Group B adenomas. Pathway enrichment analysis revealed that HTR2B-mediated calcium pathway, in terms of HTR2B , and PLCE1 was prominently downregulated in Group A adenomas. There was 51.3% of the patients with unilateral primary aldosteronism with classical group A adenomas. These patients were more likely to have hypertension-persistence after adrenalectomy. The functional signatures of Group A adenomas showed attenuated HTR2B-mediated PLC/IP3/Ca2 + pathway; this may provide some mechanistic explanation to various clinical outcomes.

In this study, we aimed to investigate the impact of aspirin on the risk of pyogenic liver abscess caused by Klebsiella pneumoniae (KP-PLA) and invasive KP-PLA syndrome (IKPS) in diabetic patients. Diabetic patients who were propensity-score matched were retrospectively included from hospital-based database. Kaplan–Meier approach with a log-rank test was used to compare the cumulative incidences of KP-PLA including IKPS between aspirin users and non-users. Totally, 63,500 patients were analyzed after propensity-score matching (1:1). Compared with that of non-users, the incidence of KP-PLA was significantly reduced in aspirin users (0.31% vs. 0.50%, p p = 0.29). Patients taking aspirin for ≥ 90 days had a significantly lower risk for KP-PLA (hazard ratio, 0.67; 95%CI, 0.50–0.90). Females, taking clopidogrel or metformin for ≥ 90 days, and taking H2-blockers or proton pump inhibitors (PPIs) for ≥ 5 days were also associated with a lower risk of KP-PLA. However, cholangitis and a glycated hemoglobin ≥ 8.5% were associated with an increased risk of KP-PLA.

Nano Fe-BTC materials were successfully synthesized by mechanical chemical grinding method. Samples were characterized by X-ray difraction (XRD), Fourier-transform infrared spectroscopy (FTIR), N2 adsorption–desorption, Scanning electron microscopy (SEM), Energy-dispersive X-ray spectroscopy (EDS). SEM image of Fe-BTC-60 showed the particle size of 40–60 nm. Fe-BTC nanocomposites were tested for the photocatalytic degradation of reactive yellow 145 (RY-145) in aqueous solution. Fe-BTC composites exhibited high photocatalytic activity. Thus, at pH of 3 and high initial concentration of 100 mg RY-145/L, removal efficiency reached the value of 97.45% after 90 min of reaction.

While high-performance piezoelectric polymeric nanofibers such as polyvinylidene fluoride and its derivatives have been extensively studied to various applications, limited works examined other fun...

The early detection of volatile organic compounds (VOCs) is crucial for sustainable development. Improving the binding properties of crystalline materials for special VOC guests is a tough challeng...

Integrating multiple photosensitive properties into an “all-in-one” photosensitizer (PS) shows great promise for the treatment of cancers owing to synergistic effect among them. However, the development of such PSs, especially those that need a single laser source, remains a challenge. Herein, we report an orchestration of electron donors and acceptors in a propeller-like pentad, PBI-4Cz, where four carbazole (Cz) units are covalently linked to the ortho-positions of the perylene bisimide (PBI) core. Strong intramolecular donor-acceptor interaction significantly quenches the luminescence and largely extends the absorption spectra to near-infrared region. Excited-state dynamics investigated via femto- and nano-second transient absorption spectroscopy revealed exclusive charge separation of the PBI-4Cz within initial 0.5 ps when photoexcited regardless of which intermediate is involved. Energy dissipation of the resulting charge-separated state (PBI•−-4Cz•−) is subjected to the toggle between intersystem-crossing toward excited triplet states and charge recombination toward ground states. Relative importance of the two pathways can be tuned by micro-environmental polarity, which endows PBI-4Cz remarkable performances of singlet-oxygen generation (>90.0%) in toluene and photothermal conversion (∼28.6%) in DMSO. Harnessing intrinsic photostability and excited-state processes of heavy-atom-free PBI derivatives not only holds a promise for multifunctional phototheranostics, but also provides a prototype for designing high-performance PSs with tunable photoconversion pathways.

Herein, we report the first example showing the reversible on-off switching of spin-crossover (SCO) property by solid state photochemical [2+2] reaction. The ultraviolet (UV) light-induced [2+2] cycloaddition reaction of 3-spy ligands in a two-dimensional (2D) Hofmann-type framework [Fe(3-spy)2{Pd(CN)4}] (1, 3-spy=3-styrylpyridine), which shows a hysteretic two-step SCO behavior, gives a 3D Hofmann-type framework [Fe(rctt-3-ppcb){Pd(CN)4}] (2, rctt-3-ppcb=rctt-1,3-bis(3-pyridyl)-2,4-bis(phenyl)cyclobutane, r=reference group, c=cis and t=trans) accompanied with the disappearing of SCO properties. Moreover, upon heating at 250 °C for 12 h, the rctt-3-ppcb ligand in 2 could be partially dedimerized to 3-spy with 68% completion through single-crystal-to-single-crystal (SCSC) transformation, giving the annealing complexes [Fe(3-spy)1.36(rctt-3-ppcb)0.32{Pd(CN)4}] (3) which display an incomplete SCO behavior. The 2 ⇌ 3 interconversion is successfully achieved via continuous UV irradiation and thermal annealing, demonstrating the effectiveness of photochemical [2+2] reaction on switching on-off SCO properties.

Rechargeable aqueous zinc-ion batteries present low-cost, safe, and environmentally-friendly battery technology but suffer from the limited choice of cathode materials because of the sluggish kinetics of divalent zinc-ion associated with the high adsorption and migration energy barrier. Herein, a reversible zinc/bismuth selenide mild aqueous system was demonstrated for the first time, where bismuth selenide nanoplate cathode delivers a high specific capacity of 263.2 mA h g−1 at 0.1 A g−1 and robust rate capability of 100.6 mA h g−1 even at 10 A g−1 with long-term lifespan (82.3% retention after 1000 cycles). Benefiting from the layered structure and nanoplate morphology of the bismuth selenide cathode, surface-dominated ion storage is verified by a quantitative kinetics analysis, particularly at high current rates. Notably, unlike conventional batteries with only the reversible intercalation of alkali ions into metal chalcogenides, zinc/bismuth selenide aqueous batteries possess a sequential proton and zinc-ion insertion/extraction process, identified by in situ synchrotron radiation-based X-ray diffraction. Density functional theory analysis approves the low adsorption energy and preferential embedding process of protons, and that can further optimize Zn2+ adsorption and migration abilities in bismuth selenide nanoplate, which is mainly responsible for the excellent performance.

In this study, some transitional metal carbides (Ti3C2, Ni3C, Mo2C, Cr3C2 and NbC) were prepared to enhance the hydrogen storage behaviors of magnesium-based materials. The carbides with a weight ratio of 5 wt% were introduced into magnesium hydride (MgH2) by mechanical ball milling, and the microstructure, phase composition and hydrogen storage properties of the composites were studied in detail. The phase compositions of Ni3C, Mo2C, Cr3C2 and NbC in the ball-milled composites have not changed during hydrogen absorption and desorption cycles. However, Ti3C2 decompose into multivalent Ti during hydrogenation process. All of these metal carbides can enhance the hydrogen absorption and desorption kinetics of MgH2. Among them, Ti3C2 shows the best catalytic effect on dehydrogenation kinetic properties of MgH2, followed by the Ni3C, NbC, Mo2C and Cr3C2.

Background and purpose Overweight or obese patients exhibit poorer platelet responses to clopidogrel; however, the mechanisms behind this phenotype remain to be elucidated. Here, we sought to dissect whether and why obesity could affect the metabolic activation of and/or platelet response to clopidogrel in obese patients and high-fat diet-induced obese mice. Experimental approach A post hoc stratified analysis of an observational clinical study was performed to investigate changes in residual platelet reactivity with increasing body weight in patients taking clopidogrel. Furthermore, high-fat diet-induced obese mice were used to reveal alterations in systemic exposure of clopidogrel thiol active metabolite H4, ADP-induced platelet activation and aggregation, the expression of genes responsible for the metabolic activation of clopidogrel, count of circulating reticulated and mature platelets, and proliferation profiles of megakaryocyte in bone marrow. The relevant genes and potential signaling pathways were predicted and enriched according to the GEO datasets available from obese patients. Key results Obese patients exhibited significantly attenuated antiplatelet effect of clopidogrel. In diet-induced obese mice, systemic exposure of clopidogrel active metabolite H4 was significantly reduced but that of its hydrolytic metabolite was increased due to down-regulation of certain P450s but up-regulation of Ces1 in the liver. Moreover, enhanced proliferation of megakaryocytes and elevated platelet count also contributed. Conclusion and implications Obesity attenuates metabolic activation of clopidogrel and increases counts of circulating reticulated and mature platelets, leading to impaired platelet responsiveness to the drug in mice, suggesting that clopidogrel dosage may need to be adjusted adequately in overweight or obese patients.

A series of diindeno[2,1-b:2',1'-h]biphenylenes with open-shell singlet ground states and interesting properties were prepared. The studied compounds consist of p-quinodimethane moieties, which suffer from geometric perturbation with bond angles of around 90°. The substituent effects on structural parameters, local aromaticity, and properties were systematically explored.

Among various polycyclic aromatic hydrocarbons, C 6 -C 5 -C 6 -C 7 -C 6 fused pentacyclic aromatic hydrocarbons have the unique potential to adopt quinonoid, zwitterion, singlet, or triplet biradical electronic configurations. Two such hybrid structures between pentacene and azulene were synthesized and their ground state electronic configuration was deduced from the reactivity patterns they exhibit respectively. Compound 6, where the radicaloid carbons are linked through a para-phenylene, forms a head-to-head dimer like a singlet biradical. In contrast, isomer 7 , where the para-linkage was switched to meta, reacts readily with oxygen which resembles the reactivity of a triplet state. The oxidized intermediate(s) then undergoes rearrangement to furnish the C 6 -C 5 -C 6 -C 6 -C 6 ring contraction product 13 . Cation 14 , the protonated form of 7 , was synthesized, which implies 7 also reacts like a zwitterion. It was revealed the oxidative rearrangement takes place even with mesityl dibenzotropylium cation despite its perceived aromaticity. DFT calculations confirm the most stable forms of 6 and 7 are singlet and triplet diradical, which is consistent with the observed reactivity of respective molecules.

Supramolecular self-assembly of Fe3+ and tannic acid (TA) has received great attention in the fields of materials science and interface engineering because of its exceptional surface coating properties. Although advances in coating strategies often suggest that kinetics in the generation of interface-active Fe3+-TA species is deeply involved in the film formation, there is no acceptable elucidation for the coating process. In this work, we developed the enzyme-mediated kinetic control of Fe2+ oxidation to Fe3+ in a Fe2+-TA complex in the iron-gall-ink-revisited coating method. Specifically, hydrogen peroxide, produced in the glucose oxidase (GOx)-catalyzed reaction of d-glucose, accelerated Fe2+ oxidation, and the optimized kinetics profoundly facilitated the film formation to be about 9 times thicker. We also proposed a perspective considering the coating process as nucleation and growth. From this viewpoint, the kinetics in the generation of interface-active Fe3+-TA species should be optimized because it determines whether the interface-active species forms a film on the substrate (i.e., heterogeneous nucleation and film growth) or flocculates in solution (i.e., homogeneous nucleation and particle growth). Moreover, GOx was concomitantly embedded into the Fe3+-TA films with sustained catalytic activities, and the GOx-mediated coating system was delightfully adapted to catalytic single-cell nanoencapsulation.

An ultra-thin and highly sensitive SARS-CoV-2 detection platform was demonstrated using a nano-porous anodic aluminum oxide (AAO) membrane. The membrane surface was functionalized to enable efficient trapping and identification of SARS-CoV-2 genomic targets through DNA-DNA and DNA-RNA hybridization. To immobilize the probe oligonucleotides on the AAO membrane, the pore surface was first coated with the linking reagents, 3-aminopropyltrimethoxysilane (APTMS) and glutaraldehyde (GA), by a compact vacuum infiltration module. After that, complementary target oligos with fluorescent modifier was pulled and infiltrated into the nano-fluidic channels formed by the AAO pores. The fluorescent signal applying the AAO membrane sensors was two orders stronger than a flat glass template. In addition, the dependence between the nano-pore size and the fluorescent intensity was evaluated. The optimized pore diameter d is 200 nm, which can accommodate the assembled oligonucleotide and aminosilane layers without blocking the AAO nano-fluidic channels. Our DNA functionalized membrane sensor is an accurate and high throughput platform supporting rapid virus tests, which is critical for population-wide diagnostic applications result in a page being rejected by search engines.

The efficiency of whole-cell biotransformation is often affected by genetic instability of plasmid-based expression systems, which require selective pressure to maintain the stability of the plasmids. To circumvent this shortcoming, we constructed a chromosome engineering strain for synthesis of phenylpyruvic acid (PPA) from L-phenylalanine. Firstly, L-amino acid deaminase (pmLAAD) from Proteus myxofaciens was incorporated into E. coli BL21 (DE3) chromosome and the copy-numbers of pmLAAD were increased by chemically induced chromosomal evolution (CIChE). 59 copies of pmLAAD was obtained in E. coli BL8. The PPA titer of E. coli BL8 reached 2.22 g/L at 6 h. Furthermore, the deletion of lacI improved PPA production. In the absence of Isopropyl-β-D-thiogalactopyranoside (IPTG), the resulting strain, E. coli BL8△recA△lacI, produced 2.65 g/L PPA at 6 h and yielded a 19.37 % increase in PPA production compared to E. coli BL8△recA. Finally, the engineered E. coli BL8△recA△lacI strain achieved 19.14 g/L PPA at 24 h in 5 L bioreactor. The culture of the strain does not require the addition of antibiotics and inducers. The production level of CIChE strains can catch up with plasmid expression strains. This work extends production methods for whole-cell biotransformation. This article is protected by copyright. All rights reserved.

A judicious strategy was utilized to envision the substantial regio-positional effects of substituents on the photophysical properties of the 2H-chromen-2-one-3-benzothiazole scaffold-based push-pull framework, named 6-X-CUMs. Among them, 6-NEt2-CUM reveals prominent excited-state intramolecular charge transfer with a large change of dipole moment (Δμ ∼ 18.23 D), hence displaying remarkable emission solvatochromism from the green (536 nm in cyclohexane) to far-red region (714 nm in dimethyl sulfoxide) and a high-temperature sensitivity (-0.23 nm °C-1). These, together with unique basicity and acido-/vaporchromism upon acidification elucidated by NMR and photospectroscopic studies, show stark contrast to the conventional 7-NEt2-CUM. The new series of these tailored 6-X-CUMs represents a new dimension in tailoring the photophysical properties for the development of a promising class of multistimuli-responsive materials.

In this study, total polyphenol, flavonoid and anthocyanin content (TPC, TFC and TAC), antioxidant activity (AA) and individual phenolic composition of potato peel and flesh from four potato varieties were investigated. On average, TPC, TFC and TAC in the peel were 1.59 times, 2.91 times and 1.46 times higher than in the flesh, respectively. As well, the AA measured by FRAP, DPPH and ABTS was 1.64 times, 2.19 times and 1.66 times higher than in the flesh, respectively. A total of thirteen individual phenolic compounds (gallic acid, protocatechuic acid, chlorogenic acid, caffeic acid, p-coumaric acid, ferulic acid, myricetrin, kaempferol, delphinidin, petunidin, pelargonidin, peonidin, malvidin) and ascorbic acid were identified by HPLC. Phenolic acid (chlorogenic acid) and anthocyanidins (petunidin and peonidin) were predominant in both potato peels and flesh. In addition, a very high positive correlation was found between TPC, TFC and AA, suggesting that AA could be attributed to high polyphenol content. Potato peel could be used as an important source material in the production of functional food for consumers and food industry.

Regulation of hexavalent chromium is based on Waste Framework Directive 1994/62/EC, European Commission and publication of the World Health Organization. Herein, detection of hexavalent chromium was performed by alkaline digestion and instrumental analysis which was demonstrated in USEPA methods. However, UV-vis detection method could be affected by some metal ions reacted with diphenylcarbizide. Actually, various interfering elements, such as Ni, Fe, Al, and Cu, were detected and selected by ED-XRF in paper materials. In order to improve accuracy of analysis results of hexavalent chromium in paper materials based on USEPA methods, the interfering elements was removed by liquid–liquid extraction with carbonate media using tricaprylmethylammonium chloride and chloroform after alkaline digestion. Consequently, the temperature for alkaline digestion was between 85 and 95 °C. Hydrochloric acid was proper complex tricaprylmethylammonium-Cr(VI) in the procedure of liquid extraction. After that hexavalent chromium was completely extracted using of 1 M sodium hydroxide solution. The technique for analyzing the hexavalent chromium used in liquid–liquid extraction significantly reduced the errors caused by the interfering elements, Fe and Cu. Thus, application of the extraction method was efficient in removing the interfering elements, which increased the recovery ratio of the hexavalent chromium from paper materials by 90 %.

Nature manifests diverse and complicated patterns through efficient physical, chemical, and biological processes. One of the approaches to generate complex patterns, as well as simple patterns, is the use of the cellular automata algorithm. However, there are certain limitations to produce such patterns experimentally due to the difficulty of finding candidate programmable building blocks. Here, we demonstrated the feasibility of generating an ocellated lizard skin-like pattern by simulation considering the probabilistic occurrence of cells and constructed the simulation results on DNA lattices via bottom-up self-assembly. To understand the similarity between the simulated pattern (SP) and the observed pattern (OP) of lizard skin, a unique configuration scheme (unit configuration was composed of 7 cells) was conceived. SPs were generated through a computer with a controlling population of gray and black cells in a given pattern. Experimental patterns (EPs) on DNA lattices, consisting of double-crossover (DX) tiles without and with protruding hairpins, were fabricated and verified through atomic force microscopy (AFM). For analyzing the similarity of the patterns, we introduced deviation of the average configuration occurrence for SP and EP with respect to OP, i.e., σα(SO) and σα(EO). The configuration and deviation provide characteristic information of patterns. We recognized that the minimum values of and occurred when 50% (55%) of black cells in given SPs (DX tiles with hairpins in given EPs) appeared to be most similar to the OP. Our study provides a novel platform for the applicability of DNA molecules to systematically demonstrate other naturally existing complex patterns or processes with ease.

Purpose This study aimed to compare the safety and efficacy of clarithromycin-naproxen-oseltamivir combination therapy to that of oseltamivir therapy alone in hospitalized pediatric influenza patients. Methods This prospective, single-blind study included children aged 1–18 years hospitalized with influenza, in MacKay Children’s Hospital, Taiwan, between December 2017 and December 2019. The primary outcomes were the time to defervescence and decrease of the Pediatric Respiratory Severity Score (PRESS) during hospitalization. The secondary outcomes were serial changes in virus titers, measured using real-time polymerase chain reaction. Results Fifty-four patients were enrolled (28 in the control group and 26 in the combination group) in total. There were no differences in the patients’ baseline characteristics between the groups. The time to defervescence was significantly shorter in the combination group than the oseltamivir group (13.2 hours vs. 32.1 hours, p=0.002). The decrease in the virus titer from days 1 to 3 (log Δ13) was more pronounced in the combination group than the oseltamivir group. (39% vs. 19%, p=0.001). There were no differences in adverse effects such as vomiting, diarrhea, and abdominal pain during the study or within 30 days after antiviral therapy. Conclusion The clarithromycin-naproxen-oseltamivir combination group experienced a more rapid defervescence and a more rapid decline of influenza virus titer than the group treated with oseltamivir alone. Further consideration should be given to whether the overall benefits of combination therapy in hospitalized pediatric influenza patients outweigh the risks.

Background and Purpose: Data on clinical outcomes for nonvitamin K antagonist oral anticoagulant (NOACs) and warfarin in patients with atrial fibrillation and cancer are limited, and patients with active cancer were excluded from randomized trials. We investigated the effectiveness and safety for NOACs versus warfarin among patients with atrial fibrillation with cancer. Methods: In this nationwide retrospective cohort study from Taiwan National Health Insurance Research Database, we identified a total of 6274 and 1681 consecutive patients with atrial fibrillation with cancer taking NOACs and warfarin from June 1, 2012, to December 31, 2017, respectively. Propensity score stabilized weighting was used to balance covariates across study groups. Results: There were 1031, 1758, 411, and 3074 patients treated with apixaban, dabigatran, edoxaban, and rivaroxaban, respectively. After propensity score stabilized weighting, NOAC was associated with a lower risk of major adverse cardiovascular events (hazard ratio, 0.63 [95% CI, 0.50–0.80]; P =0.0001), major adverse limb events (hazard ratio, 0.41 [95% CI, 0.24–0.70]; P =0.0010), venous thrombosis (hazard ratio, 0.37 [95% CI, 0.23–0.61]; P P =0.0171) compared with warfarin. The outcomes were consistent with either direct thrombin inhibitor (dabigatran) or factor Xa inhibitor (apixaban, edoxaban, and rivaroxaban) use, among patients with stroke history, and among patients with different type of cancer and local, regional, or metastatic stage of cancer ( P interaction >0.05). When compared with warfarin, NOAC was associated with lower risk of major adverse cardiovascular event, and venous thrombosis in patients aged P interaction Conclusions: Thromboprophylaxis with NOACs rather than warfarin should be considered for the majority of the atrial fibrillation population with cancer.

Summary Drought and salt stresses impose major constraints on soybean production worldwide. However, improving agronomically valuable soybean traits under drought conditions can be challenging due to trait complexity and multiple factors that influence yield. Here, we identified a nuclear factor Y C subunit (NF‐YC) family transcription factor member, GmNF‐YC14, which formed a heterotrimer with GmNF‐YA16 and GmNF‐YB2 to activate the GmPYR1‐mediated abscisic acid (ABA) signalling pathway to regulate stress tolerance in soybean. Notably, we found that CRISPR/Cas9‐generated GmNF‐YC14 knockout mutants were more sensitive to drought than wild‐type soybean plants. Furthermore, field trials showed that overexpression of GmNF‐YC14 or GmPYR1 could increase yield per plant, grain plumpness, and stem base circumference, thus indicating improved adaptation of soybean plants to drought conditions. Taken together, our findings expand the known functional scope of the NF‐Y transcription factor functions and raise important questions about the integration of ABA signalling pathways in plants. Moreover, GmNF‐YC14 and GmPYR1 have potential for application in the improvement of drought tolerance in soybean plants.

The applications of silica aerogels are restricted due to their intrinsic fragile property. Polymerization of di-isocyanates can be templated onto the mesoporous surface of the –NH2 group modified silica clusters, resulting in the conformal crosslinked coating on surface of silica clusters. Aminopropyltriethoxysilane (APTES), as the silica co-precursor and amine group modification agent, is involved containing tetramethyl orthosilicate (TMOS) silica precursor, while hexamethylene diisocyanate (HDI) is incorporated as the polymer crosslinking agent. The effects of different amounts of APTES on the physicochemical properties of the resulting crosslinked aerogels are investigated. The results show that the optimized APTES/TMOS volume ratio can be determined at 0.5:1. The resulting optimal crosslinked silica aerogel possesses large BET specific surface area of 150.9 m2/g, low thermal conductivity of 0.037 W/(m·K), and the Young's modulus is as large as 18 MPa under strain of 4.2%, much higher than that in the previously published works. The polymerization reaction mechanism forming the polyurethane chains has also been proposed. In addition, the interactions between silica clusters and polymer chains are studied by molecular mechanics and molecular dynamics. The interactions are mainly dependent on non-bonding energy, and the electrostatic energy has decisive impact on the combination of silica clusters and polymer chains. The density field of C, H, N, O, and Si elements overlaps with each other, indicating that the polymer crosslinked silica aerogel maintains typical three-dimensional porous structure. The N element enriches in the region between silica clusters, further verifying the formation –CONH–(CH2)6–CONH- polyurethane chains, which is actually responsible for the much enhanced mechanical property.

Background/purpose: Our previous study found that 70 of 884 burning mouth syndrome (BMS) patients have serum gastric parietal cell antibody (GPCA) positivity but without thyroglobulin antibody (TGA) and thyroid microsomal antibody (TMA) (so-called GPCA+TGAˉTMAˉBMS patients). This study assessed whether these 70 GPCA+TGAˉTMAˉBMS patients had significantly higher frequencies of macrocytosis, anemia, hematinic deficiencies, and hyperhomocysteinemia than 553 GPCA-negative, TGA-negative, and TMA-negative BMS (GPCAˉTGAˉTMAˉBMS) patients or 442 healthy control subjects. Materials and methods: Complete blood count, serum iron, vitamin B12, folic acid, homocysteine, GPCA, TGA, and TMA levels in 70 GPCA+TGAˉTMAˉBMS patients, 553 GPCAˉTGAˉTMAˉBMS patients, and 442 healthy control subjects were measured and compared. Results: We found that 15.7%, 28.6%, 20.0%, 11.4%, 2.9%, and 25.7% of 70 GPCA+TGAˉTMAˉBMS patients and 3.8%, 17.7%, 15.9%, 3.8%, 2.7%, and 20.1% of 553 GPCAˉTGAˉTMAˉBMS patients had macrocytosis, blood hemoglobin, iron, vitamin B12, and folic acid deficiencies, and hyperhomocysteinemia, respectively. Moreover, both 70 GPCA+TGAˉTMAˉBMS patients and 553 GPCAˉTGAˉTMAˉBMS patients had significantly greater frequencies of macrocytosis, blood hemoglobin, serum iron, vitamin B12, and folic acid deficiencies, and hyperhomocysteinemia than 442 healthy control subjects (all P-values

Due to the threat to health of heavy metal contamination, simple and rapid detection methods for heavy metals are an urgent needed in environment protection and food safety. In this work, we have developed a fluorescent aptasensor for the 'turn-off' model detection of Pb2+ . The key feature of the aptasensor is that the dye-labelled nucleic acid strand can be folded into a G-quadruplex structure in the presence of Pb2+ . This conformational change induces photoinduced electron transfer (PET) between a G-quadruplex-hemin complex and 6-carboxyrhodamine X (ROX), which results in fluorescence quenching of ROX. We systematically investigated the interaction mechanism between Pb2+ and the aptasensor and the effects of several environmental parameters were also studied. Under the optimum conditions, the proposed method exhibited a good liner relationship between the concentration of Pb2+ and fluorescence quenching efficiency in the range 25-500 nM and the limit of detection was 1.02 nM. In addition, this method also manifested good performance in spiked lettuce samples with satisfactory recoveries of 87.10-109.6%. This target-induced PET platform can be further expanded to other heavy metal analysis.

Novel ZrB2-matrix composites were designed and prepared by in-situ introducing SiC and Zr2[Al(Si)]4C5 simultaneously for the first time. The obtained composites were dense and showed good mechanical properties, especially the strength and toughness, 706 MPa and 7.33 MPa·m1/2, respectively, coupled with high hardness of 21.3 GPa, and stiffness of 452 GPa. SiC and Zr2[Al(Si)]4C5 constituted a reinforcing system with synergistic effects including grain refinement, grain pull-out as well as crack branching, bridging, and deflection. Besides, the oxidation results of the composites showed that the oxidation kinetics followed the parabolic law at 1600 °C, and the oxidation rate constants increased with the increase of Zr2[Al(Si)]4C5 content. The formation and evolution model of the oxidation structure was also investigated, and the oxide scale of the composite exhibited a three-layer structure.

Six pyrophosphate analogues are prepared from zerumbone, murrayafoline A, acridone, and 4-hydroxycoumarin via 1,3-dipolar cycloaddition reactions. Their in vitro cytotoxic activity is evaluated against HepG2, LU-1, and HeLa cancer cell lines. Among them, diisopropyl ((ethoxy((4-((1-methoxy-3-methyl-9 H-carbazol-9-yl)methyl)-1 H-1,2,3-triazol-1-yl)methyl)phosphoryl)methyl)phosphonate (6a) and diisopropyl ((ethoxy((4-(((3-methyl-9 H-carbazol-1-yl)oxy)methyl)-1 H-1,2,3-triazol-1-yl)methyl)phosphoryl)methyl)phosphonate (6b) are found to show activity against HepG2, LU-1, and HeLa cancer cell lines, with IC50 values ranging from 7.31 to 17.88 μM.

BackgroundARID1A (AT-rich interactive domain containing protein 1A) loss-of-function mutations have been reported in gynecological cancers, including rarer subtypes such as clear cell carcinoma. Preclinical studies indicate that ARID1A mutant cancers display sensitivity to ATR inhibition while tumors without ARID1A mutations may be sensitive to Ataxia telangiectasia and Rad3 related (ATR) inhibitors in combination with poly-ADP ribose polymerase (PARP) inhibitors.Primary ObjectiveTo determine whether the ATR inhibitor, ceralasertib, has clinical activity as a single agent and in combination with the PARP inhibitor, olaparib, in patients with ARID1A ‘loss’ and ‘no loss’ clear cell carcinomas and other relapsed gynecological cancers.Study HypothesisARID1A deficient clear cell carcinoma of the ovary or endometrium is sensitive to ATR inhibition, while the combination of ATR and PARP inhibition has activity in other gynecological tumors, irrespective of ARID1A status.Trial DesignATARI (ENGOT/GYN1/NCRI) is a multicenter, international, proof-of-concept, phase II, parallel cohort trial assessing ceralasertib activity as a single agent and in combination with olaparib in ARID1A stratified gynecological cancers. Patients with relapsed ovarian/endometrial clear cell carcinoma with ARID1A loss will receive ceralasertib monotherapy (cohort 1A). Relapsed ovarian/endometrial clear cell carcinoma patients with no ARID1A loss (cohort 2) or patients with other histological subtypes (endometrioid, carcinosarcoma, cervical) (cohort 3) will receive combination therapy (olaparib/ceralasertib). Treatment will continue until disease progression.Major Inclusion/Exclusion CriteriaPatients with histologically confirmed recurrent clear cell (ovarian, endometrial, or endometriosis related), endometrioid (ovarian, endometrial, or endometriosis related), cervical (adenocarcinomas or squamous), or carcinosarcomas (ovarian or endometrial) are eligible. Patients progressing after ≥1 prior platinum with evidence of measurable (RECIST v1.1) radiological disease progression since last systemic anticancer therapy and prior to trial entry are eligible. Previous ATR or PARP inhibitor treatment is not permissible.Primary EndpointBest overall objective response rate (RECIST v1.1).Sample SizeA minimum of 40 and a maximum of 116.Estimated Dates for Completing Accrual and Presenting ResultsAccrual is anticipated to be complete by the second quarter of 2022, with reporting of results by the fourth quarter of 2022. Overall accrual targets and reporting timelines are dependent on individual cohort progression to stage 2.Trial Registration NumberNCT0405269.

Using commercial API-ZYM screening kits, highly active α-glucosidase, β-glucosidase, and β-N-acetylglucosaminidase were found in Grifola frondosa, having potential for carbohydrate utilization. Of these, β-N-acetylglucosaminidase, which converts chitin to N-acetylglucosamine, was purified and characterized. The recovery was 24.5%, and the purified enzyme had a specific activity 0.67 U/mg protein. Chitinase activity was confirmed by zymogram analysis. The enzyme was also shown to be β-N-acetylglucosaminidase, as N-acetylglucosamine was the main hydrolysis product from colloidal chitin. Thus, the molecule was named NAG38, to indicate β-N-acetylglucosaminidase activity and a molecular weight of 38 kDa, as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Enzymatic activity was optimal at pH 7.0 and 50 °C, with Km and Vmax values of 0.112 mM and 0.570 μmol/min/mg protein against p-nitrophenyl N-acetyl-β-D-glucosaminide. The bioactivity was inhibited by Hg2+, Ag+, Mg2+, Zn2+, Ca2+, and Mn2+, with residual enzyme bioactivity only 11.1% after incubation in Hg2+, but was not substantially inhibited by Ba2+, K+, and Na+.

BACKGROUND AND PURPOSE Aberrant lipid metabolism is recognized as a key feature of cancer cells. Our initial research on MS-based analysis of lipids in a multiple myeloma (MM) cell line showed a significant accumulation of lipids in multiple myeloma cells after proteasome inhibition. This finding prompted us to hypothesize that multiple myeloma cell survival depends on the maximal utilization of abnormally accumulated lipids. Therefore, we explored whether lipid metabolism-modulating agents would synergize with proteasome inhibitors. EXPERIMENTAL APPROACH Lipid accumulation in multiple myeloma cells was measured by MS. Synergism between lipid regulators and proteasome inhibitors was assessed by cell viability and apoptosis. A novel stable derivative of fenofibrate (FCE) was synthesized and used to treat multiple myeloma cells in vitro and in vivo along with the proteasome inhibitor ixazomib. ChIP-seq, western blotting and RT-qPCR were performed to explore the potential mechanism(s) underlying the increase in lipid levels in multiple myeloma cells after proteasome inhibition. KEY RESULTS Accumulation of lipids in multiple myeloma cells was induced by proteasome inhibition. Lipid-lowering drugs and MG-132 exerted a synergistic effect to kill multiple myeloma cells. FCE showed significant synergistic activity in vitro and in vivo with ixazomib. The abnormal lipid accumulation in multiple myeloma cells that was enhanced by proteasome inhibitors might be due to the elevated SREBP1/2 expression induced by ATF4. CONCLUSIONS AND IMPLICATIONS Our results provide a proof of principle and support for the further clinical evaluation of the combination of lipid-modulating drugs with proteasome inhibitors in the treatment of multiple myeloma.

A new icetexane diterpenoid, 11, 12, 20α-trihydroxyl-7β-methoxyicetexa-8, 11, 13-triene-19, 10-lactone [Phyllane A (1)], and a new abietane diterpenoid, 7β, 20-epoxy-3β, 17-acetoxy-abieta-8, 11, 13...