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Salt reduction in food has been employed to improve public health. The effects of salt coatings on sodium content, sensory properties, structural breakdown, microstructure, salt release properties, and shelf life of yellow alkaline noodles (YAN) were evaluated. 15 g/dL resistant starch HYLON™ VII (HC) or 5% (v/v) Semperfresh™ (SC) with 10, 20, and 30 g/dL sodium chloride (NaCl) were used. HC-Na30 and SC-Na30 had the highest sodium content and came closest to commercial YAN in taste and saltiness perception. Structural improvement was demonstrated with HC-Na10 and SC-Na10 as both noodles required maximum work to be broken down. Moreover, SEM micrographs of these noodles showed a more compact and dense appearance with increased continuity of the matrix and fewer voids and hollows. However, ruptured surfaces were observed in noodles coated with 20 and 30% salt. The enhanced salt release from the coatings was demonstrated in an in vivo analysis, with the released salt occurring rapidly from HC and SC coatings. HC-Na10 and SC-Na10 noodles had a shelf life of more than 8 days when stored at 4 °C, which is longer than HC-Na0 and SC-Na0 noodles. Storage at 4 °C decelerated the microbiological growth, changes in pH and CIE L* values in salt-coated noodles than storage at 25 °. Thus, HC-Na10 and SC-Na10 could be suitable formulations to replace commercial YAN.

The F1 FO -ATP synthase is required for growth and viability of Mycobacterium tuberculosis and is a validated clinical target. A mycobacterium-specific loop of the enzyme's rotary γ subunit plays a role in the coupling of ATP synthesis within the enzyme complex. We report the discovery of a novel antimycobacterial, termed GaMF1, that targets this γ subunit loop. Biochemical and NMR studies show that GaMF1 inhibits ATP synthase activity by binding to the loop. GaMF1 is bactericidal and is active against multidrug- as well as bedaquiline-resistant strains. Chemistry efforts on the scaffold revealed a dynamic structure activity relationship and delivered analogues with nanomolar potencies. Combining GaMF1 with bedaquiline or novel diarylquinoline analogues showed potentiation without inducing genotoxicity or phenotypic changes in a human embryonic stem cell reporter assay. These results suggest that GaMF1 presents an attractive lead for the discovery of a novel class of anti-tuberculosis F-ATP synthase inhibitors. National Research Foundation (NRF) Accepted version This research was supported by the National ResearchFoundation (NRF) Singapore,NRF Competitive Research Programme (CRP), Grant Award Number NRF-CRP18-2017-01. A. Hotra is grateful to receive an IGS PremiumScholarship,Institute of Technology in Health and Medicineat NTU,and J. P. Sarathy received aPhD scholarship from theSchool of Medicine,NUS,Singapore.Wethank Dr. YongxinLi for the X-ray crystallographic structure determinations.

We report an efficient process to dehydrogenate formaldehyde in alkaline solution, catalyzed by carbon nanotubes (CNTs) via a unique reaction mechanism involving molecular O2. The superior catalytic performance of carbon nanotubes (CNTs) compared to the other carbon-based catalysts is attributed to their sp2-carbon-rich surface, hydrophilicity and abundant surface defects, which are the most plausible active sites. Peroxide species originating from the activation of adsorbed molecular oxygen on the CNTs is found to be a key to C–H activation, leading to efficient hydrogen production. The cost-effective carbon-based dehydrogenation catalysts offer new opportunities to the development of novel liquid organic hydrogen carrier technologies. National Research Foundation (NRF) Submitted/Accepted version The authors are grateful for financial supports from the National Natural Science Foundation of China (No. 21872123 and 22172143). H.L.Tan and W.Liu acknowledge funding from National Research Foundation of Singapore under its Campus for Research Excellence and Technological Enterprise (CREATE) programme.

Routine mammography screening is currently the standard tool for finding cancers at an early stage, when treatment is most successful. Current breast screening programmes are one-size-fits-all which all women above a certain age threshold are encouraged to participate. However, breast cancer risk varies by individual. The BREAst screening Tailored for HEr (BREATHE) study aims to assess acceptability of a comprehensive risk-based personalised breast screening in Singapore. Advancing beyond the current age-based screening paradigm, BREATHE integrates both genetic and non-genetic breast cancer risk prediction tools to personalise screening recommendations. BREATHE is a cohort study targeting to recruit ~3,500 women. The first recruitment visit will include questionnaires and a buccal cheek swab. After receiving a tailored breast cancer risk report, participants will attend an in-person risk review, followed by a final session assessing the acceptability of our risk stratification programme. Risk prediction is based on: a) Gail model (non-genetic), b) mammographic density and recall, c) BOADICEA predictions (breast cancer predisposition genes), and d) breast cancer polygenic risk score. For national implementation of personalised risk-based breast screening, exploration of the acceptability within the target populace is critical, in addition to validated predication tools. To our knowledge, this is the first study to implement a comprehensive risk-based mammography screening programme in Asia. The BREATHE study will provide essential data for policy implementation which will transform the health system to deliver a better health and healthcare outcomes.

Nitrogen doping of graphene with systematically controlled dopant content and distribution of nitrogen species is demonstrated to improve the size distribution of the deposited platinum (Pt) nanoparticles. While the dopant content can be tuned by varying the urea dosage, the doped nitrogen species (namely pyridinic N, pyrrolic N, and graphitic N) can be controlled through the annealing temperature. Chemically reduced Pt nanoparticles were found to be evenly distributed on the nitrogen-doped graphene sheets (NRGO) with particle size centred at 2.7 nm. In comparison, the decoration of Pt on the non-doped graphene (RGO) yielded a composite material with larger Pt (7.8 nm) and poorer size distribution. The loading of Pt nanoparticles is shown to correlate with the concentration of the nitrogen dopant, in particular that of the graphitic N species. Owing to the smaller and better distributed Pt nanoparticles which facilitated more active sites for reaction, the Pt-loaded NRGO photocatalytically generated H2 gas ten times higher than that of Pt-loaded RGO when coupled with photoactive graphitic carbon nitride (g-C3N4).

BackgroundProspective review and feedback (PRF) of antibiotic prescriptions and compulsory computerized decision support system (CDSS) are 2 strategies of antimicrobial stewardship. There are limited studies investigating their combined effects. We hypothesized that the use of on-demand (voluntary) CDSS would achieve similar patient outcomes compared with automatically triggered (compulsory) CDSS whenever broad-spectrum antibiotics are ordered.MethodsA parallel-group, 1:1 block cluster randomized crossover study was conducted in 32 medical and surgical wards from March to August 2017. CDSS use for piperacillin-tazobactam or carbapenem in the intervention clusters was at the demand of the doctor, while in the control clusters CDSS use was compulsory. PRF was continued for both arms. The primary outcome was 30-day mortality.ResultsSix hundred forty-one and 616 patients were randomized to voluntary and compulsory CDSS, respectively. There were no differences in 30-day mortality (hazard ratio [HR], 0.87; 95% CI, 0.67–1.12), re-infection and re-admission rates, antibiotic duration, length of stay, or hospitalization cost. The proportion of patients receiving PRF recommendations was not significantly lower in the voluntary CDSS arm (62 [10%] vs 81 [13%]; P = .05). Appropriate indication of antibiotics was high in both arms (351/448 [78%] vs 330/433 [74%]; P = .18). However, in geriatric medicine patients where antibiotic appropriateness was ConclusionsVoluntary broad-spectrum antibiotics with PRF via CDSS did not result in differing clinical outcomes, antibiotic duration, or length of stay. However, in the setting of low antibiotic appropriateness, compulsory CDSS may be beneficial.

The effects of sodium chloride (NaCl) and commercial salt substitutes (SS) on cooking qualities, microstructure, textural and sensory properties of fresh wheat noodles were studied. NaCl and four types of SS were added at 1, 4 and 8% of flour weight. White salted noodles (WSN) had shorter optimum cooking time than zero-salted noodles (ZSN). Cooking yield of ZSN, WSN-NaCl-1, WSN-NaCl-8, WSN-SS3-1 and WSN-SS3-4 were significantly (P 0.05) springiness of noodles. Addition of salts into noodles, except WSN-NaCl-1, WSN-NaCl-8, and WSN-SS2-8 were firmer than ZSN. WSN-SS2 and WSN-SS4 exhibited densest microstructure than ZSN and WSN-NaCl. Ranking test indicated that replacing NaCl with SS2, SS3 and SS4 up to 8% in noodles could retain elasticity of noodles. SS2 and SS4 may be useful to replace NaCl due to better noodles qualities than ZSN and WSN-NaCl.

The utilization of Na2S/Na2SO3 mixture as the electrolyte solution to stabilize sulfide anode in a photoelectrochemical cell for hydrogen evolution generally compromises the current-to-hydrogen efficiency ( η current) of the system. Here, the employment of a dual-electrolyte system, that is, Na2S/Na2SO3 mixture and pH-neutral Na2SO4 as the respective electrolyte solutions in the anode and cathode chambers of a water splitting cell is demonstrated to suppress the photocorrosion of CuInS2-In2O3-TiO2 nanotube (CIS- In2O3- TNT) heterostructure, while simultaneously boosts the η current. Although n-type CIS and In2O3 nanoparticles can be easily formed on TNT array via facile pulse-assisted electrodeposition method, conformal deposition of the nanoparticles homogeneously on the nanotubes wall with preservation of the TNT hollow structure is shown to be essential for achieving efficient charge generation and separation within the heterostructure. In comparison to Na2S/Na2SO3 solution as the sole electrolyte in both the anode and cathode chambers, introduction of dual electrolyte is shown to not only enhance the photostability of the CIS-In2O3-TNT anode, but also lead to near-unity η current as opposed to the merely 20% η current of the single-electrolyte system.

Addition of reduced graphene oxide (RGO) to P25 TiO2 was made and its impacts on photocatalytic oxidation of various organic substances were studied. Although the presence of RGO in TiO2 can enhance certain TiO2-based photocatalytic reactions, it is not a universal observation that can be expected in all types of organic substances. The factor of photocatalytic activity enhancement is strongly affected by the various functional groups appeared in the organic substances. In this work, it is realised that the length of alkyl chain in alcohols and carboxylic acids have the minimum influence on the overall activity while the number of hydroxyl groups can promote the further activity enhancement in the presence of RGO.

E7820 and indisulam are two examples of aryl sulfonamides that recruit RBM39 to Rbx-Cul4-DDA1-DDB1-DCAF15 E3 ligase complex, leading to its ubiquitination and degradation by the proteasome. In order to understand their mechanism of action, we carried out kinetic analysis on the recruitment of RBM39 to DCAF15 and solved a crystal structure of DDA1-DDB1-DCAF15 in complex with E7820 and the RRM2 domain of RBM39. E7820 packs in a shallow pocket on the surface of DCAF15 and the resulting modified interface binds RBM39 through the α1 helix of RRM2 domain. Our kinetic studies revealed that aryl sulfonamide and RBM39 bind to DCAF15 in a synergistic manner. The structural and kinetic studies confirm aryl sulfonamides as molecular glues in the recruitment of RBM39 and provide a framework for future efforts to utilize DCAF15 to degrade other protein of interests.

E7820 and indisulam are two examples of aryl sulfonamides that recruit RBM39 to Rbx-Cul4-DDA1-DDB1-DCAF15 E3 ligase complex, leading to its ubiquitination and degradation by the proteasome. To understand their mechanism of action, we performed kinetic analysis on the recruitment of RBM39 to DCAF15 and solved a crystal structure of DDA1-DDB1-DCAF15 in complex with E7820 and the RRM2 domain of RBM39. E7820 packs in a shallow pocket on the surface of DCAF15 and the resulting modified interface binds RBM39 through the α1 helix of the RRM2 domain. Our kinetic studies revealed that aryl sulfonamide and RBM39 bind to DCAF15 in a synergistic manner. The structural and kinetic studies confirm aryl sulfonamides as molecular glues in the recruitment of RBM39 and provide a framework for future efforts to utilize DCAF15 to degrade other proteins of interest.

Photocatalytic and photoelectrochemical processes are two key systems in harvesting sunlight for energy and environmental applications. As both systems are employing photoactive semiconductors as the major active component, strategies have been formulated to improve the properties of the semiconductors for better performances. However, requirements to yield excellent performances are different in these two distinctive systems. Although there are universal strategies applicable to improve the performance of photoactive semiconductors, similarities and differences exist when the semiconductors are to be used differently. Here, considerations on selected typical factors governing the performances in photocatalytic and photoelectrochemical systems, even though the same type of semiconductor is used, are provided. Understanding of the underlying mechanisms in relation to their photoactivities is of fundamental importance for rational design of high-performing photoactive materials, which may serve as a general guideline for the fabrication of good photocatalysts or photoelectrodes toward sustainable solar fuel generation.

The functionality of a photoactive semiconductor (i.e., photocatalysts, photoelectrodes, etc.) is largely dictated by three key aspects: (i) band gap; (ii) absolute potentials of the conduction band minimum and the valence band maximum; and (iii) bulk and surface charge carrier dynamics. Their relevance to governing the energetics and the photo(electro)chemical mechanisms of the semiconductor has prompted development of a multitude of characterization tools to probe the specific characteristic of the material. This review aims to summarize the current experimental techniques, including the conventional and the state-of-the-art tools, directed at examining the key aspects (i), (ii), and (iii) of semiconductors. Although not being exhaustive, this didactic review can be useful to apprise the research community of the sophisticated research tools currently available for characterization of photo(electro)catalyst semiconductors as well as to bridge the multidisciplinary knowledge.

Efficient interfacial charge transfer is essential in graphene-based semiconductors to realize their superior photoactivity. However, little is known about the factors (for example, semiconductor morphology) governing the charge interaction. Here, it is demonstrated that the electron transfer efficacy in reduced graphene oxide-bismuth oxide (RGO/BiVO4) composite is improved as the relative exposure extent of {010}/{110} facets on BiVO4 increases, indicated by the greater extent of photocurrent enhancement. The dependence of charge transfer ability on the exposure degree of {010} relative to {110} is revealed to arise due to the difference in electronic structures of the graphene/BiVO4{010} and graphene/BiVO4{110} interfaces, as evidenced by the density functional theory calculations. The former interface is found to be metallic with higher binding energy and smaller Schottky barrier than that of the latter semiconducting interface. The facet-dependent charge interaction elucidated in this study provides new aspect for design of graphene-based semiconductor photocatalyst useful in manifold applications.

It is intriguing that some pan-caspase inhibitors such as zVAD-fmk (zVAD) are capable of inducing necrotic cell death in a selected group of cells. As earlier reports from our laboratory have ruled out the original notion that zVAD-induced necrosis in mouse fibrosarcoma L929 cells was autophagic cell death, the main objective of this study was thus to determine the underlying mechanism of this form of cell death. In this study, we provided clear evidence that zVAD-induced necroptosis in L929 cells and such cell death is dependent on autocrine production of tumor necrosis factor-α (TNFα) at the transcriptional level. More importantly, we identified that activating protein-1 (AP-1), but not nuclear factor κ-B, is the transcription factor controlling zVAD-induced TNFα transcription. Moreover, zVAD is able to activate AP-1 through activation of two upstream mitogen-activated kinases (MAPKs), c-Jun N-terminal kinase and extracellular signal-regulated kinase. Finally, we found that protein kinase C is the important upstream signaling molecule in mediating zVAD-induced activation of MAPKs and AP-1, and subsequent autocrine production of TNFα and cell death. Data from this study reveal the molecular mechanisms underlying zVAD-induced necroptosis, an important form of programmed necrotic cell death with increasing understanding of its biological significance in health and diseases.

Under oxidative stress, poly(ADP-ribose) polymerase-1 (PARP-1) is activated and contributes to necrotic cell death through ATP depletion. On the other hand, oxidative stress is known to stimulate autophagy, and autophagy may act as either a cell death or cell survival mechanism. This study aims to explore the regulatory role of PARP-1 in oxidative stress-mediated autophagy and necrotic cell death. Here, we first show that hydrogen peroxide (H(2)O(2)) induces necrotic cell death in Bax-/- Bak-/- mouse embryonic fibroblasts through a mechanism involving PARP-1 activation and ATP depletion. Next, we provide evidence that autophagy is activated in cells exposed to H(2)O(2). More importantly, we identify a novel autophagy signaling mechanism linking PARP-1 to the serine/threonine protein kinase LKB1-AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway, leading to stimulation of autophagy. Finally, we demonstrate that autophagy plays a cytoprotective role in H(2)O(2)-induced necrotic cell death, as suppression of autophagy by knockdown of autophagy-related gene ATG5 or ATG7 greatly sensitizes H(2)O(2)-induced cell death. Taken together, these findings demonstrate a novel function of PARP-1: promotion of autophagy through the LKB1-AMPK-mTOR pathway to enhance cell survival in cells under oxidative stress.

At present, the signaling pathways controlling reactive nitrogen species (RNS)-induced non-apoptotic cell death are relatively less understood. In this work, various RNS donors are found to induce caspase-independent non-apoptotic cell death in mouse embryonic fibroblasts (MEF). In search of the molecular mechanisms, we first established the role of c-Jun N-terminal kinase (JNK) in RNS-induced non-apoptotic cell death. RNS readily activate JNK, and the jnk1-/- MEF are resistant to RNS-induced cell death. Moreover, the reconstitution of JNK1 effectively restores the sensitivity to RNS. Next, we identified tumor necrosis factor receptor-associated factor 2 (TRAF2) and apoptosis signal-regulating kinase 1 (ASK1) as the essential upstream molecules for RNS-induced JNK activation and cell death. RNS fail to activate JNK and induce cell death in traf2-/- MEF; and reconstitution of TRAF2 effectively restores the responsiveness of traf2-/- MEF to RNS. Moreover, RNS-induced ASK1 activation is impaired in traf2-/- cells and overexpression of a mutant ASK1 protein suppresses RNS-induced cell death in wild-type MEF cells. Last, we explored the signaling events upstream of TRAF2 and found that translocation of TRAF2 and JNK1 onto membrane lipid rafts is required for RNS-mediated JNK1 activation and cell death. Taken together, data from our study reveal a novel signaling pathway regulating RNS-induced JNK1 activation and non-apoptotic cell death.

A group of phosphoinositide 3-kinase (PI3K) inhibitors, such as 3-methyladenine (3-MA) and wortmannin, have been widely used as autophagy inhibitors based on their inhibitory effect on class III PI3K activity, which is known to be essential for induction of autophagy. In this study, we systematically examined and compared the effects of these two inhibitors on autophagy under both nutrient-rich and deprivation conditions. To our surprise, 3-MA is found to promote autophagy flux when treated under nutrient-rich conditions with a prolonged period of treatment, whereas it is still capable of suppressing starvation-induced autophagy. We first observed that there are marked increases of the autophagic markers in cells treated with 3-MA in full medium for a prolonged period of time (up to 9 h). Second, we provide convincing evidence that the increase of autophagic markers is the result of enhanced autophagic flux, not due to suppression of maturation of autophagosomes or lysosomal function. More importantly, we found that the autophagy promotion activity of 3-MA is due to its differential temporal effects on class I and class III PI3K; 3-MA blocks class I PI3K persistently, whereas its suppressive effect on class III PI3K is transient. Because 3-MA has been widely used as an autophagy inhibitor in the literature, understanding the dual role of 3-MA in autophagy thus suggests that caution should be exercised in the application of 3-MA in autophagy study.

Our previous work has shown that autophagy plays a pro-survival function in two necrotic cell death models: zVAD-treated L929 cells as well as H(2)O(2)-treated Bax(-/-)Bak(-/-) mouse embryonic fibroblasts (DKO MEF). This study aims to further explore the regulatory role of autophagy in necrosis by examining the functional role of the phosphoinositide-3 kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway. Our initial intriguing finding was that insulin is able to promote necrotic cell death induced by zVAD and MNNG in L929 cells or by H(2)O(2) in DKO MEF cells cultured in full-growth medium. The pro-necrosis function of insulin was further supported by the observations that insulin is capable of abolishing the protective effect of starvation on necrotic cell death induced by zVAD in L929 cells. Next, we demonstrated that insulin acts on the PI3K-Akt-mTOR pathway to promote necrosis as the suppression of the above pathway by either chemical inhibitors (LY294002 and rapamycin) or mTOR knockdown is able to mitigate the pro-death function of insulin. Finally, we provided evidence that the pro-death function of insulin is dependent on its inhibitory effect on autophagy, which serves as an important pro-survival function in necrosis. Taken together, here we provide compelling evidence to show that activation of the PI3K-Akt-mTOR signaling pathway can promote necrotic cell death via suppression of autophagy, at least in the necrosis models defined in our study in which autophagy serves as a pro-survival function. Data from this study not only further underscore the pro-survival function of autophagy in necrotic cell death, but also provide a novel insight into the intricate connections linking the PI3K-Akt-mTOR signaling pathway with cell death via modulation of autophagy.

The aim of this study is to examine the role of autophagy in cell death by using a well-established system in which zVAD, a pan-caspase inhibitor, induces necrotic cell death in L929 murine fibrosarcoma cells. First, we observed the presence of autophagic hallmarks, including an increased number of autophagosomes and the accumulation of LC3-II in zVAD-treated L929 cells. Since the presence of such autophagic hallmarks could be the result of either increased flux of autophagy or blockage of autophagosome maturation (lysosomal fusion and degradation), we next tested the effect of rapamycin, a specific inhibitor for mTOR, and chloroquine, a lysosomal enzyme inhibitor, on zVAD-induced cell death. To our surprise, rapamycin, known to be an autophagy inducer, blocked zVAD-induced cell death, whereas chloroquine greatly sensitized zVAD-induced cell death in L929 cells. Moreover, similar results with rapamycin and chloroquine were also observed in U937 cells when challenged with zVAD. Consistently, induction of autophagy by serum starvation offered significant protection against zVAD-induced cell death, whereas knockdown of Atg5, Atg7 or Beclin 1 markedly sensitized zVAD-induced cell death in L929 cells. More importantly, Atg genes knockdown completely abolished the protective effect of serum starvation on zVAD-induced cell death. Finally, we demonstrated that zVAD was able to inhibit lysosomal enzyme cathepsin B activity, and subsequently blocked autophagosome maturation. Taken together, in contrast to the previous conception that zVAD induces autophagic cell death, here we provide compelling evidence suggesting that autophagy serves as a cell survival mechanism and suppression of autophagy via inhibition of lysosomal function contributes to zVAD-induced necrotic cell death.

PR-3 Under oxidative stress, poly(ADP-ribose) polymerase-1 (PARP-1) is activated and contributes to necrotic cell death through ATP depletion. On the other hand, oxidative stress is known to stimulate autophagy, and autophagy may act as either a cell death or cell survival mechanism. This study aims to explore the regulatory role of PARP-1 in oxidative stress-mediated autophagy and necrotic cell death. Here we first show that hydrogen peroxide (H2O2) induces necrotic cell death in Bax-/- Bak -/- mouse embryonic fibroblasts (MEFs) through a mechanism involving PARP-1 activation and ATP depletion. Next, we provide evidence that autophagy is activated in cells exposed to H2O2. More importantly, we identify a novel autophagy signaling mechanism linking PARP-1 to the serine/threonine protein kinase LKB1-AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway, leading to stimulation of autophagy. Finally, we demonstrate that autophagy plays a cytoprotective role in H2O2-induced necrotic cell death as suppression of autophagy by knockdown of autophagy-related gene ATG5 or ATG7 greatly sensitizes H2O2-induced cell death. Taken together, these findings demonstrate a novel function of PARP-1: promotion of autophagy via the LKB1-AMPK-mTOR pathway to enhance cell survival in cells under oxidative stress. Citation Information: Cancer Prev Res 2008;1(7 Suppl):PR-3.