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Background: Copper complex has been gaining much attention in anticancer research as a targeted agent since cancer cells uptake more copper than non-cancerous cells. Our group synthesised a ternary copper complex, which is composed of 1,10-phenanthroline and tyrosine [Cu(phen)(L-tyr)Cl].3H20. These two payloads have been designed to cleave DNA and inhibit protein degradation system (proteasome) concurrently in cancer cells, making this copper complex a dual-target compound. Objective: The current study was carried out to investigate the mode of cell death and the role of autophagy induced by [Cu(phen)(L-tyr)Cl].3H20 in MCF-7 and MDA-MB-231 breast cancer cells. Methods: Growth inhibition of [Cu(phen)(L-tyr)Cl].3H20 towards MDA-MB-231 and human non-cancerous MCF10A breast cells was determined by MTT assay. Annexin-V-FITC/PI and cell cycle analysis were evaluated by flow cytometry. The expression of p53, Bax, caspase-9, caspase-7, caspase-3 and LC3 was determined using western blot analysis. The cells were then co-treated with hydroxychloroquine to ascertain the role of autophagy induced by [Cu(phen)(L-tyr)Cl].3H20. Results: [Cu(phen)(L-tyr)Cl].3H20 inhibited the growth of cancer cells dose-dependently with less toxicity towards MCF10A cells. Additionally, [Cu(phen)(L-tyr)Cl].3H20 induced apoptosis and cell cycle arrest towards MCF-7 and MDA-MB-231 breast cancer cells possibly via regulation of p53, Bax, caspase-9, caspase-3 and capase-7. The expression of LC3II was upregulated in both cancer cell lines upon treatment with [Cu(phen)(L-tyr) Cl].3H20, indicating the induction of autophagy. Co-treatment with autophagy inhibitor hydroxychloroquine significantly enhanced growth inhibition of both cell lines, suggesting that autophagy induced by [Cu(phen)(L-tyr) Cl].3H20 in both breast cancer cells promoted cell survival. Conclusion: [Cu(phen)(L-tyr)Cl].3H20 holds great potential to be developed for breast cancer treatment.

Straw is an abundant natural bioresource, especially in developing and agricultural countries. Bio-hydrogen production from this renewable biomass through biological methods is an active research area. Because of its distinctive characteristic of being rich in cellulose, straw has been extensively considered as a promising raw material for clean energy production. In this paper, the recent progress of bio-hydrogen production from straw was reviewed with the emphasis on the advances in pretreatment and hydrolysis technologies. The future development of straw-based biohydrogen production was also analyzed. Based on the physicochemical properties of straw biomass and mechanisms of bio-hydrogen fermentation, various pretreatment procedures have been developed to make the straw substrate more available for hydrogen-producing bacteria to realize large-scale bio-hydrogen production from straw. This review summarized the recent technologies of straw pretreatment and hydrolysis as well as elaborated on the bottlenecks in the field of straw biotransformation in great detail. Furthermore, based on the current technology status and potential, the challenges, prospects and future directions of the production methods were further proposed.

This study presents a simple technique for strengthening the adhesive-bond strength between aluminium (Al) substrate and carbon fibre reinforced polymer (CFRP) utilising resin pre-coating (RPC) with carbon nanotubes (CNTs). The CNT-containing RPC solution with 90 ​wt% acetone and 10 ​wt% resin (without hardener) was applied onto Al substrates, where micro-/nano-vertical channels had been created by chemical or mechanical surface treatments to accommodate CNTs. RPC was able to fill all micro-/nano-cavities over the Al substrate surface, then CNTs were pulled into those vertical micro-channels by the capillary action generated from acetone evaporation. Normal epoxy adhesive (resin ​+ ​hardener) was applied after the CNT-containing RPC treatment. CNTs bridging across the interface between the adhesive joint and Al substrate and sealing of micro-/nano-cavities by RPC effectively enhanced the interfacial shear bond strength between the Al substrate and CFRP by 30–100% depending on the Al substrate surface profiles. Al substrates with two different chemical treatments were compared in this study for the effectiveness of CNT interfacial reinforcement. Results from a steel substrate after sandblasting were also included for comparison.

Seven new tropane alkaloids, including five monomeric (1-5), one dimeric (6), and one trimeric (7) 3α-nortropane ester, along with two known monomeric nortropane alkaloids (8 and 9), were isolated from the leaves and bark of Pellacalyx saccardianus. Their structures, including the absolute configuration of the enantiomeric pair of (±)-6, were elucidated by comprehensive spectroscopic analyses. Alkaloids 6 and 7 showed cytotoxicity toward human pancreatic cancer cell lines (AsPC-1, BxPC3, PANC-1, and SW1990). Alkaloids 1, 4, and 9 induced a smooth muscle relaxation effect comparable to that of atropine (Emax 106.1 ± 7.5%, 97.0 ± 5.2%, 100.9 ± 1.4%, 111.7 ± 1.7%, respectively) on isolated rat tracheal rings.

Targeted therapies against human epidermal growth factor receptor 2 (HER2) are associated with increased interstitial lung disease (ILD). Trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine have markedly extended HER2 breast cancer survival but current knowledge on how these HER2-targeted agents induce interstitial lung disease is still poorly defined due to limited cases in the literature. Physicians mostly managed this complication by dose interruption, dose de-escalation, or discontinuation with success. In 2019, the FDA had granted accelerated approval on trastuzumab deruxtecan (T-Dxd) in HER2 breast cancer in the late line setting. Severe ILD incidence rate was over ten percent and led to fatal outcomes in 2.2% of patients in the T-Dxd trial. Searching for biomarkers to detect ILD incidence before it becomes clinically fulminant or for treatment response monitoring is of high clinical value. A Case of life-threatening trastuzumab-induced ILD was encountered in our facility. The ILD was confirmed to be antineutrophil cytoplasmic antibody (ANCA) pulmonary capillaritis. The biomarker of neutrophil extracellular traps (NETs), serum MPO-DNA complex, showed a good correlation with the clinical severity. Soon after B cell depleting agent rituximab usage, the serum MPO-DNA outperformed ANCA autoantibody and maintained its correlation with clinical severity. In addition to the trastuzumab-induced ILD case, a prospective cohort in our facility also confirmed the usefulness of MPO-DNA in monitoring vasculitis activity. We postulated that upfront testing with biomarkers of vasculitis during HER2 targeted treatment with high ILD incidence may be beneficial in the future., Graphical abstract Interaction Between Anti-HER2 Antibody and ANCA-Associated Vasculitis and Neutrophil In lung tissues, only bronchial epithelial cells express human epidermal growth factor 2 (HER2) protein in the cell surfaces. Once trastuzumab binds to the HER2 protein, trastuzumab acts as a stimulus to activate neutrophils to express autoantigen, including leukocyte proteinase 3 (PR3) and myeloperoxidase (MPO). The neutrophils could also directly release PR3 and MPO with cell-free DNA and histone through exocytosis to form a neutrophil extracellular trap (NETs). NETs containing PR3 and MPO could further trigger autoreactive B cells to produce ANCA antibodies, resulting in more neutrophil activation and alveolar-capillary endothelial as well as alveolar epithelial damage, although alveolar epithelial cells do not express HER2. A two-step mechanism explains how all previously reported cases that we identified manifests late with a median time of onset two months after the first trastuzumab exposure.Image 1, Highlights • Drug-induced Interstitial lung disease (DIILD) induced by HER2-targeted therapies, is a well-known adverse drug reaction, but the mechanism is ill-defined and no effective strategy for monitoring and prevention were reported. • We report a Case of trastuzumab-related interstitial lung disease induced by anti-neutrophil cytoplasmic antibody, which was never reported in previous literature. • As neutrophils dominate the inflammatory infiltrate in vasculitis, serum MPO-DNA, a biomarker of neutrophil activity, was performed in this Case and within a prospective vasculitis cohort in our facility and showed promising clinical severity correlation. • Monitoring with vasculitis-related autoantibodies and serum MPO-DNA may be helpful in future HER2-targeted agents since high rates of DIILD were reported due to this group of HER2-targeted agents.

A single-step and rapid chromatographic method-based purification of Gracilaria corticata (J. Agardh) R-phycoerythrin (R-PE) was attained using polyacrylamide gel electrophoresis (PAGE) technique without affecting structural integrity. The purified R-PE had a characteristic UV–Vis spectrum with three absorbance maxima at 496, 535, and 565 nm, and fluorescence at 575 nm. R-PE was obtained with a purity index of 4.2 and a recovery yield of 44.3%. SDS-PAGE analysis exhibited three sub-units i.e., 18, 21, and 31 kDa, which corresponds to α, β, and γ, respectively. This report's purification process was considered less time-consuming and could be efficiently applied to purify phycobiliproteins. The purified R-PE showed optimal stability up to 6 h at pH 7.0 when exposed to light (3000 lx), while the temperature at which the maximum stability was retained was at 20 °C. The cellular imaging property of R-PE was effectively implemented to evaluate its credentials without affecting the cell proliferation of Vero and Hep-2 cell lines with the higher IC50 concentrations in vitro. Under fluorescence microscopy and flow cytometry analysis, purified R-PE displayed the characteristic affinity towards cell imaging functions in preliminary in vitro studies.

The impact of different nitrogen sources on the microalga, Chlorella vulgaris, was studied in a newly developed microalgal-bacterial photobioreactor via a dual nutrient heterogeneity mode. The mechanisms of nitrogen transformation and valorisation were unveiled, and subsequently, optimized via dual nutrient heterogeneity feeding modes comprising of various NH4+-N and NO3−-N concentrations. The nitrogen-assimilation mechanism from the microalgal-bacterial consortium was found to reduce microalgal growth inhibition, stemming at high NH4+-N concentrations. Accordingly, the total nitrogen removal efficiency was enhanced from 40.91% to 96.38% accompanied with maximum microalgal biomass production of up to 792 mg/L at a balanced or higher NH4+-N loading from mixed nitrogen environment. The harvested microalgal biomass contained high lipid accumulation of approximately 30% when fed with optimum NH4+-N and NO3−-N loadings at 60 and 58 mg/d, respectively. At this mixed nitrogen species loadings, high unsaturated fatty acid methyl esters (FAME) were attained. Indeed, the major FAME species (97%–100%) fell within the C16-18 range, signifying biodiesel characteristics conformity to the requirements for quality biodiesel application. Therefore, the dual heterogeneity modes of balanced NH4+-N and NO3−-N loadings into photobioreactor could offer effective microalgal nitrogen assimilation for sustainable wastewater treatment and microalgae-based biodiesel production simultaneously.

Two pairs of enantiomeric diarylheptanoid-phenylpropanoid adducts bearing a cyclohexenone core, (±)-saccardianones A and B (1 and 2), an alkaloidal diarylheptanoid-phenylpropanoid adduct bearing a 4-piperidone core, (±)-saccardianine A (3), a pair of enantiomeric dimeric diarylheptanoid alkaloids bearing a tetrahydropyridine core, (±)-saccardianine B (4), and a suspected degradation product, saccardianine C (5), in addition to a known diarylheptanoid, platyphyllenone (6), were isolated from the leaves of Pellacalyx saccardianus. Their chemical structures were elucidated based on detailed analyses of the NMR and MS data. The structure of (±)-(1) was also confirmed by X-ray diffraction analysis. Compounds (±)-2 and 6 exhibited selective cytotoxicity towards the AsPC-1 and PANC-1 pancreatic cancer cell lines, respectively.

Spontaneous coal combustion was proved to cause methane accumulation and methane explosions in coal mine goafs. To avoid possible methane explosions, the empirical engineering measure, ventilation dilution, is proposed in coal mines though its disaster prevention mechanism has not been well understood. Through experimental and numerical simulations, the superposition effect of the air leakage and coal combustion-induced chimney effect was studied to reveal disaster prevention effect of ventilation dilution. Research results show that the high temperature area of coal combustion is steady and can provide continuous buoyancy force to form upward airflow even under ventilation dilution; the drifting methane accumulation is observed under the superposition effect of air leakage and upward airflow; ventilation dilution can weaken and even eliminate methane accumulation by overcoming chimney effect, but an increase in coal combustion temperature will enhance the upward airflow of chimney effect to cause methane accumulation again. The competitive relationship between the coal combustion-induced chimney effect and air leakage provides a new insight to study methane migration for the disaster formation and prevention mechanism.

Current fire retardants are known to be toxic to humans and our environment. As environmental-friendly flame retardants (FRs), protein-based flame retardants have been studied extensively recently, even though they are not durable. In this study, we designed, synthesized and tested a durable protein-based FR through the fusion of the adhesion domain from either mussel foot protein-5 (mfp-5) or cellulose-binding domain (CBD) with flame retardant protein (SR protein and alpha casein). We first verified the expression of the recombinant proteins in Escherichia coli using Western blot. Then, we coated the fusion protein (carrying cell lysates) to cotton fabrics and wood and verified with Infrared (IR) spectroscopy. Using a vertical burning test and wood flammability test, we confirmed the flame retardancy of the materials after the protein coating. In the vertical burning test, the SR protein and alpha casein flame retardant proteins with the CBD adhesion domain showed a 50.0% and 43.3% increase in flame retardancy. The data is also consistent in the wood flame retardancy test. Confocal imaging experiments also suggested these new fire retardants can be preserved on the materials well even after washing. Overall, our results showed that flame-retardant proteins with adhesion domains are high potential candidates of green alternative flame retardants.

INTRODUCTION Image-guided thermal ablation, preferably with ultrasonography (US), is increasingly used for treatment of small liver tumours. Perfluorobutane-contrast-enhanced US (pCEUS) is a promising tool that may allow for targeting of tumours that are otherwise imperceptible on greyscale US. Although pCEUS has been reported to be effective, the literature has been limited outside of Japan and South Korea. We aimed to provide data that supports the use of pCEUS in the thermal ablation of sonographically occult liver tumours. METHODS We conducted a retrospective single-centre study of 35 consecutive patients who underwent pCEUS-guided ablation of 48 liver tumours with a median size of 1.2 cm. Periprocedural, one-month post-treatment and relevant follow-up imaging studies were reviewed. Electronic records were also obtained, with long-term follow-up data of 12–28 months being available for 32 patients. RESULTS 36 (75%) tumours that were imperceptible on greyscale US became visible with pCEUS. Overall, complete tumour ablation at one month was 89%. 1 (3%) patient developed a major complication following treatment, while 6 (17%) had minor post-treatment complaints. The local tumour progression rate was 17%, with a median time of 14 months. CONCLUSION pCEUS has a role in US-guided thermal ablation of liver tumours, offering a high technical success rate that is comparable to reported data. Additional benefits may include improved procedural time and freedom from ionising radiation.

Much has been learned about the protein coronae and their biological implications within the context of nanomedicine and nanotoxicology. However, no data is available about the protein coronae associated with nanoparticles undergoing spontaneous surface-energy minimization, a common phenomenon during the synthesis and shelf life of nanomaterials. Accordingly, here we employed gold nanoparticles (AuNPs) possessing the three initial states of spiky, midspiky, and spherical shapes and determined their acquisition of human plasma protein coronae with label-free mass spectrometry. The AuNPs collected coronal proteins that were different in abundance, physicochemical parameters, and interactive biological network. The size and structure of the coronal proteins matched the morphology of the AuNPs, where small globular proteins and large fibrillar proteins were enriched on spiky AuNPs, while large proteins were abundant on spherical AuNPs. Furthermore, the AuNPs induced endothelial leakiness to different degrees, which was partially negated by their protein coronae as revealed by confocal fluorescence microscopy, in vitro and ex vivo transwell assays, and signaling pathway assays. This study has filled a knowledge void concerning the dynamic protein corona of nanoparticles possessing an evolving morphology and shed light on their implication for future nanomedicine harnessing the paracellular pathway.

PURPOSE To describe the vascular anatomy and intraluminal flow characteristics of segmental retinal arteritis (SRA) using structural and angiographic optical coherence tomography (OCT). METHODS Retrospective case series of consecutive patients presenting with SRA. All patients were evaluated at presentation with fundus photography, spectral domain OCT, and OCT angiography. One patient was imaged with dense B-scan OCT angiography. RESULTS Three eyes of three male patients were evaluated. All examinations were consistent with reactivation of ocular toxoplasmosis with an area of active retinochoroiditis adjacent to a focal chorioretinal scar. Spectral domain OCT through areas of SRA noted on clinical examination demonstrated areas of hyperreflectivity circumscribing the affected vessel with a normoreflective lumen. Optical coherence tomography angiography and dense B-scan OCT angiography demonstrated narrowing of the intraluminal flow signal that correlated with areas of segmental hyperreflectivity on spectral domain OCT. Vascular sections proximal and distal to areas of SRA showed normal flow signal. CONCLUSION Vessels with SRA demonstrated hyperreflectivity highlighting the vessel wall on spectral domain OCT. Optical coherence tomography angiography showed narrowing of the flow signal within these segments suggesting reduced lumen diameter. Coupling these finding with previous indocyanine green imaging findings in SRA, the collective data suggest the plaques are localized within the vessel wall to either the endothelium or the muscular tunica media without occlusion of the vessel lumen.

Summary Treatments that target single mediators of sepsis have failed to reduce its high mortality rate. Here we developed multifunctional tannic acid-Zn2+-gentamicin nanoparticles (TA-Zn-Gen NPs) that target multiple mediators of sepsis to improve sepsis treatment. TA-Zn-Gen NPs with lower gentamicin content possessed net negative surface charge but still bound cell-free DNA (cfDNA) with high affinity. The TA-Zn-Gen NPs exhibited five modes of anti-sepsis activity: (1) scavenged cfDNA and inhibited cfDNA-initiated activation of toll-like receptors and NF-κB signaling; (2) inhibited activated macrophage-induced macrophage recruitment; (3) scavenged reactive oxygen species (ROS) and reduced ROS-induced DNA damage and cell death; (4) inhibited nitric oxide production induced by lipopolysaccharides; and (5) potent antibacterial activity. The NPs reduced multiple organ damage and increased the survival rate of mice with severe sepsis. Together, the results demonstrate the potency of targeting multiple mediators for sepsis treatment, and support the development of multifunctional NPs for treating other intractable inflammation-related diseases.

PURPOSE Ibrutinib reduces mortality in chronic lymphocytic leukemia (CLL). It increases the risk of atrial fibrillation (AF) and bleeding and there are concerns about heart failure (HF) and central nervous system ischemic events. The magnitude of these risks remains poorly quantified. METHODS Using linked administrative databases, we conducted a population-based cohort study of Ontario patients who were treated for CLL diagnosed between 2007 and 2019. We matched ibrutinib-treated patients with controls treated with chemotherapy but unexposed to ibrutinib on prior AF, age ≥ 66 years, anticoagulant exposure, and propensity for receiving ibrutinib. Study outcomes were AF-related health care contact, hospital-diagnosed bleeding, new diagnoses of HF, and hospitalizations for stroke and acute myocardial infarction (AMI). The cumulative incidence function was used to estimate absolute risks. We used cause-specific regression to study the association of ibrutinib with bleeding rates, while adjusting for anticoagulation as a time-varying covariate. RESULTS We matched 778 pairs of ibrutinib-treated and unexposed patients with CLL (N = 1,556). The 3-year incidence of AF-related health care contact was 22.7% (95% CI, 19.0 to 26.6) in ibrutinib-treated patients and 11.7% (95% CI, 9.0 to 14.8) in controls. The 3-year risk of hospital-diagnosed bleeding was 8.8% (95% CI, 6.5 to 11.7) in ibrutinib-treated patients and 3.1% (95% CI, 1.9 to 4.6) in controls. Ibrutinib-treated patients were more likely to start anticoagulation after the index date. After adjusting for anticoagulation as a time-varying covariate, ibrutinib remained positively associated with bleeding (HR, 2.58; 95% CI, 1.76 to 3.78). The 3-year risk of HF was 7.7% (95% CI, 5.4 to 10.6%) in ibrutinib-treated patients and 3.6% (95% CI, 2.2 to 5.4) in controls. There was no significant difference in the risk of ischemic stroke or AMI. CONCLUSION Ibrutinib is associated with higher risk of AF, bleeding, and HF, but not AMI or stroke.

A set of metal carbonyl cluster-boronic acid conjugates of the group VIII metals (Fe, Ru, and Os) were synthesized and their antiproliferative effects measured against two breast cancer cell lines (MCF-7 and MDA-MB-231) and a noncancerous breast epithelial (MCF-10A) cell line. The cytotoxicity followed the order Ru > Os > Fe for the MDA-MB-231 cells, although the latter two exhibited similar cytotoxicity against MCF-7 and MCF-10A cells. The osmium species {Os3(CO)10(μ-H)[μ-SC6H4-p-B(OH)2]} (2) could be chemically oxidized to its hydroxy analogue [Os3(CO)10(μ-H)(μ-SC6H4-p-OH)] (2-OH), which showed comparable cytotoxicity. Mode of action studies pointed to an apoptotic pathway for cell death. Ministry of Education (MOE) Nanyang Technological University Published version This work was supported by Nanyang Technological University and the Ministry of Education (Research grant no. RG121/18).

Electronic regulation of two-dimensional (2D) transition metal dichalcogenides (TMDCs) is a crucial step towards next-generation optoelectronics and electronics. Here, we demonstrate controllable and selective-area defect engineering in 2D molybdenum disulfide (MoS2) using a focused ion beam with a low-energy gallium ion (Ga+) source. We find that the surface defects of MoS2 can be tuned by the precise control of ion energy and dose. Furthermore, the field-effect transistors based on the monolayer MoS2 show a significant threshold voltage modulation over 70 V after Ga+ irradiation. First-principles calculations reveal that the Ga impurities in the monolayer MoS2 introduce a defect state near the Fermi level, leading to a shallow acceptor level of 0.25 eV above the valence band maximum. This defect engineering strategy enables direct writing of complex pattern at the atomic length scale in a controlled and facile manner, tailoring the electronic properties of 2D TMDCs for novel devices.

Palm biodiesel-ethanol blends could be the better automotive fuel over palm biodiesel alone owing to the high oxygen content and high volatility of ethanol. The evaporation and burning characteristics of palm biodiesel with 10%, 20%, and 30% ethanol by volume concentration respectively, were investigated by using the droplet experiment. Rapid bubble growth and bubble explosions during the heating stage were observed to be substantial for the palm biodiesel droplet added with 30% volume of ethanol (BE30). Adding ethanol in palm biodiesel increased the ignition delay and burn-rate constant by up to 38.6% and 23.2%, respectively whereas, the evaporation duration and burning period decreased by up to 20.6% and 22.5%, respectively. Overall, the relatively shorter evaporation duration and higher burn-rate found for the BE30 droplet could promote high thermal efficiency and has the potential to achieve ultra-low carbon monoxide (CO) and unburned hydrocarbons (UHCs) emissions in diesel and gas turbine engines.

Summary A 37-year-old female of South Asian origin was referred to our diabetes clinic for evaluation of an unusual finding during her retinal screening. Her retinal blood vessels appeared white in contrast to the normal pink-red colour. She had type I hyperlipidaemia, confirmed by genotype, and was recently diagnosed with diabetes, secondary to pancreatic insufficiency, for which she had suboptimal control and multiple hospitalisations with recurrent pancreatitis. On examination, she had multiple naevi on her skin; the rest of the examination was unremarkable. The patient did not report any visual disturbances and had intact visual acuity. Investigations showed raised total cholesterol (12.5 mmol/L) and triglycerides (57.7 mmol/L). Following evaluation, the patient was diagnosed with lipaemia retinalis, secondary to type I hyperlipidaemia. The patient was managed conservatively to reduce the cholesterol and triglyceride burdens. However, therapies with orlistat, statin, fibrates and cholestyramine failed. Only a prudent diet, omega-3 fish oil, medium-chain triglycerides oil and glycaemic control optimised with insulin showed some improvements in her lipid profile. Unfortunately, this led her to becoming fat-soluble vitamin deficient; hence, she was treated with appropriate supplementation. She was also recently started on treatment with volanesorsen. Following this, her lipid parameters improved and lipaemia retinalis resolved. Learning points Lipaemia retinalis is an uncommon incidental finding of type I hyperlipidaemia that may not affect vision. Management of associated dyslipidaemia is challenging with minimal response to conventional treatment. Increased awareness of lipaemia retinalis and specialist management is needed as part of regular patient monitoring and personalised management.

This study was performed to establish anti-diabetic and anti-oxidant properties, and to carry out phytochemical analysis of selected local plants which are traditionally used as medicinal plants. Local plants involved in this study were Lawsonia inermis, Punica granatum, Dryobalanops aromatica, Ziziphus mauritiana, and Ocimum basilicum. Solvent extraction was performed using maceration method with solvents of increasing polarity. Alpha-glucosidase inhibition assay was performed on all extracts to ascertain their anti-diabetic potentials. The extracts were screened for antioxidant activity using anti-oxidant assays (FRAP, DPPH, TAOC, ABTS, and BCB) and quantitative phytochemical analyses (TPC and TFC). Chemical profiling using LCMS and GCMS was performed on extracts with high biological activities. Methanol extracts of D. aromatica bark and leaves showed the most potent inhibition of alpha-glucosidase with IC50 values of 0.63 ± 0.03 µg/mL and 0.98 ± 0.02 µg/mL, respectively. Both extracts exhibited similar anti-oxidant activity on all five assays and possessed high phenolic contents with values of 266.79 and 261.69 GAE, respectively. The results obtained suggested that amongst the selected plants studied, D. aromatica showed high anti-oxidant activity and anti-diabetic activity (via inhibition of alpha-glucosidase). This is the first report that highlights the anti-diabetic potential of D. aromatica.

Background Streptococcus thermophilus (TCI633) is a probiotic that has been newly isolated from human breast milk, and it can produce hyaluronic acid (HA) when colonizing the gastrointestinal (GI) tract of rodents and humans. A recent study has the established that TCI633 can alleviate synovial tissue inflammation and has potential to mitigate the progression of osteoarthritis. Objective TCI633 has not been available for use in skincare and this preliminary clinical study will assess its improvement of the skin. Methods In this study, DNA protection, Hyaluronidase assay, cell viability, and collagen synthesis on human fibroblasts of TCI633 were assessed. Subjects were enrolled in this clinical study and randomly assigned to the TCI633 or placebo group. Each subject was informed to intake two tablets daily for 8 weeks. Each subject was required to undergo skin condition inspection at weeks 0, 4, and 8 and hematology tests to monitor HA, superoxide dismutase (SOD) and catalase levels, and kidney and liver function at weeks 0 and 8. Results The effects of TCI633 supplementation, including the promotion of skin cell proliferation, the increase of their collagen content, their protection against DNA damage, and the inhibition of hyaluronidase activities, are investigated. Subjects were recruited for an 8-week long clinical trial to confirm the efficacy of TCI633 in improving the serum biochemical HA, SOD and catalase levels, and anti-skin age markers. Conclusions This work provides an alternative approach to improving health, indicating the potential of TCI633 supplementation to delay the aging of skin and improve its condition.

Herein, we report a detailed study on creating heterojunction between graphitic carbon nitride (g-C3N4) and bismuth phosphate (BiPO4), enhancing the unpaired free electron mobility. This leads to an accelerated photocatalysis of 2,4-dichlorophenols (2,4-DCPs) under sunlight irradiation. The heterojunction formation was efficaciously conducted via a modest thermal deposition technique. The function of g-C3N4 plays a significant role in generating free electrons under sunlight irradiation. Together, the generated electrons at the g-C3N4 conduction band (CB) are transferred and trapped by the BiPO4 to form active superoxide anion radicals (•O2-). These active radicals will be accountable for the photodegradation of 2,4-DCPs. The synthesized composite characteristics were methodically examined through several chemical and physical studies. Due to the inimitable features of both g-C3N4 and BiPO4, its heterojunction formation, 2.5wt% BiPO4/g-C3N4 achieved complete 2,4-DCP removal (100%) in 90 min under sunlight irradiation. This is due to the presence of g-C3N4 that enhanced electron mobility through the formation of heterojunctions that lengthens the electron-hole pairs' lifetime and maximizes the entire solar spectrum absorption to generate active electrons at the g-C3N4 conduction band. Thus, this formation significantly draws the attention for future environmental remediation, especially in enhancing the entire solar spectrum's harvesting.

Nanomaterials are threatening the environment and human health, but there has been little discussion about the stability and mobility of nanoparticles (NPs) in saturated porous media at environmentally relevant concentrations of surfactants, which is a knowledge gap in exploring the fate of engineered NPs in groundwater. Therefore, the influences of the anionic surfactant (sodium dodecylbenzene sulfonate, SDBS), the cationic surfactant (cetyltrimethylammonium bromide, CTAB), and the nonionic surfactant (Tween-80) with environmentally relevant concentrations of 0, 5, 10, and 20 mg/L on nano-TiO2 (nTiO2, negatively charged) and nano-CeO2 (nCeO2, positively charged) transport through saturated porous media were examined by column experiments. On the whole, with increasing SDBS concentration from 0 to 20 mg/L, the concentration peak of nTiO2 and nCeO2 in effluents increased by approximately 0.2 and 0.3 (dimensionless concentration, C/C0), respectively, because of enhanced stability and reduced aggregate size resulting from enhanced electrostatic and steric repulsions. By contrast, the transportability of NPs significantly decreased with increasing CTAB concentration due to the attachment of positive charges, which was opposite to the charge on the medium surface and facilitated the NP deposition. On the other hand, the addition of Tween-80 had no significant influence on the stability and mobility of nTiO2 and nCeO2. The results were also demonstrated by the colloid filtration theory (CFT) modeling and the Derjaguin-Landau-Verwey-Overbeek (DLVO) interaction calculations; it might promote the assessment and remediation of NP pollution in subsurface environments.

Haemoglobin (Hb) Cheverly is a rare, low oxygen affinity haemoglobinopathy. It is a result of point mutation at the 45 codon of the beta globin genes that leads to substitution of phenylalanine by serine. It is characterised by spuriously low peripheral oxygen saturation with normal arterial oxygen saturation. We describe a family of three with Hb Cheverly in Sarawak General Hospital, Malaysia. It was discovered through incidental finding during hospital admission for unrelated complaints. Laboratory testing revealed abnormal haemoglobin detected at the C window of the high performance liquid chromatography. Subsequent DNA analysis detected replacement of thymidine by cytosine at the beta globin genes. Hb Cheverly may or may not have clinical significance as most of the patients live a normal life; however, it is crucial for us to make early diagnosis to prevent unnecessary extensive investigations for hypoxaemia detected via pulse oximetry, especially in the midst of COVID-19 pandemic.

This study investigated the effect of manufacturing process variables of mini-tablets, in particular, the effect of process variables concerning fluidized bed granulation on tablet weight variation. Test granules were produced with different granulation conditions according to a definitive screening design (DSD). The five evaluated factors assigned to DSD were: the grinding speed of the sample mill at the grinding process of the active pharmaceutical ingredient (X1), microcrystalline cellulose content in granules (X2), inlet air temperature (X3), binder concentration (X4) and the spray speed of the binder solution (X5) at the granulation process. First, the relationships between the evaluated factors and the granule properties were investigated. As a result of the DSD analysis, the mode of action of granulation parameters on the granule properties was fully characterized. Subsequently, the variation in tablet weight was examined. In addition to mini-tablets (3 mm diameter), this experiment assessed regular tablets (8 mm diameter). From the results for regular tablets, the variation in tablet weight was affected by the flowability of granules. By contrast, regarding the mini-tablets, no significant effect on the variation of tablet weight was found from the evaluated factors. From this result, this study further focused on other important factors besides the granulation process, and then the effect of the die-hole position of the multiple-tip tooling on tablet weight variation was proven to be significant. Our findings provide a better understanding of manufacturing mini-tablets.

Complexing self-assembled DNA nanostructures with various functional guest species is the key to unlocking new and exciting biomedical applications. Cationic guest species not only induce magnesium-free DNA to self-assemble into defined structures but also endow the final complex nanomaterials with new properties. Herein, we propose a novel strategy that employs naturally occurring cationic amino acids to induce DNA self-assembly into defined nanostructures. Natural l-arginine and l-lysine can readily induce the assembly of tile-based DNA nanotubes and DNA origami sheets in a magnesium-free manner. The self-assembly processes are demonstrated to be pH- and concentration-dependent and are achieved at constant temperatures. Moreover, the assembled DNA/amino acid complex nanomaterials are stable at a physiological temperature of 37 °C. Substituting l-arginine with its D form enhances its serum stability. Further preliminary examination of this complex nanomaterial platform for biomedical applications indicates that DNA/amino acids exhibit distinct cellular uptake behaviors compared with their magnesium-assembled counterparts. The nanomaterial mainly clusters around the cell membrane and might be utilized to manipulate molecular events on the membrane. Our study suggests that the properties of DNA nanostructures can be tuned by complexing them with customized guest molecules for a designed application. The strategy proposed herein might be promising to advance the biomedical applications of DNA nanostructures., Graphical abstract Image 1, Highlights • A “noncanonical DNA self-assembly” strategy is proposed. • Cationic amino acids can assemble DNA nanostructures in a magnesium-free system. • The complex nanomaterial exhibited high structural and serum stability. • DNA nanostructures can be engineered with customized guest molecules for multiple applications.

Plant and fungal THI4 thiazole synthases produce the thiamin thiazole moiety in aerobic conditions via a single-turnover suicide reaction that uses an active-site Cys residue as sulfur donor. Multipleturnover (i.e. catalytic) THI4s lacking an active-site Cys (non-Cys THI4s) that use sulfide as sulfur donor have been characterized – but only from archaeal methanogens that are anaerobic, O2-sensitive hyperthermophiles from sulfide-rich habitats. These THI4s prefer iron as cofactor. A survey of prokaryote genomes uncovered non-Cys THI4s in aerobic mesophiles from sulfide-poor habitats, suggesting that multiple-turnover THI4 operation is possible in aerobic, mild, low-sulfide conditions. This was confirmed by testing 23 representative non-Cys THI4s for complementation of an Escherichia coli ΔthiG thiazole auxotroph in aerobic conditions. Sixteen were clearly active, and more so when intracellular sulfide level was raised by supplying Cys, demonstrating catalytic function in the presence of O2 at mild temperatures and indicating use of sulfide or a sulfide metabolite as sulfur donor. Comparative genomic evidence linked non-Cys THI4s with proteins from families that bind, transport, or metabolize cobalt or other heavy metals. The crystal structure of the aerotolerant bacterial Thermovibrio ammonificans THI4 was determined to probe the molecular basis of aerotolerance. The structure suggested no large deviations compared to the structures of THI4s from O2-sensitive methanogens, but is consistent with an alternative catalytic metal. Together with complementation data, the use of cobalt rather than iron was supported. We conclude that catalytic THI4s can indeed operate aerobically and that the metal cofactor inserted is a likely natural determinant of aerotolerance.

BACKGROUND AND AIMS High-risk alcohol consumption is associated with compromised health. This study aimed to compare the incidence of alcohol-related cancers, diabetes, ischemic heart disease (IHD) and mortality between those with and without an indication of alcohol use disorder (AUD). DESIGN Retrospective, population-based, matched cohort study using data from the Manitoba Population Research Data Repository. Rates were modeled using generalized linear models with either negative binomial distribution or Poisson distribution and a log offset of person-years to account for each person's time to follow-up. SETTING Manitoba, Canada. PARTICIPANTS Individuals aged ≥ 12 years with a first indication of AUD (index date) between 1 April 1990 and 31 March 2015 were matched to five controls based on age, sex and geographical region at index. This study included 53 410 individuals with AUD and 264 857 matched controls. MEASUREMENTS Adjusted rate ratios (aRR) and 95% confidence intervals (CI) were determined for each outcome from 5 years prior to and 20 years after AUD detection. FINDINGS Alcohol-related cancers (aRR = 4.85, 95% CI = 3.88-6.07 and aRR = 1.85, 95% CI = 1.35-2.53 for men and women, respectively), diabetes (aRR = 1.74, 95% CI = 1.50-2.02 and aRR = 2.43, 95% CI = 2.20-2.68) and IHD (aRR = 3.59, 95% CI = 3.31-3.90 and aRR = 2.92, 95% CI = 2.50-3.41) peaked in the 1 year prior to index for those with AUD compared with matched controls. All-cause mortality (aRR = 3.31, 95% CI = 3.09-3.55 and aRR =3.61, 95% CI = 3.21-4.04) was highest in the year of index and remained higher among cases compared with controls throughout the 20-year follow-up. CONCLUSION People with alcohol use disorder appear to have higher rates of adverse health outcomes in the year before alcohol use disorder recognition, and death at the time of alcohol use disorder recognition, compared with matched controls.

The tetraruthenium tetrahydrido carbonyl cluster Ru4(µ-H)4(CO)12 (1) reacts with diphenylvinylphosphine under thermal activation to give the substitution products Ru4(µ-H)4(CO)12−n(κ1-Ph2PCH=CH2)n, (2) (n = 3 (a); 4 (b)). Both 2a and 2b have been completely characterized, including by single-crystal X-ray diffraction analysis. Each of the diphenylvinylphosphine ligands in 2a and 2b is terminally bound, via the phosphorus atom, to a different ruthenium metal center, while the hydride positions in the Ru4(µ-H)4 cores retain the D2d symmetry of the parent cluster 1. Clusters 2a and 2b were able to retain their structural integrity at elevated temperatures. Graphic Abstract: Thermolysis of Ru4(μ-H)4(CO)12 (1) in cyclohexane with diphenylvinylphosphine afforded the tri- and tetra-substituted derivatives Ru4(μ-H)4(CO)9(κ1-Ph2PCH=CH2)3 (2a) and Ru4(μ-H)4(CO)8(κ1-Ph2PCH=CH2)4 (2b). For both substituted clusters, the diphenylvinylphosphine ligands are bound terminally to the tetraruthenium core via the phosphorus atoms while the hydride positions retain the D2d symmetry of the parent cluster 1.[Figure not available: see fulltext.] Ministry of Education (MOE) Nanyang Technological University This work was supported by Hwa Chong Institution as well as Nanyang Technological University and the Ministry of Education with a research Grant (No. M4011158).

Correction of nutritional vitamin deficiency is recommended in children with chronic kidney disease (CKD). The optimal daily dose of vitamin D to achieve or maintain vitamin D sufficiency is unknown. We conducted a phase III, double-blind, randomized trial of two doses of vitamin D3 in children ≥ 9 years of age with CKD stages 3–5 or kidney transplant recipients. Patients were randomized to 1000 IU or 4000 IU of daily vitamin D3 orally. We measured 25-hydroxvitamin D (25(OH)D) levels at baseline, 3 months and 6 months. The primary efficacy outcome was the percentage of patients who were vitamin D replete (25(OH)D ≥ 30 ng/mL) at 6 months. Ninety-eight patients were enrolled: 49 randomized into each group. Eighty (81.6%) patients completed the study and were analyzed. Baseline plasma 25(OH)D levels were ≥ 30 ng/mL in 12 (35.3%) and 12 (27.3%) patients in the 1000 IU and 4000 IU treatment groups, respectively. At 6 months, plasma 25(OH)D levels were ≥ 30 ng/mL in 33.3% (95% CI: 18.0–51.8%) and 74.4% (95% CI: 58.8–86.5%) in the 1000 IU and 4000 IU treatment groups, respectively (p = 0.0008). None of the patients developed vitamin D toxicity or hypercalcemia. In children with CKD, 1000 IU of daily vitamin D3 is unlikely to achieve or maintain a plasma 25(OH)D ≥ 30 ng/mL. In children with CKD stages 3–5, a dose of vitamin D3 4000 IU daily was effective in achieving or maintaining vitamin D sufficiency. Clinical Trial Registration: ClinicalTrials.gov identifier: NCT01909115

BACKGROUND Coffee and coffee products are known potentially to reduce levels of oxidative stress biomarkers in humans. OBJECTIVE This investigation evaluates the effects of coffee pulp extract as a functional supplement (in coffee pulp drink, CPD) and a cosmetic ingredient (coffee pulp serum, CPS). PATIENTS/METHODS The effects of CPD and CPS for anti-oxidation and anti-aging were investigated. Forty subjects were randomly allocated to CPD or placebo drink groups (50 ml of a CPD/placebo drink daily for 8 weeks for each subject), and another 40 subjects were recruited to CPS or placebo serum groups (about 3 ml of a CPS/placebo serum day and night/daily for 4 weeks for each subject) in a double-blind study. RESULTS The CPD and CPS (20%) can increase free radical scavenging activities by 93.3% and 85% (p

The stiffness of the perovskite active layer plays a critical role in influencing the flexibility of a solar cell. This is one of the important parameters which must be considered while deciding the architecture of the flexible device. Till now, there have been limited studies on the mechanical properties of 2D and 3D perovskite thin films. In this study, we report the very first time, the elastic modulus of the most commonly used 3D perovskite i.e. methylammonium lead iodide (MaPbI3), the pure 2D perovskite (5-AVA)2PbI4 which is based on 5-aminovaleric acid (5-AVA) cation as well as the 2D-3D mixed perovskites thin films through nanoindentation technique. The elastic modulus for the 3D perovskite has been found to be around 16.5 GPa, while it decreases to 6.3 GPa for pure 2D perovskite. The experimental results have also been corroborated by density functional theory calculations done for the 2D and 3D perovskite. The 2D perovskite shows a much lower modulus than the 3D perovskite and can be used within a 2D-3D mixture for improving the mechanical flexibility of the active layer. Also, it is well established that 2D perovskites are much more stable against moisture as compared to their 3D counterparts due to the presence of hydrophobic organic alkyl ammonium cation. Thus, the device containing an active layer comprising of a mixture of 3D and 2D perovskite can be used to improve the environmental stability of the overall device in addition to achieving mechanical durability.

Background and Objective Nearly all patients with multiple myeloma undergo multiple rounds of therapy. The phase III BOSTON trial of once-weekly selinexor and once-weekly bortezomib with dexamethasone (XVd) vs twice-weekly bortezomib and dexamethasone (Vd) is the basis for this cost-effectiveness analysis in previously treated multiple myeloma from a US commercial payer perspective over a lifetime horizon. Methods A partitioned survival model enabled use of direct overall survival and progression-free survival curves from BOSTON to generate four health states for XVd and Vd: progression-free survival on treatment, progression-free survival off treatment, post-progression, and mortality. Using a 1-week cycle length, benefits and costs were discounted at 3.0% annually. Additional comparators were included in an exploratory analysis that compared XVd against seven additional regimens (six triplets, one doublet). Results After considering costs, utility, progression, and survival, the base-case incremental cost-effectiveness ratio of XVd vs Vd was $475,430/quality-adjusted life-year (QALY). The 50% cost-effectiveness probability midpoint was near $470,000/QALY, based on a probabilistic sensitivity analysis. The robustness of the analysis was supported by additional scenario assessment and deterministic and probabilistic sensitivity analyses, which generally demonstrated little variance, with greatest sensitivity to variations in discount rates and utility values. In an exploratory analysis against external comparators, XVd showed a higher QALY gain with a lower cost (i.e., dominance) compared with lenalidomide/dexamethasone (Rd), pomalidomide/bortezomib/dexamethasone (PVd), and carfilzomib/pomalidomide/dexamethasone (KPd). Conclusions Addition of XVd to the previously treated multiple myeloma treatment landscape provides a novel oral treatment option, which, when compared to Vd in the base-case analysis resulted in an incremental cost-effectiveness ratio of $475,430/QALY. Exploratory analyses comparing against external comparators suggest that XVd was dominant vs Rd, PVd, and KPd. Supplementary Information The online version contains supplementary material available at 10.1007/s40273-021-01068-9., Plain Language Summary Patients with multiple myeloma often relapse and require multiple treatments to extend survival while maintaining quality of life. Many of the standard treatment regimens include twice-weekly bortezomib, which is associated with potentially severe peripheral neuropathy. The novel triplet regimen of once-weekly selinexor and once-weekly bortezomib with dexamethasone (XVd) improves cancer response and progression-free survival while decreasing the rate of peripheral neuropathy. This study used economic modeling to calculate the cost of the triplet XVd regimen per life-year gained and per quality-adjusted life-year gained. XVd had a lower cost with a higher quality-adjusted life-year benefit compared with lenalidomide/dexamethasone, pomalidomide/bortezomib/dexamethasone, and carfilzomib/pomalidomide/dexamethasone in previously treated multiple myeloma. Supplementary Information The online version contains supplementary material available at 10.1007/s40273-021-01068-9.

A new process to crystallize amorphous silicon without melting and the generation of excessive heating of nearby components is presented. We propose the addition of a molybdenum layer to improve the quality of the laser-induced crystallization over that achieved by direct irradiation of silicon alone. The advantages are that it allows the control of crystallite size by varying the applied fluence of a near-infrared femtosecond laser. It offers two fluence regimes for nanocrystallization and polycrystallization with small and large crystallite sizes, respectively. The high repetition rate of the compact femtosecond laser source enables high-quality crystallization over large areas. In this proposed method, a multilayer structure is irradiated with a single femtosecond laser pulse. The multilayer structure includes a substrate, a target amorphous Si layer coated with an additional molybdenum thin film. The Si layer is crystallized by irradiating the Mo layer at different fluence regimes. The transfer of energy from the irradiated Mo layer to the Si film causes the crystallization of amorphous Si at low temperatures (∼700 K). Numerical simulations were carried out to estimate the electron and lattice temperatures for different fluence regimes using a two-temperature model. The roles of direct phonon transport and inelastic electron scattering at the Mo-Si interface were considered in the transfer of energy from the Mo to the Si film. The simulations confirm the experimental evidence that amorphous Si was crystallized in an all-solid-state process at temperatures lower than the melting point of Si, which is consistent with the results from transmission electron microscopy (TEM) and Raman. The formation of crystallized Si with controlled crystallite size after laser treatment can lead to longer mean free paths for carriers and increased electrical conductivity.

Kratom is a substance similar to opioids that is often used for its euphoric effects, however it can be obtained legally in most of the United States. The substance is often not assessed on routine urine drug screen, however it is estimated that millions of people engage in kratom use each year and level of use is rising. Given the increasing prevalence of kratom use, and its potentially lethal consequences, it is imperative that primary care physicians be familiar with this substance and have a framework to approach identification and treatment of individuals with kratom use disorder. This manuscript offers a review of the epidemiology and pharmacology of kratom, along with guidance for care of individuals with kratom use disorder in the primary care setting.

Lithium is a mood stabilizer broadly used to prevent and treat symptoms of mania and depression in people with bipolar disorder (BD). Little is known, however, about its mode of action. Here, we analyzed the impact of lithium on synaptic vesicle (SV) cycling at presynaptic terminals releasing glutamate, a neurotransmitter previously implicated in BD and other neuropsychiatric conditions. We used the pHluorin-based synaptic tracer vGpH and a fully automated image processing pipeline to quantify the effect of lithium on both SV exocytosis and endocytosis in hippocampal neurons. We found that lithium selectively reduces SV exocytic rates during electrical stimulation, and markedly slows down SV recycling post-stimulation. Analysis of single bouton responses revealed the existence of functionally distinct excitatory synapses with varying sensitivity to lithium ― some terminals show responses similar to untreated cells, while others are markedly impaired in their ability to recycle SVs. While the cause of this heterogeneity is unclear, these data indicate that lithium interacts with the SV machinery and influences glutamate release in a large fraction of excitatory synapses. Together, our findings show that lithium down modulates SV cycling, an effect consistent with clinical reports indicating hyperactivation of glutamate neurotransmission in BD.

Background: ANDHI was done to assess the efficacy of benralizumab, including onset of effect and impact on health-related quality of life (HRQOL), exacerbation rate, lung function, and nasal polyposis symptoms. Methods: This phase 3b, randomised, double-blind, parallel-group, placebo-controlled ANDHI study was completed in adults (aged 18–75 years) with severe eosinophilic asthma with at least 2 exacerbations in the previous year, despite high-dose inhaled corticosteroid plus additional controllers, screening blood eosinophil counts of at least 150 cells per μL, and an Asthma Control Questionnaire 6 (ACQ-6) score of 1·5 or more. Patients who met eligibility criteria were randomly assigned (2:1; stratified by previous exacerbation count [two, or three or more], maintenance oral corticosteroid use, and region), using an integrated web-based response system, to receive benralizumab at 30 mg every 8 weeks (first three doses given 4 weeks apart) or matched placebo for 24 weeks. Primary efficacy measure was annualised asthma exacerbation rate, with rate ratio (RR) calculated over the approximate 24-week follow-up. Secondary efficacy measures included change from baseline to end of treatment (week 24) in St George's Respiratory Questionnaire (SGRQ) total score (key secondary endpoint), FEV1, peak expiratory flow (PEF), ACQ-6, Predominant Symptom and Impairment Assessment (PSIA), Clinician Global Impression of Change (CGI-C), Patient Global Impression of Change (PGI-C), and Sino-Nasal Outcome Test-22 (SNOT-22). All efficacy analyses, except for SNOT-22, were summarised and analysed using the full analysis set on an intention-to-treat population (all randomly assigned patients receiving investigational product, regardless of protocol adherence or continued participation in the study). SNOT-22 was summarised for the subgroup of patients with physician-diagnosed nasal polyposis with informed consent. This study is registered with ClinicalTrials.gov, NCT03170271. Findings: Between July 7, 2017, and Sept 25, 2019, 656 patients received benralizumab (n=427) or placebo (n=229). Baseline characteristics were consistent with severe eosinophilic asthma. Benralizumab significantly reduced exacerbation risk by 49% compared with placebo (RR estimate 0·51, 95% CI 0·39–0·65; p5%) were nasopharyngitis (30 [7%]), headache (37 [9%]), sinusitis (28 [7%]), bronchitis (22 [5%]), and pyrexia (26 [6%]). Fewer serious adverse events were reported for benralizumab (23 [5%]) versus placebo (25 [11%]), and the only common serious adverse event (experienced by >1% of patients) was worsening of asthma, which was reported for nine (2%) patients in the benralizumab group and nine (4%) patients in the placebo group. Interpretation: Our results extend the efficacy profile of benralizumab for patients with severe eosinophilic asthma, showing early clinical benefits in patient-reported outcomes, HRQOL, lung function, and nasal polyposis symptoms. Funding: AstraZeneca.

Mesenchymal stem cells (MSCs) are multipotent progenitor cells that are reported to be immune-privileged and immune-evasive. MSCs are capable of differentiating into specific cell types for subsequent use in cell-based therapy. They express low levels of human leucocyte antigen (HLA)-ABC and no HLA-DR. Wharton’s jelly-derived MSCs (WJ-MSCs) were also found to express human leukocyte antigen G (HLA-G), which renders them immunosuppressive. This study aimed to determine whether cultured WJ-MSCs retain their immune-privileged and immune-evasive properties after cell differentiation, and whether these properties differ among MSCs derived from different anatomical segments of the umbilical cord. Umbilical cords of healthy pregnant mothers undergoing caesarean section were obtained and grouped by three anatomical segments: fetal, middle, and maternal segments. WJ-MSCs were isolated, culture-expanded, and differentiated into osteogenic cells. Expression of HLA-DR, HLA-ABC, and HLA-G were quantified using flow cytometry. Both undifferentiated and osteodifferentiated WJ-MSCs were subsequently co-cultured with allogeneic peripheral blood mononuclear cells with/without lipopolysaccharide (LPS) stimulation for five days. Lymphocyte proliferation assay was performed using carboxyfluorescein succinimidyl ester (CFSE) as a tracker. Our results showed no significant difference existed in the HLA profiles among WJ-MSCs from different segments and between WJ-MSCs with and without osteogenic differentiation. Mean levels for HLA-G, HLABC, and HLA-DR were 24.82±17.64, 52.50±18.41, and 1.00±1.68%, respectively. Stimulation with LPS and WJ-MSCs increased peripheral blooc mononuclear cells (PBMC) proliferation. However, PBMC proliferation was significantly lower when PBMCs were co-cultured with osteodifferentiated WJ-MSCs (p < .05; with LPS stimulation and p < .001 without LPS stimulation) than when they were co-cultured with undifferentiated WJ-MSCs. These findings suggest that cultured WJ-MSCs stimulate lymphocyte proliferation and are not immune-privileged. Osteodifferentiated WJ-MSCs reduced the immunogenicity of WJ-MSCs, and this reduction in PBMC proliferation was even more pronounced in the presence of LPS (p < .05). In conclusion, cultured WJ-MSCs are not immune-privileged. Osteodifferentiated WJ-MSCs are less immunogenic than undifferentiated WJ-MSCs, in which case hypoimmunogenicity is more profound under LPS-stimulated conditions.

The ballistic regime of vibrational energy transport in oligomeric molecular chains occurs with a constant, often high, transport speed and high efficiency. Such a transport regime can be initiated by exciting a chain end group with a mid-infrared (IR) photon. To better understand the wavepacket formation process, two chemically identical end groups, azido groups with normal, 14N3-, and isotopically substituted, 15N3-, nitrogen atoms, were tested for wavepacket initiation in compounds with alkyl chains of n = 5, 10, and 15 methylene units terminated with a carboxylic acid (-a) group, denoted as 14N3Cn-a and 15N3Cn-a. The transport was initiated by exciting the azido moiety stretching mode, the νN≡N tag, at 2100 cm–1 (14N3Cn-a) or 2031 cm–1 (15N3Cn-a). Opposite to the expectation, the ballistic transport speed was found to decrease upon 14N3 → 15N3 isotope editing. Three mechanisms of the transport initiation of a vibrational wavepacket are described and analyzed. The first mechanism involves the direct formation of a wavepacket via excitation with IR photons of several strong Fermi resonances of the tag mode with the νN=N + νN–C combination state while each of the combination state components is mixed with delocalized chain states. The second mechanism relies on the vibrational relaxation of an end-group-localized tag into a mostly localized end-group state that is strongly coupled to multiple delocalized states of a chain band. Harmonic mixing of νN=N of the azido group with CH2 wagging states of the chain permits a wavepacket formation within a portion of the wagging band, suggesting a fast transport speed. The third mechanism involves the vibrational relaxation of an end-group-localized mode into chain states. Two such pathways were found for the νN≡N initiation: The νN=N mode relaxes efficiently into the twisting band states and low-frequency acoustic modes, and the νN–C mode relaxes into the rocking band states and low-frequency acoustic modes. The contributions of the three initiation mechanisms in the ballistic energy transport initiated by νN≡N tag are quantitatively evaluated and related to the experiment. We conclude that the third mechanism dominates the transport in alkane chains of 5–15 methylene units initiated with the νN≡N tag and the wavepacket generated predominantly at the CH2 twisting band. The isotope effect of the transport speed is attributed to a larger contribution of the faster wavepackets for 14N3Cn-a or to the different breadth of the wavepacket within the twisting band. The study offers a systematic description of different transport initiation mechanisms and discusses the requirements and features of each mechanism. Such analysis will be useful for designing novel materials for energy management.

The increased incidence of food spoilage has exacerbated the need to enhance the protection of processed foods. Food packaging incorporated with bioactive components can be exploited to improve the security of food products from microbiological contamination. Thus, this study aimed to generate an alginate-based film loaded with cinnamaldehyde for use in food packaging. Aspergillus niger ATCC 9029 was utilised to assess the biodegradability of the film. The fungal growth on the plate with alginate film was evident after 21 days of incubation period and 29.7% of weight loss was monitored. The mechanical characterisation of the film indicated that the resulting film was sturdy and flexible. In the cinnamaldehyde release test, no burst release was observed. The release was slow and gradual. Out of 8 test microorganisms, only 6 microorganisms were inhibited by the film with cinnamaldehyde during the cross streak test. The growth inhibition test signified that there were 4 Gram-positive bacteria with 100% growth inhibition. The application of the film showed a notable reduction of bacterial load in the cooked rice. Besides, it exhibited 5.0-log suppression of bacterial growth, which relative to control. The results indicated that the alginate film incorporated with cinnamaldehyde could be potentially used as an eco-friendly food packaging material.

Alzheimer’s disease (AD) is a major cause of dementia characterized by the overexpression of transmembrane amyloid precursor protein and its neurotoxic byproduct amyloid beta (Aβ). A small peptide of considerable hydrophobicity, Aβ is aggregation prone catalyzed by the presence of cell membrane, among other environmental factors. Accordingly, current AD mitigation strategies often take aim at breaking down the Aβ-membrane communication, yet no data is available concerning the cohesive interplay of the three key entities of cell membrane, Aβ, and its inhibitor. Using a lipophilic Laurdan dye and confocal fluorescence microscopy, we observed cell membrane perturbation and actin reorganization induced by Aβ oligomers, but not by Aβ monomers or amyloid fibrils. We further revealed recovery of membrane fluidity by ultrasmall MoS(2) quantum dots, also shown in this study as a potent inhibitor of Aβ amyloid aggregation. Using discrete molecular dynamics simulations, we uncovered the binding of MoS(2) and Aβ monomers as mediated by hydrophilic interactions between the quantum dots and the peptide N-terminus. In contrast, Aβ oligomers and fibrils were surface-coated by the ultrasmall quantum dots in distinct testudo-like, reverse protein-corona formations to prevent their further association with cell membrane and adverse effects downstream. This study offered a crucial new insight and a viable strategy for regulating the amyloid aggregation and membrane-axis of AD pathology with multifunctional nanomedicine.

Periodontitis is an inflammation of gums and bones that supporting the teeth which caused by Staphylococcus intermedius. The saliva from a patient of periodontitis or suspect to periodontitis will have higher levels of Staphylococcus intermedius. Hence, human saliva is clinically informative in diagnosing oral disease and the oral health of an individual. In this study, oral bacteria in human saliva were identified using 16S ribosomal RNA. 16S ribosomal RNA (rRNA) genes from the isolated colonies were amplified through the colony Polymerase Chain Reaction (PCR) method. 16S rRNA genes were used to determine species identity by sequencing and generating the phylogenetic tree. The results showed that Streptococcus sp. and Staphylococcus sp. were the most prevalent oral bacteria found from all the saliva samples, while Lactobacillus sp. was found from two samples. From the constructed phylogenetic trees, bacteria strains B1 and B2 clustered with the Staphylococcus sp. database. Bacteria strains B9 and B10 were categorized as Streptococcus sp. as the confidential level between Streptococcus sp. database is 100% in Neighbour-Joining tree. Sample B15 and B16 clustered with Lactobacillus sp. database. Oral bacteria species typically associated with periodontitis was detected in all saliva samples. Therefore, it is important to fully understand the nature of the oral bacteria before further research on drug design and administration of oral treatment is executed.

The objective of this study is to develop a simple protocol to isolate and characterise small extracellular vesicles (sEVs) from human umbilical cord-derived MSCs (hUC-MSCs). hUC-MSCs were characterised through analysis of morphology, immunophenotyping and multidifferentiation ability. SEVs were successfully isolated by ultrafiltration from the conditioned medium of hUC-MSCs. The sEVs' size distribution, intensity within a specific surface marker population were measured with zetasizer or nanoparticle tracking analysis. The expression of surface and internal markers of sEVs was also assessed by western blotting. Morphology of hUC-MSCs displayed as spindle-shaped, fibroblast-like adherent cells. Phenotypic analysis by flow cytometry revealed that hUC-MSCs expressed MSC surface marker, including CD90, CD73, CD105, CD44 and exhibited the capacity for osteogenic, adipogenic and chondrogenic differentiation. Populations of sEVs with CD9, CD63 and CD81 positive were detected with size distribution in the diameter of 63.2 to 162.5 nm. Typical sEVs biomarkers such as CD9, CD63, CD81, HSP70 and TSG101 were also detected with western blotting. Our study showed that sEVs from hUC-MSCs conditioned medium were successfully isolated and characterised. Downstream application of hUC-MSCs-sEVs will be further explored.

Objective Although evidence implicates striatal cholinergic impairment as a mechanism underlying tardive dyskinesia, trials of nonspecific cholinergic agents have been inconclusive. As a partial agonist at specific nicotinic receptor subtypes, varenicline reduces drug-induced dyskinesias in animal models suggesting promise as a treatment for tardive dyskinesia. Methods Three schizophrenia patients with tardive dyskinesia who were smokers underwent an open trial of varenicline. After a 2-week baseline, subjects received varenicline 1 mg twice daily. Changes from baseline on the Abnormal Involuntary Movement Scale were measured after a 4-week varenicline stabilization period, and 6 weeks after the smoking quit date in one patient. Results Varenicline had no effect on mean Abnormal Involuntary Movement Scale scores after 4 weeks. Although smoking decreased after 4 weeks on varenicline and diminished further in one patient after 10 weeks, this also appeared to have no effect on ratings of tardive dyskinesia. Conclusion In contrast to animal models, no significant change in tardive dyskinesia occurred in response to varenicline replacement in three schizophrenia patients. Further investigations of cholinergic mechanisms in tardive dyskinesia are worthwhile as agents for specific cholinergic targets become available for treatment. In addition, treatment trials of tardive dyskinesia should control for smoking status, while patients on antipsychotics receiving nicotine replacement therapies for smoking should be studied further for changes in movement.

Downstream processing of mAb charge variants is difficult owing to their similar molecular structures and surface charge properties. This study aimed to apply a novel twin‐column continuous chromatography (called N‐rich mode) to separate and enrich acidic variants of an IgG1 mAb. Besides, a comparison study with traditional scaled‐up batch‐mode cation exchange (CEX) chromatography was conducted. For the N‐rich process, two 3.93 mL columns were used, and the buffer system, flow rate and elution gradient slope were optimized. The results showed that 1.33 mg acidic variants with nearly 100% purity could be attained after a 22‐cycle accumulation. The yield was 86.21% with the productivity of 7.82 mg/L/h. On the other hand, for the batch CEX process, 4.15 mL column was first used to optimize the separation conditions, and then a scaled‐up column of 88.20 mL was used to separate 1.19 mg acidic variants with the purity of nearly 100%. The yield was 59.18% with the productivity of 7.78 mg/L/h. By comparing between the N‐rich and scaled‐up CEX processes, the results indicated that the N‐rich method displays a remarkable advantage on the product yield, i.e. 1.46‐fold increment without the loss of productivity and purity. Generally, twin‐column N‐rich continuous chromatography displays a high potential to enrich minor compounds with a higher yield, more flexibility and lower resin cost.

Fermented foods contain beneficial probiotics, which thus results in products with improved nutritional properties and healthy effects. There is however a need for research on clinical trials to measure the effects of fermented foods in clinical applications and in skincare. The composition of fermented vegetable-fruit drink (FVFD) included the fermented vegetable-fruit juice, apple juice, fructose, high methoxyl pectin, citric acid, apple flavor and water. In this study, the effects of FVFD on the free radical scavenging activities, promotion of skin cell proliferation and collagen synthesis were investigated. A randomized, controlled, double-blind study design was used to assess FVFD and basic drink (50 ml of a FVFD/placebo drink daily for 8 weeks for each subject). Thirty subjects (aged 35-55 years old) were recruited for an 8 week-long clinical trial to confirm the efficacy of FVFD in improving the serum biochemical superoxide dismutase (SOD) and catalase levels, and anti-skin age markers, including improving skin moisture, brightness and elasticity, reducing crow’s feet, skin texture, wrinkles, pores and spots, and increasing amount of skin collagen. The results suggest that fermented vegetable-fruit drink has anti-oxidant activities, promotes collagen synthesis and delays the aging of skin with potential applications in food additives.

Ample evidence supports an association between acute oxygen over-administration and harm. Australian and international guidelines consistently recommend lower oxygen saturation aims in populations with chronic obstructive pulmonary disease (COPD). We assessed adherence to acute oxygen use guidelines and outcomes in hospitalised patients with COPD at a large Australian metropolitan hospital network.

Lung cancer (LC) is one of the leading causes of cancer-related death. As one of the key features of tumor microenvironment, hypoxia conditions are associated with poor prognosis in LC patients. Upregulation of hypoxic-induced factor-1α (HIF-1α) leads to the activation of various factors that contribute to the increased drug resistance, proliferation, and migration of tumor cells. Apurinic/apyrimidinic endonuclease-1 (APEX1) is a multi-functional protein that regulates several transcription factors, including HIF-1α, that contribute to tumor growth, oxidative stress responses, and DNA damage. In this study, we explored the mechanisms underlying cell responses to hypoxia and modulation of APEX1, which regulate HIF-1α and downstream pathways. We found that hypoxia-induced APEX1/HIF-1α pathways regulate several key cellular functions, including reactive oxygen species (ROS) production, carbonic anhydrase 9 (CA9)-mediated intracellular pH, migration, and angiogenesis. Cephalomannine (CPM), a natural compound, exerted inhibitory effects in hypoxic LC cells via the inhibition of APEX1/HIF-1α interaction in vitro and in vivo. CPM can significantly inhibit cell viability, ROS production, intracellular pH, and migration in hypoxic LC cells as well as angiogenesis of HUVECs under hypoxia through the inhibition of APEX1/HIF-1α interaction. Taken together, CPM could be considered as a promising compound for LC treatment.