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Expression of ceramide anabolizing and catabolizing enzymes in MIN and CIN colorectal cells upon DL-PDMP treatment.

UGCG and SGMS1 knockdown efficiencies with different shRNA and siRNA.

DL-PDMP inhibits the proliferation of myeloid leukemia cell lines.

DL-PDMP does not affect proliferation of MEFs and colorectal cancer cells.

DL-PDMP treatment does not cause weight loss in mice.

Aneuploidy levels in Bub1b H/H and Cdc20 AAA/AAA MEFs.

Aneuploidy, a hallmark of cancer cells, poses an appealing opportunity for cancer treatment and prevention strategies. Using a cell-based screen to identify small molecules that could selectively kill aneuploid cells, we identified the compound N-[2-hydroxy-1-(4-morpholinylmethyl)-2-phenylethyl]-decanamide monohydrochloride (DL-PDMP), an antagonist of UDP-glucose ceramide glucosyltransferase. DL-PDMP selectively inhibited proliferation of aneuploid primary mouse embryonic fibroblasts and aneuploid colorectal cancer cells. Its selective cytotoxic effects were based on further accentuating the elevated levels of ceramide, which characterize aneuploid cells, leading to increased apoptosis. We observed that DL-PDMP could also enhance the cytotoxic effects of paclitaxel, a standard-of-care chemotherapeutic agent that causes aneuploidy, in human colon cancer and mouse lymphoma cells. Our results offer pharmacologic evidence that the aneuploid state in cancer cells can be targeted selectively for therapeutic purposes, or for reducing the toxicity of taxane-based drug regimens. Cancer Res; 77(19); 5272–86. ©2017 AACR.

Sphingolipid composition of aneuploid and euploid cell lines upon DL-PDMP treatment.

Table S1: Summary of compound effect in aneuploid Ts13 MEF compared to euploid wild-type MEF. Table S2: shRNA and siRNA sequences used in this study. Table S3: Primers used for quantitative Real-Time PCR.

The morbidity and mortality of lung cancer rank second and first respectively in malignant solid tumors worldwide. As we all know, surgical resection is the cornerstone of comprehensive treatment of non-small-cell lung cancer (NSCLC). The current National Comprehensive Cancer Network (NCCN) guidelines for NSCLC suggest that for medically operable disease, resection is the preferred local treatment modality, anatomic pulmonary resection is preferred for the majority of patients with NSCLC, and video-assisted thoracoscopic surgery (VATS) or minimally invasive surgery should be strongly considered for patients with no anatomic or surgical contraindications. With many advantages, uniportal VATS (u-VATS) has been widely accepted and used. Therefore, in this article, we attempted to review the essentials of lobectomy under u-VATS for NSCLC.

Particle separation from fluid interfaces is one of the major challenges due to the large capillary energy associated with particle adsorption. Previous approaches rely on physicochemical modification or tuning the electrostatic action. Here, we show experimentally that particle separation can be achieved by fast dynamics of drop impact on soap films. When a droplet wrapped with particles (liquid marble) collides with a soap film, it undergoes bouncing and coalescence, stripping and viscous separation, or tunneling through the film. Despite the violence of splashing events, the process robustly yields the stripping in a tunable range. This viscous separation is supported by the transfer front of dynamic contact among the film, particle crust, and drop and can be well controlled in a deterministic manner by selectable impact parameters. By extensive experiments, together with thermodynamic analysis, we disclose that the separation thresholds depend on the energy competition between the kinetic energy, the increased surface energy, and the viscous dissipation. The mechanical cracking of the particle crust arises from the complex coupling between interfacial stress and viscous forces. This study is of potential benefit in soft matter research and also permits the study of a drop with colloid and surface chemistry.

Enhancing the performance of the cathode materials is one of the key issues for aqueous zinc-ion batteries (AZIBs). Layered vanadium-based compounds are considered to be a candidate cathode material for AZIBs owing to their advantages of variable crystal structures and high-theoretical capacity. Nevertheless, the inherent low conductivity of V-based compounds leads to their sluggish kinetics and serious capacity degradation of AZIBs. Here, we proposed a strategy that combined morphology regulation with self-supporting electrodes to build an efficient electron/ion transport network and prepared Zn3(OH)2V2O7·2H2O (ZVO) nanowires (ZVNW) on carbon cloth (CC) by a hydrothermal method. As expected, the ZVNW-CC electrode showed excellent electrochemical performances of a high specific capacity of 361.8 mAh g-1 (50 mA g-1), high-rate capability (145.9 mAh g-1 discharge capacity at 1,000 mA g-1), and long cycling life (96.7% capacity retention after 1010 cycles at 1,000 mA g-1). The Zn2+/H2O co-intercalation mechanism for ZVNW-CC electrodes was demonstrated by ex-situ XPS and ex-situ TGA.

Background: Loss of dystrophin protein causes Duchenne muscular dystrophy (DMD), characterized by progressive degeneration of cardiac and skeletal muscles, and mortality in adolescence or young adulthood. Although cardiac failure has risen as the leading cause of mortality in patients with DMD, effective therapeutic interventions remain underdeveloped, in part, because of the lack of a suitable preclinical model. Methods: We analyzed a novel murine model of DMD created by introducing a 4-bp deletion into exon 4, one of the exons encoding the actin-binding domain 1 of dystrophin (referred to as Dmd E4* mice). Echocardiography, microcomputed tomography, muscle force measurement, and histological analysis were performed to determine cardiac and skeletal muscle defects in these mice. Using this model, we examined the feasibility of using a cytidine base editor to install exon skipping and rescue dystrophic cardiomyopathy in vivo. AAV9-based CRISPR/Cas9-AID (eTAM) together with AAV9-sgRNA was injected into neonatal Dmd E4* mice, which were analyzed 2 or 12 months after treatment to evaluate the extent of exon skipping, dystrophin restoration, and phenotypic improvements of cardiac and skeletal muscles. Results: Dmd E4* mice recapitulated many aspects of human DMD, including shortened life span (by ≈50%), progressive cardiomyopathy, kyphosis, profound loss of muscle strength, and myocyte degeneration. A single-dose administration of AAV9-eTAM instituted >50% targeted exon skipping in the Dmd transcripts and restored up to 90% dystrophin in the heart. As a result, early ventricular remodeling was prevented and cardiac and skeletal muscle functions were improved, leading to an increased life span of the Dmd E4* mice. Despite gradual decline of AAV vector and base editor expression, dystrophin restoration and pathophysiological rescue of muscular dystrophy were long lasted for at least 1 year. Conclusions: Our study demonstrates the feasibility and efficacy to institute exon skipping through an enhanced TAM (eTAM) for therapeutic application(s).

Low-cost, solution-processed photomultiplication organic photodetectors (PM-OPDs) with external quantum efficiency (EQE) above unity have attracted enormous attention. However, their weak-light detection is unpleasant because the anode Ohmic contact causes exacerbation in dark current. Here, we introduce atomic-level chemical reaction in PM-OPDs which can simultaneously suppress dark current and increase EQE via depositing a 0.8 nm thick Al2O3 by atomic layer deposition. Suppression in dark current mainly originates from the built-in anode Schottky junction as a result of work function decrease of hole-transporting layer of which the chemical groups can react chemically with the bottom surface of Al2O3 layer at the atomic-level. Such strategy of suppressing dark current is not adverse to charge injection under illumination; instead, responsivity enhancement is realized because charge injection can shift from cathode to anode, of which the neighborhood possesses increased photogenerated carriers. Consequently, weak-light detection limit of the Al2O3 treated PM-OPD reaches a remarkable level of 2.5 nW/cm2, while that of the control is 25 times inferior. Meanwhile, the PM-OPD yields a record high EQE and responsivity of 4.31×108% and 1.85×106 A/W, respectively, outperforming all other polymer-based PM-OPDs.

This study aimed to assess time to hepatitis C (HCV) treatment (i.e., the time between the initial clinic visit for HCV evaluation and the HCV treatment start date), to compare clinical characteristics between patients who received HCV treatment ≥ and < 6 months, and to identify predictors of longer time to HCV treatment in patients living with HCV. This study conducted a retrospective secondary analysis of patients living with HCV mono-infection and HIV/HCV co-infection who received HCV treatment with DAAs (n=214) at a HIV Clinic. Binomial logistic regression was used to identify predictors of longer time to treatment (i.e., ≥ 6 months). The median time to HCV treatment was 211 days. Compared to patients who were treated < 6 months, a higher proportion of patients who were treated ≥ 6 months had HIV/HCV co-infection (31% vs. 49%, p=0.01) and chronic kidney disease (8% vs. 18%, p=0.03). In multivariate analysis, HIV/HCV co-infection was positively associated with a longer time to HCV treatment (adjusted odds ratio, aOR=2.0, p=0.03). Time to HCV treatment disparities between African American and White American did not emerge from the analysis, but time to HCV treatment disfavored patients living with HIV/HCV co-infection. Studies are needed to identify and eliminate factors that disfavor patients living with HIV/HCV co-infection.

Oxide-derived copper (OD-Cu) catalysts have received widespread attention for their ability to produce energy-dense multicarbon products. Within this class of materials, nanostructured copper hydroxide (Cu(OH)

A condensed excited matter called Rydberg Matter (RM) have been studied experimentally for 30 years, but have not sparked widespread attention yet, unlike ordinary Rydberg atoms. RM formed by clusters of Rydberg atoms at a solid surface have a longer lifetime compared to Rydberg atoms, and is liquid-like. This review describes how the RM state is generated, and its potential applications. These include using RM for research into catalysis, space phenomena and sensor applications, or for producing environmentally friendly energy. A background on RM is presented, with its structure and special properties, and the working principle of RM generation. The experimental set-ups, materials, and detectors used are discussed, together with methods to improve the amount of RM produced. The materials used for the catalysts are of special interest, as this should have a large influence on the energy of the RM, and therefore also on the applications. Currently most of the catalysts used are potassium doped iron oxide designed for styrene production, which should give the possibility of improvements. And as there is little knowledge on the exact mechanisms for RM formation, suggestions are given as to where research should start.

Tingyan Zhang,1,2,* Yanfeng Lin,2,3,* Peihan Li,2,3,* Zhonghong Li,2 Xiong Liu,2 Jinhui Li,2 Lizhong Li,2 Kaiying Wang,2,3 Zhongdong Liu,1 Peng Li,2 Lanfen Lu,4 Hongyan Wang1 1School of Chemistry and Chemical Engineering, Henan University of Technology, Zhengzhou, People’s Republic of China; 2Chinese PLA Center for Disease Control and Prevention, Beijing, People’s Republic of China; 3Academy of Military Medical Sciences, Beijing, People’s Republic of China; 4Department of Laboratory Diagnosis, Sun Yat-Sen University Affiliated Zhongshan Hospital, Zhongshan, Guangdong, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng Li; Hongyan Wang Email jiekenlee@126.com; 18623717897@163.comBackground: The emergence of multidrug-resistant Citrobacter freundii poses daunting challenges to the treatment of clinical infections. The purpose of this study was to characterize the genome of a C. freundii strain with an IncX3 plasmid encoding both the blaNDM-1 and blaSHV-12 genes.Methods: Strain ZT01-0079 was isolated from a clinical urine sample. The Vitek2 system was used for identification and antimicrobial susceptibility testing. The presence of blaNDM-1 was detected by PCR and sequencing. Conjugation experiments and Southern blotting were performed to determine the transferability of the blaNDM-1- carrying plasmid. Nanopore and Illumina sequencing were performed to better understand the genomic characteristics of the strain.Results: Strain ZT01-0079 was identified as C. freundii, and the coexistence of blaNDM-1 and multiple drug resistance genes was confirmed. Electrophoresis and Southern blotting showed that blaNDM-1 was located on a ∼ 53kb IncX3 plasmid. The NDM-1-encoding plasmid was successfully transferred at a frequency of 1.68× 10− 3. Both the blaNDM-1 and blaSHV-12 genes were located on the self-transferable IncX3 plasmid.Conclusion: The rapid spread of the IncX3 plasmid highlights the importance of continuous monitoring of the prevalence of NDM-1-encoding Enterobacteriaceae. Mutations of existing carbapenem resistance genes will bring formidable challenges to clinical treatment.Keywords: C. freundii, whole-genome sequencing, genomics analysis

The rapid development and affordability of renewable energy sources necessitate innovative energy storage technologies to compensate for their intermittency. The electrochemical reduction of CO2 presents an attractive strategy for renewable energy storage, with considerable advancements in recent years. Copper-based catalysts have spearheaded this progress due to their intrinsic ability to produce valuable multicarbon reaction products. However, Cu is inherently unselective, and considerable efforts are needed to achieve the selective production of multicarbon reaction products on Cu-based catalysts. A multitude of factors affect the selectivity of Cu-catalysts, such as morphology, metal co-catalysts, and incorporation of oxidizing agents. In this review, we have summarized the current progress and the most important strategies for tuning the selectivity towards multicarbon reaction products over nanostructured Cu-based catalysts.

HighlightsThe placement and operation of exhaust fans was assessed using CFD simulation.The effective temperature was used to evaluate the indoor thermal environment.The placement and operation of the exhaust fans mainly affected the airflow patterns in the part of the layer house closest to the fans.Abstract. The thermal environment inside a layer house significantly affects the growth, production, and health of the hens. Tunnel ventilation systems have been widely applied to control the indoor climate and air quality for large-scale poultry facilities around the world. Generally, only a few of the exhaust fans operate during mild seasons (spring and fall) in a tunnel-ventilated layer house depending on the outside air temperature. The decision about which exhaust fans to turn on affects the indoor airflow pattern and temperature distribution. However, little research has been reported that investigated the effects of the locations of exhaust fans on ventilation performance. In this study, a computational fluid dynamics (CFD) model was built and validated using field-measured data. The CFD model was then used to evaluate different ventilation strategies (combinations of exhaust fans) in a typical tunnel-ventilated layer house during the fall. The effective temperature was used to assess the performance of different ventilation strategies. Results showed that the locations of the exhaust fans significantly affected the indoor thermal environment, especially in the part of the house closest to the fans, because different locations of operating fans can generate different airflow patterns and affect the airflow through the animal-occupied zone. Based on the simulations, we conclude that the placement and operation of the exhaust fans can be optimized. Turning on the fans that are lower to the ground or near the sidewalls will result in more air bypassing the animal-occupied zones. Our results can help select the best ventilation strategy during the spring and fall in layer houses with tunnel ventilation systems. Keywords: Airflow distribution, Effective temperature distribution, Indoor thermal environments, Ventilation strategy.

1,500 focalmechanisms in NW Yunnan province, China

Background A carbapenem-resistant Escherichia coli (sequence type 5415) strain was isolated from a male patient through routine surveillance in 2018 in Guangzhou, China. Materials and methods Bacteria were isolated from a sputum culture and identified by using the Vitek 2 compact system. The blaNDM-5 gene was amplified and confirmed by sequencing. Antimicrobial susceptibility testing was determined by a Vitek 2 compact system. The blaNDM-5 gene was located by Southern blotting. Whole-genome sequencing was carried out using both Illumina MiSeq and Oxford Nanopore MinION. Results S1-PFGE and Southern blotting showed that the bla NDM-5 gene was located on a novel 66-kb IncFII [F2:A-:B-] plasmid. Conjugation assays revealed that the bla NDM-5-bearing plasmid was self-transferrable. Genomic sequencing and comparative analysis suggested that plasmid p2947-NDM5 likely originated from a combination of an IncFII-type backbone and the bla NDM-5 flanking genetic elements. Conclusion This is the first report of an ST5414 E. coli strain expressing an NDM-5 β-lactamase. This study highlights the genetic complexity of bla NDM-5 carrying plasmids and the urgent need for continuous active monitoring.

Dongdong Yin,1,2,* Yanfeng Lin,1,3,* Zhonghong Li,1,4,* Hui Ma,5,* Lanfen Lu,6 Kaiying Wang,1,3 Lang Yang,1,3 Xinying Du,1 Peng Li,1 Kezong Qi,2 Hongbin Song1,* 1Center for Disease Control and Prevention of PLA, Beijing, People’s Republic of China; 2Anhui Province Key Laboratory of Veterinary Pathobiology and Disease Control College of Animal Science and Technology, Anhui Agricultural University, Hefei, People’s Republic of China; 3Institute for Disease Control and Prevention, AMMS, Beijing, People’s Republic of China; 4College of Environmental and Chemical Engineering, Nanchang Hangkong University, Nanchang, People’s Republic of China; 5The Sixth Medical Center of PLA General Hospital, Beijing, People’s Republic of China; 6Department of Laboratory Diagnosis, Sun Yat-Sen University Affiliated Zhongshan Hospital, Zhongshan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Peng Li; Kezong Qi Email jiekenlee@126.com; qkz@ahau.edu.cnBackground: A carbapenem-resistant Escherichia coli (sequence type 5415) strain was isolated from a male patient through routine surveillance in 2018 in Guangzhou, China.Materials and Methods: Bacteria were isolated from a sputum culture and identified by using the Vitek 2 compact system. The blaNDM-5 gene was amplified and confirmed by sequencing. Antimicrobial susceptibility testing was determined by a Vitek 2 compact system. The blaNDM-5 gene was located by Southern blotting. Whole-genome sequencing was carried out using both Illumina MiSeq and Oxford Nanopore MinION.Results: S1-PFGE and Southern blotting showed that the blaNDM-5 gene was located on a novel 66-kb IncFII [F2:A-:B-] plasmid. Conjugation assays revealed that the blaNDM-5-bearing plasmid was self-transferrable. Genomic sequencing and comparative analysis suggested that plasmid p2947-NDM5 likely originated from a combination of an IncFII-type backbone and the blaNDM-5 flanking genetic elements.Conclusion: This is the first report of an ST5414 E. coli strain expressing an NDM-5 β-lactamase. This study highlights the genetic complexity of blaNDM-5 carrying plasmids and the urgent need for continuous active monitoring.Keywords: Escherichia coli, ST5415, NDM-5, IncFII, carbapenem resistant

Population ageing is a phenomenon taking place in almost every global region. Current estimates indicate that 10–20% of older people in developed countries have mild cognitive impairment (MCI), with these percentages predicted to rise markedly by 2050. Our objective was to apply eye-tracking technology to investigate the information processes adopted by older people with and without MCI in determining preferences for health states in the five-level EuroQol-5 Dimensions (EQ-5D-5L) instrument. Older people (aged ≥ 65 years; including both patients and family carers) attending outpatient memory clinics in Southern Adelaide between July 2017 and June 2018, competent to read and converse in English and with a Mini-Mental State Examination (MMSE) cognition score of ≥ 19 were invited to participate. In total, 52 people met the inclusion criteria, of whom 20 (38%) provided informed consent and fully participated. Participants were categorised into two subgroups (each n = 10) for comparison based upon established MMSE cognition thresholds (19–23, lower MMSE indicative of MCI; ≥ 24, higher MMSE indicative of good cognition). A discrete-choice experiment (DCE) comprising a series of pairwise choices between alternative EQ-5D-5L health states of varying survival duration with differential levels of task complexity (approximated by the degree of attribute level overlap in each choice), was administered as a face-to-face interview with the participant wearing an eye-tracking device. Attribute non-attendance (ANA) was higher for the lower MMSE subgroup than for the higher MMSE subgroup, although these differences were generally not statistically significant. ANA remained relatively low and consistent for participants with good cognition regardless of task complexity. In contrast, ANA increased notably in participants exhibiting MCI, increasing from 10% on average per participant in the lower MMSE subgroup with five attribute level overlap to 23% on average per participant in the lower MMSE subgroup with zero attribute level overlap. This exploratory study provided important insights into the information processes adopted by older people with varying levels of cognitive functioning when choosing between alternative EQ-5D-5L health states of varying survival duration and specifically the relationships between cognitive capacity, task complexity and the extent of ANA. Recent advances in econometric modelling of health state valuation data have demonstrated the added value of capturing ANA information as this can be accounted for in the DCE data analysis, thereby improving the precision of model estimates. Eye-tracking technology can usefully inform the design, conduct and econometric modelling of DCEs, driving the inclusion of this rapidly growing population traditionally excluded from preference-elicitation studies of this nature.

The spread of carbapenem-resistant Klebsiella pneumoniae has become a significant problem for public health in recent years. In this study, we reported a New Delhi metallo-β-lactamase 1 (NDM-1)-producing K. pneumoniae strain KP14003 from a neonate in Beijing, China. Whole-genome sequencing was performed. The strain belonged to sequence type ST719. Coexistence of blaNDM-1 and blaSHV-12 was found on a self-transferable plasmid, which had a typical IncX3 backbone. The horizontal transfer of blaNDM-1 was associated with Tn125 followed by possible transposition events. Other class A extended-spectrum β-lactamase genes (blaSHV-27 and blaTEM-1) were also identified on chromosome or plasmid. The dissemination of NDM-1-producing K. pneumoniae causes great challenges to the treatment of clinical infections. Effective actions need to be taken to control the further spread of this pathogen.

Background The New Delhi metallo-β-lactamase-1 (NDM-1)-positive plasmid and its variants pose daunting threats to public health. Hospital sewage was considered as an important reservoir of antibiotic genes. Numerous and diverse taxa of multidrug-resistant (MDR) bacteria carrying NDM-1-positive plasmids have been identified during routine surveillance of hospital sewage. We herein report a carbapenem-resistant Acinetobacter towneri strain AeBJ009 with an NDM-1-positive plasmid isolated from hospital sewage. Materials and Methods Bacteria were isolated from cultures of hospital sewage and identified by using the Vitek 2 compact system and 16S rRNA sequencing. The blaNDM-1 gene was amplified and confirmed by sequencing. Antimicrobial susceptibility testing was performed using AST-GN14 on the Vitek2 compact system. In addition, the blaNDM-1 gene was located by Southern blotting. Conjugation experiment and whole-genome sequencing were performed for further analysis. Results Strain AeBJ009 was isolated from hospital sewage and identified as A. towneri. Antimicrobial susceptibility testing revealed an MDR phenotype. Pulsed-field gel electrophoresis and Southern blotting showed that strain AeBJ009 carries three plasmids and that blaNDM-1 is located on the 47kb plasmid pNDM-AeBJ009. However, the conjugation experiment to transfer pNDM-AeBJ009 to Escherichia coli strain J53 was unsuccessful. Whole-genome sequencing found that pNDM-AeBJ009 contains a Tn125 element carrying blaNDM-1 . The ble gene downstream of blaNDM-1 displayed a single-nucleotide polymorphism compared to its homologue on plasmid pM131_NDM1. BLAST analysis using the Comprehensive Antibiotic Resistance Database identified no gene polymorphisms with 100% identity to our ble variant. Conclusion The A. towneri strain AeBJ009 exhibiting an extended spectrum of antibiotic resistance was isolated from hospital sewage and may potentially exacerbate the risk of MDR bacterial infections. The prevention of nosocomial infections due to drug-resistant bacteria will require enhanced monitoring and control of MDR pathogens in environmental reservoirs.