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The austenite/ferrite interface movement during intercritical annealing of 0.15C–8.0Mn–2.1Al (wt-%) steel was simulated by DICTRA software under local equilibrium and then confirmed experimentally. The simulation results show that the austenite volume fraction exceeds the thermodynamic equilibrium amount during isothermal annealing and then decreases because the interface returns from ferrite to austenite. The reverse interface movement is verified in simulated batch annealing experiment for the first time by ex-situdetermining the austenite volume fraction using characterisation of XRD as well as by in-situmeasuring the bulk volume change led by phase transformation using dilatometric curves.

The austenite/ferrite interface movement during intercritical annealing of 0.15C–8.0Mn–2.1Al (wt-%) steel was simulated by DICTRA software under local equilibrium and then confirmed experimentally. The simulation results show that the austenite volume fraction exceeds the thermodynamic equilibrium amount during isothermal annealing and then decreases because the interface returns from ferrite to austenite. The reverse interface movement is verified in simulated batch annealing experiment for the first time by ex-situdetermining the austenite volume fraction using characterisation of XRD as well as by in-situmeasuring the bulk volume change led by phase transformation using dilatometric curves.

Over the past few decades, tetrafluoroethane (TFE, R134a Freon)-based gases have been widely used in the operation of phenolic resistive plate chambers (RPCs) in many high-energy experiments. However, TFE has a high global warming potential (GWP); therefore, a search for new eco-friendly gases to replace traditional TFE-based ones is now unavoidable. In this research, we present cosmic-ray test results of a prototype RPC for the SHiP (search for hidden particles) experiment using 1.6- and 1.4-mm-thick RPC electrodes containing mixtures of various gases, including 1,3,3,3-tetrafluoropropene (HFO1234ze), CO2, iC4H10and SF6. We compare the performance data gathered with these new gas mixtures with those gathered with a traditional TFE-based gas used for RPCs in compact muon solenoid (CMS) and a toroidal LHC apparatus (ATLAS) experiments. The addition of CO2to the HFO1234ze-based gas was found to be fairly effective in reducing the working-point high voltage (HVWP) for RPC operation. The results of our experiments lead us to the conclusion that adding 40% CO2or less, when combined with HFO1234ze-based gas, is conducive to reliable detector performance for SHiP single-gap phenolic RPCs.

L-asparaginase is a critical chemotherapeutic agent for acute lymphoblastic leukemia (ALL). It hydrolyzes plasma asparagine into aspartate and NH3, causing asparagine deficit and inhibition of protein synthesis and eventually, leukemic cell death. However, patient relapse often occurs due to development of resistance. The molecular mechanism by which ALL cells acquire resistance to L-asparaginase is unknown. Therefore, we sought to identify genes that are involved in L-asparaginase resistance in primary leukemic cells. By unbiased genome-wide RNAi screening, we found that among 10 resistant ALL clones, six hits were for opioid receptor mu 1 (oprm1), two hits were for carbonic anhydrase 1 (ca1) and another two hits were for ubiquitin-conjugating enzyme E2C (ube2c). We also found that OPRM1 is expressed in all leukemic cells tested. Specific knockdown of OPRM1 confers L-asparaginase resistance, validating our genome-wide retroviral shRNA library screening data. Methadone, an agonist of OPRM1, enhances the sensitivity of parental leukemic cells, but not OPRM1-depleted cells, to L-asparaginase treatment, indicating that OPRM1 is required for the synergistic action of L-asparaginase and methadone, and that OPRM1 loss promotes leukemic cell survival likely through downregulation of the OPRM1-mediated apoptotic pathway. Consistent with this premise, patient leukemic cells with relatively high levels of OPRM1 are more sensitive to L-asparaginase treatment compared to OPRM1-depleted leukemic cells, further indicating that OPRM1 loss has a crucial role in L-asparaginase resistance in leukemic patients. Thus, our study demonstrates for the first time, a novel OPRM1-mediated mechanism for L-asparaginase resistance in ALL, and identifies OPRM1 as a functional biomarker for defining high-risk subpopulations and for the detection of evolving resistant clones. Oprm1 may also be utilized for effective treatment of L-asparaginase-resistant ALL.

Immunotherapy drugs have effects on the activity and efficacy of T cells in cancer therapy. However, the selection of personalized medicines in the clinic is difficult. Therefore, how to simplify the process is an important issue. This study presented a three-dimensional culture in a microfluidic device. Cancer cells were cultured in the center with GelMA (Gelatin methacryloyl) to mimic the tumor tissue, while microchannels were used to mimic immune cells in peripheral blood in this chip. The T-cell infiltration into the simulated tumor environment in the chip was observed by an imaging system. In addition, a reduction in the viability of cancer cells following T-cell infiltration was also observed. Moreover, the mortality rate of cancer cells increased after cancer cells were treated with atezolizumab or pembrolizumab. In conclusion, these results demonstrate the potential of our chip for cancer research and clinical drug efficacy.

Osteoblasts (OBs) are indispensable for the maintenance of hematopoietic stem cells (HSCs) in the bone marrow microenvironment. Here we investigated how Smad4 modulates HSC fate at distinct stages of OB development. For this, we conditionally knocked out Smad4in cells expressing type I collagen (Col1a1) and osteocalcin (OC), respectively. Col1a1-expressing OBs were widely present in both the trabecular and cortical compartment, whereas OC-expressing OBs were predominantly located in the cortical compartment. HSCs from Col1a1mutants displayed senescence-associated phenotypes. OCmutants did not exhibit HSC senescence-related phenotypes, but instead showed preferential HSC death. Of note, stromal cell-derived factor 1 expression was lower in Col1a1mutants than control littermates, suggesting potential impairment of CXCR4–CXCL12-mediated HSC retention. Disruption of the CXCR4–CXCL12 axis by AMD3100 administration led to an increase in the senescence-associated ß-galactosidase activity and low competitive potential. Collectively, our findings indicate that deletion of Smad4in OBs differentially modulates HSC fate in a stage-dependent manner.

AbstractWithin the framework of linear piezoelectricity, the problem of two collinear electrically dielectric cracks in a piezoelectric layer is investigated under inplane electro-mechanical loadings. The energetically consistent crack-face boundary conditions are utilized to address the effects of a dielectric inside the cracks on the crack growth. The Fourier transform technique is applied to solve the boundary-value problem. Under the consideration of two-case electromechanical loadings, the electroelastic fields near the inner and outer crack tips are obtained through the Lobatto-Chebyshev collocation method. The special case of two collinear energetically consistent cracks in an infinite piezoelectric solid is analyzed and the closed-form solutions of the crack-tip electroelastic fields are further determined. Numerical results show the variations of stress intensity factors and energy release rates near the inner and outer crack tips on the applied electric fields, the geometry of cracks and the width of the piezoelectric layer in graphics. The observations reveal that the stress intensity factors are dependent not only on the adopted crack-face boundary conditions, but also on the applied mechanical loading.

The primary objective of this survey was to investigate the prevalence of insomnia among anaesthetists in Hong Kong. The use of sleeping aids, factors associated with insomnia and the effect of insomnia on work performance were also studied. We surveyed all locally registered anaesthesia specialists and trainees by post. The response rate was 50%. We found that the prevalence of insomnia among the respondents was 22.4% (95% confidence interval 16.7 to 28.1%). Insomnia was positively associated with the number of on-call shifts per month (P=0.002) and poor relationship with supervisors (P=0.009). Alcohol was the most frequently used aid to assist sleep, followed by Zolpidem. The majority of respondents using sleeping medication obtained the drug over-the-counter, by self-prescription or prescription by colleagues. Only 4.3% (95% confidence interval 0 to 10.2%) of respondents suffering from insomnia had formal medical consultation for sleep disturbance. Insomnia was associated with increased subjective sleepiness at work (P=0.007) and subjective decline in work performance during both daytime (P<0.001) and night-time (P<0.001). However, it was not associated with the tendency to fall asleep at work. The results of this survey suggest that insomnia is a common problem among the anaesthetists of Hong Kong. By restricting the amount of on-call duty and improving relationships with supervisors, the prevalence of insomnia may be reduced and the quality of patient care improved.

The present study elucidates how T6 heat treatment affects thermal stability and wear behaviour of Al–12·5Si–4·5Cu–1·0Mg alloy. The experimental alloys under as cast and T6 heat treated conditions were isothermally heat treated at 300°C for 100 h to investigate thermal stability and wear behaviour. Owing to the precipitation of a large amount of ?' (Al5Cu2Mg8Si6) and ?' (Al2Cu) phases, T6 heat treated alloy showed the highest hardness before isothermal heat treatment. The coarsening of ?' and ?' phases led to a large decrease in hardness following isothermal heat treatment. The thermal stability of the T6 heat treated alloy was much worse than that of the as cast alloy. For wear behaviour, the as cast and T6 heat treated alloys showed the same wear rate with 10 N load after isothermal heat treatment, which indicated that the wear rates of Al–12·5Si–4·5Cu–1·0Mg alloys were independent on T6 heat treatment. Under 40 N load, the wear resistance of as cast alloy was superior to that of T6 heat treated alloy after isothermal heat treatment.

We examine here the spot welding characteristics of transformation induced plasticity assisted steels, which contain δ-ferrite as a consequence of their aluminium concentrations of 3·5 or 5·6 wt-% and which also have high carbon contents of 0·3 or 0·4 wt-% when compared with conventional automotive steels. The resistance spot welds are tested in both shear and cross-tensile tests in order to determine the so called ductility ratio, which is a parameter associated with the fitness of such welds for automotive applications. With an increase in the δ-ferrite fraction from 0·19 to 0·5, the hardness variation across the weld and heat affected zone is decreased approximately from 400 to 150 HV. It seems that the presence of stable δ-ferrite is helpful in reducing hardness variations and in achieving a significant ductility ratio of 0·39.

Epigenetics play a critical role in controlling normal gene expression and altered epigenetics can lead to abnormal cellular differentiation, proliferation and survival. Acute lymphoblastic leukemia (ALL) is the most common malignancy in children and is characterized by numerous epigenetic abnormalities. These epigenetic changes correspond to repressed activity of some genes and inappropriate activation of others. In contrast to genetic alterations stemming from mutations, deletions or translocation, epigenetic changes are relatively reversible when treated with certain small molecule-based anticancer agents. Histone deacetylase inhibitors (HDI) are a class of drugs capable of modifying the epigenetic status of ALL cells. Several recent preclinical and clinical studies have demonstrated the potential of HDI as therapeutic agents in ALL. This review summarizes recent studies on (1) the principles of epigenetics and their importance in ALL tumorigenesis; (2) the structure, mechanism of action and anti-tumor activity of HDI; (3) the first comprehensive summary of data from preclinical and clinical studies for HDI as the therapeutic agents for ALL; and (4) novel directions for future research on HDI and ALL.

A methodology to predict and optimize the ultimate tensile strength of 6061-T6 aluminium (Al) alloy under a laser–GMA hybrid welding process is presented. Experiments were performed by changing welding process parameters. For the evaluation of weldability, the ultimate tensile strength in the weld zone was considered to be the most important criterion. In order to determine the optimum welding parameters, a robust regression analysis was performed to present a reliable prediction and a genetic algorithm was used. Based on the results of robust regression analysis and the genetic algorithm, the optimal process parameters were obtained. The ultimate tensile strength result obtained by the optimal parameters was much improved, when compared with that specified by the American Welding Society.

Strong steels are usually difficult to resistance spot weld because of the tendency to form hard phases. This applies particularly to the transformation induced plasticity (TRIP) assisted steels with relatively high carbon equivalents. A new development in this context is the δ-TRIP steel, designed to retain δ-ferrite as a stable phase at all temperatures below melting. Fully martensitic regions are therefore avoided, making it possible to weld in spite of the high carbon concentration. The authors present here the first spot welding tests on the novel alloy system.

This study was to evaluate the frequency of colorectal neoplasia in renal transplant recipients and to investigate the association with Epstein‐Barr virus (EBV) and cytomegalovirus (CMV) infection. We compared the frequency of colorectal neoplasia among renal transplant recipients with that of the healthy subjects. Specimens of colorectal neoplasia were examined for EBV and CMV using in situhybridization and immunohistochemistry, respectively. Of 796 renal transplantation cohorts, 315 were enrolled. The frequency of colorectal neoplasia among the patients was 22.9%. Compared with the healthy subjects, the odds ratio (OR) for advanced adenoma was 3.32 (95% CI, 1.81–6.10). The frequency of cancer among the patients was 1.9% (OR, 12.0; 95% CI, 1.45–99.7). A long interval between transplantation and colonoscopy was a significant factor in the development of advanced colorectal neoplasia. EBV positivity was detected in 30.6% of colorectal neoplasia specimens from renal transplant recipients, which was higher than that for the controls (p = 0.002). CMV was not detected in any lesions of patients or controls. In conclusion, renal transplant recipients have a significantly increased risk of advanced colorectal neoplasia. EBV was more frequently found in specimens of advanced colorectal neoplasm obtained from the renal transplant recipients.

Minimally invasive surgery has become mainstream in surgical management of colorectal disease. Based on evidence of oncologic safety and benefit to patients, laparoscopic colorectal surgery is regarded as a successful alternative to open surgery. Since the introduction of the da Vinci® system as another tool for minimally invasive surgery, there have been several reports regarding the feasibility and safety of the system. The authors looked at their experience with 412 robotic colorectal surgeries and found that it was feasible and safe. Incidence of operation-related morbidity was around 11 per cent and system-related problems were 2.4 per cent. There was no operation-related or system-related mortality. From a technological perspective, robotic surgery has several advantages over laparoscopic surgery, including a magnifying view with a three-dimensional image, a stable camera platform, and instruments with Endowrist® technology that allow for seven degrees of freedom of movement. However, there is still room for improvement. The revolution of robotic technology can aid in the realization of a dream: a smaller, cheaper, and more sophisticated robotic system, which will further facilitate the widespread application of robotic surgery to colorectal disease.

Hyperintense vessels (HV) on fluid-attenuated inversion recovery imaging are frequently observed in acute ischemic stroke patients. However, the exact mechanism and clinical implications of this sign have not yet been clearly defined. The features of HV and its relevance to other imaging factors are presented here.

Condition monitoring on rails and train wheels is vitally important to the railway asset management and the rail-wheel interactions provide the crucial information of the health state of both rails and wheels. Continuous and remote monitoring is always a preference for operators. With a new generation of strain sensing devices in Fibre Bragg Grating (FBG) sensors, this study explores the possibility of continuous monitoring of the health state of the rails; and investigates the required signal processing techniques and their limitations.

AbstractThe original Translation, Confinement, Sustainment (TCS) experiment was upgraded [TCS Upgrade (TCSU)] to provide an ultrahigh vacuum (UHV) environment with modern discharge cleaning and wall-coating technologies. This has allowed rotating magnetic field formed field reversed configuration plasma temperatures to increase from the TCS radiation-dominated tens of electron volts to >200 eV (Te+ Ti), and FRC magnetic fields to double. The improvements are directly attributable to reduced impurity levels and reduced plasma recycling losses. Some of the technologies utilized to achieve these results included replacing O-rings with wire and conflat seals; developing high-temperature, differentially pumped, elastomeric seals for bonding extremely large quartz tubes (needed for rapid field penetration) to the stainless steel vacuum chambers; and using heater blankets for vacuum baking. Extensive testing using electron microprobe and various spectroscopic techniques was performed to establish appropriate UHV cleaning and handling methods.

Outcomes of intensive care are important to the patient and for assessment of benefit. Short-term outcomes after critical illness are well described, but less is known about long-term outcomes. This study describes the use of data linkage, combining intensive care unit (ICU) clinical data with administrative morbidity and mortality data, to assess long-term outcomes after treatment in ICU.The hospital-based cohort study was conducted in a 22-bed general ICU in a metropolitan teaching hospital. All patient admissions admitted to ICU from 1 January 1987 to 31 December 2002 were included.The prospective ICU clinical database with patient demographics, ICU diagnoses, severity of illness, daily assessment of organ failures and common daily treatments used was linked using probabilistic methods to the state-wide hospital morbidity and mortality databases to describe long-term survival.There were 26,019 ICU admissions (22,980 patients) with 25,972 records (99.8%) linked to a hospitalization event that included the index ICU admission. Unadjusted survival was 84.7% at 1 year decreasing progressively to 50.7% at 15 years. Age, type of admission, severity of illness (measured by Acute Physiologic and Chronic Health Evaluation (APACHE) II and the presence of organ failure), ICU length of stay, comorbidity (Chronic Health Evaluation and Charlson comorbidity index) and ICU admission diagnosis, were all associated with survival at 1, 3, 5, 10, and 15 year follow-up (P<0.001 at all time points).Linkage of clinical and administrative data provides a feasible method for ascertaining long-term survival after critical illness. Age, admission severity of illness, diagnosis and comorbidity influenced long-term unadjusted survival.

Progesterone (P4) and its cognate receptor, the progesterone receptor (PGR), have important roles in the establishment and maintenance of pregnancy in the murine uterus. In previous studies, using high-density DNA microarray analysis, we identified a subset of genes whose expression is repressed by chronic P4-PGR activation in the uterus. The Clca3gene is one of the genes whose expression is the most significantly downregulated by P4 and PGR. In the present study, we performed real-time RT–PCR and in situhybridization to investigate the regulation of Clca3by P4 and determine the pattern of expression of Clca3in the uterus during early pregnancy. This analysis shows that Clca3mRNA transcripts were detected in the luminal and glandular epithelium of the pseudopregnant uterus at day 0.5 and that the expression of Clca3was not detected after day 3.5. P4 represses Clca3mRNA synthesis in the luminal epithelial and glandular epithelial cells of the uterus in ovariectomized wild-type mice, but not in Pgrknockout (PRKO) mice. Conversely, estrogen (E2) induces Clca3expression in the luminal epithelium and glandular epithelium, and this induction was repressed by P4 in the murine uterus. Analysis of the promoter region of Clca3by in silicoand transient transfection analysis in HEC-1A cells identified the regulation of Clca3by estrogen receptor-alpha (ESR1) within the first 528 bp of 5′-flanking region of the Clca3gene. Our studies identified Clca3as a novel downregulated gene of PGR that is a direct target of E2 regulation.

A first principles‐based non‐linear dynamic model for a Molten Carbonate Fuel Cell system is presented, analysed, and further developed for model‐based control applications. Transient validation results, using a laboratory‐scale test stack, are provided in support of the cell stack model. Physical arguments and time scale separation are used to derive simpler, reduced‐order, model structures useful for control analysis and design. Reduced‐order models are derived for the cell stack alone as well as for the cell stack integrated with Balance‐of‐Plant. The results are compared with the full‐order models and used in control system design.

Four new dihydropyranocoumarins were isolated from Angelica gigas roots through neuroprotective activity-guided isolation and were characterized as decursinol derivatives 4‘ ‘-hydroxytigloyldecursinol (1), 4‘ ‘-hydroxydecursin (2), (2‘ ‘S,3‘ ‘S)-epoxyangeloyldecursinol (3), and (2‘ ‘R,3‘ ‘R)-epoxyangeloyldecursinol (4), respectively. All four new dihydropyranocoumarins and major coumarin derivatives of A. gigas, decursinol and decursin, exhibited signficant protective activity against glutamate-induced neurotoxicity when added to primary cultures of rat cortical cells at concentrations ranging from 0.1 to 10 μM.

This Letter reports a novel approach to the fabrication of a biomimicking surface by modification of an end-functionalizable smooth polymer cushion constructed via chemoselective ligation with a phospholipid-like molecule containing oxyamine groups. The mobility of a phospholipid bilayer formed by vesicle fusion on the phospholipid-like molecule terminated polymer film was characterized by fluorescence recovery after bleaching. Platelet adhesion, as one measure of biocompatibility of the film was also studied and compared to other surfaces such as polyethylene or poly(dimethylsiloxane). The results show that the end-functionalized smooth polymer cushion has potential as a biocompatible platform to reconstitute membrane proteins.

Radiation dose deposited on a radiochromic film is considered as a dose image. A precise image extraction system with commensurate capabilities is required to measure the transmittance of the image and translate it to radiation dose. This paper describes the development of a spectral microdensitometer which has been designed to achieve this goal under the conditions of (a) the linearity and sensitivity of the dose response curve of the radiochromic film being highly dependent on the wavelength of the analysing light, and (b) the inherent high spatial resolution of the film. The microdensitometer consists of a monochromator which provides an analysing light of variable wavelength, a film tray on a high-precision scanning stage, a transmission microscope coupled to a thermoelectrically cooled CCD camera, a microcomputer and corresponding interfaces. The measurement of the transmittance of the radiochromic film is made at the two absorption peaks with maximum sensitivities. The high spatial resolution of the instrument, of the order of micrometres, is achieved through the use of the microscope combined with a measure-and-step technique to cover the whole film. The performance of the instrument in regard to the positional accuracy, system reproducibility and dual-peak film calibration was evaluated. The results show that the instrument fulfils the design objective of providing a precise image extraction system for radiochromic films with micrometre spatial resolution and sensitive dose response.

We have investigated the olefin metathesis from alkenyl Baylis−Hillman adducts using second-generation Grubbs catalyst. In the experiment, the ring-closing metathesis (RCM) product could not be found, while the cross-metathesis (CM) products were found. The computational studies provided consistent explanations for the experimental result. The most limiting factor for the RCM process using second-generation Grubbs catalyst is caused by the high strain and steric effect in the metallacyclobutane intermediates.

Summary The problem of an eccentric Griffith crack in an infinitely long strip of a soft ferromagnetic elastic material under a uniform magnetostatic field is considered within the framework of linear magnetoelasticity. The crack is parallel to the edges of the strip and subjected to a normal pressure. The magnetic field is perpendicular to the crack surfaces. Fourier integral transform technique is used to reduce the problem to two singular integral equations for the magnetic and elastic boundary conditions. Solutions of the singular integral equations are obtained by using the Chebyshev polynomial expansions. Numerical results on the stress intensity factors are presented graphically. The results indicate that the magnetic field, the geometric parameters and the magnetic properties of the material have considerable coupled effects on the stresses near the crack tip.

Summary A finite crack propagating at constant speed in a functionally graded piezoelectric strip (FGPS) bonded to a homogeneous piezoelectric strip is considered. It is assumed that the electroelastic material properties of the FGPS vary exponentially across the thickness of the strip, and that the bimaterial strip is under combined anti-plane mechanical shear and in-plane electrical loads. The analysis is conducted for the electrically unified crack boundary condition, which includes both the traditional permeable and the impermeable ones. By using the Fourier transform, the problem is reduced to the solution of Fredholm integral equations of the second kind. Numerical results for the stress intensity factor and the crack sliding displacement are presented to show the influences of the crack propagation speed, electric loads, FGPS gradation, crack length, electromechanical coupling coefficient, properties of the bonded homogeneous piezoelectric strip and crack location.

Surface pressure versus area isotherms have been coupled with fluorescence microscopy to compare the insertion preferences of a series of triblock copolymers of the form poly(ethylene oxide)−poly(propylene oxide)−poly(ethylene oxide) (PEO−PPO−PEO) into dipalmitoylphosphatidylcholine (DPPC) and dipalmitolylphosphatidylglyercol (DPPG) monolayers at the air−water interface at 30 °C. Previous monolayer experiments with one of the polymers of the series, Poloxamer 188 (P188), which is known to effectively seal electrically damaged cell membranes, show that P188 is able to insert into model monolayer systems of DPPC and DPPG at surface pressures close to or lower than its maximal spreading pressure¹ of 22 mN/m at 30 °C. To test whether the size of the hydrophobic PPO subunit regulates the insertion capabilities of the polymer into the lipid films, we have investigated the effect of sister poloxamers P108, P238, and P338 that have identical PPO/PEO weight percentages as compared to P188 but differ in overall molecular weight. While the smallest polymer investigated, P108, is able to insert into the lipid films at a surface pressure equal to its maximal spreading pressure, the larger polymers, P238 and P338, can insert only at pressures much lower than their respective maximal spreading pressures. However, all polymers investigated are “squeezed out” or eliminated from both monolayers at surface pressures significantly higher than those for insertion, results which mirror those obtained for P188. Although the bulkiness of the larger polymers limits their ability to insert into the lipid monolayer at pressures close to their maximal spreading pressures, their larger hydrophobic subunits seem to help them maintain their positions in the monolayer once inserted.