Yeast has been well-used as a typical microbial platform to make fermented fine chemicals. However, various stress conditions severely restrict the production costs and benefits. One effective way to resolve such bottlenecks is to engineer transcription factors (TFs) to enhance strain tolerance and production efficiency through remodeling the transcript levels of different stress resistant genes. Here, we focus on the recent advances in the mechanisms of yeast adaptive responses upon stresses of heat, acetic acid and oxidants and classify them into different modules within yeast cells. In particular, novel strategies for the enhancement of both tolerance and yield by TFs engineering are examined. In addition, the applications of artificial transcription factor (ATFs)-based fabricating in metabolic fluxes optimization and quantitative evaluation are discussed. Lastly, we discuss challenges and potential solutions in exploiting TFs engineering and for A bio-based economy products.

Neurofibromatosis type 1 (NF1) is a benign peripheral nerve sheath tumor which primarily cause neurocutaneous manifestations. We presented a rare case of periportal neurofibromatosis with intrahepatic, retroperitoneal and pelvic involvement. The patient underwent US-guided biopsy and a diagnosis of intrahepatic neurofibromatosis was made.

This case is a unique 49 years old male with clear images of diagnosis angiography, operation field and post operation findings to show total right coronary artery plaque and how full endarterectomy can help patient.

Polyaluminium chloride (PAC) and cationic polyacrylamide (CPAM) play a crucial role for separating microorganisms from bulk media. However, the mechanism of adsorption between cells and flocculants remain to be further defined to improve the flocculation efficiency (FE) in extreme conditions. This study conducted the flocculation process of Rhodotorula glutinis induced by PAC and CPAM, firstly. The result demonstrated that CPAM possessed more efficient harvesting ability for R. glutinis compared to PAC. The difference of flocculation capacity was then thermodynamically explained by the extended DLVO (eDLVO) theory, it turned out that the poor harvesting efficiency of PAC was attributed to lacking of binding sites as well as low adsorption force within particles. Based on this, the FE of PAC to R. glutinis was mechanically enhanced to 99.84% from 32.89% with 0.2 g/L CPAM modification at an optimum pH of 9.

Study of the carnivore guild is the key to understand quantitative relationship between members of the carnivore community. The aim of the study was to investigate diversity, abundance and population structure of the mongoose in Nech Sar National Park. Ecological data collection on mongoose species has been carried out from September 2017 to August 2018 in Nech Sar National Park (NSNP). Based on the habitat type and topography of NSNP, 10 transects, each of 4-5 km long were sampled to traverse the major habitat types in the park. Line transect distance sampling methodology was used to determine abundance and population status. DISTANCE (Version 6.0, Release 2) Software was used for density and abundance estimation of mongoose populations. The key to distance sampling analyses is to fit a detection function to the observed distances, and hence, the key functions hazard rate + hermite polynomial, unform + cosine polynomial and half normal + hermite polynomial models were chosen over the others on the basis of best fit. Three species of mongoose namely- Egyptian mongoose (Herpestes ichneumon,) Slender mongoose (Herpestessanguineus) and White tailed mongoose (Ichneumiaalbicauda) were identified in the study. The overall density of mongoose in the study area was 2.3048+0.16070 individuals/km2 with population estimate of 943+85.593 individuals. Based on season and habitat type, density and abundance estimates showed variation (P<0.05). However, species composition between seasons and habitats was the same. The highest species diversity (H=1.197) was recorded in bushland habitat. The population was female-baised with 1:1.171 and 1:1.59, male to female ratio during wet and dry seasons, respectively. Adult to young (subadult and juvenile) ratio was1.05:1 and 0.94: 1 during wet and dry seasons, respectively. Further researches on other ecological parameters viz. behavior, feeding habit and activity pattern are important to acquire a complete picture about mongoose ecology in the park.

Drying of microalgal slurry is one of the important steps of downstream processing which faces several technical challenges for cost-effective biodiesel production. In this investigation, drying of C. minutissima was carried out by a single rotary drum dryer with varied drum surface temperature and rotational speed. Application of machine learning tool classified the range of residual moisture content to be <10% (wet biomass) for high lipid recovery with an accuracy of 97%. Based on the drying time, lipid recovery, and energy consumption, drum drying at 80 °C drum surface temperature with 0.3 rpm depicted ˃90% lipid recovery as compared to the bone-dried biomass. The energy consumption of 7.328 kWh for 1 kg of dried biomass was recorded with profoundly lower drying time, thus could be recommended for drying of the microalgal slurry at industrial scale.

Antisense technology has been developed as the next generation drug discovery methodology by which unwanted gene expression can be inhibited by targeting mRNA specifically with antisense oligonucleotides. The computational studies of antisense modifications based on phosphorothioate (PS), methoxyethyl (MOE), locked nucleic acids (LNA) may help to design better novel modifications. In the present study, five novel LNA based modifications have been proposed. The conformational search has been done to identify the most stable and alternative stable conformations. The geometry optimization followed by single point energy calculation has been done at B3LYP/6-31G(d,p) level for gas phase and B3LYP/6-311G(d,p) level for the solvent phase for all modifications at monomer as well as base pair level. The electronic properties and the quantum chemical descriptors of the antisense modifications were derived and compared. The local and global reactivity descriptors, such as hardness, chemical potential, electronegativity, electrophilicity index, Fukui function all were calculated at the DFT level for the optimized geometries. A comparison of global reactivity descriptors confirmed that LNA based modifications are the most reactive modifications. They may form a stable duplex when bound to complementary nucleotides, compared to other modifications. Therefore, we are proposing that one of our proposed antisense modifications (A3) may show strong binding to the complementary nucleotide as LNA and may also show reduced toxic effects like MOE. The base pair studies may help us to understand the extent to which our proposed modifications can form standard Watson-Crick base pairing required for oligomer duplexes. This computational approach may be very useful to propose novel modifications prior to undergoing synthesis experimentally in the area of antisense or RNAi technology.

Aim: To investigate the difference in both numbers and acuity of presentations to the Paediatric Emergency Department (PED) during the peak time period of the current global SARS-CoV-2 pandemic. Design: This single centre retrospective observational study used routinely collected electronic health data to compare patient presentation characteristics between 21st March and 26th April 2020 compared to the equivalent time period in 2019. Results: There was a 90% decrease in attendances to PED, with a 10.23% reduction re-attendance rate. Children presenting were younger during the pandemic, with a median age difference of 2 years. They were more likely to present in an ambulance (9.63%), be admitted to hospital (5.75%) and be assigned the highest two Manchester triage categories (6.26%). There was a non-significant trend towards longer lengths of stay. The top 10 presenting complaints remained constant (although the order changed) between time periods. There was no difference in mortality or admission to PICU. Implications: Our data demonstrates that there has been a significant decrease in numbers of children seeking emergency department care. It suggests that presenting patients were proportionally sicker during the pandemic; however, we would argue that this is more in keeping with appropriate acuity for PED presentations, as there were no differences in PICU admission rate or mortality. We explore some of the possible reasons behind the decrease in presentations and the implications for service planning ahead of the winter months.

Overexpression of c-MYC protein without genomic amplification occurs in multiple cancers, including neuroblastoma and small cell lung cancer. In searching for the mechanisms of c-MYC protein overexpression, we demonstrated that the transcription factor, OCT4 mediates c-MYC transcriptional activation in progressive disease neuroblastoma. Subsequently, we identified two kinases, MAPKAPK2 (MK2) and DNA-PK, which are predicted to bind and phosphorylate OCT4 at S111 and S93 residues, respectively. Based on these novel observations, we developed a cell-based luminescence assay to screen and identify compounds that inhibit the interactions between MK2 and OCT4. By screening 79,671 compounds, we identified 65 compounds we designated as “hits”. Using a two-step validation of co-immunoprecipitation and pOCT4S111 detection, the compounds were further narrowed down to three for further studies. The three compounds were tested for their ability to inhibit kinase activity, in vitro cytotoxic activity, and anti-inflammatory activity. In conclusion, we developed a cell-based luminescence assay for the discovery of new agents targeting the c-MYC transcriptional activation pathway. Screening and subsequent validation identified a small number of compounds for further development.

The coherent interaction between localized surface plasmon resonance modes and excitons of a single or a collection of quantum emitters have fueled the development of novel applications in quantum optics and material science. In this work, using first-principles simulations, we analyse the modifications in absorption spectra and electric near-field enhancements in a structure consisting of an aluminum nanotriangle interacting with a varying number of pyridine molecules (placed at the nanotriangle tips) in close proximity. What’s more, we find very interesting spatial variation in induced electron density and electric near-field enhancements with a remarkable dependence on the number of interacting pyridine molecules and the direction of light illumination. Our results may help to improve our understanding of the light-matter interaction at the sub-nanometer scale.

DNA-based techniques are increasingly used to assess biodiversity both above- and belowground. Most effort has focussed on bioinformatics and sample collection, whereas less is known about the consequences of mixing collected environmental DNA (eDNA), post-extraction and pre-PCR. We applied varying degrees of pooling to stand-alone eDNA samples collected across a non-native plant invasion density gradient, and compared the fungal communities of pooled and unpooled samples. Pooling soil eDNA decreased observable fungal rarefied richness in our samples, led to phylum-specific shifts in proportional abundance, and increased the sensitivity of detection for the invasive plant’s overall impact on fungal diversity. We demonstrate that pooling fungal eDNA could change the outcome of similar eDNA studies where the aim is to: 1) identify the rare biosphere within a soil community, 2) estimate species richness and proportional abundance, or 3) assess the impact of an invasive plant on soil fungi. Sample pooling might be appropriate when determining larger-scale overarching responses of soil communities, as pooling increased the sensitivity of measurable effects of an invasive plant on soil fungal diversity.

Amplification-independent c-MYC overexpression is suggested in multiple cancers. Targeting c-MYC activity has therapeutic potential, but efforts thus far have been mostly unsuccessful. To find a druggable target to modulate c-MYC activity in cancer, we identified two kinases, MAPKAPK2 and the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), which phosphorylate the S111 and the S93 residues of OCT4, respectively, to transcriptionally activate c-MYC. Using these observations, we present here a novel cell-based luminescence assay to identify compounds that inhibit the interaction between DNA-PKcs and OCT4. After screening approximately 80,000 compounds, we identified 56 compounds (“hits”) that inhibited the luminescence reaction. Using a custom antibody specific for pOCT4S93, the “hits” were validated for their effect on OCT4 phosphorylation and activation. Seven compounds were selected for the second step of validation, which focused on the interaction between kinase and substrate. After further characterization, we identified two compounds that significantly impaired the ability of DNA-PKcs to bind to and phosphorylate OCT4. The compounds demonstrate a significant ability to kill cancer cells in the nanomolar range. In conclusion, we developed a cell-based luminescence assay to identify novel inhibitors targeting c-MYC transcriptional activation, and have found two compounds that may function as lead compounds for further development.

The largest populations of the human virome belong to bacteriophages. M13 filamentous bacteriophages can survive, circulate and being cleared within the body. The M13 phage has been developed as a new therapeutic application due to its ability. Being detected by innate immune cells, M13 phage triggers an immune response. Hereupon, macrophages are counted as the first immune cells stimulated by phage particles. The possible interference between immune responses with the phage-induced treatment process, necessitates determining M13 phage effect on immune responses. For this purpose, M13 phage with RGD were used as substrates for macrophage culture. Gelatin and uncoated wells were used as controls. 2 and 7 days post culture on the coated surfaces, peritoneal macrophages were analyzed in terms of morphological characteristics and metabolic profile and measurement of cytokines production. Macrophages on M13 phage containing surfaces secreted anti-inflammatory cytokines, increased efferocytosis activity and show metabolic profile of an M2 macrophage. The results demonstrate that M13 phage can modulate immune responses by polarization of macrophages toward anti-inflammatory phenotype over time. Moreover, the combination of RGD peptide motif with M13 phage was able to stimulate macrophage polarization more effectively which may introduce an Immune-modulating technology for therapy and biocontrol.

In the 1980-ies, virus inactivation steps were implemented into the manufacturing of biopharmaceuticals in response to earlier unforeseen virus transmissions. The most effective inactivation process for lipid-enveloped viruses is the treatment by a combination of detergents, often including Triton X-100 (TX-100). Based on recent environmental concerns, the use of TX-100 in Europe will be ultimately banned, which forces the pharmaceutical industry, among others, to switch to an environmentally friendly alternative detergent with fully equivalent virus inactivation performance as TX-100. In this work, a structure-activity relationship study was conducted that ultimately led to the synthesis of several new detergents. One of them, named ‘Nereid’, displays inactivation activity fully equivalent to TX-100. The synthesis of this replacement candidate has been optimized to allow for the production of several kg of detergent at lab scale, to enable the required feasibility and comparison virus inactivation studies needed to support a potential future transition. The 3-step, chromatography-free synthesis process described herein uses inexpensive starting materials, has a robust and simple work-up, and allows production in a standard organic laboratory to deliver batches of several hundred grams with >99% purity.

In order to study the fatigue damage and cycle life of TC4 titanium alloy for aero-engine blades under various load conditions, uniaxial fatigue, multi-stage loading and multiaxial fatigue tests were carried out. The critical plane method combined with von Mises criterion was used to study the fatigue life distribution under various loading paths, and the results were verified by experiments. Based on the nonlinear residual strength model and Poisson stochastic process, the reliability prediction of aero-engine compressor blade under maximum continuous working condition was completed. The results show that the fatigue damage and life distribution of TC4 titanium alloy for aeroengine blade under various conditions can be accurately predicted by the method proposed in this paper and the reliability of the blade can still be maintained above 0.9 after it works for 3000 hours under the maximum continuous working condition.

Rationale, aims and objectives Patients with anterior crucial ligament injury are faced with a choice between surgery or non-surgical treatment with intensive rehabilitation. Evidence shows that surgical treatment is not superior to non-surgical treatment. To offer patients a treatment meeting their individual values, lifestyle and conditions, patients must be involved in the decision-making. The aim of the study was to develop and evaluate a patient decision aid to support shared decision-making. Method Development of the patient decision aid was based on international criteria, current literature, and former patients’ experiences and suggestions on how to optimize the decision-making process. The patient decision aid was evaluated by the SDM-Q9 questionnaire and semi-structured interviews with patients and doctors. Results A patient decision aid for patients with and an anterior crucial ligament injury was developed. On a scale from 0-5, patients experienced a high degree of shared decision-making in their treatment decision both before (score 4.3) and after (score 4.3) implementation of the patient decision aid. No statically significant difference was found (p=0.72). From interviews, patients expressed that they found the patient decision aid very useful. Especially, reflection time was important for some patients. Doctors reported that the patient decision aid improved shared decision-making by supporting the dialogue clarifying patients’ values concerning issues important for treatment choices. Conclusion No statically significant difference in the SDM Q9 -score was found between patients’ perceptions of shared decision-making before and after implementation of a patient decision aid. However, patients experienced the decision aid as very useful when making treatment decisions, and doctors reported that it improved the dialogue clarifying patients’ values important for the treatment options. Keywords patient-centered care, evaluation, person-centered medicine

We describe a technique for particle-based simulations of heterogeneous catalysis in open-cell foam structures, which is based on isotropic Stochastic Rotation Dynamics (iSRD) together with Constructive Solid Geometry (CSG). The approach is validated by means of experimental results for the low-temperature water-gas shift reaction in an open-cell foam structure modeled as inverse sphere packing. Considering the relation between Sherwood and Reynolds number, we find two distinct regimes meeting approximately at the strut size Reynolds number 10. For typical parameters from the literature, we find that the catalyst density in the washcoat can be reduced considerably without a notable loss of conversion efficiency. We vary the porosity to determine optimum open-cell foam structures, which combine low flow resistance with high conversion efficiency and find large porosity values to be favorable not only in the mass transfer limited regime but also in the intermediate regime.

Fertilizer application in excess of plant nitrogen requirements, leading to nitrogen use inefficiency has become main culprit of nitrogen surplus, posing nonpoint pollution threats. Chao Lake has been recipient of nitrogen loadings, mainly coming from the agroecosystem surrounding it. This study was conducted in Chao Lake watershed to assess nitrogen use efficiency, crop yield and nitrogen loading, using reduced and conventional fertilizer rates, based on ten years field monitoring and experiment. Paddy rice - wheat rotational tillage arranged in a completely randomized design using 30m2 treatment plots was employed to study hypothesis. Three indicators namely agronomic efficiency (kgkg-1), recovery efficiency (%) and partial factor productivity (kgkg-1) were considered for nitrogen use efficiency. For nitrogen loading, nitrogen loading (kg ha-1yr-1), nitrogen runoff loss ratio (%) and net nitrogen runoff loss ratio (%) were taken. Results revealed, empirical formula of an exponential model explains the relationship. Reduced fertilizer levels produced high nitrogen use efficiency, high economic yield and less nitrogen loading. Nitrogen use efficiency was in order of: reduced > high > conventional fertilization treatments, while it decreased in ten years (2008 -2018) across all treatments. Nitrogen loading increased in ten years, both for rice and wheat growing seasons. Runoff volume influenced nitrogen loading more than other environmental factors considered. Such strategies that further reduce fertilizer levels by accounting for excessive supplies are critically important to consolidate effective nitrogen management measures.