Towards a new crown indicator: Some theoretical considerations

The crown indicator is a well-known bibliometric indicator of research performance developed by our institute. The indicator aims to normalize citation counts for differences among fields. We critically examine the theoretical basis of the normalization mechanism applied in the crown indicator. We also make a comparison with an alternative normalization mechanism. The alternative mechanism turns out to have more satisfactory properties than the mechanism applied in the crown indicator. In particular, the alternative mechanism has a so-called consistency property. The mechanism applied in the crown indicator lacks this important property. As a consequence of our findings, we are currently moving towards a new crown indicator, which relies on the alternative normalization mechanism

Rivals for the crown: Reply to Opthof and Leydesdorff

We reply to the criticism of Opthof and Leydesdorff [arXiv:1002.2769] on the way in which our institute applies journal and field normalizations to citation counts. We point out why we believe most of the criticism is unjustified, but we also indicate where we think Opthof and Leydesdorff raise a valid point

Multiple colliding electromagnetic pulses: a way to lower the threshold of e+e−e^+e^- pair production from vacuum

The scheme of simultaneous multiple pulse focusing on one spot naturally arises from the structural features of projected new laser systems, such as ELI and HiPER. It is shown that the multiple pulse configuration is beneficial for observing $e^+e^-$ pair production from vacuum under the action of sufficiently strong electromagnetic fields. The field of the focused pulses is described using a realistic three-dimensional model based on an exact solution of the Maxwell equations. The $e^+e^-$ pair production threshold in terms of electromagnetic field energy can be substantially lowered if, instead of one or even two colliding pulses, multiple pulses focused on one spot are used. The multiple pulse interaction geometry gives rise to subwavelength field features in the focal region. These features result in the production of extremely short $e^+e^-$ bunches.Comment: 10 pages, 4 figure

High Repetition-Rate Wakefield Electron Source Generated by Few-millijoule, 30 femtosecond Laser Pulses on a Density Downramp

We report on an experimental demonstration of laser wakefield electron acceleration using a sub-TW power laser by tightly focusing 30-fs laser pulses with only 8 mJ pulse energy on a 100 \mu m scale gas target. The experiments are carried out at an unprecedented 0.5 kHz repetition rate, allowing "real time" optimization of accelerator parameters. Well-collimated and stable electron beams with a quasi-monoenergetic peak in excess of 100 keV are measured. Particle-in-cell simulations show excellent agreement with the experimental results and suggest an acceleration mechanism based on electron trapping on the density downramp, due to the time varying phase velocity of the plasma waves.Comment: 4 pages, 5 figures, submitted to Phys. Rev. Let

The Leiden Ranking 2011/2012: Data collection, indicators, and interpretation

The Leiden Ranking 2011/2012 is a ranking of universities based on bibliometric indicators of publication output, citation impact, and scientific collaboration. The ranking includes 500 major universities from 41 different countries. This paper provides an extensive discussion of the Leiden Ranking 2011/2012. The ranking is compared with other global university rankings, in particular the Academic Ranking of World Universities (commonly known as the Shanghai Ranking) and the Times Higher Education World University Rankings. Also, a detailed description is offered of the data collection methodology of the Leiden Ranking 2011/2012 and of the indicators used in the ranking. Various innovations in the Leiden Ranking 2011/2012 are presented. These innovations include (1) an indicator based on counting a university's highly cited publications, (2) indicators based on fractional rather than full counting of collaborative publications, (3) the possibility of excluding non-English language publications, and (4) the use of stability intervals. Finally, some comments are made on the interpretation of the ranking, and a number of limitations of the ranking are pointed out

Bioimprint aided cell recognition and depletion of human leukemic HL60 cells from peripheral blood

We report a large scale preparation of bioimprints of layers of cultured human leukemic HL60 cells which can perform cell shape and size recognition from a mixture with peripheral blood mononuclear cells (PBMCs). We demonstrate that the bioimprint-cell attraction combined with surface modification and flow rate control allows depletion of the HL60 cells from peripheral blood which can be used for development of alternative therapies of acute myeloid leukaemia (AML).AML is a clonal malignant proliferation of transformed, bone-marrow derived myeloid precursors. The disease is characterised by the rapid proliferation of the neoplastic cells (myeloblasts) resulting in failure of normal haematopoiesis with consequential bone marrow failure rapidly resulting in death if untreated.1–3 In the UK, overall survival is 16% 5 years from diagnosis. The prognosis is significantly worse in the elderly which is especially relevant as the majority of patients present over the age of 60 years.1,4–7 Therapy relies on 2–3 cycles of myeloablative chemotherapy followed by allogeneic stem cell transplants for a relatively small number of fit patients with poor prognostic features.8,9 This is accompanied by significant discomfort, and long therapy for AML is also associated with prolonged inpatient stays, considerable morbidity related to anaemia, sepsis and bleeding with an attributable mortality of 5–10%. The majority of patients relapse following induction of chemotherapy for AML and subsequent therapy is associated with a low probability of cure. Outcomes for AML patients have improved marginally over the past few decades, largely due to improvements in supportive care rather than dramatic improvements in the chemotherapeutic regimen's efficacy.10Bioimprinting is a promising area of materials chemistry aimed at mimicking and exploiting the lock-and-key interactions seen ubiquitously in nature.11–14 Cell recognition systems are relatively cheap and simple to produce with few stipulations on storage and shelf life when compared with biological interventions. The scope for possible targets is also much greater, being able to target polysaccharides, enzymes, aptamers, DNA sequences, antibodies and whole cells.12,15,16,21–24 Bioimprints of whole cells were first reported by Dickert et al.17 who imprinted yeast into a sol–gel matrix. When incubated with several strains of yeast, the substrates showed a high affinity to the template yeast strain. This effect was attributed to the large contact surface areas between the cells and the imprinted cavities. Other cell bioimprinting studies have progressed to cover a range of micro-organisms and human cells. Hayden et al.18 functionalised polyurethane with erythrocyte imprints, capable of discriminating between ABO blood groups. Though all cell targets possessed the same geometrical shape and size, imprints were able to discriminate on account of varied surface antigen expression. Subsequent studies were further able to discriminate cells with identical antibodies in different quantities to separate blood groups A1 and A2.19 Recent cell bioimprint studies largely focus on biosensor applications20,26 and are hindered by the small overall size of imprinted areas that can be produced which limits their applications for large scale extraction of targeted cells from cell mixtures. This research area is undergoing a rapid expansion towards using molecularly imprinted polymers as receptor mimics for selective cell recognition and sensing, and a recent review of size and shape targeting of cancer found no evidence so far of the use of cancer cell bioimprints in a therapeutic setting.11Here we utilised for the first time AML cell bioimprints on a large scale as a vehicle to selectively target myeloblasts due to the inherent size and morphological discrepancies compared to normal peripheral blood mononuclear cells (PBMCs) (see Fig. S1, ESI†). We explore AML cells bioimprinting to develop a new method for depletion of myeloblasts from peripheral blood cells by introducing selectivity via bespoke cell size and shape discrimination aided by myeloblast-bioimprint interactions. Our idea is based on incorporating AML cells-imprinted substrates into a flow-through type of device which offers an alternative method for removal of the leukemic burden directly from patient blood. Successful leukophoresis can potentially be used more frequently in the extraction of myeloblasts from peripheral blood which is critical in stabilizing AML patients with leukostasis associated with hyperleuocytosis. By reducing the number of circulating tumour cells, the likelihood of early relapse is also diminished.25HL60 is an immortalized human cell line derived from peripheral blood lymphocytes of a patient suffering from acute promyleocytic leukaemia. HL60 was used as a very good proxy for primary (patient derived) myeloblast cells throughout our study due to their availability and ease of culture. Here we show how the desired HL60 cell bioimprints were produced from HL60 cell layers. We also discuss the integration of the produced myeloblast imprint in a PDMS-based flow-through cell, in which its selectivity towards HL60 cells over PBMCs is investigated (Fig. 1). We fabricated bioimprints by impressing a layer of cultured HL60 cells with a curable polymer, which captures information on the cell shape, size and morphology. These were further casted with another polymer to create a “positive imprint” whose surface matches the original cell layer. Using roll-to-roll printing from the positive replica we produced a very large area of HL60 cell imprints. We engineered the surface of the bioimprint to have a weak attraction with the cells, which is strongly amplified when there is a shape and size match between the individual cells and the imprinted surface. Due to inherent size and morphology differences between myeloblasts and normal blood cells, this resulted in much higher retention of the former on the bioimprint. This allows their selective trapping from peripheral blood based on cell shape and size recognition, much cheaper than using surface functionalisation with a combination of specific antibodies for myeloblasts. We tested the bioimprints selectivity in a device for depleting cultured HL60 cells from healthy white blood cells. This cell recognition technology can potentially deplete myeloblasts from the blood of AML patients and provide an alternative route for inducing minimal residual disease, which is associated with reduced relapses and improved patient outcomes

Removal of Human Leukemic Cells from Peripheral Blood Mononuclear Cells by Cell Recognition Chromatography with Size Matched Particle Imprints

We report a cell recognition chromatography approach for blood cancer cell separation from healthy peripheral blood mononuclear cells (PBMCs) based on sizematched functionalized particle imprints. Negative imprints were prepared from layers of 15 μm polymeric microbeads closely matching the size of cultured human leukemic cells (HL60). We replicated these imprints on a large scale with UV curable polyurethane resin using nanoimprinting lithography. The imprints were functionalized with branched polyethylene imine (bPEI) and passivated by Poloxamer 407 to promote a weak attraction toward cells. When a matching cell fits into an imprint cavity, its contact area with the imprint is maximized, which amplifies the attraction and the binding selectivity. We tested these imprints specificity for depleting myeloblasts from a mixture with healthy human PBMCs in a cell recognition chromatography setup hosting the imprint. The mixture of fixed HL60/PBMCs ratio was circulated over the imprint and at each step the selectivity toward HL60 was assessed by flow cytometry. The role of the imprint length, flow rate, channel depth, and the bPEI coating concentration were examined. The results show that HL60 cells, closely matching the imprint cavities, get trapped on the imprint, while the smaller PBMCs are carried away by the drag force of the flow. Lower flow rates, longer imprints, and interim channel depth favor HL60 specific retention. The bPEI concentration higher than 1 wt % on the imprint made it less selective toward the HL60 because of indiscriminate attraction with all cells. Particle imprint based cell recognition chromatography was able to achieve selective myeloblast depletion from initial 11.7% HL60 (88.3% PBMC) to less than 1.3% HL60 for 3 h of circulation. The cell recognition chromatography with size-matched microbead imprints can be employed as an efficient cell separation technique and potentially lead to alternative therapies for myeloblasts removal from peripheral blood of patients with acute myeloid leukemia

Muon pair creation from positronium in a circularly polarized laser field

We study elementary particle reactions that result from the interaction of an atomic system with a very intense laser wave of circular polarization. As a specific example, we calculate the rate for the laser-driven reaction $e^+e^- \to \mu^+\mu^-$, where the electron and positron originate from a positronium atom or, alternatively, from a nonrelativistic $e^+e^-$ plasma. We distinguish accordingly between the coherent and incoherent channels of the process. Apart from numerical calculations, we derive by analytical means compact formulas for the corresponding reaction rates. The rate for the coherent channel in a laser field of circular polarization is shown to be damped because of the destructive interference of the partial waves that constitute the positronium ground-state wave packet. Conditions for the observation of the process via the dominant incoherent channel in a circularly polarized field are pointed out

Targeted removal of blood cancer cells from mixed cell populations by cell recognition with matching particle imprints

We report a new approach for separation of blood cancer cells from healthy white blood cells based on cell recognition by surface functionalised particle imprints. We prepared polymeric particle imprints from a layer of suspension of monodisperse PMMA microbeads which closely match the size of in vitro cultured human leukaemia cells (HL60). The imprints were replicated on a large scale with UV curable polyurethane resin using nanoimprinting lithography and surface functionalized with a cationic polymer, a branched polyethylene imine (bPEI), and a Pluronic surfactant, Poloxamer 407, to engineer a weak attraction towards the cells. The latter is amplified several orders of magnitude when a cell of a closely matching size and shape fits into the imprint cavity which multiplies the contact area between the cell surface and the imprint. The particle imprints were optimised for their specificity toward blood cancer cells by treatment with oxygen plasma and then subsequent coatings with bPEI and Poloxamer 407 with various functionalisation concentrations. We tested the surface functionalised imprints for their specificity in retaining in vitro cultured human leukaemic cells (HL60) over healthy human peripheral blood mononuclear cells (PBMCs) in a flow through chamber. The effect of the flushing flow rate of the mixed cell suspension over the particle imprint and the imprint length were also investigated. At each step the selectivity towards HL60 was assessed. Selective isolation of an increased amount of HL60 tumour cells over PBMC was ultimately achieved as a function of the cell seeding ratio on the particle imprint. The effect is attributed to the substantial size difference between the HL60 cell and the PBMCs. The data presented show that relatively inexpensive PMMA microbeads imprints can be utilised as a cell separation technique which could ultimately lead to novel therapies for removal of neoplastic cells from the peripheral blood of acute myeloid leukaemia patients

Factors affecting intracellular delivery and release of hydrophilic versus hydrophobic cargo from mesoporous silica nanoparticles on 2D and 3D cell cultures

Intracellular drug delivery by mesoporous silica nanoparticles (MSNs) carrying hydrophilic and hydrophobic fluorophores as model drug cargo is demonstrated on 2D cellular and 3D tumor organoid level. Two different MSN designs, chosen on the basis of the characteristics of the loaded cargo, were used: MSNs with a surface-grown poly(ethylene imine), PEI, coating only for hydrophobic cargo and MSNs with lipid bilayers covalently coupled to the PEI layer as a diffusion barrier for hydrophilic cargo. First, the effect of hydrophobicity corresponding to loading degree (hydrophobic cargo) as well as surface charge (hydrophilic cargo) on intracellular drug release was studied on the cellular level. All incorporated agents were able to release to varying degrees from the endosomes into the cytoplasm in a loading degree (hydrophobic) or surface charge (hydrophilic) dependent manner as detected by live cell imaging. When administered to organotypic 3D tumor models, the hydrophilic versus hydrophobic cargo-carrying MSNs showed remarkable differences in labeling efficiency, which in this case also corresponds to drug delivery efficacy in 3D. The obtained results could thus indicate design aspects to be taken into account for the development of efficacious intracellular drug delivery systems, especially in the translation from standard 2D culture to more biologically relevant organotypic 3D cultures.</p