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Funder: Amgen Pharmaceuticals; Grant(s): ISS: 20167888, Novel biomarkers for tumour burden and bone disease are required to guide clinical management of plasma cell dyscrasias. Recently, bone turnover markers (BTMs) and Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) have been explored, although their role in the prospective assessment of multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS) is unclear. Here, we conducted a pilot observational cohort feasibility study combining serum BTMs and DW-MRI in addition to standard clinical assessment. Fifty-five patients were recruited (14 MGUS, 15 smouldering MM, 14 new MM and 12 relapsed MM) and had DW-MRI and serum biomarkers (P1NP, CTX-1, ALP, DKK1, sclerostin, RANKL:OPG and BCMA) measured at baseline and 6-month follow-up. Serum sclerostin positively correlated with bone mineral density (r = 0.40-0.54). At baseline, serum BCMA correlated with serum paraprotein (r = 0.42) and serum DKK1 correlated with serum free light chains (r = 0.67); the longitudinal change in both biomarkers differed between International Myeloma Working Group (IMWG)-defined responders and non-responders. Myeloma Response Assessment and Diagnosis System (MY-RADS) scoring of serial DW-MRI correlated with conventional IMWG response criteria for measuring longitudinal changes in tumour burden. Overall, our pilot study suggests candidate radiological and serum biomarkers of tumour burden and bone loss in MM/MGUS, which warrant further exploration in larger cohorts to validate the findings and to better understand their clinical utility., Funding: The study was funded by Amgen Pharmaceuticals (ISS: 20167888).

BACKGROUND: Patients in psychiatric inpatient settings are at increased risk of developing physical health complications due to the structure of inpatient wards, the metabolic side-effects of antipsychotic medications and socioeconomic factors. Robust physical health monitoring and interventions are paramount in reducing this health inequality. OBJECTIVE: To improve the quality of physical health interventions in the ward environment and empower patients to follow healthy lifestyle guidance to reduce their risk of metabolic syndrome. METHODS: Patient weight and waist circumference data were collected at baseline and weekly throughout the 8-week intervention period. A questionnaire was recorded from baseline to week-5 to assess patient understanding. Two Plan-Do-Study-Act (PDSA) cycles were completed: (1) Series of weekly psychoeducation sessions and group exercise and (2) Implementation of healthy living diaries. RESULTS: Our data did not demonstrate any definitive impact upon the waist circumference and weight of participants. However, analysis of the questionnaires showed a consistent trend in knowledge improvement. CONCLUSION: Whilst our aim of reducing patient weight and waist circumference was not realised, there was a significant impact on participant’s knowledge, demonstrating a subjective benefit of our interventions. Our project also highlighted inconsistencies in physical health measurements and data collection, providing vital information for further quality improvement measures.

The study of plasma physics under conditions of extreme temperatures, densities and electromagnetic field strengths is significant for our understanding of astrophysics, nuclear fusion and fundamental physics. These extreme physical systems are strongly non-linear and very difficult to understand theoretically or optimize experimentally. Here, we argue that machine learning models and data-driven methods are in the process of reshaping our exploration of these extreme systems that have hitherto proven far too non-linear for human researchers. From a fundamental perspective, our understanding can be helped by the way in which machine learning models can rapidly discover complex interactions in large data sets. From a practical point of view, the newest generation of extreme physics facilities can perform experiments multiple times a second (as opposed to ~daily), moving away from human-based control towards automatic control based on real-time interpretation of diagnostic data and updates of the physics model. To make the most of these emerging opportunities, we advance proposals for the community in terms of research design, training, best practices, and support for synthetic diagnostics and data analysis., 14 pages, 4 figures. This work was the result of a meeting at the Lorentz Center, University of Leiden, 13th-17th January 2020. This is a preprint of Hatfield et al., Nature, 593, 7859, 351-361 (2021) https://www.nature.com/articles/s41586-021-03382-w

The spread of cancer to bone is invariably fatal, with complex cross-talk between tumor cells and the bone microenvironment responsible for driving disease progression. By combining in silico analysis of patient datasets with metabolomic profiling of prostate cancer cells cultured with bone cells, we demonstrate the changing energy requirements of prostate cancer cells in the bone microenvironment, identifying the pentose phosphate pathway (PPP) as elevated in prostate cancer bone metastasis, with increased expression of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD) associated with a reduction in progression-free survival. Genetic and pharmacologic manipulation demonstrates that G6PD inhibition reduces prostate cancer growth and migration, associated with changes in cellular redox state and increased chemosensitivity. Genetic blockade of G6PD in vivo results in reduction of tumor growth within bone. In summary, we demonstrate the metabolic plasticity of prostate cancer cells in the bone microenvironment, identifying the PPP and G6PD as metabolic targets for the treatment of prostate cancer bone metastasis.

Amyloid-β 42 peptide (Aβ1-42 (Aβ42)) is well-known for its involvement in the development of Alzheimer’s disease (AD). Aβ42 accumulates and aggregates in fibers that precipitate in the form of plaques in the brain causing toxicity, however, like other forms of Aβ peptide, the role of these peptides remains unclear. Here we analyze and compare the effects of oligomeric and fibrillary Aβ42 peptide on the biology (cell death, proliferative rate, and cell fate specification) of differentiating human neural stem cells (hNS1 cell line). By using the hNS1 cells we found that, at high concentrations, oligomeric and fibrillary Aβ42 peptides provoke apoptotic cellular death and damage of DNA in these cells, but Aβ42 fibrils have the strongest effect. The data also show that both oligomeric and fibrillar Aβ42 peptides decrease cellular proliferation but Aβ42 oligomers have the greatest effect. Finally, both, oligomers and fibrils favor gliogenesis and neurogenesis in hNS1 cells, although, in this case, the effect is more prominent in oligomers. All together the findings of this study may contribute to a better understanding of the molecular mechanisms involved in the pathology of AD and to the development of human neural stem cell-based therapies for AD treatment.

Review of scientific instruments 92(3), 039901 (2021). doi:10.1063/5.0043951, This article was originally published online on 4 January 2021 with an error in the title and Ref. 6 should have been deleted from the reference section and the text. The title is correct above. All online and printed versions of the article were corrected on 7 January 2021. AIP Publishing apologizes for this error., Published by American Institute of Physics, [S.l.]

Although amyloid-β peptide is considered neurotoxic, it may mediate several physiological processes during embryonic development and in the adult brain. The pathological function of amyloid-β peptide has been extensively studied due to its implication in Alzheimer's disease, but its physiological function remains poorly understood. Amyloid-β peptide can be detected in non-aggregated (monomeric) and aggregated (oligomeric and fibrillary) forms. Each form has different cytotoxic and/or physiological properties, so amyloid-β peptide and its role in Alzheimer's disease need to be studied further. Neural stem cells and neural precursor cells are good tools for the study on neurodegenerative diseases and can provide future therapeutic applications in diseases such as Alzheimer's disease. In this review, we provide an outline of the effects of amyloid-β peptide, in monomeric and aggregated forms, on the biology of neural stem cells/neural precursor cells, and discuss the controversies. We also describe the possible molecular targets that could be implicated in these effects, especially GSK3β. A better understanding of amyloid-β peptide (both physiological and pathological), and the signaling pathways involved are essential to advance the field of Alzheimer's disease. Funding: This work was supported by grants from the MICINN-ISCIII (PI-10/00291 and MPY1412/09), MINECO (SAF2015-71140-R) and Comunidad de Madrid (NEUROSTEMCM consortium; S2010/BMD-2336) Sí

The pathological implication of amyloid precursor protein (APP) in Alzheimer's disease has been widely documented due to its involvement in the generation of amyloid-β peptide. However, the physiological functions of APP are still poorly understood. APP is considered a multimodal protein due to its role in a wide variety of processes, both in the embryo and in the adult brain. Specifically, APP seems to play a key role in the proliferation, differentiation and maturation of neural stem cells. In addition, APP can be processed through two canonical processing pathways, generating different functionally active fragments: soluble APP-α, soluble APP-β, amyloid-β peptide and the APP intracellular C-terminal domain. These fragments also appear to modulate various functions in neural stem cells, including the processes of proliferation, neurogenesis, gliogenesis or cell death. However, the molecular mechanisms involved in these effects are still unclear. In this review, we summarize the physiological functions of APP and its main proteolytic derivatives in neural stem cells, as well as the possible signaling pathways that could be implicated in these effects. The knowledge of these functions and signaling pathways involved in the onset or during the development of Alzheimer's disease is essential to advance the understanding of the pathogenesis of Alzheimer's disease, and in the search for potential therapeutic targets. Financial support: This work was supported by grants from the Ministerio de Ciencia e Innovación-Instituto de Salud Carlos III (PI-10/00291 and MPY1412/09), Ministerio de Economía y Competitividad (SAF2015-71140-R) and Comunidad de Madrid (Neurostem-Comunidad de Madrid consortium; S2010/BMD-2336). RC was supported by grants from Plan de Empleo Juvenil-Ministerio de Economía y Competitividad. Sí

Review of scientific instruments 92(1), 013101 (2021). doi:10.1063/5.0022886, We introduce a setup to measure high-resolution inelastic x-ray scattering at the High Energy Density scientific instrument at the European X-Ray Free-Electron Laser (XFEL). The setup uses the Si (533) reflection in a channel-cut monochromator and three spherical diced analyzer crystals in near-backscattering geometry to reach a high spectral resolution. An energy resolution of 44 meV is demonstrated for the experimental setup, close to the theoretically achievable minimum resolution. The analyzer crystals and detector are mounted on a curved-rail system, allowing quick and reliable changes in scattering angle without breaking vacuum. The entire setup is designed for operation at 10 Hz, the same repetition rate as the high-power lasers available at the instrument and the fundamental repetition rate of the European XFEL. Among other measurements, it is envisioned that this setup will allow studies of the dynamics of highly transient laser generated states of matter., Published by American Institute of Physics, [S.l.]

Primary bone tumors or bone metastasis from solid tumors result in painful osteolytic, osteoblastic, or mixed osteolytic/osteoblastic lesions. These lesions compromise bone structure, increase the risk of pathologic fracture, and leave patients with limited treatment options. Primary bone tumors metastasize to distant organs, with some types capable of spreading to other skeletal sites. However, recent evidence suggests that with many solid tumors, cancer cells that have spread to bone may be the primary source of cells that ultimately metastasize to other organ systems. Most syngeneic or xenograft mouse models of primary bone tumors involve intra-osseous (orthotopic) injection of tumor cell suspensions. Some animal models of skeletal metastasis from solid tumors also depend on direct bone injection, while others attempt to recapitulate additional steps of the bone metastatic cascade by injecting cells intravascularly or into the organ of the primary tumor. However, none of these models develop bone metastasis reliably or with an incidence of 100%. In addition, direct intra-osseous injection of tumor cells has been shown to be associated with potential tumor embolization of the lung. These embolic tumor cells engraft but do not recapitulate the metastatic cascade. We reported a mouse model of osteosarcoma in which fresh or cryopreserved tumor fragments (consisting of tumor cells plus stroma) are implanted directly into the proximal tibia using a minimally invasive surgical technique. These animals developed reproducible engraftment, growth, and, over time, osteolysis and lung metastasis. This technique has the versatility to be used to model solid tumor bone metastasis and can readily employ grafts consisting of one or multiple cell types, genetically-modified cells, patient-derived xenografts, and/or labeled cells that can be tracked by optical or advanced imaging. Here, we demonstrate this technique, modeling primary bone tumors and bone metastasis using solid tumor graft implantation into bone.

Scientific reports 10(1), 14564 (2020). doi:10.1038/s41598-020-71350-x, Published by Macmillan Publishers Limited, part of Springer Nature, [London]

Understanding magnetic-field generation and amplification in turbulent plasma is essential to account for observations of magnetic fields in the universe. A theoretical framework attributing the origin and sustainment of these fields to the so-called fluctuation dynamo was recently validated by experiments on laser facilities in low-magnetic-Prandtl-number plasmas ($\mathrm{Pm} < 1$). However, the same framework proposes that the fluctuation dynamo should operate differently when $\mathrm{Pm} \gtrsim 1$, the regime relevant to many astrophysical environments such as the intracluster medium of galaxy clusters. This paper reports a new experiment that creates a laboratory $\mathrm{Pm} \gtrsim 1$ plasma dynamo for the first time. We provide a time-resolved characterization of the plasma's evolution, measuring temperatures, densities, flow velocities and magnetic fields, which allows us to explore various stages of the fluctuation dynamo's operation. The magnetic energy in structures with characteristic scales close to the driving scale of the stochastic motions is found to increase by almost three orders of magnitude from its initial value and saturate dynamically. It is shown that the growth of these fields occurs exponentially at a rate that is much greater than the turnover rate of the driving-scale stochastic motions. Our results point to the possibility that plasma turbulence produced by strong shear can generate fields more efficiently at the driving scale than anticipated by idealized MHD simulations of the nonhelical fluctuation dynamo; this finding could help explain the large-scale fields inferred from observations of astrophysical systems., 12 pages, 9 figures

Amyloid-β 42 [Aβ1–42 (Aβ42)] is one of the main Aβ peptide isoforms found in amyloid plaques of brains with Alzheimer’s disease (AD). Although Aβ42 is associated with neurotoxicity, it might mediate several normal physiological processes during embryonic brain development and in the adult brain. However, due to the controversy that exists in the field, relatively little is known about its physiological function. In the present work, we have analyzed the effects of different concentrations of monomeric Aβ42 on cell death, proliferation, and cell fate specification of human neural stem cells (hNSCs), specifically the hNS1 cell line, undergoing differentiation. Our results demonstrate that at higher concentrations (1 μM), Aβ42 increases apoptotic cell death and DNA damage, indicating that prolonged exposure of hNS1 cells to higher concentrations of Aβ42 is neurotoxic. However, at lower concentrations, Aβ42 significantly promotes cell proliferation and glial cell specification of hNS1 cells by increasing the pool of proliferating glial precursors, without affecting neuronal differentiation, in a concentration-dependent manner. At the molecular level, these effects could be mediated, at least in part, by GSK3β, whose expression is increased by treatment with Aβ42 and whose inhibition prevents the glial specification induced by Aβ42. Since the cellular and molecular effects are known to appear decades before the first clinical symptoms, these types of studies are important in discovering the underlying pathophysiological processes involved in the development of AD. This knowledge could then be used in diagnosing the disease at early stages and be applied to the development of new treatment options.

Amyloid precursor protein (APP) is implicated in neural development as well as in the pathology of Alzheimer's disease (AD); however, its biological function still remains unclear. It has been reported that APP stimulates the proliferation and neuronal differentiation of neural stem cells (NSCs), while other studies suggest an important effect enhancing gliogenesis in NSCs. As expected, APP protein/mRNA is detected in hNS1 cells, a model cell line of human NSCs, both under proliferation and throughout the differentiation period. To investigate the potential function that APP plays in cell fate specification and differentiation of hNS1 cells, we transiently increased human APP levels in these cells and analyzed its cell intrinsic effects. Our data indicate that increased levels of APP induce early cell cycle exit and instructively direct hNS1 cell fate towards a glial phenotype, while decreasing neuronal differentiation. Since elevated APP levels also enhanced APP intracellular domain (AICD)-immunoreactivity, these effects could be, in part, mediated by the APP/AICD system. The AICD domain can play a potential role in signal transduction by its molecular interaction with different target genes such as GSK3B, whose expression was also increased in APP-overexpressing cells that, in turn, may contribute to promoting gliogenesis and inhibiting neurogenesis in NSCs. These data suggest an important action of APP in modulating hNSCs differentiation (probably in an AICD-GSK-3β-dependent manner) and may thus be important for the future development of stem cell therapy strategies for the diseased mammalian brain.

Magnetic reconnection is a process that contributes significantly to plasma dynamics and energy transfer in a wide range of plasma and magnetic field regimes, including inertial confinement fusion experiments, stellar coronae, and compact, highly magnetized objects like neutron stars. Laboratory experiments in different regimes can help refine, expand, and test the applicability of theoretical models to describe reconnection. Laser-plasma experiments exploring magnetic reconnection at a moderate intensity (IL ∼1014 W cm-2) have been performed previously, where the Biermann battery effect self-generates magnetic fields and the field dynamics studied using proton radiography. At high laser intensities (ILλL2>1018 Wcm-2μm2), relativistic surface currents and the time-varying electric sheath fields generate the azimuthal magnetic fields. Numerical modeling of these intensities has shown the conditions that within the magnetic field region can reach the threshold where the magnetic energy can exceed the rest mass energy such that σcold = B2/(μ0nemec2) > 1 [A. E. Raymond et al., Phys. Rev. E 98, 043207 (2018)]. Presented here is the analysis of the proton radiography of a high-intensity (∼1018 W cm-2) laser driven magnetic reconnection geometry. The path integrated magnetic fields are recovered using a "field-reconstruction algorithm" to quantify the field strengths, geometry, and evolution.

Physical review letters 122(3), 034801 (2019). doi:10.1103/PhysRevLett.122.034801, A tunable plasma-based energy dechirper has been developed at FLASHForward to remove thecorrelated energy spread of a 681 MeV electron bunch. Through the interaction of the bunch withwakefields excited in plasma the projected energy spread was reduced from a FWHM of 1.31% to 0.33%without reducing the stability of the incoming beam. The experimental results for variable plasma densityare in good agreement with analytic predictions and three-dimensional simulations. The proof-of-principledechirping strength of $1.8$ $ GeV/mm/m$ significantly exceeds those demonstrated for competing state-of-the-art techniques and may be key to future plasma wakefield-based free-electron lasers and high energyphysics facilities, where large intrinsic chirps need to be removed, Published by APS, College Park, Md.

In this work, two-dimensional (2D) hydrodynamic simulations of a variable length gas cell were performed using the open source fluid code OpenFOAM. The gas cell was designed to study controlled injection of electrons into a laser-driven wakefield at the Astra Gemini laser facility. The target consists of two compartments: an accelerator and an injector section connected via an aperture. A sharp transition between the peak and plateau density regions in the injector and accelerator compartments, respectively, was observed in simulations with various inlet pressures. The fluid simulations indicate that the length of the down-ramp connecting the sections depends on the aperture diameter, as does the density drop outside the entrance and the exit cones. Further studies showed, that increasing the inlet pressure leads to turbulence and strong fluctuations in density along the axial profile during target filling, and consequently, is expected to negatively impact the accelerator stability.

Women with pre-existing type 1 and 2 diabetes have an increased risk of adverse pregnancy outcomes, including miscarriage, fetal congenital anomaly and perinatal death. There is a further group of women who develop diabetes during pregnancy, who are also at increased risk of adverse pregnancy outcomes. Since the original publication of the National Institute for Health and Care Excellence (NICE) guidance on diabetes in pregnancy in 2008, there have been several developments that prompted an update. Recently published guidance from NICE (2015) has reviewed studies on the diagnosis and treatment of gestational diabetes and those with pre-existing type 1 and 2 diabetes. This article outlines the background to diabetes, preconception care and the management and prevention of complications throughout pregnancy.

International audience; Many supernova remnants (SNRs), such as G296.5 + 10.0, exhibit an axisymmetric or barrel shape. Such morphologies have previously been linked to the direction of the Galactic magnetic field (GMF) although this remains uncertain. These SNRs generate magnetohydrodynamic (MHD) shocks in the interstellar medium (ISM), modifying its physical and chemical properties. The ability to study these shocks through observations is difficult due to the small spatial scales involved. In order to answer these questions, we perform a scaled laboratory experiment in which a laser-generated blast wave expands under the influence of a uniform magnetic field. The blast wave exhibits a spheroidal shape, whose major axis is aligned with the magnetic field, in addition to a more continuous shock front. The implications of our results are discussed in the context of astrophysical systems.

The second most common neurodegenerative disease, Parkinson’s disease (PD) is characterized by progressive loss of dopaminergic neurons which in turn causes the occurrence of several motor symptoms.

We report on the depletion and power amplification of the driving laser pulse in a strongly-driven laser wakefield accelerator. Simultaneous measurement of the transmitted pulse energy and temporal shape indicate an increase in peak power from $187 \pm 11$ TW to a maximum of $318 \pm 12$ TW after 13 mm of propagation in plasma density of $0.9 \times 10^{18}$ cm$^{-3}$. The power amplification is correlated with the injection and acceleration of electrons in the nonlinear wakefield. This process is modeled by including localized redshift and subsequent group delay dispersion at the laser pulse front., 6 pages, 4 figures. Published in PRL

The amyloid -β peptide (Aβ) is the main component of the amyloid plaques in Alzheimer's disease (AD). It has been widely demonstrated that Aβ is toxic to neurons and is associated with AD pathology. However, Aβ also appears to have an important biological function both in the adult brain and throughout embryonic development of the nervous system, acting as a trophic factor at low concentrations.It is known that Neural Stem Cells (NSCs) are capable of self-renewal and differentiate into functional glial and neuronal cells. Therefore, human NSCs may be a hope for future therapeutic application in neurodegenerative diseases such as AD. The effects of Aβ peptides on NSCs are still not well understood and remain controversial.In this chapter we outline the materials and methods used for the culture and differentiation of hNS1 cells, a cell line of human NSCs. We describe the preparation of different forms (monomeric, oligomeric and fibrillary) of Aβ peptide and subsequent cell treatment, followed by the analysis of the effects on toxicity, cell proliferation and cell fate specification of hNS1 cells.

Significance High-resolution microcomputed tomography with benchtop X-ray sources requires long scan times because of the heat load limitation on the anode. We present an alternative, high-brightness plasma-based X-ray source that does not suffer from this restriction. A demonstration of tomography of a centimeter-scale complex organism achieves equivalent quality to a commercial scanner. We will soon be able to record such scans in minutes, rather than the hours required by conventional X-ray tubes., In the field of X-ray microcomputed tomography (μCT) there is a growing need to reduce acquisition times at high spatial resolution (approximate micrometers) to facilitate in vivo and high-throughput operations. The state of the art represented by synchrotron light sources is not practical for certain applications, and therefore the development of high-brightness laboratory-scale sources is crucial. We present here imaging of a fixed embryonic mouse sample using a compact laser–plasma-based X-ray light source and compare the results to images obtained using a commercial X-ray μCT scanner. The radiation is generated by the betatron motion of electrons inside a dilute and transient plasma, which circumvents the flux limitations imposed by the solid or liquid anodes used in conventional electron-impact X-ray tubes. This X-ray source is pulsed (duration 1010 photons per pulse), small (diameter 15 keV. Stable X-ray performance enabled tomographic imaging of equivalent quality to that of the μCT scanner, an important confirmation of the suitability of the laser-driven source for applications. The X-ray flux achievable with this approach scales with the laser repetition rate without compromising the source size, which will allow the recording of high-resolution μCT scans in minutes.

The amyloid -β peptide (Aβ) is the main component of the amyloid plaques in Alzheimer's disease (AD). It has been widely demonstrated that Aβ is toxic to neurons and is associated with AD pathology. However, Aβ also appears to have an important biological function both in the adult brain and throughout embryonic development of the nervous system, acting as a trophic factor at low concentrations.It is known that Neural Stem Cells (NSCs) are capable of self-renewal and differentiate into functional glial and neuronal cells. Therefore, human NSCs may be a hope for future therapeutic application in neurodegenerative diseases such as AD. The effects of Aβ peptides on NSCs are still not well understood and remain controversial.In this chapter we outline the materials and methods used for the culture and differentiation of hNS1 cells, a cell line of human NSCs. We describe the preparation of different forms (monomeric, oligomeric and fibrillary) of Aβ peptide and subsequent cell treatment, followed by the analysis of the effects on toxicity, cell proliferation and cell fate specification of hNS1 cells.

Organoids from human pluripotent stem cells are becoming suitable models for studies of organ development, drug screening, regenerative medicine, and disease modeling. Three-dimensional minilungs in Matrigel culture have recently been generated from human embryonic stem cells. These particular organoids, named lung bud organoids, showed branching airway and early alveolar structures resembling those present in lungs from the second trimester of human gestation. We show here that the treatment of such organoids with a lung and airway epithelial maturation cocktail containing dexamethasone drives lung bud organoids to the formation of paddle-racquet like structures. This strategy may help to increase the versatility of lung organoids and to generate structures more advanced than the original branching texture. This work was supported by grants MPY-1038/14 and MPY-1146/16 from ISCIII to AZ and SAF-2015-71140-R from MINECO to IL. Sí

44th EPS Conference on Plasma Physics, Belfast, Northern Ireland, 26 Jun 2017 - 30 Jun 2017; Plasma physics and controlled fusion 60(1), 014022 (2018). doi:10.1088/1361-6587/aa8f0e, We report on the evaluation of the performance of self-guiding over extended distances with $f/20$ and $f/40$ focussing geometries. Guiding over $39\,\mathrm{mm}$ or more than 100 Rayleigh ranges was observed with the $f/20$ optic at ${n}_{e}=1.5\times {10}^{18}\,{\mathrm{cm}}^{-3}$. Analysis of guiding performance found that the extent of the exiting laser spatial mode closely followed the matched spot size predicted by 3D nonlinear theory. Self-guiding with an $f/40$ optic was also characterised, with guided modes observed for a plasma length of $90\,\mathrm{mm}$ and a plasma density of ${n}_{e}=9.5\times {10}^{17}\,{\mathrm{cm}}^{-3}$. This corresponds to self-guided propagation over 53 Rayleigh ranges and is similar to distances obtained with discharge plasma channel guiding., Published by IOP Publ., Bristol

9th International Particle Accelerator Conference, IPAC18, Vancouver, Kanada, 29 Apr 2018 - 4 May 2018; Journal of physics / Conference Series Conference Series 1067, 042010 (2018). doi:10.1088/1742-6596/1067/4/042010, Density modulations in plasma caused by a high-intensity laser or a high chargedensity electron pulse can generate extreme acceleration fields. Acceleration of electrons in suchfields may produce ultra-relativistic, quasi-monoenergetic, ultra-short electron bunches overdistances orders of magnitudes shorter than in state-of-the-art radio-frequency accelerators.FLASHForward is a beam-driven plasma wakefield accelerator (PWFA) project at DESY withthe goal of producing, characterizing, and utilizing such beams. Temporal characterization ofthe acceleration process is of crucial importance for improving the stability and control in PWFAbeams. While measurement of the transient field of the femtosecond bunch in a single shot ischallenging, in recent years novel techniques with great promise have been developed [1, 2]. Thiswork discusses the plans and status of the transverse diagnostics at FLASHForward., Published by IOP Publ., Bristol

Physiological responses to, and recovery from, exposure to 3 concentrations of a pharmaceutical mixture (diclofenac and propranolol) were examined experimentally in Baltic Sea blue mussels Mytilus ...

Amyloid precursor protein (APP) is a member of the APP family of proteins, and different enzymatic processing leads to the production of several derivatives that are shown to have distinct biological functions. APP is involved in the pathology of Alzheimer's disease (AD), the most common neurodegenerative disorder causing dementia. Furthermore, it is believed that individuals with Down syndrome (DS) have increased APP expression, due to an extra copy of chromosome 21 (Hsa21), that contains the gene for APP. Nevertheless, the physiological function of APP remains unclear. It is known that APP plays an important role in neural growth and maturation during brain development, possibly by influencing proliferation, cell fate specification and neurogenesis of neural stem cells (NSCs). Proteolytic cleavage of APP occurs mainly via two mutually exclusive pathways, the non-amyloidogenic pathway or the amyloidogenic pathway. Other alternative pathways (η-secretase, δ-secretase and meprin pathways) have also been described for the physiological processing of APP. The different metabolites generated from these pathways, including soluble APPα (sAPPα), soluble APPβ (sAPPβ), β-amyloid (Aβ) peptides and the APP intracellular domain (AICD), have different functions determined by their structural differences, equilibrium and concentration with respect to other fragments derived from APP. This review discusses recent observations regarding possible functions of APP and its proteolytic derivatives in the biology and phenotypic specification of NSCs. This can be important for a better understanding of the pathogenesis and the development of future therapeutic applications for AD and/or DS, diseases in which alterations in neurogenesis have been described.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the progressive death of dopaminergic neurons (DAn) in the substantia nigra pars compacta (SNpc). The primary motor symptoms include tremors, rigidity and bradykinesia. Current treatments for PD are only symptomatic and do not prevent disease progression. In recent years, stem cells have become an attractive option to investigate and treat PD. In fact, transplants of fetal ventral mesencephalic cells (which are rich in dopaminergic neuroblasts) have provided proof of concept that cell replacement therapy may be a good option for improving motor symptoms in some PD patients. Although its widespread clinical use is still not possible due to ethical aspects and limited availability of tissue. It is therefore necessary to find alternative cellular sources such as stem cells. Stem cell therapies may exert their action through several mechanisms such as cell replacement, trophic and immunomodulatory actions. In this book chapter we summarize the most recent and relevant clinical studies based on cell therapy for PD treatment. We provide an overview of the different types of human stem cells available, their main properties and how they are being used as a possible therapy for the treatment of PD.

In a plasma with a transverse density gradient, laser wavefront tilt develops gradually due to phase velocity differences in different plasma densities. The wavefront tilt leads to a parabolic trajectory of the plasma wakefield and hence the accelerated electron beam, which leads to an angular streaking of the emitted betatron radiation. In this way, the temporal evolution of the betatron X-ray spectra will be converted into angular “streak,” i.e., having a critical energy-angle correlation. An analytical model for the curved trajectory of a laser pulse in a transverse density gradient is presented. This gives the deflection angle of the electron beam and the betatron X-rays as a function of the plasma and laser parameters, and it was verified by particle-in-cell simulations. This angular streaking could be used as a single-shot diagnostic technique to reveal the temporal evolution of betatron X-ray spectra and hence the electron acceleration itself.In a plasma with a transverse density gradient, laser wavefront tilt develops gradually due to phase velocity differences in different plasma densities. The wavefront tilt leads to a parabolic trajectory of the plasma wakefield and hence the accelerated electron beam, which leads to an angular streaking of the emitted betatron radiation. In this way, the temporal evolution of the betatron X-ray spectra will be converted into angular “streak,” i.e., having a critical energy-angle correlation. An analytical model for the curved trajectory of a laser pulse in a transverse density gradient is presented. This gives the deflection angle of the electron beam and the betatron X-rays as a function of the plasma and laser parameters, and it was verified by particle-in-cell simulations. This angular streaking could be used as a single-shot diagnostic technique to reveal the temporal evolution of betatron X-ray spectra and hence the electron acceleration itself.

We report a case of a woman with chronic right-sided pelvic pain with an unusual combination of broad ligament defects and associated terminal ileum and caecum herniation. Reduction of the hernia and closure of the defects at laparoscopy resulted in resolution of the patient’s painful symptoms. Review of the literature suggests that, although rare, such defects should be considered in the differential diagnosis of persistent pelvic pain. Where found incidentally, broad ligament defects should be repaired in order to prevent sinister complications such as bowel obstruction and strangulation.

A picosecond CO2 laser was used successfully in a number of experiments exploring advanced methods of particle acceleration [1]. Proton acceleration from gas-jet plasma exemplifies another advantage of employing the increase in laser wavelength from the optical to the mid-IR region. Recent theoretical- and experimental-studies of ion acceleration from laser-generated plasma point to better ways to control the ion beam’s energy when plasma approaches the critical density. Studying this regime with solid-state lasers is problematic due to the dearth of plasma sources at the critical electron density ∼1021 cm−3, corresponding to laser wavelength λ = 1 μm. CO2 laser offers a solution. The CO2 laser’s 10 μm wavelength shifts the critical plasma density to 1019 cm−3, a value attainable with gas jets. Capitalizing on this approach, we focused a circular polarized 1-TW CO2 laser beam onto a hydrogen gas jet and observed a monoenergetic proton beam in the 1–2 MeV range. Simultaneously, we optically probed the laser/plasma interaction region with visible light, revealing holes bored by radiation pressure, as well as quasi-stationary soliton-like plasma formations. Our findings from 2D PIC simulations agree with experimental results and aid in their interpretation.