Ion emission from warm dense matter produced by irradiation with a soft x-ray free-electron laser

We report on an experiment performed at the FLASH2 free-electron laser(FEL)aimed at producing warm dense matter via soft x-ray isochoric heating.In the experiment,we focus on study of the ions emitted during the soft x-ray ablation process using time-of-flight electron multipliers and a shifted Maxwell–Boltzmann velocity distribution model.We find that most emitted ions are thermal,but that some impurities chemisorbed on the target surface,such as protons,are accelerated by the electrostatic field created in the plasma by escaped electrons.The morphology of the complex crater structure indicates the presence of several ion groups with varying temperatures.We find that the ion sound velocity is controlled by the ion temperature and show how the ion yield depends on the FEL radiation attenuation length in different materials.

Mechanistically Novel Frontal-Inspired In Situ Photopolymerization:An Efficient Electrode|Electrolyte Interface Engineering Method for High Energy Lithium Metal Polymer Batteries

The solvent-free in situ polymerization technique has the potential to tailor-make conformal interfaces that are essential for developing durable and safe lithium metal polymer batteries(LMPBs).Hence,much attention has been given to the eco-friendly and rapid ultraviolet(UV)-induced in situ photopolymerization process to prepare solid-state polymer electrolytes.In this respect,an innovative method is proposed here to overcome the challenges of UV-induced photopolymerization(UV-curing)in the zones where UV-light cannot penetrate,especially in LMPBs where thick electrodes are used.The proposed frontal-inspired photopolymerization(FIPP)process is a diverged frontal-based technique that uses two classes(dual)of initiators to improve the slow reaction kinetics of allyl-based monomers/oligomers by at least 50%compared with the conventional UV-curing process.The possible reaction mechanism occurring in FIPP is demonstrated using density functional theory calculations and spectroscopic investigations.Indeed,the initiation mechanism identified for the FIPP relies on a photochemical pathway rather than an exothermic propagating front forms during the UV-irradiation step as the case with the classical frontal photopolymerization technique.Besides,the FIPP-based in situ cell fabrication using dual initiators is advantageous over both the sandwich cell assembly and conventional in situ photopolymerization in overcoming the limitations of mass transport and active material utilization in high energy and high power LMPBs that use thick electrodes.Furthermore,the LMPB cells fabricated using the in situ-FIPP process with high mass loading LiFePO_(4)electrodes(5.2 mg cm^(-2))demonstrate higher rate capability,and a 50%increase in specific capacity against a sandwich cell encouraging the use of this innovative process in large-scale solid-state battery production.

Fecal cytolysin does not predict disease severity in acutely decompensated cirrhosis and acute-on-chronic liver failure

Background:Cirrhosis with acute decompensation(AD)and acute-on-chronic liver failure(ACLF)are characterized by high morbidity and mortality.Cytolysin,a toxin from Enterococcus faecalis(E.faecalis),is associated with mortality in alcohol-associated hepatitis(AH).It is unclear whether cytolysin also contributes to disease severity in AD and ACLF.Methods:We studied the role of fecal cytolysin in 78 cirrhotic patients with AD/ACLF.Bacterial DNA from fecal samples was extracted and real-time quantitative polymerase chain reaction(PCR)was performed.The association between fecal cytolysin and liver disease severity in cirrhosis with AD or ACLF was analyzed.Results:Fecal cytolysin and E.faecalis abundance did not predict chronic liver failure(CLIF-C)AD and ACLF scores.Presence of fecal cytolysin was not associated with other liver disease markers,including Fibrosis-4(FIB-4)index,‘Age,serum Bilirubin,INR,and serum Creatinine(ABIC)’score,Child-Pugh score,model for end-stage liver disease(MELD)nor MELD-Na scores in AD or ACLF patients.Conclusions:Fecal cytolysin does not predict disease severity in AD and ACLF patients.The predictive value of fecal cytolysin positivity for mortality appears to be restricted to AH.

Loss of Notch signaling in skeletal stem cells enhances bone formation with aging

Skeletal stem and progenitor cells(SSPCs) perform bone maintenance and repair. With age, they produce fewer osteoblasts and more adipocytes leading to a loss of skeletal integrity. The molecular mechanisms that underlie this detrimental transformation are largely unknown. Single-cell RNA sequencing revealed that Notch signaling becomes elevated in SSPCs during aging. To examine the role of increased Notch activity, we deleted Nicastrin, an essential Notch pathway component, in SSPCs in vivo. Middle-aged conditional knockout mice displayed elevated SSPC osteo-lineage gene expression, increased trabecular bone mass, reduced bone marrow adiposity, and enhanced bone repair. Thus, Notch regulates SSPC cell fate decisions, and moderating Notch signaling ameliorates the skeletal aging phenotype, increasing bone mass even beyond that of young mice. Finally, we identified the transcription factor Ebf3 as a downstream mediator of Notch signaling in SSPCs that is dysregulated with aging, highlighting it as a promising therapeutic target to rejuvenate the aged skeleton.

Comparative analysis of ERCP,IDUS,EUS and CT in predicting malignant bile duct strictures

AIM: To compare endoscopic retrograde cholangio-pancreatography (ERCP), intraductal ultrasound (IDUS), endosonography (EUS), endoscopic transpapillary forceps biopsies (ETP) and computed tomography (CT) with respect to diagnosing malignant bile duct strictures.

Effects of testosterone replacement and its pharmacogenetics on physical performance and metabolism

In men, testosterone （T） deficiency is associated with decreased physical performance, as defined by adverse traits in body composition, namely increased body fat content and reduced muscle mass. Physical abilities in androgen-deficient men are further attenuated by lower oxygen supply due to decreased hemoglobin concentrations and by poor glucose utilization. Dysthymia and a lack of necessary aggressiveness also contribute to deteriorate physical effectiveness. Substitution of T can improve lipid and insulin metabolism as well as growth of muscle fibers and decreasing fat depots, which consequently will result in changes of body composition. Increment of bone density will further contribute to increase physical fitness. The effects of T replacement therapy （TRT） are strongly influenced by age, training, and also pharmacogenetics： the CAG repeat polymorphism in exon 1 of the androgen receptor （AR） gene modulates androgen effects. In vitro, transcription of androgen-dependent target genes is attenuated with increasing length of triplet residues, Clinically, the CAG repeat polymorphism causes significant modulations of androgenicity in healthy eugonadal men as well as efficacy of TRT. Thresholds at which T treatment should be initiated, as well as androgen dosage, could be tailored according to this polymorphism.

Detection and characterization of murine colitis and carcinogenesis by molecularly targeted contrast-enhanced ultrasound

AIM To study mucosal addressin cellular adhesion molecule-1(MAd CAM-1) and vascular endothelial growth factor(VEGF)-targeted contrast enhanced ultrasound(CEUS) for the assessment of murine colitis and carcinogenesis. METHODS C57BL/6 mice were challenged with 3% dextran sodium-sulfate(DSS) for three, six or nine days to study the development of acute colitis. Ultrasound was performed with and without the addition of unspecific contrast agents. MAd CAM-1-targeted contrast agent was used to detect and quantify MAd CAM-1 expression. Inflammatory driven colorectal azoxymethane(AOM)/DSS-induced carcinogenesis was examined on day 42 and 84 using VEGF-targeted contrast agent. Highly specific tissue echogenicity was quantified using specialized software. Sonographic findings were correlated to tissue staining, western blot analysis and immunohistochemistry to quantify the degree of inflammation and stage of carcinogenesis. RESULTS Native ultrasound detected increased general bowel wall thickening that correlated with more progressed and more severe DSS-colitis(healthy mice: 0.3 mm ± 0.03 vs six days DSS: 0.5 mm ± 0.2 vs nine days DSS: 0.6 mm ± 0.2, P < 0.05). Moreover, these sonographic findings correlated well with clinical parameters such as weight loss(r2 = 0.74) and histological damage(r2 = 0.86)(P < 0.01). In acute DSS-induced murine colitis, CEUS targeted against MAd CAM-1 detected and differentiated stages of mild, moderate and severe colitis via calculation of mean pixel contrast intensity in decibel(9.6 d B ± 1.6 vs 12.9 d B ± 1.4 vs 18 d B ± 3.33, P < 0.05). Employing the AOM/DSSinduced carcinogenesis model, tumor development was monitored by CEUS targeted against VEGF and detected a significantly increased echogenicity in tumors as compared to adjacent healthy mucosa(healthy mucosa, 1.6 d B ± 1.4 vs 42 d, 18.2 d B ± 3.3 vs 84 d, 18.6 d B ± 4.9, P < 0.01). Tissue echogenicity strongly correlated with histological analysis and immunohistochemistry findings(VEGF-positive cells in 10 high power fields of healthy mucosa: 1 ± 1.2 vs 42 d after DSS start: 2.4 ± 1.6 vs 84 d after DSS start: 3.5 ± 1.3, P < 0.01). CONCLUSION Molecularly targeted CEUS is a highly specific and noninvasive imaging modality, which characterizes murine intestinal inflammation and carcinogenesis in vivo.

Blood-brain barrier modeling: challenges and perspectives

The blood-brain barrier （BBB） forms a highly selective inter- face between blood and brain. Extensive research efforts have completely changed our view of the BBB in the last years, from a static, impermeable barrier to a dynamic, highly regulated and specific cellular system. The BBB ultrastructurally consists of specialized brain microvascular endothelial cells （BMEC） characterized by low pinocytic activity,

Timescales of interface-coupled dissolution-precipitation reactions oncarbonates

In the Earth's upper crust, where aqueous fluids can circulate freely, most mineral transformations are controlled by the coupling between the dissolution of a mineral that releases chemical species into the fluid and precipitation of new minerals that contain some of the released species in their crystal structure, the coupled process being driven by a reduction of the total free-energy of the system. Such coupled dissolution-precipitation processes occur at the fluid-mineral interface where the chemical gradients are highest and heterogeneous nucleation can be promoted, therefore controlling the growth kinetics of the new minerals. Time-lapse nanoscale imaging using Atomic Force Microscopy(AFM) can monitor the whole coupled process under in situ conditions and allow identifying the time scales involved and the controlling parameters. We have performed a series of experiments on carbonate minerals(calcite, siderite, dolomite and magnesite) where dissolution of the carbonate and precipitation of a new mineral was imaged and followed through time. In the presence of various species in the reacting fluid(e. g. antimony, selenium, arsenic, phosphate), the calcium released during calcite dissolution binds with these species to form new minerals that sequester these hazardous species in the form of a stable solid phase. For siderite, the coupling involves the release of Fe^(2+) ions that subsequently become oxidized and then precipitate in the form of FeIIIoxyhydroxides. For dolomite and magnesite,dissolution in the presence of pure water(undersaturated with any possible phase) results in the immediate precipitation of hydrated Mg-carbonate phases. In all these systems, dissolution and precipitation are coupled and occur directly in a boundary layer at the carbonate surface. Scaling arguments demonstrate that the thickness of this boundary layer is controlled by the rate of carbonate dissolution,the equilibrium concentration of the precipitates and the kinetics of diffusion of species in a boundary layer. From these parameters a characteristic time scale and a characteristic length scale of the boundary layer can be derived. This boundary layer grows with time and never reaches a steady state thickness as long as dissolution of the carbonate is faster than precipitation of the new mineral. At ambient temperature, the surface reactions of these dissolving carbonates occur on time-scales of the order of seconds to minutes, indicating the rapid surface rearrangement of carbonates in the presence of aqueous fluids. As a consequence, many carbonate-fluid reactions in low temperature environments are controlled by local thermodynamic equilibria rather than by the global equilibrium in the whole system.

Influence of tacrolimus metabolism rate on renal function after solid organ transplantation

The calcineurin inhibitor(CNI) tacrolimus(TAC) is an integral part of the immunosuppressive regimen after solid organ transplantation. Although TAC is very effective in prevention of acute rejection episodes, its highly variable pharmacokinetic and narrow therapeutic window require frequent monitoring of drug levels and dose adjustments. TAC can cause CNI nephrotoxicity even at low blood trough levels(4-6 ng/m L). Thus, other factors besides the TAC trough level might contribute to CNI-related kidney injury. Unfortunately, TAC pharmacokinetic is determined by a whole bunch of parameters. However, for daily clinical routine a simple application strategy is needed. To address this problem, we and others have evaluated a simple calculation method in which the TAC blood trough concentration(C) is divided by the daily dose(D). Fast TAC metabolism(C/D ratio < 1.05) was identified as a potential risk factor for an inferior kidney function after transplantation. In this regard, we recently showed a strong association between fast TAC metabolism and CNI nephrotoxicity as well as BKV infection. Therefore, the TAC C/D ratio may assist transplant clinicians in a simple way to individualize the immunosuppressive regimen.

Diagnostic imaging advances in murine models of colitis

Inflammatory bowel diseases(IBD) such as Crohn's disease and ulcerative colitis are chronic-remittent inflammatory disorders of the gastrointestinal tract still evoking challenging clinical diagnostic and therapeutic situations. Murine models of experimental colitis are a vital component of research into human IBD concerning questions of its complex pathogenesis or the evaluation of potential new drugs. To monitor the course of colitis, to the present day, classical parameters like histological tissue alterations or analysis of mucosal cytokine/chemokine expression often require euthanasia of animals. Recent advances mean revolutionary noninvasive imaging techniques for in vivo murine colitis diagnostics are increasingly available. These novel and emerging imaging techniques not only allow direct visualization of intestinal inflammation, but also enable molecular imaging and targeting of specific alterations of the inflamed murine mucosa. For the first time, in vivo imaging techniques allow for longitudinal examinations and evaluation of intra-individual therapeutic response. This review discusses the latest developments in the different fields of ultrasound, molecularly targeted contrast agent ultrasound, fluorescence endoscopy, confocal laser endomicroscopy as well as tomographic imaging with magnetic resonance imaging, computed tomography and fluorescence-mediated tomography,discussing their individual limitations and potential future diagnostic applications in the management of human patients with IBD.

Imaging-based diagnosis of acute renal allograft rejection

Kidney transplantation is the best available treatment for patients with end stage renal disease. Despite the introduction of effective immunosuppressant drugs, episodes of acute allograft rejection still endanger graft survival. Since efficient treatment of acute rejection is available, rapid diagnosis of this reversible graft injury is essential. For diagnosis of rejection, invasive core needle biopsy of the graft is the "gold-standard". However, biopsy carries the risk of significant graft injury and is not immediately feasible in patients taking anticoagulants. Therefore, a non-invasive tool assessing the whole organ for specific and fast detection of acute allograft rejection is desirable. We herein review current imaging-based state of the art approaches for non-invasive diagnostics of acute renal transplant rejection. We especially focus on new positron emission tomography-based as well as targeted ultrasoundbased methods.

The consensus on liver autotransplantation from an international panel of experts

IntroductionMore than 1.0 million patients worldwide are diagnosed with space-occupying lesions in the liver every year, with the number approaching 0.5 million per year in China, and only 20% of the lesions are resectable Due to a lack of available donors, only a limited number of patients underwent allogeneic liver transplantation, the remaining patients simply receive palliative care. Therefore, discovering new options for treating these patients is a high priority. Liver autotransplantation （LAT） is a surgical technique that adopts liver transplantation skills to radically treat spaceoccupying hepatic lesions, benign or malignant,

LPS-Induced Proliferation and Chemokine Secretion from BEAS-2B Cells

The surface antigen CD14 plays an important role in innate immunity, serving as a pattern recognition receptor for lipopolysaccharides (LPS). The aim of this study was to investigate the proliferation, NFκB activation, and chemokine secretion of BEAS-2B cells, a human bronchial epithelial cell line, after LPS stimulation, and some details of inVolved signaling. The presence of CD14 was investigated by flow cytometry. Cell proliferation was measured with a [3H]-thymidine incorporation assay. sCD14, RANTES, and IL-8 concentrations in cell supernatants were measured by ELISA. BEAS-2B cells express CD14 on their surface and secrete soluble CD14 into the supernatant. Cells react on LPS with increased proliferation, activation of NFκB, and the secretion of the pro-inflammatory chemotactic cytokines IL-8 and RANTES, which proves the functionality of the CD14 receptor. Neither CD14 nor sCD14 are regulated by LPS. Specific inhibitors of various intracellular signaling pathways diminish the LPS-induced proliferation and IL-8 secretion: Thus MAP-Kinases p38 and JNK, tyrosine kinases, and PI3-kinase are involved in the signaling cascade from the LPS-CD14-complex on the cell surface to the increased cell proliferation and expression of IL-8;furthermore, ERK 1/2, IRAK 1/4, and the NFκB pathway are inVolved in the latter. The data show the existence and functionality of CD14 receptors on BEAS-2B cells and elucidate the signaling pathways inVolved. LPS is able to increase cell prolife-ration, various cytokines which are dependent on endogenous CD14. Three MAPK pathways, PI3 kinase and tyrosine kinase may be involved. Also CD14 is present/involved which was controversial.

Crohn's disease complicated by intestinal infection with methicillin-resistant Staphylococcus aureus

We report on a 24-year-old male patient with history of bloody diarrhea, abdominal pain and vomiting. Endoscopy revealed massive ulcerative discontinuous proctosigmoiditis with deep, sharply demarcated epithelial denudations and enterotoxigenic methicillin-resistant Staphylococcus aureus (MRSA) was detected in mucosal biopsies. After treatment with linezolide and steroids, a significant amelioration of colitis was detected and testing for MRSA became negative. In face of the case presented here, we suggest that in patients with refractory inflammatory bowel disease (IBD), microbiological assessment should be performed to detect a possible Staphylococcus aureus infection in order to initiate an antimicrobial treatment in addition to IBDspecific treatment.

Regionalization of epididymal duct and epithelium in rats and mice by automatic computer-aided morphometric analysis

Aim： To establish a rat and mouse epididymal map based on the use of the Epiquatre automatic software for histologic image analysis. Methods： Epididymides from five adult rats and five adult mice were fixed in alcoholic Bouin＇s fixative and embedded in paraffin. Serial longitudinal sections through the medial aspect of the organ were cut at 10 jam and stained with hematoxylin and eosin. As determined from major connective tissue septa, nine subdivisions of the rat epididymis and seven for the mouse were determined, consisting of five sub-regions in the caput （rat and mouse）, one （mouse） or three （rat） in the corpus and one in the cauda （rat and mouse）. Using the Epiquatre software, several tubular, luminal and epithelial morphometric parameters were evaluated. Results： Statistical comparison of the quantitative parameters revealed regional differences （2-5 in the rat, 3-6 in the mouse, dependent on parameters） with caput regions 1 and 2 being largely distinguishable from the similar remaining caput and corpus, which were in turn recognizable from the cauda regions in both species. Conclusion： The use of the Epiquatre software allowed us to establish regression curves for different morphometric parameters that can permit the detection of changes in their values under different pathological or experimental conditions. （Asian J Androl 2005 Sep; 7： 267-275）

Lithosphere structures dynamics in the central High Atlas(Morocco)by seismic tomography and gravimetric data

We investigate sedimentological and tectonic processes at the central High Atlas, in order to understand their functioning and to build a geodynamic model that placed the area in its current geological frame.The analysis used here is based on the numerical enhancement of a Landsat image where the main goal is to map surface sedimentary deposits throughout the central High Atlas in order to delimit the large geological structures. The sediment distribution throughout central High Atlas indicates that this one is a large tectonic subsiding basin, where the ongoing tectonic events and the geodynamical evolution remain to be explained by other prospecting techniques.3-D structure velocities obtained by local seismic tomography and enhancement techniques of gravimetric anomalies are used to explore and define deep structure beneath the central High Atlas. The goal is to establish the evolution of the deep structure related to the geodynamical processes. Modest crustal thickness variation beneath the central High Atlas(~20-~40 km) define by local tomography and gravimetric anomalies, confirms that, a major part of the lower crust is detached into the lithosphere by delamination. Gravimetric anomaly, local seismic tomography and vertical cross sections throughout the central High Atlas, suggest that the lower crust detached is related to the broken slab of remain northward subduction beneath High and Middle Atlas. Meanwhile, extrusions of heated Asthenosphere materials induce the rifting stage concomitant to tectonic subsidence of the basin.

Simulation of the oxidative metabolization pattern of netupitant,an NK1 receptor antagonist,by electrochemistry coupled to mass spectrometry

Considering the frequent use of netupitant in polytherapy,the elucidation of its oxidative metabolization pattern is of major importance.However,there is a lack of published research on the redox behavior of this novel neurokinin-1 receptor antagonist.Therefore,this study was performed to simulate the intensive hepatic biotransformation of netupitant using an electrochemically driven method.Most of the known enzyme-mediated reactions occurring in the liver(i.e.,N-dealkylation,hydroxylation,and Noxidation)were successfully mimicked by the electrolytic cell using a boron-doped diamond working electrode.The products were separated by reversed-phase high-performance liquid chromatography and identified by high-resolution mass spectrometry.Aside from its ability to pinpoint formerly unknown metabolites that could be responsible for the known side effects of netupitant or connected with any new perspective concerning future therapeutic indications,this electrochemical process also represents a facile alternative for the synthesis of oxidation products for further in vitro and in vivo studies.

Embryonic stem cell-derived neural progenitors as non-tumorigenic source for dopaminergic neurons

AIM:To find a safe source for dopaminergic neurons,we generated neural progenitor cell lines from human embryonic stem cells.METHODS:The human embryonic stem(hES)cell line H9 was used to generate human neural progenitor(HNP)cell lines.The resulting HNP cell lines were differentiated into dopaminergic neurons and analyzed by quantitative real-time polymerase chain reaction and immunofluorescence for the expression of neuronal differentiation markers,including beta-III tubulin(TUJ1)and tyrosine hydroxylase(TH).To assess the risk of teratoma or other tumor formation,HNP cell lines and mouse neuronal progenitor(MNP)cell lines were injected subcutaneously into immunodeficient SCID/beige mice.RESULTS:We developed a fairly simple and fast protocol to obtain HNP cell lines from hES cells.These cell lines,which can be stored in liquid nitrogen for several years,have the potential to differentiate in vitro into dopaminergic neurons.Following day 30 of differentiation culture,the majority of the cells analyzed expressed the neuronal marker TUJ1 and a high proportion of these cells were positive for TH,indicating differentiation into dopaminergic neurons.In contrast to H9 ES cells,the HNP cell lines did not form tumors in immunodeficient SCID/beige mice within 6 mo after subcutaneous injection.Similarly,no tumors developed after injection of MNP cells.Notably,mouse ES cells or neuronal cells directly differentiated from mouse ES cells formed teratomas in more than 90%of the recipients.CONCLUSION:Our findings indicate that neural progenitor cell lines can differentiate into dopaminergic neurons and bear no risk of generating teratomas or other tumors in immunodeficient mice.

Preventing Pressure Oscillations Does Not Fix Local Linear Stability Issues of Entropy-Based Split-Form High-Order Schemes

Recently,it was discovered that the entropy-conserving/dissipative high-order split-form discontinuous Galerkin discretizations have robustness issues when trying to solve the sim-ple density wave propagation example for the compressible Euler equations.The issue is related to missing local linear stability,i.e.,the stability of the discretization towards per-turbations added to a stable base flow.This is strongly related to an anti-diffusion mech-anism,that is inherent in entropy-conserving two-point fluxes,which are a key ingredi-ent for the high-order discontinuous Galerkin extension.In this paper,we investigate if pressure equilibrium preservation is a remedy to these recently found local linear stability issues of entropy-conservative/dissipative high-order split-form discontinuous Galerkin methods for the compressible Euler equations.Pressure equilibrium preservation describes the property of a discretization to keep pressure and velocity constant for pure density wave propagation.We present the full theoretical derivation,analysis,and show corresponding numerical results to underline our findings.In addition,we characterize numerical fluxes for the Euler equations that are entropy-conservative,kinetic-energy-preserving,pressure-equilibrium-preserving,and have a density flux that does not depend on the pressure.The source code to reproduce all numerical experiments presented in this article is available online(https://doi.org/10.5281/zenodo.4054366).