SppC based energy frontier lepton-proton colliders: luminosity and physics

In this study, main parameters of Super proton-proton Collider (SppC) based lepton-proton colliders are estimated. For electron beam parameters, highest energy International Linear Collider (ILC) and Plasma Wake Field Accelerator-Linear Collider (PWFA-LC) options are taken into account. For muon beams, 1.5 TeV and 3 TeV center of mass energy Muon Collider parameters are used. In addition, ultimate $\mu$p collider which assumes construction of additional 50 TeV muon ring in the SppC tunnel is considered as well. It is shown that $L_{ep}$ $\sim$ $10^{32}$ $cm^{-2}s^{-1}$ can be achieved with moderate upgrade of the SppC proton beam parameters. Physics search potential of proposed lepton-proton colliders is illustrated by considering small Bjorken x region as an example of SM physics and resonant production of color octet leptons as an example of BSM physics.Comment: 11 pages, 3 figures, 8 table

Investigating the Single Production of Vector-Like Quarks Decaying into Top Quark and W Boson through Hadronic Channels at the HL-LHC

We investigate the single production of vector-like quarks at the High Luminosity LHC (HL-LHC). With the assumed (enhanced) couplings to third generation quarks of the standard model, vector-like quarks $B/X$ are produced in association with a bottom ($b$) or top ($t$) quark, which correspond to $Bbq$ and $Btq/Xtq$ production modes, including an additional soft forward jet from the spectator quark ($q$). This study focuses on high-mass vector-like quarks $B/X$ decaying into a top quark and a $W$ boson, resulting in the final state jets emerging from hadronically decaying top quark ($t\to Wb$) and $W$ boson ($W\to q\bar{q}'$). The events with $W$ boson and $t$ quark have been analysed using tagging techniques for large-radius jets. The scan ranges of the mass ($1000<m_{B}<3000$ GeV) for the relative width $\Gamma_{B/X}/m_{B/X}=0.1$ of vector-like $B/X$ quarks have been investigated. From the results of the analysis, the masses of vector like quarks B (X) up to 2550 (2450) GeV can be excluded at $95\%$ CL depending on the type and branching scenarios at integrated luminosity projection of $3$ ab$^{-1}$ at the HL-LHC.Comment: 18 pages, 5 Tables, 6 Figure

Galactic Model Parameters and Space Density of Cataclysmic Variables in Gaia Era: New Constraints to Population Models

The spatial distribution, Galactic model parameters and luminosity function of cataclysmic variables (CVs) are established using re-estimated trigonometric parallaxes of {\it Gaia} DR3. The data sample of 1,587 CVs in this study is claimed to be suitable for Galactic model parameter estimation as the distances are based on trigonometric parallaxes and the {\it Gaia} DR3 photometric completeness limits were taken into account when the sample was created. According to the analysis, the scale height of All CVs increases from 248$\pm$2 to 430$\pm$4 pc towards shorter periods near the lower limit of the period gap and suddenly drops to 300$\pm$2 pc for the shortest orbital period CVs. The exponential scale heights of All CVs and magnetic systems are found to be 375$\pm$2 and 281$\pm$3 pc, respectively, considerably larger than those suggested in previous observational studies. The local space density of All CVs and magnetic systems in the sample are $6.8^{+1.3}_{-1.1}\times$10$^{-6}$ and $2.1^{+0.5}_{-0.4}\times10^{-6}$ pc$^{-3}$, respectively. Our measurements strengthen the 1-2 order of magnitude discrepancy between CV space densities predicted by population synthesis models and observations. It is likely that this discrepancy is due to objects undetected by CV surveys, such as the systems with very low $\dot{M}$ and the ones in the period gap. The comparisons of the luminosity function of white dwarfs with the luminosity function of All CVs in this study show that 500 times the luminosity function of CVs fits very well to the luminosity function of white dwarfs. We conclude that the estimations and data sample in this study can be confidently used in further analysis of CVs.Comment: 23 pages, including 12 figures and 6 tables, accepted for publication in the Astronomical Journa

A Rare Case of Propofol-Induced Acute Liver Failure and Literature Review

The incidence of drug-induced acute liver failure is increasing. A number of drugs can inhibit mitochondrial functions, alter β-oxidation and cause accumulation of free fatty acids within the hepatocytes. This may result in hepatic steatosis, cell death and liver injury. In our case, propofol, an anesthetic drug commonly used in adults and children, is suspected to have induced disturbance of the mitochondrial respiratory chain, which in consequence led to insufficient energy supply and finally liver failure. We report the case of a 35-year-old Caucasian woman with acute liver failure after anesthesia for stripping of varicose veins. Liver histology, imaging and laboratory data indicate drug-induced acute liver failure, presumably due to propofol. Hepatocyte death and microvesicular fatty degeneration of 90% of the liver parenchyma were observed before treatment with steroids. Six months later, a second biopsy was performed, which revealed only minimal steatosis and minimal periportal hepatitis. We suggest that propofol led to impaired fatty acid oxidation possibly due to a genetic susceptibility. This caused free fatty acid accumulation within hepatocytes, which presented as hepatocellular fatty degeneration and cell death. Large scale hepatocyte death was followed by impaired liver function and, consecutively, progressed to acute liver failure

Glutathione-S-transferase subtypes α and π as a tool to predict and monitor graft failure or regeneration in a pilot study of living donor liver transplantation

<p>Abstract</p> <p>Objective</p> <p>Glutathione-S-Transferase (GST) subtype α and π are differentially expressed in adult liver tissue. Objective of the study was if GST α and p may serve as predictive markers for liver surgery, especially transplantations.</p> <p>Methods</p> <p>13 patients receiving living donor liver transplantation (LDLT) and their corresponding donors were analyzed for standard serum parameters (ALT, AST, gGT, bilirubin) as well as GST-α and -π before LDLT and daily for 10 days after LDLT. Patients (R) and donors (D) were grouped according to graft loss (R1/D1) or positive outcome (R2/D2) and above named serum parameters were compared between the groups.</p> <p>Results</p> <p>R1 showed significantly increased GST-α and significantly lower GST-π levels than R2 patients or the donors. There was a positive correlation between GST-α and ALT, AST as well as bilirubin and a negative correlation to γGT. However, γGT correlated positively with GST-π. Graft failure was associated with combined low GST-π levels in donors and their recipients before living donor liver transplantation.</p> <p>Conclusion</p> <p>Our data suggest that high GST-α serum levels reflect ongoing liver damage while GST-P indicates the capacity and process of liver regeneration. Additionally, GST-π may be useful as marker for optimizing donor and recipient pairs in living donor liver transplantation.</p

Identification of Patients with Advanced Fibrosis Due to Nonalcoholic Fatty Liver Disease: Considerations for Best Practice

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) prevalence has increased in the past two decades, resulting in a significant but under-recognised public health burden. This impacts the prevalence of advanced fibrosis, end-stage liver disease and associated extrahepatic manifestations. To understand the challenges in recognising patients with advanced fibrosis due to NASH and develop a standardised approach to screen these patients, the authors of this document provided their opinions and expertise from practice and published evidence to identify key challenges and current approaches for diagnosing NASH. The severity of liver fibrosis due to NASH is the main indicator of associated morbidity and mortality outcomes. Therefore, identifying patients with, or at risk of, advanced fibrosis due to NASH and linking them to appropriate care is critical. This can be challenging due to a lack of awareness of NASH among healthcare professionals and a lack of standardised protocols for identifying patients. Simple noninvasive tests may provide an opportunity to facilitate early identification of these patients. This article proposes a simple, universally applicable diagnostic algorithm for use in clinical practice, that includes sequential use of noninvasive tests, ideally a biological marker and an imaging technique, which may help to facilitate early diagnosis of these patients. In the opinion of the authors, early detection of advanced fibrosis is fundamental in the efforts to halt the progression of NASH and diagnostic algorithms may facilitate pre-emptive interventions to curtail the disease

NLRP3 inflammasome activation is required for fibrosis development in NAFLD

NLR inflammasomes, caspase 1 activation platforms critical for processing key pro-inflammatory cytokines, have been implicated in the development of nonalcoholic fatty liver disease (NAFLD). As the direct role of the NLRP3 inflammasome remains unclear, we tested effects of persistent NLRP3 activation as a contributor to NAFLD development and, in particular, as a modulator of progression from benign hepatic steatosis to steatohepatitis during diet-induced NAFLD. Gain of function tamoxifen-inducible Nlrp3 knock-in mice allowing for in vivo temporal control of NLRP3 activation and loss of function Nlrp3 knockout mice were placed on short-term choline-deficient amino acid-defined (CDAA) diet, to induce isolated hepatic steatosis or long-term CDAA exposure, to induce severe steatohepatitis and fibrosis, respectively. Expression of NLRP3 associated proteins was assessed in liver biopsies of a well-characterized group of patients with the full spectrum of NAFLD. Nlrp3−/− mice were protected from long-term feeding CDAA-induced hepatomegaly, liver injury, and infiltration of activated macrophages. More importantly, Nlrp3−/− mice showed marked protection from CDAA-induced liver fibrosis. After 4 weeks on CDAA diet, wild-type (WT) animals showed isolated hepatic steatosis while Nlrp3 knock-in mice showed severe liver inflammation, with increased infiltration of activated macrophages and early signs of liver fibrosis. In the liver samples of patients with NAFLD, inflammasome components were significantly increased in those patients with nonalcoholic steatohepatitis (NASH) when compared to those with non-NASH NAFLD with mRNA levels of pro-IL1 beta correlated to levels of COL1A1. Our study uncovers a crucial role for the NLRP3 inflammasome in the development of NAFLD. These findings may lead to novel therapeutic strategies aimed at halting the progression of hepatic steatosis to the more severe forms of this disease.Fil: Wree, Alexander. University of California at San Diego; Estados Unidos. University Hospital Essen; AlemaniaFil: McGeough, Matthew D.. University of California at San Diego; Estados UnidosFil: Peña, Carla A.. University of California at San Diego; Estados UnidosFil: Schlattjan, Martin. University Hospital Essen; AlemaniaFil: Li, Hongying. University of California at San Diego; Estados UnidosFil: Inzaugarat, Maria Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Inmunología, Genética y Metabolismo. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Inmunología, Genética y Metabolismo; ArgentinaFil: Messer, Karen. University of California at San Diego; Estados UnidosFil: Canbay, Ali. University Hospital Essen; AlemaniaFil: Hoffman, Hal M.. University of California at San Diego; Estados Unidos. Ludwig Institute of Cancer Research; Estados UnidosFil: Feldstein, Ariel E.. University of California at San Diego; Estados Unido

Effect of intracellular lipid accumulation in a new model of non-alcoholic fatty liver disease

<p>Abstract</p> <p>Background</p> <p><it>In vitro </it>exposure of liver cells to high concentrations of free fatty acids (FFA) results in fat overload which promotes inflammatory and fibrogenic response similar to those observed in patients with Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH). Since the mechanisms of this event have not been fully characterized, we aimed to analyze the fibrogenic stimuli in a new <it>in vitro </it>model of NASH.</p> <p>Methods</p> <p>HuH7 cells were cultured for 24 h in an enriched medium containing bovine serum albumin and increasing concentrations of palmitic and oleic acid at a molar ratio of 1:2 (palmitic and oleic acid, respectively). Cytotoxic effect, apoptosis, oxidative stress, and production of inflammatory and fibrogenic cytokines were measured.</p> <p>Results</p> <p>FFA induces a significant increment in the intracellular content of lipid droplets. The gene expression of interleukin-6, interleukin-8 and tumor necrosis factor alpha was significantly increased. The protein level of interleukin-8 was also increased. Intracellular lipid accumulation was associated to a significant up-regulation in the gene expression of transforming growth factor beta 1, alpha 2 macroglobulin, vascular endothelial growth factor A, connective tissue growth factor, insulin-like growth factor 2, thrombospondin 1. Flow cytometry analysis demonstrated a significant increment of early apoptosis and production of reactive oxygen species.</p> <p>Conclusions</p> <p>The exposure of hepatocytes to fatty acids elicits inflammation, increase of oxidative stress, apoptosis and production of fibrogenic cytokines. These data support a primary role of FFA in the pathogenesis of NAFLD and NASH.</p

Combined activities of JNK1 and JNK2 in hepatocytes protect against toxic liver injury

Background & Aims: c-Jun N-terminal kinase (JNK)1 and JNK2 are expressed in hepatocytes and have overlapping and distinct functions. JNK proteins are activated, via phosphorylation, in response to acetaminophen- or CCl4-induced liver damage; the level of activation correlates with the degree of injury. SP600125, a JNK inhibitor, has been reported to block acetaminophen-induced liver injury. We investigated the role of JNK in drug-induced liver injury (DILI) in liver tissues from patients and in mice with genetic deletion of JNK in hepatocytes. Methods: We studied liver sections from patients with DILI (due to acetaminophen, phenprocoumon, non-steroidal anti-inflammatory drugs or autoimmune hepatitis), or patients without acute liver failure (controls), collected from a DILI Biobank in Germany. Levels of total and activated (phosphorylated) JNK were measured by immunohistochemistry and western blotting. Mice with hepatocyte-specific deletion ofJnk1 (Jnk1Δhepa) or combination of Jnk1 and Jnk2 (JnkΔhepa), as well as Jnk1-floxed C57BL/6 (control) mice, were given injections of CCl4 (to induce fibrosis) or acetaminophen (to induce toxic liver injury). We performed gene expression microarray, and phosphoproteomic analyses to determine mechanisms of JNK activity in hepatocytes.  Results: Liver samples from DILI patients contained more activated JNK, predominantly in nuclei of hepatocytes and in immune cells, than healthy tissue. Administration of acetaminophen to JnkΔhepa mice produced a greater level of liver injury than that observed in Jnk1Δhepa or control mice, based on levels of serum markers and microscopic and histologic analysis of liver tissues. Administration of CCl4 also induced stronger hepatic injury in JnkΔhepa mice, based on increased inflammation, cell proliferation, and fibrosis progression, compared to Jnk1Δhepa or control mice. Hepatocytes from JnkΔhepamice given acetaminophen had an increased oxidative stress response, leading to decreased activation of AMPK, total protein AMPK levels, and pJunD and subsequent necrosis. Administration of SP600125 before or with acetaminophen protected JnkΔhepaand control mice from liver injury. Conclusions: In hepatocytes, JNK1 and JNK2 appear to have combined effects in protecting mice from CCl4- and acetaminophen-induced liver injury. It is important to study the tissue-specific functions of both proteins, rather than just JNK1, in the onset of toxic liver injury. JNK inhibition with SP600125 shows off-target effects