Plasma levels of apelin are reduced in patients with liver fibrosis and cirrhosis but are not correlated with circulating levels of bone morphogenetic protein 9 and 10

Background: The peptide apelin is expressed in human healthy livers and is implicated in the development of hepatic fibrosis and cirrhosis. Mutations in the bone morphogenetic protein receptor type II (BMPR-II) result in reduced plasma levels of apelin in patients with heritable pulmonary arterial hypertension. Ligands for BMPR-II include bone morphogenetic protein 9 (BMP9), highly expressed in liver, and BMP10, expressed in heart and to a lesser extent liver. However, it is not known whether reductions in BMP9 and/or BMP10, with associated reduction in BMPR-II signalling, correlate with altered levels of apelin in patients with liver fibrosis and cirrhosis. Methods: Plasma from patients with liver fibrosis (n = 14), cirrhosis (n = 56), and healthy controls (n = 25) was solid-phase extracted using a method optimised for recovery of apelin, which was measured by ELISA. Results: Plasma apelin was significantly reduced in liver fibrosis (8.3 ± 1.2 pg/ml) and cirrhosis (6.5 ± 0.6 pg/ml) patients compared with controls (15.4 ± 2.0 pg/ml). There was no obvious relationship between apelin and BMP 9 or BMP10 previously measured in these patients. Within the cirrhotic group, there was no significant correlation between apelin levels and disease severity scores, age, sex, or treatment with β-blockers. Conclusions: Apelin was significantly reduced in plasma of patients with both early (fibrosis) and late-stage (cirrhosis) liver disease. Fibrosis is more easily reversible and may represent a potential target for new therapeutic interventions. However, it remains unclear whether apelin signalling is detrimental in liver disease or is beneficial and therefore, whether an apelin antagonist or agonist have clinical use

Studying perceptual bias in favor of the from-above Necker cube perspective in a goal-directed behavior

When viewing a completely ambiguous image, different interpretations can switch involuntarily due to internal top-down processing. In the case of the Necker cube, an entirely ambiguous stimulus, observers often display a bias in perceptual switching between two interpretations based on their perspectives: one with a from-above perspective (FA) and the other with a from-below perspective (FB). Typically, observers exhibit a priori top-down bias in favor of the FA interpretation, which may stem from a statistical tendency in everyday life where we more frequently observe objects from above. However, it remains unclear whether this perceptual bias persists when individuals voluntarily decide on the Necker cube's interpretation in goal-directed behavior, and the impact of ambiguity in this context is not well-understood. In our study, we instructed observers to voluntarily identify the orientation of a Necker cube while manipulating its ambiguity from low (LA) to high (HA). Our investigation aimed to test two hypotheses: (i) whether the perspective (FA or FB) would result in a bias in response time, and (ii) whether this bias would depend on the level of stimulus ambiguity. Additionally, we analyzed electroencephalogram (EEG) signals to identify potential biomarkers that could explain the observed perceptual bias. The behavioral results confirmed a perceptual bias in favor of the from-above perspective, as indicated by shorter response times. However, this bias diminished for stimuli with high ambiguity. For the LA stimuli, the occipital theta-band power consistently exceeded the frontal theta-band power throughout most of the decision-making time. In contrast, for the HA stimuli, the frontal theta-band power started to exceed the occipital theta-band power during the 0.3-s period preceding the decision. We propose that occipital theta-band power reflects evidence accumulation, while frontal theta-band power reflects its evaluation and decision-making processes. For the FB perspective, occipital theta-band power exhibited higher values and dominated over a longer duration, leading to an overall increase in response time. These results suggest that more information and more time are needed to encode stimuli with a FB perspective, as this template is less common for the observers compared to the template for a cube with a FA perspective

Human Hsp70 and Hsp40 Chaperone Proteins Facilitate Human Papillomavirus-11 E1 Protein Binding to the Origin and Stimulate Cell-free DNA Replication

Human papillomavirus replication initiator, the E1 helicase, binds weakly to the origin of DNA replication. Purified human chaperone proteins Hsp70 and Hsp40 (HDJ-1 and HDJ-2) independently and additively enhanced E1 binding to the origin. The interaction between E1 and Hsp70 was transient and required ATP hydrolysis, whereas Hsp40 bound to E1 directly and remained in the complex. A peptide of 20 residues spanning the HPD loop and helix II of the J domain of YDJ-1 also stimulated E1 binding to the origin, alone or in combination with Hsp70 or Hsp40. A mutated peptide (H34Q) had a reduced activity, while an adjacent or an overlapping peptide had no effect. Neither Hsp70 nor the J peptide altered the E1/DNA ratio in the complex. Electron microscopy showed that E1 mainly bound to DNA as a hexamer. In the presence of Hsp40, E1 primarily bound to DNA as a dihexamer. Preincubation of chaperones with viral E1 and template shortened the lag time and increased replication in a cell-free system. Since two helicases are essential for bidirectional replication of human papillomavirus DNA, these results demonstrate that, as in prokaryotes, chaperones play an important role in the assembly of preinitiation complexes on the origin

Delay in Hospital Presentation Is the Main Reason Large Vessel Occlusion Stroke Patients Do Not Receive Intravenous Thrombolysis

OBJECTIVES: Intravenous thrombolysis (IVT) and endovascular therapy (EVT) are the mainstays of treatment for large vessel occlusion stroke (LVOS). Prior studies have examined why patients have not received IVT, the most cited reasons being last-known-well (LKW) to hospital arrival of \u3e4.5 hours and minor/resolving stroke symptoms. Given that LVOS patients typically present moderate-to-severe neurologic deficits, these patients should be easier to identify and treat than patients with minor strokes. This investigation explores why IVT was not administered to a cohort of LVOS patients who underwent EVT. METHODS: This is an analysis of the Optimizing the Use of Prehospital Stroke Systems of Care (OPUS-REACH) registry, which contains patients from 9 endovascular centers who underwent EVT between 2015 and 2020. The exposure of interest was the receipt of intravenous thrombolysis. Descriptive summary statistics are presented as means and SDs for continuous variables and as frequencies with percentages for categorical variables. Two-sample RESULTS: Two thousand forty-three patients were included and 60% did not receive IVT. The most common reason for withholding IVT was LKW to arrival of \u3e4.5 (57.2%). The second most common contraindication was oral anticoagulation (15.5%). On multivariable analysis, 2 factors were associated with not receiving IVT: increasing age (odds ratio [OR] 0.86; 95% confidence interval [CI] 0.78-0.93) and increasing time from LKW-to hospital arrival (OR 0.45 95% CI 0.46-0.49). CONCLUSION: Like prior studies, the most frequent reason for exclusion from IVT was a LKW to hospital presentation of \u3e4.5 hours; the second reason was anticoagulation. Efforts must be made to increase awareness of the time-sensitive nature of IVT and evaluate the safety of IVT in patients on oral anticoagulants

A Shorter Door-In-Door-Out Time Is Associated with Improved Outcome in Large Vessel Occlusion Stroke.

Introduction: Endovascular thrombectomy (EVT) significantly improves outcomes in large vessel occlusion stroke (LVOS). When a patient with a LVOS arrives at a hospital that does not perform EVT, emergent transfer to an endovascular stroke center (ESC) is required. Our objective was to determine the association between door-in-door-out time (DIDO) and 90-day outcomes in patients undergoing EVT. Methods: We conducted an analysis of the Optimizing Prehospital Stroke Systems of Care-Reacting to Changing Paradigms (OPUS-REACH) registry of 2,400 LVOS patients treated at nine ESCs in the United States. We examined the association between DIDO times and 90-day outcomes as measured by the modified Rankin scale. Results: A total of 435 patients were included in the final analysis. The mean DIDO time for patients with good outcomes was 17 minute shorter than patients with poor outcomes (122 minutes [min] vs 139 min, P = 0.04). Absolute DIDO cutoff times of ≤60 min, ≤90 min, or ≤120 min were not associated with improved functional outcomes (46.4 vs 32.3%, P = 0.12; 38.6 vs 30.6%, P = 0.10; and 36.4 vs 28.9%, P = 0.10, respectively). This held true for patients with hyperacute strokes of less than four-hour onset. Lower baseline National Institutes of Health Stroke Scale (NIHSS) score (11.9 vs 18.2, P = \u3c.001) and younger age (62.5 vs 74.9 years (P \u3c .001) were associated with improved outcomes. On multiple regression analysis, age (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.45-2.02) and baseline NIHSS score (OR 1.67, 95% CI 1.42-1.98) were associated with improved outcomes while DIDO time was not associated with better outcome (OR 1.13, 95% CI 0.99-1.30). Conclusion: Although the DIDO time was shorter for patients with a good outcome, this was non-significant in multiple regression analysis. Receipt of intravenous thrombolysis and time to EVT were not associated with better outcomes, while male gender, lower age, arrival by private vehicle, and lower NIHSS score portended better outcomes. No absolute DIDO-time cutoff or modifiable factor was associated with improved outcomes for LVOS. This study underscores the need to streamline DIDO times but not to set an artificial DIDO time benchmark to meet

Challenges in QCD matter physics - The Compressed Baryonic Matter experiment at FAIR

Substantial experimental and theoretical efforts worldwide are devoted to explore the phase diagram of strongly interacting matter. At LHC and top RHIC energies, QCD matter is studied at very high temperatures and nearly vanishing net-baryon densities. There is evidence that a Quark-Gluon-Plasma (QGP) was created at experiments at RHIC and LHC. The transition from the QGP back to the hadron gas is found to be a smooth cross over. For larger net-baryon densities and lower temperatures, it is expected that the QCD phase diagram exhibits a rich structure, such as a first-order phase transition between hadronic and partonic matter which terminates in a critical point, or exotic phases like quarkyonic matter. The discovery of these landmarks would be a breakthrough in our understanding of the strong interaction and is therefore in the focus of various high-energy heavy-ion research programs. The Compressed Baryonic Matter (CBM) experiment at FAIR will play a unique role in the exploration of the QCD phase diagram in the region of high net-baryon densities, because it is designed to run at unprecedented interaction rates. High-rate operation is the key prerequisite for high-precision measurements of multi-differential observables and of rare diagnostic probes which are sensitive to the dense phase of the nuclear fireball. The goal of the CBM experiment at SIS100 (sqrt(s_NN) = 2.7 - 4.9 GeV) is to discover fundamental properties of QCD matter: the phase structure at large baryon-chemical potentials (mu_B > 500 MeV), effects of chiral symmetry, and the equation-of-state at high density as it is expected to occur in the core of neutron stars. In this article, we review the motivation for and the physics programme of CBM, including activities before the start of data taking in 2022, in the context of the worldwide efforts to explore high-density QCD matter.Comment: 15 pages, 11 figures. Published in European Physical Journal

Comparison of endothelin receptors in normal versus cirrhotic human liver and in the liver from endothelial cell-specific ETB knockout mice

AbstractAimsEndothelin (ET) antagonists show promise in animal models of cirrhosis and portal hypertension. The aim was to pharmacologically characterise the expression of endothelin receptors in human liver, hepatic artery and portal vein.Main methodsImmunofluorescence staining, receptor autoradiography and competition binding assays were used to localise and quantify ET receptors on hepatic parenchyma, hepatic artery and portal vein in human cirrhotic or normal liver. Additional experiments were performed to determine the affinity and selectivity of ET antagonists for liver ET endothelin receptors. An endothelial cell ETB knockout murine model was used to examine the function of sinusoid endothelial ETB receptors.Key findingsETB receptors predominated in normal human liver and displayed the highest ratio (ETB:ETA 63:47) compared with other peripheral tissues. In two patients examined, liver ETB expression was up-regulated in cirrhosis (ETB:ETA 83:17). Both sub-types localised to the media of normal portal vein but ETB receptors were downregulated fivefold in the media of cirrhotic portal vein. Sinusoid diameter was fourfold smaller in endothelial cell ETB knockout mice. The liver morphology of ETB knockout mice was markedly different to normal murine liver, with loss of the wide spread sinusoidal pattern. In the knockout mice, sinusoids were reduced in both number and absolute diameter, while large intrahepatic veins were congested with red blood cells.SignificanceThese data support a role for the ET system in cirrhosis of the liver and suggest that endothelial ETB blockade may cause sinusoidal constriction which may contribute to hepatotoxicity associated with some endothelin antagonists

Synthesis of Tridentate Ligands and Their Platinum Complexes

Senior Project submitted to The Division of Science, Mathematics and Computing of Bard College

Monitoring Brain State and Behavioral Performance during Repetitive Visual Stimulation

We tested whether changes in prestimulus neural activity predict behavioral performance (decision time and errors) during a prolonged visual task. The task was to classify ambiguous stimuli—Necker cubes; manipulating the degree of ambiguity from low ambiguity (LA) to high ambiguity (HA) changed the task difficulty. First, we assumed that the observer’s state changes over time, which leads to a change in the prestimulus brain activity. Second, we supposed that the prestimulus state produces a different effect on behavioral performance depending on the task demands. Monitoring behavioral responses, we revealed that the observer’s decision time decreased for both LA and HA stimuli during the task performance. The number of perceptual errors lowered for HA, but not for LA stimuli. EEG analysis revealed an increase in the prestimulus 9–11 Hz EEG power with task time. Finally, we found associations between the behavioral and neural estimates. The prestimulus EEG power negatively correlated with the decision time for LA stimuli and the erroneous responses rate for HA stimuli. The obtained results confirm that monitoring prestimulus EEG power enables predicting perceptual performance on the behavioral level. The observed different time-on-task effects on the LA and HA stimuli processing may shed light on the features of ambiguous perception