We present HepatoNet1, a manually curated large-scale metabolic network of the human hepatocyte that encompasses >2500 reactions in six intracellular and two extracellular compartments.Using constraint-based modeling techniques, the network has been validated to replicate numerous metabolic functions of hepatocytes corresponding to a reference set of diverse physiological liver functions.Taking the detoxification of ammonia and the formation of bile acids as examples, we show how these liver-specific metabolic objectives can be achieved by the variable interplay of various metabolic pathways under varying conditions of nutrients and oxygen availability.

for the Berlin_PRehospital Or Usual Delivery in stroke care (B_PROUD) study group IMPORTANCE Effects of thrombolysis in acute ischemic stroke are time-dependent. Ambulances that can administer thrombolysis (mobile stroke units [MSUs]) before arriving at the hospital have been shown to reduce time to treatment. OBJECTIVE To determine whether dispatch of MSUs is associated with better clinical outcomes for patients with acute ischemic stroke. DESIGN, SETTING, AND PARTICIPANTSThis prospective, nonrandomized, controlled intervention study was conducted in Berlin, Germany, from February 1, 2017, to October 30, 2019. If an emergency call prompted suspicion of stroke, both a conventional ambulance and an MSU, when available, were dispatched. Functional outcomes of patients with final diagnosis of acute cerebral ischemia who were eligible for thrombolysis or thrombectomy were compared based on the initial dispatch (both MSU and conventional ambulance or conventional ambulance only).EXPOSURE Simultaneous dispatch of an MSU (computed tomographic scanning with or without angiography, point-of-care laboratory testing, and thrombolysis capabilities on board) and a conventional ambulance (n = 749) vs conventional ambulance alone (n = 794). MAIN OUTCOMES AND MEASURESThe primary outcome was the distribution of modified Rankin Scale (mRS) scores (a disability score ranging from 0, no neurological deficits, to 6, death) at 3 months. The coprimary outcome was a 3-tier disability scale at 3 months (none to moderate disability; severe disability; death) with tier assignment based on mRS scores if available or place of residence if mRS scores were not available. Common odds ratios (ORs) were used to quantify the association between exposure and outcome; values less than 1.00 indicated a favorable shift in the mRS distribution and lower odds of higher levels of disability. RESULTSOf the 1543 patients (mean age, 74 years; 723 women [47%]) included in the adjusted primary analysis, 1337 (87%) had available mRS scores (primary outcome) and 1506 patients (98%) had available the 3-tier disability scale assessment (coprimary outcome). Patients with an MSU dispatched had lower median mRS scores at month 3 (1; interquartile range [IQR], 0-3) than did patients without an MSU dispatched (2; IQR, 0-3; common OR for worse mRS, 0.71; 95% CI, 0.58-0.86; P < .001). Similarly, patients with an MSU dispatched had lower 3-month coprimary disability scores: 586 patients (80.3%) had none to moderate disability; 92 (12.6%) had severe disability; and 52 (7.1%) had died vs patients without an MSU dispatched: 605 (78.0%) had none to moderate disability; 103 (13.3%) had severe disability; and 68 (8.8%) had died (common OR for worse functional outcome, 0.73, 95% CI, 0.54-0.99; P = .04). CONCLUSIONS AND RELEVANCEIn this prospective, nonrandomized, controlled intervention study of patients with acute ischemic stroke in Berlin, Germany, the dispatch of mobile stroke units, compared with conventional ambulances alone, was significantly associated with lower global ...

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Background and Purpose-Changes in the blood-oxygen-level-dependent (BOLD) signal provide a noninvasive measure of blood flow, but a detailed comparison with established perfusion parameters in acute stroke is lacking. We investigated the relationship between BOLD signal temporal delay and dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) in stroke patients. Methods-In 30 patients with acute (<24 hours) ischemic stroke, we performed Pearson correlation and multiple linear regression between DSC-MRI parameters (time to maximum [Tmax], mean transit time, cerebral blood flow, and cerebral blood volume) and BOLD-based parameters (BOLD delay and coefficient of BOLD variation). Prediction of severe hypoperfusion (Tmax >6 seconds) was assessed using receiver-operator characteristic (ROC) analysis. Results-Correlation was highest between Tmax and BOLD delay (venous sinus reference; time shift range 7; median r=0.60; interquartile range=0.49-0.71). Coefficient of BOLD variation correlated with cerebral blood volume (median r= 0.37; interquartile range=0.24-0.51). Mean R 2 for predicting BOLD delay by DSC-MRI was 0.54 (SD=0.2) and for predicting coefficient of BOLD variation was 0.37 (SD=0.17). BOLD delay (whole-brain reference, time shift range 3) had an area under the curve of 0.76 for predicting severe hypoperfusion (sensitivity=69.2%; specificity=80%), whereas BOLD delay (venous sinus reference, time shift range 3) had an area under the curve of 0.76 (sensitivity=67.3%; specificity=83.5%). Conclusions-BOLD delay is related to macrovascular delay and microvascular hypoperfusion, can identify severely hypoperfused tissue in acute stroke, and is a promising alternative to gadolinium contrast agent-based perfusion assessment in acute stroke. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00715533 and NCT02077582.