Discovering Networks of Perturbed Biological Processes in Hepatocyte Cultures

The liver plays a vital role in glucose homeostasis, the synthesis of bile acids and the detoxification of foreign substances. Liver culture systems are widely used to test adverse effects of drugs and environmental toxicants. The two most prevalent liver culture systems are hepatocyte monolayers (HMs) and collagen sandwiches (CS). Despite their wide use, comprehensive transcriptional programs and interaction networks in these culture systems have not been systematically investigated. We integrated an existing temporal transcriptional dataset for HM and CS cultures of rat hepatocytes with a functional interaction network of rat genes. We aimed to exploit the functional interactions to identify statistically significant linkages between perturbed biological processes. To this end, we developed a novel approach to compute Contextual Biological Process Linkage Networks (CBPLNs). CBPLNs revealed numerous meaningful connections between different biological processes and gene sets, which we were successful in interpreting within the context of liver metabolism. Multiple phenomena captured by CBPLNs at the process level such as regulation, downstream effects, and feedback loops have well described counterparts at the gene and protein level. CBPLNs reveal high-level linkages between pathways and processes, making the identification of important biological trends more tractable than through interactions between individual genes and molecules alone. Our approach may provide a new route to explore, analyze, and understand cellular responses to internal and external cues within the context of the intricate networks of molecular interactions that control cellular behavior

Impaired Myocardial Calcium Uptake in Patients With Diabetes Mellitus: A Manganese-Enhanced Cardiac Magnetic Resonance Study

The pathophysiology of diabetic cardiomyopathy is complex and may involve dysregulated myocardial calcium uptake, which has been demonstrated in animal models.1 Manganese is a paramagnetic calcium analog for voltage-gated L-type calcium channels on cardiac myocytes, and manganese-enhanced cardiac magnetic resonance (CMR) provides a novel method of assessing myocardial calcium uptake in vivo.2 We aimed to determine whether myocardial calcium uptake is altered in people with type 1 or type 2 diabetes without cardiac disease. This was a prospective, 2-center, case-control study. We enrolled subjects with type 1 or type 2 diabetes, 18 to 75 years of age, with no prior history or symptoms of cardiac disease. Age-matched control volunteers without diabetes or known cardiac disease were recruited for comparison. Ethical approval was granted by the United Kingdom National Research Ethics Service (17/WM/0192, 20/NS/0037 and 20/WM/0304). Where applicable, subjects taking calcium-channel blockers withheld these medications 48 hours prior to study entry. All participants underwent manganese-enhanced CMR, performed using standardized imaging protocols on 3.0-T scanners. Initial imaging assessment of cardiac structure and function was performed with cine imaging. T1 mapping was then performed precontrast in a mid–short-axis slice position using a modified Look-Locker inversion recovery sequence (Siemens MyoMaps). An intravenous infusion of manganese dipyridoxyl diphosphate (5 μmol/kg [0.1 mL/kg] at 1 mL/min; Exova SL Pharma) was commenced and repeated T1 maps at the same location were performed every 2.5 minutes for 30 minutes. Image analysis was performed at a core laboratory blinded to all participant details. Cardiac chamber volumes, mass, and function were assessed using cvi42 software (v5.13.5; Circle CVI) as described previously.3 Participants with regional wall motion abnormalities or reduced left ventricular ejection fraction were excluded. For analysis of manganese uptake, regions of interest were drawn in the midventricular inferoseptal segment and the myocardial blood pool for all T1 maps from 0 to 30 minutes (Figure 1A).</p

Early Triassic Marine Biotic Recovery: The Predators' Perspective

Examining the geological past of our planet allows us to study periods of severe climatic and biological crises and recoveries, biotic and abiotic ecosystem fluctuations, and faunal and floral turnovers through time. Furthermore, the recovery dynamics of large predators provide a key for evaluation of the pattern and tempo of ecosystem recovery because predators are interpreted to react most sensitively to environmental turbulences. The end-Permian mass extinction was the most severe crisis experienced by life on Earth, and the common paradigm persists that the biotic recovery from the extinction event was unusually slow and occurred in a step-wise manner, lasting up to eight to nine million years well into the early Middle Triassic (Anisian) in the oceans, and even longer in the terrestrial realm. Here we survey the global distribution and size spectra of Early Triassic and Anisian marine predatory vertebrates (fishes, amphibians and reptiles) to elucidate the height of trophic pyramids in the aftermath of the end-Permian event. The survey of body size was done by compiling maximum standard lengths for the bony fishes and some cartilaginous fishes, and total size (estimates) for the tetrapods. The distribution and size spectra of the latter are difficult to assess because of preservation artifacts and are thus mostly discussed qualitatively. The data nevertheless demonstrate that no significant size increase of predators is observable from the Early Triassic to the Anisian, as would be expected from the prolonged and stepwise trophic recovery model. The data further indicate that marine ecosystems characterized by multiple trophic levels existed from the earliest Early Triassic onwards. However, a major change in the taxonomic composition of predatory guilds occurred less than two million years after the end-Permian extinction event, in which a transition from fish/amphibian to fish/reptile-dominated higher trophic levels within ecosystems became apparent