TY  - JOUR
A1  - Zirkel, J.
A1  - Cecil, A.
A1  - Schäfer, F.
A1  - Rahlfs, S.
A1  - Ouedraogo, A.
A1  - Xiao, K.
A1  - Sawadogo, S.
A1  - Coulibaly, B.
A1  - Becker, K.
A1  - Dandekar, T.
T1  - Analyzing Thiol-Dependent Redox Networks in the Presence of Methylene Blue and Other Antimalarial Agents with RT-PCR-Supported in silico Modeling
JF  - Bioinformatics and Biology Insights
N2  - BACKGROUND: In the face of growing resistance in malaria parasites to drugs, pharmacological combination therapies are important. There is accumulating evidence that methylene blue (MB) is an effective drug against malaria. Here we explore the biological effects of both MB alone and in combination therapy using modeling and experimental data.
RESULTS: We built a model of the central metabolic pathways in P. falciparum. Metabolic flux modes and their changes under MB were calculated by integrating experimental data (RT-PCR data on mRNAs for redox enzymes) as constraints and results from the YANA software package for metabolic pathway calculations. Several different lines of MB attack on Plasmodium redox defense were identified by analysis of the network effects. Next, chloroquine resistance based on pfmdr/and pfcrt transporters, as well as pyrimethamine/sulfadoxine resistance (by mutations in DHF/DHPS), were modeled in silico. Further modeling shows that MB has a favorable synergism on antimalarial network effects with these commonly used antimalarial drugs.
CONCLUSIONS: Theoretical and experimental results support that methylene blue should, because of its resistance-breaking potential, be further tested as a key component in drug combination therapy efforts in holoendemic areas.
KW  - methylene blue
KW  - malaria
KW  - elementary mode analysis
KW  - drug
KW  - resistance
KW  - combination therapy
KW  - pathway
KW  - metabolic flux
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123751
N1  - This is an open access article. Unrestricted non-commercial use is permitted provided the original work is properly cited.
VL  - 6
ER  - 
TY  - JOUR
A1  - Deane, Katrina E.
A1  - Brunk, Michael G. K.
A1  - Curran, Andrew W.
A1  - Zempeltzi, Marina M.
A1  - Ma, Jing
A1  - Lin, Xiao
A1  - Abela, Francesca
A1  - Aksit, Sümeyra
A1  - Deliano, Matthias
A1  - Ohl, Frank W.
A1  - Happel, Max F. K.
T1  - Ketamine anaesthesia induces gain enhancement via recurrent excitation in granular input layers of the auditory cortex
JF  - The Journal of Physiology
N2  - Ketamine is commonly used as an anaesthetic agent and has more recently gained attention as an antidepressant. It has been linked to increased stimulus‐locked excitability, inhibition of interneurons and modulation of intrinsic neuronal oscillations. However, the functional network mechanisms are still elusive. A better understanding of these anaesthetic network effects may improve upon previous interpretations of seminal studies conducted under anaesthesia and have widespread relevance for neuroscience with awake and anaesthetized subjects as well as in medicine. Here, we investigated the effects of anaesthetic doses of ketamine (15 mg kg\(^{-1}\) h\(^{-1}\)i.p.) on the network activity after pure‐tone stimulation within the auditory cortex of male Mongolian gerbils (Meriones unguiculatus). We used laminar current source density (CSD) analysis and subsequent layer‐specific continuous wavelet analysis to investigate spatiotemporal response dynamics on cortical columnar processing in awake and ketamine‐anaesthetized animals. We found thalamocortical input processing within granular layers III/IV to be significantly increased under ketamine. This layer‐dependent gain enhancement under ketamine was not due to changes in cross‐trial phase coherence but was rather attributed to a broadband increase in magnitude reflecting an increase in recurrent excitation. A time–frequency analysis was indicative of a prolonged period of stimulus‐induced excitation possibly due to a reduced coupling of excitation and inhibition in granular input circuits – in line with the common hypothesis of cortical disinhibition via suppression of GABAergic interneurons.
KW  - auditory cortex
KW  - continuous wavelet analysis
KW  - current source density
KW  - ketamine anaesthesia
KW  - laminar recording
KW  - mesoscopic
KW  - microcircuitry
KW  - population dynamics
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-216123
VL  - 598
IS  - 13
SP  - 2741
EP  - 2755
ER  - 
TY  - JOUR
A1  - Liu, Fengming
A1  - Han, Kun
A1  - Blair, Robert
A1  - Kenst, Kornelia
A1  - Qin, Zhongnan
A1  - Upcin, Berin
A1  - Wörsdörfer, Philipp
A1  - Midkiff, Cecily C.
A1  - Mudd, Joseph
A1  - Belyaeva, Elizaveta
A1  - Milligan, Nicholas S.
A1  - Rorison, Tyler D.
A1  - Wagner, Nicole
A1  - Bodem, Jochen
A1  - Dölken, Lars
A1  - Aktas, Bertal H.
A1  - Vander Heide, Richard S.
A1  - Yin, Xiao-Ming
A1  - Kolls, Jay K.
A1  - Roy, Chad J.
A1  - Rappaport, Jay
A1  - Ergün, Süleyman
A1  - Qin, Xuebin
T1  - SARS-CoV-2 Infects Endothelial Cells In Vivo and In Vitro
JF  - Frontiers in Cellular and Infection Microbiology
N2  - SARS-CoV-2 infection can cause fatal inflammatory lung pathology, including thrombosis and increased pulmonary vascular permeability leading to edema and hemorrhage. In addition to the lung, cytokine storm-induced inflammatory cascade also affects other organs. SARS-CoV-2 infection-related vascular inflammation is characterized by endotheliopathy in the lung and other organs. Whether SARS-CoV-2 causes endotheliopathy by directly infecting endothelial cells is not known and is the focus of the present study. We observed 1) the co-localization of SARS-CoV-2 with the endothelial cell marker CD31 in the lungs of SARS-CoV-2-infected mice expressing hACE2 in the lung by intranasal delivery of adenovirus 5-hACE2 (Ad5-hACE2 mice) and non-human primates at both the protein and RNA levels, and 2) SARS-CoV-2 proteins in endothelial cells by immunogold labeling and electron microscopic analysis. We also detected the co-localization of SARS-CoV-2 with CD31 in autopsied lung tissue obtained from patients who died from severe COVID-19. Comparative analysis of RNA sequencing data of the lungs of infected Ad5-hACE2 and Ad5-empty (control) mice revealed upregulated KRAS signaling pathway, a well-known pathway for cellular activation and dysfunction. Further, we showed that SARS-CoV-2 directly infects mature mouse aortic endothelial cells (AoECs) that were activated by performing an aortic sprouting assay prior to exposure to SARS-CoV-2. This was demonstrated by co-localization of SARS-CoV-2 and CD34 by immunostaining and detection of viral particles in electron microscopic studies. Moreover, the activated AoECs became positive for ACE-2 but not quiescent AoECs. Together, our results indicate that in addition to pneumocytes, SARS-CoV-2 also directly infects mature vascular endothelial cells in vivo and ex vivo, which may contribute to cardiovascular complications in SARS-CoV-2 infection, including multipleorgan failure.
KW  - endothelial cell infection
KW  - animal models
KW  - SARS-CoV-2
KW  - aorta ring
KW  - hACE2
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241948
SN  - 2235-2988
VL  - 11
ER  -