TY  - JOUR
A1  - Ulbricht, Andrea
A1  - Nickel, Lisa
A1  - Weidenbach, Katrin
A1  - Vargas Gebauer, Herman
A1  - Kießling, Claudia
A1  - Förstner, Konrad U.
A1  - Schmitz, Ruth A.
T1  - The CARF protein MM_0565 affects transcription of the casposon-encoded cas1-solo gene in Methanosarcina mazei Gö1
JF  - Biomolecules
N2  - Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) loci are found in bacterial and archaeal genomes where they provide the molecular machinery for acquisition of immunity against foreign DNA. In addition to the cas genes fundamentally required for CRISPR activity, a second class of genes is associated with the CRISPR loci, of which many have no reported function in CRISPR-mediated immunity. Here, we characterize MM_0565 associated to the type I-B CRISPR-locus of Methanosarcina mazei Gö1. We show that purified MM_0565 composed of a CRISPR-Cas Associated Rossmann Fold (CARF) and a winged helix-turn-helix domain forms a dimer in solution; in vivo, the dimeric MM_0565 is strongly stabilized under high salt stress. While direct effects on CRISPR-Cas transcription were not detected by genetic approaches, specific binding of MM_0565 to the leader region of both CRISPR-Cas systems was observed by microscale thermophoresis and electromobility shift assays. Moreover, overexpression of MM_0565 strongly induced transcription of the cas1-solo gene located in the recently reported casposon, the gene product of which shows high similarity to classical Cas1 proteins. Based on our findings, and taking the absence of the expressed CRISPR locus-encoded Cas1 protein into account, we hypothesize that MM_0565 might modulate the activity of the CRISPR systems on different levels.
KW  - methanoarchaea
KW  - CRISPR-Cas system
KW  - transcriptional regulation
KW  - adaptation phase
KW  - casposon
KW  - Methanosarcina mazei
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-211097
SN  - 2218-273X
VL  - 10
IS  - 8
ER  - 
TY  - JOUR
A1  - Linz, Benedikt
A1  - Hohl, Mathias
A1  - Lang, Lisa
A1  - Wong, Dickson W. L.
A1  - Nickel, Alexander G.
A1  - De La Torre, Carolina
A1  - Sticht, Carsten
A1  - Wirth, Klaus
A1  - Boor, Peter
A1  - Maack, Christoph
A1  - Speer, Thimoteus
A1  - Jespersen, Thomas
A1  - Schotten, Ulrich
A1  - Sanders, Prashanthan
A1  - Böhm, Michael
A1  - Linz, Dominik
T1  - Repeated exposure to transient obstructive sleep apnea–related conditions causes an atrial fibrillation substrate in a chronic rat model
JF  - Heart Rhythm
N2  - Background
High night-to-night variability in obstructive sleep apnea (OSA) is associated with atrial fibrillation (AF). Obstructive apneas are characterized by intermittent deoxygenation-reoxygenation and intrathoracic pressure swings during ineffective inspiration against occluded upper airways.

Objective
We elucidated the effect of repeated exposure to transient OSA conditions simulated by intermittent negative upper airway pressure (INAP) on the development of an AF substrate.

Methods
INAP (48 events/4 h; apnea-hypopnea index 12 events/h) was applied in sedated spontaneously breathing rats (2% isoflurane) to simulate mild-to-moderate OSA. Rats without INAP served as a control group (CTR). In an acute test series (ATS), rats were either killed immediately (n = 9 per group) or after 24 hours of recovery (ATS-REC: n = 5 per group). To simulate high night-to-night variability in OSA, INAP applications (n = 10; 24 events/4 h; apnea-hypopnea index 6/h) were repeated every second day for 3 weeks in a chronic test series (CTS).

Results
INAP increased atrial oxidative stress acutely, represented in decreases of reduced to oxidized glutathione ratio (ATS: INAP: 0.33 ± 0.05 vs CTR: 1 ± 0.26; P = .016), which was reversible after 24 hours (ATS-REC: INAP vs CTR; P = .274). Although atrial oxidative stress did not accumulate in the CTS, atrial histological analysis revealed increased cardiomyocyte diameters, reduced connexin 43 expression, and increased interstitial fibrosis formation (CTS: INAP 7.0% ± 0.5% vs CTR 5.1% ± 0.3%; P = .013), which were associated with longer inducible AF episodes (CTS: INAP: 11.65 ± 4.43 seconds vs CTR: 0.7 ± 0.33 seconds; P = .033).

Conclusion
Acute simulation of OSA was associated with reversible atrial oxidative stress. Cumulative exposure to these transient OSA-related conditions resulted in AF substrates and was associated with increased AF susceptibility. Mild-to-moderate OSA with high night-to-night variability may deserve intensive management to prevent atrial substrate development.
KW  - atrial fibrillation
KW  - night-to-night variability
KW  - obstructive sleep apnea
KW  - rats
KW  - substrate
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369298
VL  - 18
ER  -