Baikal-GVD: status and prospects

Baikal-GVD is a next generation, kilometer-scale neutrino telescope under construction in Lake Baikal. It is designed to detect astrophysical neutrino fluxes at energies from a few TeV up to 100 PeV. GVD is formed by multi-megaton subarrays (clusters). The array construction started in 2015 by deployment of a reduced-size demonstration cluster named "Dubna". The first cluster in its baseline configuration was deployed in 2016, the second in 2017 and the third in 2018. The full scale GVD will be an array of ~10000 light sensors with an instrumented volume of about 2 cubic km. The first phase (GVD-1) is planned to be completed by 2020-2021. It will comprise 8 clusters with 2304 light sensors in total. We describe the design of Baikal-GVD and present selected results obtained in 2015-2017.Comment: 9 pages, 8 figures. Conference proceedings for QUARKS201

Mitochondrial respiration and membrane potential after low-flow ischemia are not affected by ischemic preconditioning

Mitochondrial function following prolonged ischemia and subsequent reperfusion is better preserved by ischemic preconditioning (IP). In the present study, we analyzed whether or not IP has an impact on mitochondrial function at the end of a sustained ischemic period. G\uf6ttinger minipigs were subjected to 90-min low-flow ischemia without (n=5) and with (n=5) a preconditioning cycle of 10-min ischemia and 15-min reperfusion. Mitochondria were isolated from the ischemic or preconditioned anterior wall (AW) and the control posterior wall (PW) at the end of ischemia. Basal mitochondrial respiration was not different between AW and PW. The ADP-stimulated (state 3) respiration in AW mitochondria compared to PW mitochondria was equally decreased in non-preconditioned and preconditioned pigs. The uncoupled respiration as well as the membrane potential (rhodamine 123 fluorescence) were not significantly different between groups. However, the recovery of the membrane potential (Delta rhodamine 123 fluorescence/s) after the addition of ADP was delayed in mitochondria obtained from AW compared to PW, both in non-preconditioned and in preconditioned pig hearts. Neither the amount of marker proteins for complexes of the electron transport chain nor the level of reactive oxygen species were affected by ischemia without or with IP. State 3 respiration and recovery of membrane potential were impaired in pig mitochondria after 90 min of low-flow ischemia. IP did not improve mitochondrial function during ischemia. Therefore, the preservation of mitochondrial function by IP may occur during reperfusion rather than during the sustained ischemic period

Oxidative modification of tropomyosin and myocardial dysfunction following coronary microembolization

AIMS: We addressed a potential mechanism of myocardial dysfunction following coronary microembolization at the level of myofibrillar proteins. METHODS AND RESULTS: Anaesthetized pigs underwent intracoronary infusion of microspheres. After 6 h, the microembolized areas (MEA) had decreased systolic wall thickening to 38 +/- 7% of baseline and a 2.62 +/- 0.40-fold increase in the formation of disulphide cross-bridges (DCB) in tropomyosin relative to that in remote areas. The impairment in contractile function correlated inversely with DCB formation (r = -0.68; P = 0.015) and was associated with increased TNF-alpha content. DCB formation was reflected by increased tropomyosin immunoreactivity and abolished in vitro by dithiothreitol. Ascorbic acid prevented contractile dysfunction as well as increased DCB and TNF-alpha. In anaesthetized dogs, 8 h after intracoronary microspheres infusion, contractile function was reduced to 8+/-10% of baseline and DCB in MEA was 1.48+/-0.12 higher than that in remote areas. In conscious dogs, 6 days after intracoronary microspheres infusion, myocardial function had returned to baseline and DCB was no longer different between remote and MEA. Again contractile function correlated inversely with DCB formation (r = -0.83; P = 0.005). CONCLUSION: Myofibrillar protein oxidation may represent a mechanistic link between inflammation and contractile dysfunction following coronary microembolization

Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning

OBJECTIVE: Connexin 43 (Cx43) is involved in infarct size reduction by ischemic preconditioning (IP); the underlying mechanism of protection, however, is unknown. Since mitochondria have been proposed to be involved in IP's protection, the present study analyzed whether Cx43 is localized at mitochondria of cardiomyocytes and whether such localization is affected by IP. METHODS AND RESULTS: Western blot analysis on mitochondrial preparations isolated from rat, mouse, pig, and human hearts showed the presence of Cx43. The preparations were not contaminated with markers for other cell compartments. The localization of Cx43 to mitochondria was also confirmed by FACS sorting (double staining with MitoTracker Red and Cx43) and immuno-electron and confocal microscopy. To study the role of Cx43 in IP, mitochondria were isolated from the ischemic anterior wall (AW) and the control posterior wall (PW) of pig myocardium at the end of 90 min low-flow ischemia without (n=13) or with (n=13) a preceding preconditioning cycle of 10 min ischemia and 15 min reperfusion. With IP, the mitochondrial Cx43/adenine nucleotide transporter ratio was 3.4+/-0.7 fold greater in AW than in PW, whereas the ratio remained unchanged in non-preconditioned myocardium (1.1+/-0.2, p<0.05). The enhancement of the mitochondrial Cx43 protein level occurred rapidly, since an increase of mitochondrial Cx43 was already detected with two cycles of 5 min ischemia/reperfusion in isolated rat hearts to 262+/-63% of baseline. CONCLUSION: These data demonstrate that Cx43 is localized at cardiomyocyte mitochondria and that IP enhances such mitochondrial localization

A hypomorphic mutation in lpin1 induces progressively improving peripheral neuropathy in the rat

The Lpin1 gene encodes the phosphatidate phosphatase (PAP1) enzyme Lipin 1, which plays a critical role in lipid metabolism. In this study we describe the identification and characterization of a rat with a mutated Lpin1 gene (Lpin11Hubr ), generated by N-ethyl-N-nitrosourea mutagenesis. Lpin11Hubr rats are characterized by hindlimb paralysis that is detectable from the second postnatal week. Sequencing of Lpin1 identified a missense mutation in the 5'-end splice site of exon 18 resulting in mis-splicing, a reading frame shift and a premature stop codon. As this mutation does not induce nonsense-mediated decay, it allows the production of a truncated Lipin 1 protein lacking PAP1 activity. As a consequence, Lpin11Hubr rats develop hypomyelination rather than the pronounced demyelination defect characteristic of Lpin1fld/fld mice, which carry a null allele for Lpin1. Furthermore, histological and molecular analyses revealed that this lesion improve in older Lpin11Hubr rats as compared to young Lpin11Hubr rats and Lpin1fld/fld mice. The observed differences between the murine Lpin1fld/fld mutant, with a complete loss of Lipin 1 function, and the Lpin1Hubr rat, with a truncated PAP1 activitydeficient form of Lipin 1, provide additional evidence for suggested non-enzymatic Lipin1 function residing outside of its PAP1 domain. While we are cautious in making a direct parallel between the presented rodent model and human disease, our data may provide new insight into pathogenicity of recently identified human Lpin1 mutations. *These authors contributed equally