Treatment of Porphyromonas gulae infection and downstream pathology in the aged dog by lysine-gingipain inhibitor COR388.

COR388, a small-molecule lysine-gingipain inhibitor, is currently being investigated in a Phase 2/3 clinical trial for Alzheimer's disease (AD) with exploratory endpoints in periodontal disease. Gingipains are produced by two species of bacteria, Porphyromonas gingivalis and Porphyromonas gulae, typically associated with periodontal disease and systemic infections in humans and dogs, respectively. P. gulae infection in dogs is associated with periodontal disease, which provides a physiologically relevant model to investigate the pharmacology of COR388. In the current study, aged dogs with a natural oral infection of P. gulae and periodontal disease were treated with COR388 by oral administration for up to 90 days to assess lysine-gingipain target engagement and reduction of bacterial load and downstream pathology. In a 28-day dose-response study, COR388 inhibited the lysine-gingipain target and reduced P. gulae load in saliva, buccal cells, and gingival crevicular fluid. The lowest effective dose was continued for 90 days and was efficacious in continuous reduction of bacterial load and downstream periodontal disease pathology. In a separate histology study, dog brain tissue showed evidence of P. gulae DNA and neuronal lysine-gingipain, demonstrating that P. gulae infection is systemic and spreads beyond its oral reservoir, similar to recent observations of P. gingivalis in humans. Together, the pharmacokinetics and pharmacodynamics of COR388 lysine-gingipain inhibition, along with reduction of bacterial load and periodontal disease in naturally occurring P. gulae infection in the dog, support the use of COR388 in targeting lysine-gingipain and eliminating P. gingivalis infection in humans

Ceramide-induced BOK promotes mitochondrial fission in preeclampsia

Mitochondria are in a constant balance of fusing and dividing in response to cellular cues. Fusion creates healthy mitochondria, whereas fission results in removal of non-functional organelles. Changes in mitochondrial dynamics typify several human diseases. However, the contribution of mitochondrial dynamics to preeclampsia, a hypertensive disorder of pregnancy characterized by placental cell autophagy and death, remains unknown. Herein, we show that the mitochondrial dynamic balance in preeclamptic placentae is tilted toward fission (increased DRP1 expression/activation and decreased OPA1 expression). Increased phosphorylation of DRP1 (p-DRP1) in mitochondrial isolates from preeclamptic placentae and transmission electron microscopy corroborated augmented mitochondrial fragmentation in cytotrophoblast cells of PE placentae. Increased fission was accompanied by build-up of ceramides (CERs) in mitochondria from preeclamptic placentae relative to controls. Treatment of human choriocarcinoma JEG3 cells and primary isolated cytrophoblast cells with CER 16:0 enhanced mitochondrial fission. Loss- and gain-of-function experiments showed that Bcl-2 member BOK, whose expression is increased by CER, positively regulated p-DRP1/DRP1 and MFN2 expression, and localized mitochondrial fission events to the ER/MAM compartments. We also identified that the BH3 and transmembrane domains of BOK were vital for BOK regulation of fission. Moreover, we found that full-length PTEN-induced putative kinase 1 (PINK1) and Parkin, were elevated in mitochondria from PE placentae, implicating mitophagy as the process that degrades excess mitochondria fragments produced from CER/BOK-induced fission in preeclampsia. In summary, our study uncovered a novel CER/BOK-induced regulation of mitochondrial fission and its functional consequence for heightened trophoblast cell autophagy in preeclampsia

Present status and preliminary results of the VLF/LF radio recording European network installed in 2009.

In January 2009 a European network of receivers able to measure the electric field intensity from various VLF/LF broadcasting stations located throughout Europe, was installed. Five new receivers constructed by an Italian enterprise have been delivered to Greece, Romania, Turkey and to the Italian team. The motivation of this effort is to study the possible connections between the preparatory phase of earthquakes and perturbations in the transmitted radio signals. The receivers can be reached via ftp and gsm mobile connection, thus allowing a real time data collection. We present here the status of the network and the various testing steps performed in order to achieve a correct set up. We show how antennas variations, receivers locations and changes of selected frequencies affect the performances of the whole network. After this necessary testing period, several LF/VLF radio signals are now simultaneously and continuously being sampled by the five receivers. As a preliminary result we inspect also specific cases in which an anomaly in the radio signals is clearly related to the transmitter or to the receiver (e.g. meteorological conditions around the sampling site). At a basic level, the analysis adopted consists in a simple statistical evaluation of the signals by comparing the instantaneous values to the trend of the signal

Disturbances in groundwater chemical parameters related to seismic and volcanic activity in Kamchatka (Russia)

International audienceStarting from 1992 geochemical data are being collected with a mean sampling frequency of three days in the form of the pH value and of the most common ions and gases in the groundwater in one deep well located in Petropavlovsk, the capital city of Kamchatka (Russia). On 1 January 1996 a strong eruption started from the Karymsky volcano, that is located about 100km far from the well, in the north-northeastern direction. At the same time, a large earthquake (M=6.9) occurred in the Karymsky area. On 5 December 1997 a very large earthquake (M=7.7) occurred offshore, at a distance of 350km from the well and towards the same direction. The analysis of the geochemical data shows clear variations in the raw temporal trends on both cases. For the first event, a clear premonitory phase appeared; for the second one, some pre-seismic variations could be revealed but permanent modifications of the chemistry of the water subsequent to the earthquake are very clear. In both cases the feature of the geochemical variations is consistent with an afflux of new water in the aquifer connected with the well and with an escape of the Carbon dioxide gas from the ground in different directions. A schematic model able to justify such a phenomenology and the connections of the geochemical variations with the previous tectonic activities is proposed

A possible radio anomaly observed on the occasion of the MW=6.0 earthquake occurred in Dodecanese islands at the end of January 2020

Since 2009, several VLF/LF radio receivers have been installed throughout Europe in order to realize a European radio network for studying the radio precursors of earthquakes, called the INFREP network. The current network has nine VLF/LF receiving stations, two in Romania and Greece, one in Italy, Austria, Portugal, Cyprus, and Serbia. The receivers can measure with 1 min sampling rate the intensity of 10 radio signals in the band VLF (10-50 kHz) and LF (150-300 kHz). The scope of existing transmitters is manifold, e.g. they are used for radio broadcast (LF), for radio- navigation or time signals and mainly for military purposes in the VLF range. At the end of January 2020 an intense seismic crisis occurred in Dodecanese Islands; the main event (Mw= 6.0) occurred on January 30. This seismic activity occurred in the "sensitive" area of the INFREP network. The analysis of the data collected by INFREP receivers has revealed clear anomalies in three VLF signals appearing some days before the main earthquake. The anomalies appear in the trends collected by the Cyprus receiver and the epicenter is inside the 5th Fresnel ellipses defined by transmitters- receiver. Here we report the data analysis and we present in detail the anomalies. The possibility that they are precursors of the quoted earthquake seems significant. Biagi, P.F., Colella, R., Schiavulli, L., Ermini, A., Boudjada, M., Eichelberger, H., Schwingenschuh, K., Katzis, K., Contadakis, M.E., Skeberis, C., Moldovan, I.A. and Bezzeghoud, M. (2019) The INFREP Network: Present Situation and Recent Results. Open Journal of Earthquake Research,8, 101-115. https://doi.org/10.4236/ojer.2019.8200

Retrospective analysis for detecting seismic precursors in groundwater argon content

We examined the groundwater Argon content data sampled from 1988 to 2001 at two wells in Kamchatka (Russia) and anomalous increases appeared clearly during June-July&nbsp;1996. On 21&nbsp;June, a shallow (1km) earthquake with <i>M</i>=7.1 occurred at a distance less than 250km from the wells and so the previous increases could be related to this earthquake and, in particular, could be considered premonitory anomalies. In order to support this raw interpretation, we analysed the data collected in details. At first we smoothed out the high frequency fluctuations arising from the errors in a single measurement. Next we considered the known external effects on the water of a well that are the slow tectonic re-adjustment processes, the meteorology and the gravity tides and we separated these effects applying band-pass filters to the Argon content raw trends. Then we identified the largest fluctuations in these trends applying the 3 σ criterion and we found three anomalies in a case and two anomalies in other case. Comparing the time occurrence of the anomalies at the two wells we found out that a coincidence exists only in the case of the premonitory anomalies we are studying. The simultaneous appearance of well definite anomalies in the residual trends of the same parameter at two different sites supports their meaning and the possibility that they are related to some large scale effect, as the occurrence of a strong earthquake. But, other earthquakes similar to the June&nbsp;1996 event took place during the Argon content measurements time and no anomaly appeared in this content. In the past, some of the authors of this paper studied the Helium content data collected in three natural springs of the Caucasus during seven years. A very similar result, that is the simultaneous appearance of clear premonitory anomalies only on the occasion of a strong (<i>M</i>=7.0) but shallow (2–4km) earthquake, was obtained. The correspondence with the case of the Caucasus validates the interpretation of the Kamchatkian anomalies as precursors

North Atlantic mid-latitude surface-circulation changes through the Plio-Pleistocene intensification of northern hemisphere glaciation

This is the final version. Available from American Geophysical Union (AGU) / Wiley via the DOI in this record.All new data presented are available at https://doi.pangaea.de/10.1594/PANGAEA.892805The North Atlantic Current (NAC) transports warm salty water to high northern latitudes, with important repercussions for ocean circulation and global climate. A southward displacement of the NAC and Subarctic Front, which separate subpolar and subtropical water masses, is widely suggested for the last glacial maximum (LGM) and may have acted as a positive feedback in glacial expansion at this time. However, the role of the NAC during the intensification of northern hemisphere glaciation (iNHG) ~3.5 to 2.5 Ma, is less clear. Here, we present new records from IODP Site U1313 (41°N) spanning ~2.8-2.4 Ma to trace the influence of Subarctic Front waters above this mid-latitude site. We reconstruct surface and permanent pycnocline temperatures and seawater δ18O using paired Mg/Ca-δ18O measurements on the planktic foraminifers Globigerinoides ruber and Globorotalia crassaformis, and determine abundances of the subpolar foraminifer Neogloboquadrina atlantica. We find that the first significant glacial incursions of Subarctic Front surface waters above Site U1313 did not occur until ~2.6 Ma. At no time during our study interval was (sub)surface reorganisation in the mid-latitude North Atlantic analogous to the LGM. Our findings suggest that LGM-like processes sensu stricto cannot be invoked to explain interglacial-glacial cycle amplification during iNHG. They also imply that increased glacial productivity at Site U1313 during iNHG was not only driven by southward deflections of the Subarctic Front. We suggest nutrient injection from cold-core eddies and enhanced glacial dust delivery may have played additional roles in increasing export productivity in the mid-latitude North Atlantic from 2.7 Ma.Funding for this research was provided by IODP France (CTB) and the German Research Foundation (DFG) (grant OF 2544/2 to OF). IB is grateful to the UK IODP for financial support for shipboard and post-cruise participation in IODP Exp. 306. CTB, KT, TDG, LV, CS, and ME acknowledge OSU Pythéas. MMR acknowledges support by the USGS Land Change Science Program. Any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the U.S. Government. PAW acknowledges NERC UK IODP NE/F00141X/1 and a Royal Society Wolfson Merit Award

Ray paths of VLF/LF transmitter radio signals in the seismic Adriatic regions

We analyze the radio wave propagations of VLF/LF transmitter signals along subionospheric paths using two different reception systems localized in the Graz seismo-electromagnetic facility (15.43E,47.06N). Those systems allow the simultaneous detection of more than fifteen transmitter signals emitting in the northern (i.e. France, Germany and United Kingdom) and southern (i.e. Italy and Turkey) parts of Europe. In this work, we investigate the transmitter radio wave propagations associated with two earthquakes (EQs) which occurred, at two occasions, in nearly the same Croatian regions (Geo. Long.=16°E; Geo. Lat.=45°N). The first and second EQs happened, respectively, on March 22 and December 29, 2020, with magnitudes Mw equal to 5.4 and 6.4. The use of two complementary reception systems, i.e. INFREP (Biagi et al., Open Journal of Earthquake Research, 8, 2019) and UltraMSK (Schwingenschuh et al., Nat. Hazards Earth Syst. Sci., 11, 2011), and the proximity to the epicenters lead us to characterize the behavior of the transmitter signal amplitudes particularly above the Croatian seismic regions. We analyze the amplitude variation for a given transmitter frequency starting few weeks before the earthquakes occurrences. We discuss the observed anomalies in the transmitter signals which may be considered as precursors due to the ionospheric disturbances of the transmitter ray paths above the earthquakes preparation zones