Neuronal calcium sensor-1 enhancement of InsP3 receptor activity is inhibited by therapeutic levels of lithium

Author Posting. © American Society for Clinical Investigation, 2006. This article is posted here by permission of American Society for Clinical Investigation for personal use, not for redistribution. The definitive version was published in Journal of Clinical Investigation 116 (2006): 1668-1674, doi:10.1172/JCI22466.Regulation and dysregulation of intracellular calcium (Ca2+) signaling via the inositol 1,4,5-trisphosphate receptor (InsP3R) has been linked to many cellular processes and pathological conditions. In the present study, addition of neuronal calcium sensor-1 (NCS-1), a high-affinity, low-capacity, calcium-binding protein, to purified InsP3R type 1 (InsP3R1) increased the channel activity in both a calcium-dependent and -independent manner. In intact cells, enhanced expression of NCS-1 resulted in increased intracellular calcium release upon stimulation of the phosphoinositide signaling pathway. To determine whether InsP3R1/NCS-1 interaction could be functionally relevant in bipolar disorders, conditions in which NCS-1 is highly expressed, we tested the effect of lithium, a salt widely used for treatment of bipolar disorders. Lithium inhibited the enhancing effect of NCS-1 on InsP3R1 function, suggesting that InsP3R1/NCS-1 interaction is an essential component of the pathomechanism of bipolar disorder.This work was supported by a grant from the NIH (GM63496 to B.E. Ehrlich), German National Merit Foundation scholarships (C. Schlecker and W. Boehmerle), and a National Kidney Foundation Fellowship (A. Varshney)

The CARMENES search for exoplanets around M dwarfs -- Planet occurrence rates from a subsample of 71 stars

The CARMENES exoplanet survey of M dwarfs has obtained more than 18 000 spectra of 329 nearby M dwarfs over the past five years as part of its guaranteed time observations (GTO) program. We determine planet occurrence rates with the 71 stars from the GTO program for which we have more than 50 observations. We use injection-and-retrieval experiments on the radial-velocity (RV) time series to measure detection probabilities. We include 27 planets in 21 planetary systems in our analysis. We find 0.06+0.04-0.03 giant planets (100 M_Earth < M_pl sin i < 1000 M_Earth) per star in periods of up to 1000 d, but due to a selection bias this number could be up to a factor of five lower in the whole 329-star sample. The upper limit for hot Jupiters (orbital period of less than 10 d) is 0.03 planets per star, while the occurrence rate of planets with intermediate masses (10 M_Earth < M_pl sin i < 100 M_Earth) is 0.18+0.07-0.05 planets per star. Less massive planets with 1 M_Earth < M_pl sin i < 10 M_Earth are very abundant, with an estimated rate of 1.32+0.33-0.31 planets per star for periods of up to 100 d. When considering only late M dwarfs with masses M_star < 0.34 M_sol, planets more massive than 10 M_Earth become rare. Instead, low-mass planets with periods shorter than 10 d are significantly overabundant. For orbital periods shorter than 100 d, our results confirm the known stellar mass dependences from the Kepler survey: M dwarfs host fewer giant planets and at least two times more planets with M_pl sin i < 10 M_Earth than G-type stars. In contrast to previous results, planets around our sample of very low-mass stars have a higher occurrence rate in short-period orbits of less than 10 d. Our results demonstrate the need to take into account host star masses in planet formation models.Comment: 15 pages, 12 figures. Accepted for publication in Astronomy & Astrophysic

A Highly Eccentric Warm Jupiter Orbiting TIC 237913194

The orbital parameters of warm Jupiters serve as a record of their formation history, providing constraints on formation scenarios for giant planets on close and intermediate orbits. Here, we report the discovery of TIC 237913194b, detected in full frame images from Sectors 1 and 2 of TESS, ground-based photometry (CHAT, LCOGT), and FEROS radial velocity time series. We constrain its mass to $M_\mathrm{P} = 1.942_{-0.091}^{+0.091}\,{\rm M_{J}}$, and its radius to $R_\mathrm{P} = 1.117_{-0.047}^{+0.054}\,{\rm R_J}$, implying a bulk density similar to Neptune's. It orbits a G-type star (${\rm M}_{\star} = 1.026_{-0.055}^{+0.057}\,{\rm M}_{\odot}$, $V = 12.1$ mag) with a period of $15.17\,$d on one of the most eccentric orbits of all known warm giants ($e \approx 0.58$). This extreme dynamical state points to a past interaction with an additional, undetected massive companion. A tidal evolution analysis showed a large tidal dissipation timescale, suggesting that the planet is not a progenitor for a hot Jupiter caught during its high-eccentricity migration. TIC 237913194b further represents an attractive opportunity to study the energy deposition and redistribution in the atmosphere of a warm Jupiter with high eccentricity.Comment: 20 pages, 14 figures. Accepted for publication in A

Salinomycin induces calpain and cytochrome c-mediated neuronal cell death

Salinomycin is a polyether antibiotic with properties of an ionophore, which is commonly used as cocciodiostatic drug and has been shown to be highly effective in the elimination of cancer stem cells (CSCs) both in vitro and in vivo. One important caveat for the potential clinical application of salinomycin is its marked neural and muscular toxicity. In the present study we show that salinomycin in concentrations effective against CSCs exerts profound toxicity towards both dorsal root ganglia as well as Schwann cells. This toxic effect is mediated by elevated cytosolic Na+ concentrations, which in turn cause an increase of cytosolic Ca2+ by means of Na+/Ca2+ exchangers (NCXs) in the plasma membrane as well as the mitochondria. Elevated Ca2+ then leads to calpain activation, which triggers caspase-dependent apoptosis involving caspases 12, 9 and 3. In addition, cytochrome c released from depolarized mitochondria directly activates caspase 9. Combined inhibition of calpain and the mitochondrial NCXs resulted in significantly decreased cytotoxicity and was comparable to caspase 3 inhibition. These findings improve our understanding of mechanisms involved in the pathogenesis of peripheral neuropathy and are important to devise strategies for the prevention of neurotoxic side effects induced by salinomycin

The CARMENES search for exoplanets around M dwarfs, Wolf 1069 b: Earth-mass planet in the habitable zone of a nearby, very low-mass star

We present the discovery of an Earth-mass planet ($M_b\sin i = 1.26\pm0.21M_\oplus$) on a 15.6d orbit of a relatively nearby ($d\sim$9.6pc) and low-mass ($0.167\pm0.011 M_\odot$) M5.0V star, Wolf 1069. Sitting at a separation of $0.0672\pm0.0014$au away from the host star puts Wolf 1069b in the habitable zone (HZ), receiving an incident flux of $S=0.652\pm0.029S_\oplus$. The planetary signal was detected using telluric-corrected radial-velocity (RV) data from the CARMENES spectrograph, amounting to a total of 262 spectroscopic observations covering almost four years. There are additional long-period signals in the RVs, one of which we attribute to the stellar rotation period. This is possible thanks to our photometric analysis including new, well-sampled monitoring campaigns undergone with the OSN and TJO facilities that supplement archival photometry (i.e., from MEarth and SuperWASP), and this yielded an updated rotational period range of $P_{rot}=150-170$d, with a likely value at $169.3^{+3.7}_{-3.6}$d. The stellar activity indicators provided by the CARMENES spectra likewise demonstrate evidence for the slow rotation period, though not as accurately due to possible factors such as signal aliasing or spot evolution. Our detectability limits indicate that additional planets more massive than one Earth mass with orbital periods of less than 10 days can be ruled out, suggesting that perhaps Wolf 1069 b had a violent formation history. This planet is also the 6th closest Earth-mass planet situated in the conservative HZ, after Proxima Centauri b, GJ 1061d, Teegarden's Star c, and GJ 1002 b and c. Despite not transiting, Wolf 1069b is nonetheless a very promising target for future three-dimensional climate models to investigate various habitability cases as well as for sub-ms$^{-1}$ RV campaigns to search for potential inner sub-Earth-mass planets in order to test planet formation theories.Comment: 26 pages, 15 figure

TOI-150b And TOI-163b: Two Transiting Hot Jupiters, One Eccentric And One Inflated, Revealed By TESS Near And At The Edge Of The JWST CVZ

We present the discovery of TYC9191-519-1b (TOI-150b, TIC 271893367) and HD271181b (TOI-163b, TIC 179317684), two hot Jupiters initially detected using 30-min cadence Transiting Exoplanet Survey Satellite (TESS) photometry from Sector 1 and thoroughly characterized through follow-up photometry (CHAT, Hazelwood, LCO/CTIO, El Sauce, TRAPPIST-S), high-resolution spectroscopy (FEROS, CORALIE), and speckle imaging (Gemini/DSSI), confirming the planetary nature of the two signals. A simultaneous joint fit of photometry and radial velocity using a new fitting package juliet reveals that TOI-150b is a 1.254±0.016 RJ⁠, massive (⁠2.61+0.19−0.12 MJ⁠) hot Jupiter in a 5.857-d orbit, while TOI-163b is an inflated (⁠RP = 1.478+0.022−0.029RJ⁠, MP = 1.219±0.11MJ⁠) hot Jupiter on a P = 4.231-d orbit; both planets orbit F-type stars. A particularly interesting result is that TOI-150b shows an eccentric orbit (⁠e=0.262+0.045−0.037⁠), which is quite uncommon among hot Jupiters. We estimate that this is consistent, however, with the circularization time-scale, which is slightly larger than the age of the system. These two hot Jupiters are both prime candidates for further characterization – in particular, both are excellent candidates for determining spin-orbit alignments via the Rossiter–McLaughlin (RM) effect and for characterizing atmospheric thermal structures using secondary eclipse observations considering they are both located closely to the James Webb Space Telescope (JWST) Continuous Viewing Zone (CVZ)

Skin sensitization in silico protocol

The assessment of skin sensitization has evolved over the past few years to include in vitro assessments of key events along the adverse outcome pathway and opportunistically capitalize on the strengths of in silico methods to support a weight of evidence assessment without conducting a test in animals. While in silico methods vary greatly in their purpose and format; there is a need to standardize the underlying principles on which such models are developed and to make transparent the implications for the uncertainty in the overall assessment. In this contribution, the relationship of skin sensitization relevant effects, mechanisms, and endpoints are built into a hazard assessment framework. Based on the relevance of the mechanisms and effects as well as the strengths and limitations of the experimental systems used to identify them, rules and principles are defined for deriving skin sensitization in silico assessments. Further, the assignments of reliability and confidence scores that reflect the overall strength of the assessment are discussed. This skin sensitization protocol supports the implementation and acceptance of in silico approaches for the prediction of skin sensitization

Mitochondrial Redox Metabolism in Trypanosomatids Is Independent of Tryparedoxin Activity

Tryparedoxins (TXNs) are oxidoreductases unique to trypanosomatids (including Leishmania and Trypanosoma parasites) that transfer reducing equivalents from trypanothione, the major thiol in these organisms, to sulfur-dependent peroxidases and other dithiol proteins. The existence of a TXN within the mitochondrion of trypanosomatids, capable of driving crucial redox pathways, is considered a requisite for normal parasite metabolism. Here this concept is shown not to apply to Leishmania. First, removal of the Leishmania infantum mitochondrial TXN (LiTXN2) by gene-targeting, had no significant effect on parasite survival, even in the context of an animal infection. Second, evidence is presented that no other TXN is capable of replacing LiTXN2. In fact, although a candidate substitute for LiTXN2 (LiTXN3) was found in the genome of L. infantum, this was shown in biochemical assays to be poorly reduced by trypanothione and to be unable to reduce sulfur-containing peroxidases. Definitive conclusion that LiTXN3 cannot directly reduce proteins located within inner mitochondrial compartments was provided by analysis of its subcellular localization and membrane topology, which revealed that LiTXN3 is a tail-anchored (TA) mitochondrial outer membrane protein presenting, as characteristic of TA proteins, its N-terminal end (containing the redox-active domain) exposed to the cytosol. This manuscript further proposes the separation of trypanosomatid TXN sequences into two classes and this is supported by phylogenetic analysis: i) class I, encoding active TXNs, and ii) class II, coding for TA proteins unlikely to function as TXNs. Trypanosoma possess only two TXNs, one belonging to class I (which is cytosolic) and the other to class II. Thus, as demonstrated for Leishmania, the mitochondrial redox metabolism in Trypanosoma may also be independent of TXN activity. The major implication of these findings is that mitochondrial functions previously thought to depend on the provision of electrons by a TXN enzyme must proceed differently

The CARMENES search for exoplanets around M dwarfs

Context. The CARMENES instrument, installed at the 3.5 m telescope of the Calar Alto Observatory in Almería, Spain, was conceived to deliver high-accuracy radial velocity (RV) measurements with long-term stability to search for temperate rocky planets around a sample of nearby cool stars. Moreover, the broad wavelength coverage was designed to provide a range of stellar activity indicators to assess the nature of potential RV signals and to provide valuable spectral information to help characterise the stellar targets. Aims: We describe the CARMENES guaranteed time observations (GTO), spanning from 2016 to 2020, during which 19 633 spectra for a sample of 362 targets were collected. We present the CARMENES Data Release 1 (DR1), which makes public all observations obtained during the GTO of the CARMENES survey. Methods: The CARMENES survey target selection was aimed at minimising biases, and about 70% of all known M dwarfs within 10 pc and accessible from Calar Alto were included. The data were pipeline-processed, and high-level data products, including 18 642 precise RVs for 345 targets, were derived. Time series data of spectroscopic activity indicators were also obtained. Results: We discuss the characteristics of the CARMENES data, the statistical properties of the stellar sample, and the spectroscopic measurements. We show examples of the use of CARMENES data and provide a contextual view of the exoplanet population revealed by the survey, including 33 new planets, 17 re-analysed planets, and 26 confirmed planets from transiting candidate follow-up. A subsample of 238 targets was used to derive updated planet occurrence rates, yielding an overall average of 1.44 ± 0.20 planets with 1 M⊕ &lt; Mpl sin i &lt; 1000 M⊕ and 1 day &lt; Porb &lt; 1000 days per star, and indicating that nearly every M dwarf hosts at least one planet. All the DR1 raw data, pipeline-processed data, and high-level data products are publicly available online. Conclusions: CARMENES data have proven very useful for identifying and measuring planetary companions. They are also suitable for a variety of additional applications, such as the determination of stellar fundamental and atmospheric properties, the characterisation of stellar activity, and the study of exoplanet atmospheres

Two super-Earths at the edge of the habitable zone of the nearby M dwarf TOI-2095

The main scientific goal of TESS is to find planets smaller than Neptune around stars bright enough to allow further characterization studies. Given our current instrumentation and detection biases, M dwarfs are prime targets to search for small planets that are in (or nearby) the habitable zone of their host star. Here we use photometric observations and CARMENES radial velocity measurements to validate a pair of transiting planet candidates found by TESS. The data was fitted simultaneously using a Bayesian MCMC procedure taking into account the stellar variability present in the photometric and spectroscopic time series. We confirm the planetary origin of the two transiting candidates orbiting around TOI-2095 (TIC 235678745). The star is a nearby M dwarf ($d = 41.90 \pm 0.03$ pc, $T_{\rm eff} = 3759 \pm 87$ K, $V = 12.6$ mag) with a stellar mass and radius of $M_\star = 0.44 \pm 0.02 \; M_\odot$ and $R_\star = 0.44 \pm 0.02 \; R_\odot$, respectively. The planetary system is composed of two transiting planets: TOI-2095b with an orbital period of $P_b = 17.66484 \pm (7\times 10^{-5})$ days and TOI-2095c with $P_c = 28.17232 \pm (14\times 10^{-5})$ days. Both planets have similar sizes with $R_b = 1.25 \pm 0.07 \; R_\oplus$ and $R_c = 1.33 \pm 0.08 \; R_\oplus$ for planet b and c, respectively. We put upper limits on the masses of these objects with $M_b < 4.1 \; M_\oplus$ for the inner and $M_c < 7.4 \; M_\oplus$ for the outer planet (95\% confidence level). These two planets present equilibrium temperatures in the range of 300 - 350 K and are close to the inner edge of the habitable zone of their star.Comment: Submitted to Astronomy & Astrophysic