Nucleotide receptors in hepatic stellate cells of the rat

AbstractWhen hepatic stellate cells were stimulated by UTP, ATP, or ADP, cellular levels of inositol phosphates significantly increased (UTP > ATP > ADP > 5′-O-(3-thiotriphosphate). Thirty min after incubation with 100 μM of UTP, ATP, or ADP, levels of inositol monophosphate increased to 1318 ± 116, 616 ± 87 and 591 ± 234% of control levels, respectively, with concomitant increase in the production of inositol trisphosphate and bisphosphate. These nucleotides transiently increased the [Ca2+]i of fura-2-loaded stellate cells. Moreover, UTP, ATP, ADP and adenosine 5′-O-(3-thiotriphosphate) were able to induce contraction of stellate cells as detected using the silicone-rubber membrane method. These results suggested that hepatic stellate cells have nucleotide receptors which react predominantly with extracellular UTP and ATP and trigger the receptormediated contraction of the cells

The BH3-Only SNARE BNip1 Mediates Photoreceptor Apoptosis in Response to Vesicular Fusion Defects

SummaryIntracellular vesicular transport is important for photoreceptor function and maintenance. However, the mechanism underlying photoreceptor degeneration in response to vesicular transport defects is unknown. Here, we report that photoreceptors undergo apoptosis in a zebrafish β-soluble N-ethylmaleimide-sensitive factor attachment protein (β-SNAP) mutant. β-SNAP cooperates with N-ethylmaleimide-sensitive factor to recycle the SNAP receptor (SNARE), a key component of the membrane fusion machinery, by disassembling the cis-SNARE complex generated in the vesicular fusion process. We found that photoreceptor apoptosis in the β-SNAP mutant was dependent on the BH3-only protein BNip1. BNip1 functions as a component of the syntaxin-18 SNARE complex and regulates retrograde transport from the Golgi to the endoplasmic reticulum. Failure to disassemble the syntaxin-18 cis-SNARE complex caused BNip1-dependent apoptosis. These data suggest that the syntaxin-18 cis-SNARE complex functions as an alarm factor that monitors vesicular fusion competence and that BNip1 transforms vesicular fusion defects into photoreceptor apoptosis

1H, 15N, and 13C chemical shift assignments of calcium-binding protein 1 with Ca2+ bound at EF1, EF3 and EF4

Calcium-binding protein 1 (CaBP1) regulates inositol 1,4,5-trisphosphate receptors (InsP3Rs) and a variety of voltage-gated Ca2+ channels in the brain. We report complete NMR chemical shift assignments of the Ca2+-saturated form of CaBP1 with Ca2+ bound at EF1, EF3 and EF4 (residues 1–167, BMRB no. 16862)

Intracellular calcium strongly potentiates agonist-activated TRPC5 channels

TRPC5 is a calcium (Ca2+)-permeable nonselective cation channel expressed in several brain regions, including the hippocampus, cerebellum, and amygdala. Although TRPC5 is activated by receptors coupled to phospholipase C, the precise signaling pathway and modulatory signals remain poorly defined. We find that during continuous agonist activation, heterologously expressed TRPC5 currents are potentiated in a voltage-dependent manner (∼5-fold at positive potentials and ∼25-fold at negative potentials). The reversal potential, doubly rectifying current–voltage relation, and permeability to large cations such as N-methyl-d-glucamine remain unchanged during this potentiation. The TRPC5 current potentiation depends on extracellular Ca2+: replacement by Ba2+ or Mg2+ abolishes it, whereas the addition of 10 mM Ca2+ accelerates it. The site of action for Ca2+ is intracellular, as simultaneous fura-2 imaging and patch clamp recordings indicate that potentiation is triggered at ∼1 µM [Ca2+]. This potentiation is prevented when intracellular Ca2+ is tightly buffered, but it is promoted when recording with internal solutions containing elevated [Ca2+]. In cell-attached and excised inside-out single-channel recordings, increases in internal [Ca2+] led to an ∼10–20-fold increase in channel open probability, whereas single-channel conductance was unchanged. Ca2+-dependent potentiation should result in TRPC5 channel activation preferentially during periods of repetitive firing or coincident neurotransmitter receptor activation

Search for solar flare neutrinos with the KamLAND detector

We report the result of a search for neutrinos in coincidence with solar flares from the GOES flare database. The search was performed on a 10.8 kton-year exposure of KamLAND collected from 2002 to 2019. This large exposure allows us to explore previously unconstrained parameter space for solar flare neutrinos. We found no statistical excess of neutrinos and established 90% confidence level upper limits of 8.4 × 10^7 cm^−2 (3.0 × 10^9 cm^−2) on the electron antineutrino (electron neutrino) fluence at 20 MeV normalized to the X12 flare, assuming that the neutrino fluence is proportional to the X-ray intensity.https://arxiv.org/abs/2105.0245

Low-energy astrophysics with KamLAND

We present two results of a search for MeV-scale neutrino and anti-neutrino events correlated with gravitational wave events/candidates and large solar flares with KamLAND. The KamLAND detector is a large-volume neutrino detector using liquid scintillator, which is located at 1 km underground under the top of Mt. Ikenoyama in Kamioka, Japan. KamLAND has multiple reaction channels to detect neutrinos. Electron antineutrino can be detected via inverse-beta decay with 1.8 MeV neutrino energy threshold. All flavors of neutrinos can be detected via neutrino-electron scattering without neutrino energy threshold. KamLAND has continued the neutrino observation since 2002 March. We use the data set of 60 gravitational waves provided by the LIGO/Virgo collaboration during their second and third observing runs and search for coincident electron antineutrino events in KamLAND. We find no significant coincident signals within a ±500 s timing window from each gravitational wave and present 90% C.L. upper limits on the electron antineutrino fluence between 108–1013 cm−2 for neutrino energies of 1.8–111 MeV. For a solar-flare neutrino search at KamLAND, we determine the timing window using the solar X-ray data set provided by the GOES satellite series from 2002 to 2019 and search for the excess of coincident event rate on the all-flavor neutrinos. We find no significant event rate excess in the flare time windows and get 90% C.L. upper limits on the fluence of neutrinos of all flavors (electron anti-neutrinos) between 1010–1013 cm−2 (108–1013 cm−2) for neutrino energies in the energy range of 0.4–35 MeV

KamLAND's search for correlated low-energy electron antineutrinos with astrophysical neutrinos from IceCube

We report the results of a search for MeV-scale astrophysical neutrinos in KamLAND presented as an excess in the number of coincident neutrino interactions associated with the publicly available high-energy neutrino datasets from the IceCube Neutrino Observatory. We find no statistically significant excess in the number of observed low-energy electron antineutrinos in KamLAND, given a coincidence time window of $\pm$500s, $\pm$1,000s, $\pm$3,600s, and $\pm$10,000s around each of the IceCube neutrinos. We use this observation to present limits from 1.8 MeV to 100 MeV on the electron antineutrino fluence, assuming a mono-energetic flux. We then compare the results to several astrophysical measurements performed by IceCube and place a limit at the 90% confidence level on the electron antineutrino isotropic thermal luminosity from the TXS 0506+056 blazar.Comment: 12 pages, 5 figure

Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair

UV-sensitive syndrome (UVSS) is a genodermatosis characterized by cutaneous photosensitivity without skin carcinoma1, 2, 3, 4. Despite mild clinical features, cells from individuals with UVSS, like Cockayne syndrome cells, are very UV sensitive and are deficient in transcription-coupled nucleotide-excision repair (TC-NER)2, 4, 5, which removes DNA damage in actively transcribed genes6. Three of the seven known UVSS cases carry mutations in the Cockayne syndrome genes ERCC8 or ERCC6 (also known as CSA and CSB, respectively)7, 8. The remaining four individuals with UVSS, one of whom is described for the first time here, formed a separate UVSS-A complementation group1, 9, 10; however, the responsible gene was unknown. Using exome sequencing11, we determine that mutations in the UVSSA gene (formerly known as KIAA1530) cause UVSS-A. The UVSSA protein interacts with TC-NER machinery and stabilizes the ERCC6 complex; it also facilitates ubiquitination of RNA polymerase IIo stalled at DNA damage sites. Our findings provide mechanistic insights into the processing of stalled RNA polymerase and explain the different clinical features across these TC-NER–deficient disorders