Fast rebinding increases dwell time of Src homology 2 (SH2)-containing proteins near the plasma membrane

Receptor tyrosine kinases (RTKs) control a host of biological functions by phosphorylating tyrosine residues of intracellular proteins upon extracellular ligand binding. The phosphotyrosines (p-Tyr) then recruit a subset of ∼100 Src homology 2 (SH2) domain-containing proteins to the cell membrane. The in vivo kinetics of this process are not well understood. Here we use total internal reflection (TIR) microscopy and single-molecule imaging to monitor interactions between SH2 modules and p-Tyr sites near the cell membrane. We found that the dwell time of SH2 modules within the TIR illumination field is significantly longer than predictions based on chemical dissociation rate constants, suggesting that SH2 modules quickly rebind to nearby p-Tyr sites after dissociation. We also found that, consistent with the rebinding model, the effective diffusion constant is negatively correlated with the respective dwell time for different SH2 domains and the dwell time is positively correlated with the local density of RTK phosphorylation. These results suggest a mechanism whereby signal output can be regulated through the spatial organization of multiple binding sites, which will prompt reevaluation of many aspects of RTK signaling, such as signaling specificity, mechanisms of spatial control, and noise suppression

Subaru high-z exploration of low-luminosity quasars (SHELLQs). I. Discovery of 15 quasars and bright galaxies at 5.7 < z < 6.9

We report the discovery of 15 quasars and bright galaxies at 5.7 < z < 6.9. This is the initial result from the Subaru High-z Exploration of Low-Luminosity Quasars (SHELLQs) project, which exploits the exquisite multiband imaging data produced by the Subaru Hyper Suprime-Cam (HSC) Strategic Program survey. The candidate selection is performed by combining several photometric approaches including a Bayesian probabilistic algorithm to reject stars and dwarfs. The spectroscopic identification was carried out with the Gran Telescopio Canarias and the Subaru Telescope for the first 80 deg2 of the survey footprint. The success rate of our photometric selection is quite high, approaching 100 % at the brighter magnitudes (zAB < 23.5 mag). Our selection also recovered all the known high-z quasars on the HSC images. Among the 15 discovered objects, six are likely quasars, while the other six with interstellar absorption lines and in some cases narrow emission lines are likely bright Lyman-break galaxies. The remaining three objects have weak continua and very strong and narrow Ly alpha lines, which may be excited by ultraviolet light from both young stars and quasars. These results indicate that we are starting to see the steep rise of the luminosity function of z > 6 galaxies, compared with that of quasars, at magnitudes fainter than M1450 ~ -22 mag or zAB ~24 mag. Follow-up studies of the discovered objects as well as further survey observations are ongoing.Comment: Published in ApJ (828:26, 2016

The Structural Features of Trask That Mediate Its Anti-Adhesive Functions

Trask/CDCP1 is a transmembrane protein with a large extracellular and small intracellular domains. The intracellular domain (ICD) undergoes tyrosine phosphorylation by Src kinases during anchorage loss and, when phosphorylated, Trask functions to inhibit cell adhesion. The extracellular domain (ECD) undergoes proteolytic cleavage by serine proteases, although the functional significance of this remains unknown. There is conflicting evidence regarding whether it functions to signal the phosphorylation of the ICD. To better define the structural determinants that mediate the anti-adhesive functions of Trask, we generated a series of deletion mutants of Trask and expressed them in tet-inducible cell models to define the structural elements involved in cell adhesion signaling. We find that the ECD is dispensable for the phosphorylation of the ICD or for the inhibition of cell adhesion. The anti-adhesive functions of Trask are entirely embodied within its ICD and are specifically due to tyrosine phosphorylation of the ICD as this function is completely lost in a phosphorylation-defective tyrosine-phenylalanine mutant. Both full length and cleaved ECDs are fully capable of phosphorylation and undergo phosphorylation during anchorage loss and cleavage is not an upstream signal for ICD phosphorylation. These data establish that the anti-adhesive functions of Trask are mediated entirely through its tyrosine phosphorylation. It remains to be defined what role, if any, the Trask ECD plays in its adhesion functions

High-efficiency GaAs and GaInP solar cells grown by all solid-state molecular-beam-epitaxy

We report the initial results of GaAs and GaInP solar cells grown by all solid-state molecular-beam-epitaxy (MBE) technique. For GaAs single-junction solar cell, with the application of AlInP as the window layer and GaInP as the back surface field layer, the photovoltaic conversion efficiency of 26% at one sun concentration and air mass 1.5 global (AM1.5G) is realized. The efficiency of 16.4% is also reached for GaInP solar cell. Our results demonstrate that the MBE-grown phosphide-contained III-V compound semiconductor solar cell can be quite comparable to the metal-organic-chemical-vapor-deposition-grown high-efficiency solar cell

Dietary flavan-3-ols intake and metabolic syndrome risk in Korean adults

Flavan-3-ols are a subclass of flavonoids found in a variety of foods including teas. The effects of flavan-3-ols on the risk of metabolic syndrome (MetS) have been investigated, generally focusing on tea catechins or individual flavan-3-ol rich foods, but there is little information on dietary flavan-3-ols intake and risk of MetS in population-based studies. In this cross-sectional study, we examined the association between dietary flavan-3-ols intake and the risk of MetS in Korean adults. Subjects comprised 1,827 men and 2,918 women aged 20-69 years whose data was included in the 2008 Korean National Health and Nutrition Examination Survey. This survey was conducted between January 2008 and December 2008. Total flavan-3-ols intakes were calculated from 24-hour dietary recalls using a flavonoids database. Thirty percent of the male subjects and 24% of the female subjects were reported as having MetS. In the female subjects, flavan3-ols intake was inversely associated with the risk of MetS after adjusting for potential confounders (5th vs. 1st quintile, OR = 0.64, 95% CI = 0.45-0.91, P for trend = 0.384). The main food source of flavan-3-ols was green tea followed by apples and grapes. Among MetS components, flavan3-ols intake was inversely associated with the risk of high blood pressure after adjusting for potential confounders (5th vs. 1st quintile, OR = 0.64, 95% CI = 0.45-0.90, P for trend = 0.005). No significant association between flavan-3-ols intake and risk of MetS was found in the male subjects. After stratified analysis by obesity (BMI ≥ 25 or BMI < 25), however, flavan3-ols intake was inversely related to the risk of hypertension in non-obese men. These results suggest that dietary flavan-3-ols intake may have beneficial effects on MetS risk by reducing the risk of hypertension. The effects of flavan-3-ols intake dependent on obesity need further investigation

The expression of corticotropin-releasing factor and its receptors in the spinal cord and dorsal root ganglion in a rat model of neuropathic pain

Corticotropin-releasing factor (CRF) is a peptide involved in the activation of the hypothalamic-pituitary-adrenal (HPA) axis. CRF is distributed not only along the HPA axis but also throughout pain-relevant anatomical sites. CRF elicits potent antinociception at the three main levels of pain transmissions: namely, the brain, spinal cord, and peripheral sensory neurons. The widespread distribution of CRF receptors 1 and 2 in the brain offers several targets wherein CRF could alter pain, some of which may be independent of the HPA axis. In this study, we assessed the expression of CRF and its receptors, CRF receptor type (CRFR)1 and CRFR2, in the spinal dorsal horn and dorsal root ganglion (DRG) in a rat model of neuropathic pain induced by spinal nerve injury (SNI). CRF was expressed in a few DRG neurons and primary afferent fibers in the dorsal horns of naїve rats, and the CRF-positive neurons in DRG and fibers in the spinal dorsal horn were found to have increased after SNI. CRFR1 was not expressed in DRG or the dorsal horn and CRFR2 was expressed weakly in the small neurons in DRG in the naїve rats. After SNI, CRFR1 was expressed in the activated microglia in the ipsilateral dorsal horn, and immunoreaction for CRFR2 was increased in the contralateral DRG following SNI. Consequently, it has been suggested that the increased expression of CRF and CRFR2 in DRG neurons and primary afferent fibers in dorsal horn, and CRFR1 in the activated microglia, may be involved in the mediation of stress responses as well as in microglial activation in the neuropathic pain state following SNI

A VCP modulator, KUS121, as a promising therapeutic agent for post-traumatic osteoarthritis

京大開発の薬剤「KUS121」の変形性膝関節症への効果を確認 --外傷性変形性関節症の治療薬として臨床応用へ--. 京都大学プレスリリース. 2020-12-17.Post-traumatic osteoarthritis (PTOA) is a major cause which hinders patients from the recovery after intra-articular injuries or surgeries. Currently, no effective treatment is available. In this study, we showed that inhibition of the acute stage chondrocyte death is a promising strategy to mitigate the development of PTOA. Namely, we examined efficacies of Kyoto University Substance (KUS) 121, a valosin-containing protein modulator, for PTOA as well as its therapeutic mechanisms. In vivo, in a rat PTOA model by cyclic compressive loading, intra-articular treatments of KUS121 significantly improved the modified Mankin scores and reduced damaged-cartilage volumes, as compared to vehicle treatment. Moreover, KUS121 markedly reduced the numbers of TUNEL-, CHOP-, MMP-13-, and ADAMTS-5-positive chondrocytes in the damaged knees. In vitro, KUS121 rescued human articular chondrocytes from tunicamycin-induced cell death, in both monolayer culture and cartilage explants. It also significantly downregulated the protein or gene expression of ER stress markers, proinflammatory cytokines, and extracellular-matrix-degrading enzymes induced by tunicamycin or IL-1β. Collectively, these results demonstrated that KUS121 protected chondrocytes from cell death through the inhibition of excessive ER stress. Therefore, KUS121 would be a new, promising therapeutic agent with a protective effect on the progression of PTOA

Discovery of the First Low-Luminosity Quasar at z > 7

We report the discovery of a quasar at z = 7.07, which was selected from the deep multi-band imaging data collected by the Hyper Suprime-Cam (HSC) Subaru Strategic Program survey. This quasar, HSC J124353.93+010038.5, has an order of magnitude lower luminosity than do the other known quasars at z > 7. The rest-frame ultraviolet absolute magnitude is M1450 = -24.13 +/- 0.08 mag and the bolometric luminosity is Lbol = (1.4 +/- 0.1) x 10^{46} erg/s. Its spectrum in the optical to near-infrared shows strong emission lines, and shows evidence for a fast gas outflow, as the C IV line is blueshifted and there is indication of broad absorption lines. The Mg II-based black hole mass is Mbh = (3.3 +/- 2.0) x 10^8 Msun, thus indicating a moderate mass accretion rate with an Eddington ratio 0.34 +/- 0.20. It is the first z > 7 quasar with sub-Eddington accretion, besides being the third most distant quasar, known to date. The luminosity and black hole mass are comparable to, or even lower than, those measured for the majority of low-z quasars discovered by the Sloan Digital Sky Survey, and thus this quasar likely represents a z > 7 counterpart to quasars commonly observed in the low-z universe.Comment: Accepted for publication in ApJ Letter