The proteolysis-assisted protein quality control system guards the proteome from potentially detrimental aberrant proteins. How miscellaneous defective proteins are specifically eliminated and which ...molecular characteristics direct them for removal are fundamental questions. We reveal a mechanism, DesCEND (destruction via C-end degrons), by which CRL2 ubiquitin ligase uses interchangeable substrate receptors to recognize the unusual C termini of abnormal proteins (i.e., C-end degrons). C-end degrons are mostly less than ten residues in length and comprise a few indispensable residues along with some rather degenerate ones. The C-terminal end position is essential for C-end degron function. Truncated selenoproteins generated by translation errors and the USP1 N-terminal fragment from post-translational cleavage are eliminated by DesCEND. DesCEND also targets full-length proteins with naturally occurring C-end degrons. The C-end degron in DesCEND echoes the N-end degron in the N-end rule pathway, highlighting the dominance of protein “ends” as indicators for protein elimination.
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•CRL2 ubiquitin ligase functions in protein quality control•CRL2 recognizes the unusual C-termini of aberrant proteins (i.e., C-end degrons)•CRL2 recognizes various C-end degrons through interchangeable substrate receptors•CRL2 also targets full-length proteins with naturally occurring C-end degrons
Lin et al. uncover a protein degradation mechanism, DesCEND (destruction via C-end degrons), by which CRL2 ubiquitin ligase recognizes and eliminates proteins with exposed C-end degrons through interchangeable substrate receptors. The C-end degron in DesCEND echoes the N-end degron in the N-end rule pathway, highlighting the dominance of protein “ends” in directing protein elimination.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The FORMOSAT‐7/COSMIC‐2 (F7/C2) satellite mission was launched on 25 June 2019 with six low‐Earth‐orbit satellites and can provide thousands of daily radio occultation (RO) soundings in the ...low‐latitude and midlatitude regions. This study shows the preliminary results of space weather data products based on F7/C2 RO sounding: global ionospheric specification (GIS) electron density and Ne‐aided Abel and Abel electron density profiles. GIS is the ionospheric data assimilation product based on the Gauss‐Markov Kalman filter, assimilating the ground‐based Global Positioning System and space‐based F7/C2 RO slant total electron content, providing continuous global three‐dimensional electron density distribution. The Ne‐aided Abel inversion implements four‐dimensional climatological electron density constructed from previous RO observations, which has the advantage of providing altitudinal information on the horizontal gradient to reduce the retrieval error due to the spherical symmetry assumption of the Abel inversion. The comparisons show that climatological structures are consistent with each other above 300 km altitude. Both the Abel electron density profiles and GIS detect electron density variations during a minor geomagnetic storm that occurred within the study period. Moreover, GIS is further capable of reconstructing the variation of equatorial ionization anomaly crests. Detailed validations of all the three products are carried out using manually scaled digisonde NmF2 (hmF2), yielding correlation coefficients of 0.885 (0.885) for both Abel inversions and 0.903 (0.862) for GIS. The results show that both GIS and Ne‐aided Abel are reliable products in studying ionosphere climatology, with the additional advantage of GIS for space weather research and day‐to‐day variations.
Plain Language Summary
This study presents two ionosphere products from the innovative satellite constellation mission launched recently. Global ionospheric specification is an ionospheric data product that assimilates ground‐based Global Positioning System and FORMOSAT‐7/COSMIC‐2 radio occultation observation of total electron content, to generate hourly global three‐dimensional electron density for monitoring space weather condition. Ne‐aided Abel electron density profile is an improved retrieval product of FORMOSAT‐7/COSMIC‐2 radio occultation observations by imposing asymmetry information of ionosphere to mitigate the error introduced by the assumption of spherical symmetry in the Abel inversion. The comparisons and validations confirm that these two data products are reliable for the study of ionosphere climatology and weather. They are operationally produced and released at Taiwan Analysis Center for COSMIC.
Key Points
All the three F7/C2 products capture similar climatological structure of ionosphere in longitudes (Wave 4) and latitudes (EIA crests)
Abel electron density profiles detect responses to geomagnetic storm, but GIS performs better in reconstructing the EIA crests variations
Digisonde validations demonstrate that the GIS NmF2 has excellent performance when there are RO observations available for assimilation
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Dysfunction of degradation machineries causes cancers, including hepatocellular carcinoma (HCC). Overexpression of cyclin D1 in HCC has been reported. We previously reported that autophagy ...preferentially recruits and degrades the oncogenic microRNA (miR)‐224 to prevent HCC. Therefore, in the present study, we attempted to clarify whether cyclin D1 is another oncogenic factor selectively regulated by autophagy in HCC tumorigenesis. Initially, we found an inverse correlation between low autophagic activity and high cyclin D1 expression in tumors of 147 HCC patients and three murine models, and these results taken together revealed a correlation with poor overall survival of HCC patients, indicating the importance of these two events in HCC development. We found that increased autophagic activity leads to cyclin D1 ubiquitination and selective recruitment to the autophagosome (AP) mediated by a specific receptor, sequestosome 1 (SQSTM1), followed by fusion with lysosome and degradation. Autophagy‐selective degradation of ubiquitinated cyclin D1 through SQSTM1 was confirmed using cyclin D1/ubiquitin binding site (K33‐238R) and phosphorylation site (T286A) mutants, lentivirus‐mediated silencing autophagy‐related 5 (ATG5), autophagy‐related 7 (ATG7), and Sqstm1 knockout cells. Functional studies revealed that autophagy‐selective degradation of cyclin D1 plays suppressive roles in cell proliferation, colony, and liver tumor formation. Notably, an increase of autophagic activity by pharmacological inducers (amiodarone and rapamycin) significantly suppressed tumor growth in both the orthotopic liver tumor and subcutaneous tumor xenograft models. Our findings provide evidence of the underlying mechanism involved in the regulation of cyclin D1 by selective autophagy to prevent tumor formation. Conclusion: Taken together, our data demonstrate that autophagic degradation machinery and the cell‐cycle regulator, cyclin D1, are linked to HCC tumorigenesis. We believe these findings may be of value in the development of alternative therapeutics for HCC patients. (Hepatology 2018;68:141‐154).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
MEC-17, a newly identified alpha-tubulin-N-acetyltransferase 1, serves as the major α-tubulin acetyltransferase to promote α-tubulin acetylation in vitro and in vivo. Alteration of α-tubulin ...acetylation may be involved in morphology regulation, cell migration, and tumour metastasis. However, MEC-17's role in cell physiology and its effect on epithelial-mesenchymal transition (EMT) and cell polarity remain elusive. In the present study, we characterized the overexpressed or downregulated cell models through gene targeting as MEC-17 gain- or loss-of-function. Overexpression of MEC-17 enhanced the cell spreading area, suppressed pseudopods formation in a three-dimensional (3D) culture system, and inhibited cancer cell migratory and invasive ability and tumour metastasis by orthotopic lung cancer animal model. Furthermore, morphological change and migration inhibition of cancer cells were accompanied by EMT repression, Golgi reorientation, and polarity disruption caused by alteration of cdc42 activity via a decrease in Rho-GAP, ARHGAP21. By contrast, a reduction in endogenous MEC-17 accelerated the pseudopods formation and EMT, and facilitated cell migration and invasion. These results demonstrated the crucial role of MEC-17 in the modulation of intrinsic cell morphogenesis, migration, and invasive function through regulation of EMT and cell polarity.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Polymers with an abundant amorphous domain should facilitate energy dissipation upon stretching, making near amorphous π-conjugated polymers have immense potential in realizing intrinsically ...stretchable field-effect transistor (FET) devices. In this study, high mobility preservation under the stretched state is attempted by replacing typical alkyl-monothienyl (T-R) on a benzo1,2-b:4,5-b’dithiophene-difluorobenzothiadiazole backbone with three other biaxially extended side-chains, including alkyl-dithienyl (2T-R), branching alkyl-trithienyl (3T-R), and alkyl-benzotrithienyl (B3T-R) groups. Despite showing near amorphous features, the semi-2D BDT-based polymers with bulkier biaxially extended side chains (PBDT-2T, PBDT-3T, and PBDT-B3T) still present comparable mobility to the reference semicrystalline polymer (PBDT-T). Although these four polymers yield comparable mobility, they show distinctly different mobility retention in the stretched state. From the study of their mobility-stretchability relationship, the interdigitating and/or entanglement of these biaxially extended conjugated side chains are shown to play a nontrivial role in the resultant mechanical robustness against the stretching force. Owing to the proper spatial mobility and geometry, the branched 3T-R side chain possesses a more intense interdigitating and/or entanglement capability than the linear 2T-R one and the fused B3T-R one, providing better mechanical strength under stretched states. Meanwhile, it maintains sufficient interchain connectivity for intermittent interchain hopping to compensate for the 1D charge transport along the backbone, ensuring good charge transport even in the stretched state. As a result, the printed PBDT-3T film is demonstrated to deliver a high mobility retention of 73% at a 60% strain exerted parallel to the charge-transporting direction and a very stable mobility retention of 88% after 1000 stretching-releasing cycles at a 60% strain, being one of the best stretchable near amorphous conjugated polymers reported thus far. Our result underlines the effectiveness of using biaxially extended conjugated side chains to realize high-performance stretchable polymers.
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IJS, KILJ, NUK, PNG, UL, UM
The devastating Hunga Tonga-Hunga Ha’apai underwater volcano erupted at ~04:15 UT on 15 January 2022. We captured the waves that erupted from the volcano propagating in the ionosphere by monitoring ...total electron content (TEC) perturbations utilizing ground-based global navigation satellite system (GNSS) receivers that receive electromagnetic signals transmitted from the geostationary satellites operated by the BeiDou Navigation Satellite System (BDS). Meanwhile, ground barometers detected unusual enhancements of air pressure traveling in the troposphere. A novel phenomenon shows that the waves can individually propagate with a speed of ~335 m/s in the ionosphere, which is faster than its’ ~305 m/s in the troposphere. We further examined multiple geophysical data at the particular site of the novel instrumental array. Analytical results show that the pressure enhancements traveling in the troposphere not only downward trigger ground vibrations mainly in the horizontal components without obvious time difference, but also upward, leading the secondary TEC perturbations with a ~12-min delay.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The ionospheric total electron content (TEC) derived from dense ground‐based Global Navigation Satellite System receivers over the continental United States and those from global ionosphere maps are ...utilized to find the ionosphere response to the August 21, 2017 total solar eclipse. Maximum obscurations and their associated TEC major depressions appear simultaneously at midlatitudes, while major depressions elongate toward the magnetic equator with some delays in the equatorial ionization anomaly (EIA) region. The former is due to the photochemical loss process, while the latter is caused by the plasma transport of E×B drifts and lunar gravitation forces. TECs of predawn reductions, morning enhancements, afternoon reductions, and nighttime enhancements reveal that the semidiurnal lunar tide are essential. Since a solar eclipse always occurs on a new moon day, the lunar tide results in the early EIA appearance and major depressions being underestimated/diminished before and overestimated/enhanced after about 14:00 local time.
Plain Language Summary
Observations during an eclipse offer a special opportunity for studying the Earth's ionospheric response to changes in solar ionizing radiation. Although ionospheric solar eclipse signatures in many events have been studied, we report the lunar tide effect on the signatures for the first time. A total solar eclipse swept across the continental United States (CONUS) from the west to east coast on August 21, 2017. The total electron content (TEC) along seven longitudes of the US continent derived from more than 2,200 ground‐based Global Navigation Satellite System receivers in the CONUS and extracted from global ionosphere maps (GIMs) is employed to study ionospheric solar eclipse signatures. The most prominent solar eclipse signature is major depressions (MDs) in both the CONUS and GIM TECs, when the maximum obscuration occurs. TEC extrema of predawn reductions, morning enhancements, afternoon reductions, and nighttime enhancements reveal that the semidiurnal lunar tide of about 12.42‐h period is prominent. The lunar tide causes the early appearance of equatorial ionization anomalies, which further results in the MDs being weakened in the morning and enhanced in the afternoon on the solar eclipse day. The lunar tide has to be taken into consideration for studying ionospheric solar eclipse effects.
Key Points
The lunar tide results in the early appearance of the equatorial ionization anomaly on solar eclipse days
Total electron contents tend to enhance before and decrease after 14:00 local time (LT) on a solar eclipse day
The lunar tide causes major depressions being weakened before and enhanced after 14:00 LT
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Animal cells and cell lines, such as HEK-293 cells, are commonly cultured at 37°C. These cells are often used to express recombinant proteins. Having a higher expression level or a higher protein ...yield is generally desirable. As we demonstrate in this study, dropping culture temperature to 33°C, but not lower, 24 hours after transient transfection in HEK-293S cells will give rise to ~1.5-fold higher expression of green fluorescent protein (GFP) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. By following the time course of the GFP-expressing cells growing at 37°C and 33°C from 24 hours after transfection (including 19 hours recovery at 37°C in the normal growth medium), we found that a mild hypothermia (i.e., 33°C) reduces the growth rate of HEK-293S cells, while increasing cellular productivity of recombinant proteins. As a result, green cells remain undivided in a longer period of time. Not surprisingly, the property of a recombinant protein expressed in the cells grown at 33°C is unaffected, as shown by the use of AMPA receptors. We further demonstrate with the use of PC12 cells that this method may be especially useful when a recombinant protein is difficult to express using a chemical-based, transient transfection method.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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