54 research outputs found
E3 ligase ligand optimization of Clinical PROTACs
Proteolysis targeting chimeras (PROTACs) technology can realize the development of drugs for non-druggable targets that are difficult to achieve with traditional small molecules, and therefore has attracted extensive attention from both academia and industry. Up to now, there are more than 600 known E3 ubiquitin ligases with different structures and functions, but only a few have developed corresponding E3 ubiquitin ligase ligands, and the ligands used to design PROTAC molecules are limited to a few types such as VHL (Von-Hippel-Lindau), CRBN (Cereblon), MDM2 (Mouse Doubleminute 2 homolog), IAP (Inhibitor of apoptosis proteins), etc. Most of the PROTAC molecules that have entered clinical trials were developed based on CRBN ligands, and only DT2216 was based on VHL ligand. Obviously, the structural optimization of E3 ubiquitin ligase ligands plays an instrumental role in PROTAC technology from bench to bedside. In this review, we review the structure optimization process of E3 ubiquitin ligase ligands currently entering clinical trials on PROTAC molecules, summarize some characteristics of these ligands in terms of druggability, and provide some preliminary insights into their structural optimization. We hope that this review will help medicinal chemists to develop more druggable molecules into clinical studies and to realize the greater therapeutic potential of PROTAC technology
MS1, a direct target of MS188, regulates the expression of key sporophytic pollen coat protein genes in Arabidopsis
© 2020 Oxford University Press. All rights reserved. Sporophytic pollen coat proteins (sPCPs) derived from the anther tapetum are deposited into pollen wall cavities and function in pollen-stigma interactions, pollen hydration, and environmental protection. In Arabidopsis, 13 highly abundant proteins have been identified in pollen coat, including seven major glycine-rich proteins GRP14, 16, 17, 18, 19, 20, and GRP-oleosin; two caleosin-related family proteins (AT1G23240 and AT1G23250); three lipase proteins EXL4, EXL5 and EXL6, and ATA27/BGLU20. Here, we show that GRP14, 17, 18, 19, and EXL4 and EXL6 fused with green fluorescent protein (GFP) are translated in the tapetum and then accumulate in the anther locule following tapetum degeneration. The expression of these sPCPs is dependent on two essential tapetum transcription factors, MALE STERILE188 (MS188) and MALE STERILITY 1 (MS1). The majority of sPCP genes are up-regulated within 30 h after MS1 induction and could be restored by MS1 expression driven by the MS188 promoter in ms188, indicating that MS1 is sufficient to activate their expression; however, additional MS1 downstream factors appear to be required for high-level sPCP expression. Our ChIP, in vivo transactivation assay, and EMSA data indicate that MS188 directly activates MS1. Together, these results reveal a regulatory cascade whereby outer pollen wall formation is regulated by MS188 followed by synthesis of sPCPs controlled by MS1
Establishment and characterization of immortalized human eutopic endometrial stromal cells.
PROBLEM(#br)The application of primary eutopic endometrial cells from endometriosis patients in research is restricted for short life span, dedifferentiation of hormone responsiveness.(#br)METHOD OF STUDY(#br)Human telomerase reverse transcriptase (hTERT)-induced immortalized cells (iheESCs) were infected by lentivirus. mRNA level was examined by qRT-PCR, and protein expression was quantified by Western blot. CCK-8 and EdU assay were assigned to assess the proliferation. The migration and invasion of cells were assessed by transwell assay. Clone formation assay and nude mouse tumorigenicity assay were used to evaluate colony-formation and tumorigenesis abilities.(#br)RESULTS(#br)hTERT mRNA and protein were significantly expressed higher in iheESCs compared to primary cells. iheESCs grew without morphological change for 42 passages which is much longer than 18 passages of primary cells. There was no obvious difference between primary cells and iheESCs in growth, mobility, and chromosome karyotype. Furthermore, the expression of epithelial-mesenchymal transition (EMT) markers and estrogen/progesterone receptors remained unchanged. The decidualization of iheESCs could be induced by progesterone and cAMP. Estrogen increased the proliferation and mobility of iheESCs, and lipopolysaccharides (LPS) induced the IL-1β and IL-6 promoting inflammatory response. The colony-forming ability of iheESCs, like primary cells, was lower than Ishikawa cells. In addition, tumorigenicity assay indicated that iheESCs were unable to trigger tumor formation in BALB/c nude mouse.(#br)CONCLUSIONS(#br)This study established and characterized iheESCs that kept the cellular physiology of primary cells and were not available with tumorigenic ability. Thus, iheESCs would be useful as in vitro cell model to investigate pathogenesis of endometriosis
Search for Quasi-Periodical Oscillations in Precursors of Short and Long Gamma Ray Bursts
The precursors of short and long Gamma Ray Bursts (SGRBs and LGRBs) can serve
as probes of their progenitors, as well as shedding light on the physical
processes of mergers or core-collapse supernovae. Some models predict the
possible existence of Quasi-Periodically Oscillations (QPO) in the precursors
of SGRBs. Although many previous studies have performed QPO search in the main
emission of SGRBs and LGRBs, so far there was no systematic QPO search in their
precursors. In this work, we perform a detailed QPO search in the precursors of
SGRBs and LGRBs detected by Fermi/GBM from 2008 to 2019 using the power density
spectrum (PDS) in frequency domain and Gaussian processes (GP) in time domain.
We do not find any convinced QPO signal with significance above 3 ,
possibly due to the low fluxes of precursors. Finally, the PDS continuum
properties of both the precursors and main emissions are also studied for the
first time, and no significant difference is found in the distributions of the
PDS slope for precursors and main emissions in both SGRBs and LGRBs.Comment: submitte
Genome-Wide Histone H3K27 Acetylation Profiling Identified Genes Correlated With Prognosis in Papillary Thyroid Carcinoma
Thyroid carcinoma (TC) is the most common endocrine malignancy, and papillary TC (PTC) is the most frequent subtype of TC, accounting for 85–90% of all the cases. Aberrant histone acetylation contributes to carcinogenesis by inducing the dysregulation of certain cancer-related genes. However, the histone acetylation landscape in PTC remains elusive. Here, we interrogated the epigenomes of PTC and benign thyroid nodule (BTN) tissues by applying H3K27ac chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) along with RNA-sequencing. By comparing the epigenomic features between PTC and BTN, we detected changes in H3K27ac levels at active regulatory regions, identified PTC-specific super-enhancer-associated genes involving immune-response and cancer-related pathways, and uncovered several genes that associated with disease-free survival of PTC. In summary, our data provided a genome-wide landscape of histone modification in PTC and demonstrated the role of enhancers in transcriptional regulations associated with prognosis of PTC
The Minimum Variation Timescales of X-ray bursts from SGR J1935+2154
The minimum variation timescale (MVT) of soft gamma-ray repeaters can be an
important probe to estimate the emission region in pulsar-like models, as well
as the Lorentz factor and radius of the possible relativistic jet in gamma-ray
burst (GRB)-like models, thus revealing their progenitors and physical
mechanisms. In this work, we systematically study the MVTs of hundreds of X-ray
bursts (XRBs) from SGR J1935+2154 observed by {\it Insight}-HXMT, GECAM and
Fermi/GBM from July 2014 to Jan 2022 through the Bayesian Block algorithm. We
find that the MVTs peak at 2 ms, corresponding to a light travel time
size of about 600 km, which supports the magnetospheric origin in pulsar-like
models. The shock radius and the Lorentz factor of the jet are also constrained
in GRB-like models. Interestingly, the MVT of the XRB associated with FRB
200428 is 70 ms, which is longer than that of most bursts and implies
its special radiation mechanism. Besides, the median of MVTs is 7 ms, shorter
than the median MVTs of 40 ms and 480 ms for short GRBs or long GRBs,
respectively. However, the MVT is independent of duration, similar to GRBs.
Finally, we investigate the energy dependence of MVT and suggest that there is
a marginal evidence for a power-law relationship like GRBs but the rate of
variation is at least about an order of magnitude smaller. These features may
provide an approach to identify bursts with a magnetar origin.Comment: accepted for publication in ApJ
Calibration of the Timing Performance of GECAM-C
As a new member of the Gravitational wave high-energy Electromagnetic
Counterpart All-sky Monitor (GECAM) after GECAM-A and GECAM-B, GECAM-C
(originally called HEBS), which was launched on board the SATech-01 satellite
on July 27, 2022, aims to monitor and localize X-ray and gamma-ray transients
from 6 keV to 6 MeV. GECAM-C utilizes a similar design to GECAM but
operates in a more complex orbital environment. In this work, we utilize the
secondary particles simultaneously produced by the cosmic-ray events on orbit
and recorded by multiple detectors, to calibrate the relative timing accuracy
between all detectors of GECAM-C. We find the result is 0.1 , which
is the highest time resolution among all GRB detectors ever flown and very
helpful in timing analyses such as minimum variable timescale and spectral
lags, as well as in time delay localization. Besides, we calibrate the absolute
time accuracy using the one-year Crab pulsar data observed by GECAM-C and
Fermi/GBM, as well as GECAM-C and GECAM-B. The results are and , respectively. Finally, we investigate the
spectral lag between the different energy bands of Crab pulsar observed by
GECAM and GBM, which is .Comment: submitte
Synchrotron Radiation Dominates the Extremely Bright GRB 221009A
The brightest Gamma-ray burst, GRB 221009A, has spurred numerous theoretical
investigations, with particular attention paid to the origins of ultra-high
energy TeV photons during the prompt phase. However, analyzing the mechanism of
radiation of photons in the MeV range has been difficult because the high
flux causes pile-up and saturation effects in most GRB detectors. In this
letter, we present systematic modeling of the time-resolved spectra of the GRB
using unsaturated data obtained from Fermi/GBM (precursor) and
SATech-01/GECAM-C (main emission and flare). Our approach incorporates the
synchrotron radiation model, which assumes an expanding emission region with
relativistic speed and a global magnetic field that decays with radius, and
successfully fits such a model to the observational data. Our results indicate
that the spectra of the burst are fully in accordance with a synchrotron origin
from relativistic electrons accelerated at a large emission radius. The lack of
thermal emission in the prompt emission spectra supports a
Poynting-flux-dominated jet composition.Comment: 12 pages, 6 figures, 2 tables. Accepted for publication in ApJ
- …