Although it is well-established that p53-mediated tumor suppression mainly acts through its ability in transcriptional regulation, the molecular mechanisms of this regulation are not completely ...understood. Among a number of regulatory modes, acetylation of p53 attracts great interests. p53 was one of the first non-histone proteins found to be functionally regulated by acetylation and deacetylation, and subsequent work has established that reversible acetylation is a general mechanism for regulation of non-histone proteins. Unlike other types of posttranslational modifications occurred during stress responses, the role of p53 acetylation has been recently validated in vivo by using the knock-in mice with both acetylation-defective and acetylation-mimicking p53 mutants. Here, we review the role of acetylation in p53-mediated activities, with a focus on which specific acetylation sites are critical for p53-dependent transcription regulation during tumor suppression and how acetylation of p53 recruits specific "readers" to execute its promoter-specific regulation of different targets. We also discuss the role of p53 acetylation in differentially regulating its classic activities in cell cycle arrest, senescence and apoptosis as well as newly identified unconventional functions such as cell metabolism and ferroptosis.
We monitored the chromospheric activity in the Ca II H and K lines of 13 solar-type stars (including the Sun): 8 of them over 3 years at the Canada-France-Hawaii Telescope (CFHT) and 5 in a single ...run at the Very Large Telescope (VLT). A total of 10 of the 13 targets have close planetary companions. All of the stars observed at the CFHT show long-term (months to years) changes in H and K intensity levels. Four stars display short-term (days) cyclical activity. For two, HD 73256 and Kappa super(1) Cet, the activity is likely associated with an active region rotating with the star; however, the flaring in excess of the rotational modulation may be associated with a hot Jupiter. A planetary companion remains a possibility for Kappa super(1) Cet. For the other two, HD 179949 and upsilon And, the cyclic variation is synchronized to the hot Jupiter's orbit. For both stars this synchronicity with the orbit is clearly seen in two out of three epochs. The effect is only marginal in the third epoch at which the seasonal level of chromospheric activity had changed for both stars. Short-term chromospheric activity appears weakly dependent on the mean K line reversal intensities for the sample of 13 stars. In addition, a suggestive correlation exists between this activity and the M sub(p) sin i of the star's hot Jupiter. Because of their small separation ( less than or equal to 0.1 AU), many of the hot Jupiters lie within the Alfven radius of their host stars, which allows a direct magnetic interaction with the stellar surface. We discuss the conditions under which a planet's magnetic field might induce activity on the stellar surface and why no such effect was seen for the prime candidate, tau Boo. This work opens up the possibility of characterizing planet-star interactions, with implications for extrasolar planet magnetic fields and the energy contribution to stellar atmospheres.
Purpose - The purpose of this paper is to investigate the mechanisms controlling the bond formation among extruded polymer filaments in the fused deposition modeling (FDM) process. The bonding ...phenomenon is thermally driven and ultimately determines the integrity and mechanical properties of the resultant prototypes.Design methodology approach - The bond quality was assessed through measuring and analyzing changes in the mesostructure and the degree of healing achieved at the interfaces between the adjoining polymer filaments. Experimental measurements of the temperature profiles were carried out for specimens produced under different processing conditions, and the effects on mesostructures and mechanical properties were observed. Parallel to the experimental work, predictions of the degree of bonding achieved during the filament deposition process were made based on the thermal analysis of extruded polymer filaments.Findings - Experimental results showed that the fabrication strategy, the envelope temperature and variations in the convection coefficient had strong effects on the cooling temperature profile, as well as on the mesostructure and overall quality of the bond strength between filaments. The sintering phenomenon was found to have a significant effect on bond formation, but only for the very short duration when the filament's temperature was above the critical sintering temperature. Otherwise, creep deformation was found to dominate changes in the mesostructure.Originality value - This study provides valuable information about the effect of deposition strategies and processing conditions on the mesostructure and local mechanical properties within FDM prototypes. It also brings a better understanding of phenomena controlling the integrity of FDM products. Such knowledge is essential for manufacturing functional parts and diversifying the range of application of this process. The findings are particularly relevant to work conducted on modeling of the process and for the formulation of materials new to the FDM process.
Chromosomal aberrations are a hallmark of human cancers, with complex cytogenetic rearrangements leading to genetic changes permissive for cancer initiation and progression. Protection of Telomere 1 ...(POT1) is an essential component of the shelterin complex and functions to maintain chromosome stability by repressing the activation of aberrant DNA damage and repair responses at telomeres. Sporadic and familial mutations in the oligosaccharide-oligonucleotide (OB) folds of POT1 have been identified in many human cancers, but the mechanism underlying how hPOT1 mutations initiate tumorigenesis has remained unclear. Here we show that the human POT1's OB-folds are essential for the protection of newly replicated telomeres. Oncogenic mutations in hPOT1 OB-fold fail to bind to single-stranded telomeric DNA, eliciting a DNA damage response at telomeres that promote inappropriate chromosome fusions via the mutagenic alternative non-homologous end joining (A-NHEJ) pathway. hPOT1 mutations also result in telomere elongation and the formation of transplantable hematopoietic malignancies. Strikingly, conditional deletion of both mPot1a and p53 in mouse mammary epithelium resulted in development of highly invasive breast carcinomas and the formation of whole chromosomes containing massive arrays of telomeric fusions indicative of multiple breakage-fusion-bridge cycles. Our results reveal that hPOT1 OB-folds are required to protect and prevent newly replicated telomeres from engaging in A-NHEJ mediated fusions that would otherwise promote genome instability to fuel tumorigenesis.
We report the detection and characterization of the transiting sub-Neptune TOI-1759 b, using photometric time series from the Transiting Exoplanet Survey Satellite (TESS) and near-infrared ...spectropolarimetric data from the Spectro-Polarimètre Infra Rouge (SPIRou) on the Canada-France-Hawaii Telescope. TOI-1759 b orbits a moderately active M0V star with an orbital period of 18.849975 ± 0.000006 days, and we measured a planetary radius and mass of 3.06 ± 0.22
R
⊕
and 6.8 ± 2.0
M
⊕
. Radial velocities were extracted from the SPIRou spectra using both the cross-correlation function and the line-by-line methods, optimizing the velocity measurements in the near-infrared domain. We analyzed the broadband spectral energy distribution of the star and the high-resolution SPIRou spectra to constrain the stellar parameters and thus improve the accuracy of the derived planet parameters. A least squares deconvolution analysis of the SPIRou Stokes V polarized spectra detects Zeeman signatures in TOI-1759. We modeled the rotational modulation of the magnetic stellar activity using a Gaussian process regression with a quasi-periodic covariance function and find a rotation period of 35.65
−0.15
+0.17
days. We reconstructed the large-scale surface magnetic field of the star using Zeeman-Doppler imaging, which gives a predominantly poloidal field with a mean strength of 18 ± 4 G. Finally, we performed a joint Bayesian Markov chain Monte Carlo analysis of the TESS photometry and SPIRou radial velocities to optimally constrain the system parameters. At 0.1176 ± 0.0013 au from the star, the planet receives 6.4 times the bolometric flux incident on Earth, and its equilibrium temperature is estimated at 433 ± 14 K. TOI-1759 b is a likely gas-dominated sub-Neptune with an expected high rate of photoevaporation. Therefore, it is an interesting target to search for neutral hydrogen escape, which may provide important constraints on the planetary formation mechanisms responsible for the observed sub-Neptune radius desert.
Objective
The imbalance of gut microbiota has been linked to manifold endocrine diseases, but the association with Graves’ disease (GD) is still unclear. The purpose of this study was to investigate ...the correlation between human gut microbiota and clinical characteristics and thyroidal functional status of GD.
Methods
14 healthy volunteers (CG) and 15 patients with primary GD (HG) were recruited as subjects. 16SrDNA high-throughput sequencing was performed on IlluminaMiSeq platform to analyze the characteristics of gut microbiota in patients with GD. Among them, the thyroid function of 13 patients basically recovered after treatment with anti-thyroid drugs (oral administration of Methimazole for 3–5 months). The fecal samples of patients after treatment (TG) were sequenced again, to further explore and investigate the potential relationship between dysbacteriosis and GD.
Results
In terms of alpha diversity index, the observed OTUs, Simpson and Shannon indices of gut microbiota in patients with GD were significantly lower than those in healthy volunteers (
P
< 0.05).The difference of bacteria species was mainly reflected in the genus level, in which the relative abundance of
Lactobacillus
,
Veillonella
and
Streptococcus
increased significantly in GD. After the improvement of thyroid function, a significant reduction at the genus level were
Blautia
,
Corynebacter
,
Ruminococcus
and
Streptococcus
, while
Phascolarctobacterium
increased significantly (
P
< 0.05). According to Spearman correlation analysis, the correlation between the level of thyrotropin receptor antibody (TRAb) and the relative abundance of
Lactobacillus
and
Ruminococcus
was positive, while
Synergistetes
and
Phascolarctobacterium
showed a negative correlation with TRAb. Besides, there were highly significant negative correlation between
Synergistetes
and clinical variables of TRAb, TPOAb and TGAb (
P
< 0.05,
R
< − 0.6).
Conclusions
This study revealed that functional status and TRAb level in GD were associated with composition and biological function in the gut microbiota, with
Synergistetes
and
Phascolarctobacterium
protecting the thyroid probably, while
Ruminococcus
and
Lactobacillus
may be novel biomarkers of GD.
To analyze the risk factors for patients' postoperative gastrointestinal disorders (POGD) after surgery of thoracolumbar fusion.
This retrospective study was based on clinical data of 434 patients ...who underwent thoracolumbar fusion from January 2021 to December 2021 in Nanjing Drum Tower Hospital.According to the occurrence of POGD, the patients were divided into POGD group(
=70) and non-POGD group(
=364). The clinical data of the two groups were compared, and the risk factors of POGD were discussed by binary logistic regression.
There were 23 males and 47 females in POGD group, with an average age of (60±6) years, and 133 males and 231 females in the non-POGD group, with an average age of (62±7) years. There were significant differences in operation duration, blood loss, intraoperative spinal decompression, intraoperative hypotension, white blood cell count 24 h postoperatively, C-reactive protein 24 h postoperatively, and postoperative hospitalization days between the two groups (
<0.05). Binary logistic re
Traditional Chinese medicine (TCM) is gaining increasing attention with the emergence of integrative medicine and personalized medicine, characterized by pattern differentiation on individual ...variance and treatments based on natural herbal synergism. Investigating the effectiveness and safety of the potential mechanisms of TCM and the combination principles of drug therapies will bridge the cultural gap with Western medicine and improve the development of integrative medicine. Dealing with rapidly growing amounts of biomedical data and their heterogeneous nature are two important tasks among modern biomedical communities. Bioinformatics, as an emerging interdisciplinary field of computer science and biology, has become a useful tool for easing the data deluge pressure by automating the computation processes with informatics methods. Using these methods to retrieve, store and analyze the biomedical data can effectively reveal the associated knowledge hidden in the data, and thus promote the discovery of integrated information. Recently, these techniques of bioinformatics have been used for facilitating the interactional effects of both Western medicine and TCM. The analysis of TCM data using computational technologies provides biological evidence for the basic understanding of TCM mechanisms, safety and efficacy of TCM treatments. At the same time, the carrier and targets associated with TCM remedies can inspire the rethinking of modern drug development. This review summarizes the significant achievements of applying bioinformatics techniques to many aspects of the research in TCM, such as analysis of TCM-related '-omics' data and techniques for analyzing biological processes and pharmaceutical mechanisms of TCM, which have shown certain potential of bringing new thoughts to both sides.
Adiponectin, a cytokine secreted by adipocytes, plays an important role in regulating glucose and lipid metabolism. However, the role of adiponectin in pain conditions is largely unknown. This study ...aimed to identify the role and mechanism of adiponectin in nociceptive sensitivity under physiological and pathological states utilising adiponectin knockout (KO) mice.
Wild type (WT) and adiponectin KO mice were subjected to partial sciatic nerve ligation (pSNL) or sham operation. Pain-like behavioural tests, including thermal allodynia, hyperalgesia, and mechanical allodynia, were performed before and after pSNL from Day 3–21. Dorsal root ganglions (DRGs), lumbar spinal segments at L3-5, and somatosensory cortex were collected for protein measurement via western blotting and immunofluorescence staining.
Compared with WT mice, KO mice had significantly lower (40–50%) paw withdrawal latency to innocuous and noxious stimuli before and after pSNL. In DRG neurones from KO mice, where adiponectin receptor (AdipoR) 2 is located, phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) and heat-sensitive transient receptor potential cation channel subfamily V member 1 (TRPV1) were significantly higher (by two- to three-fold) than from WT mice. In spinal microglia and somatosensory cortical neurones, where AdipoR1 is mainly located, p-p38 MAPK and TRPV1 were also higher (by two- to three-fold) in KO compared with WT mice, and altered signalling of these molecules was exacerbated (1.2- to 1.3-fold) by pSNL.
Our results show that adiponectin regulates thermal nociceptive sensitivity by inhibiting activation of DRG neurones, spinal microglia, and somatosensory cortical neurones in physiological and neuropathic pain states. This study has relevance for patients with adiponectin disorders, such as obesity and diabetes.
The metastable helium triplet in the near-infrared (10 833 Å) is among the most important probes of exoplanet atmospheres. It can trace their extended outer layers and constrain mass loss. We used ...the near-infrared high-resolution spectropolarimeter SPIRou on the CFHT to search for the spectrally resolved helium triplet in the atmospheres of eleven exoplanets, ranging from warm mini-Neptunes to hot Jupiters and orbiting G, K, and M dwarfs. Observations were obtained as part of the SPIRou Legacy Survey and complementary open-time programs. We applied a homogeneous data reduction to all datasets and set constraints on the presence of metastable helium, despite the presence of systematics in the data. We confirm published detections for HAT-P-11 b, HD 189733 b, and WASP-69 b and set upper limits for the other planets. We applied the
p–winds
open source code to set upper limits on the mass-loss rate for the nondetections and to constrain the thermosphere temperature, mass-loss rate, line-of-sight velocity, and the altitude of the thermosphere for the detections. We confirm that the presence of metastable helium correlates with the stellar mass and the extreme-ultraviolet flux received by the planets. We investigated the correlation between the mass-loss rate and the presence of metastable helium, but it remains difficult to draw definitive conclusions. Finally, some of our results are in contradiction with previous results in the literature, and therefore we stress the importance of repeatable, homogeneous, and larger-scale analyses of the helium triplet to obtain robust statistics, study temporal variability, and better understand how the helium triplet can be used to explore the evolution of exoplanets.
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