Transcriptional activity of Forkhead box transcription factor class O (FOXO) proteins can result in a variety of cellular outcomes depending on cell type and activating stimulus. These transcription ...factors are negatively regulated by the phosphoinositol 3-kinase (PI3K)-protein kinase B (PKB) signaling pathway, which is thought to have a pivotal role in regulating survival of tumor cells in a variety of cancers. Recently, it has become clear that FOXO proteins can promote resistance to anti-cancer therapeutics, designed to inhibit PI3K-PKB activity, by inducing the expression of proteins that provide feedback at different levels of this pathway. We questioned whether such a feedback mechanism may also exist directly at the level of FOXO-induced transcription. To identify critical modulators of FOXO transcriptional output, we performed gene expression analyses after conditional activation of key components of the PI3K-PKB-FOXO signaling pathway and identified FOXP1 as a direct FOXO transcriptional target. Using chromatin immunoprecipitation followed by next-generation sequencing, we show that FOXP1 binds enhancers that are pre-occupied by FOXO3. By sequencing the transcriptomes of cells in which FOXO is specifically activated in the absence of FOXP1, we demonstrate that FOXP1 can modulate the expression of a specific subset of FOXO target genes, including inhibiting expression of the pro-apoptotic gene BIK. FOXO activation in FOXP1-knockdown cells resulted in increased cell death, demonstrating that FOXP1 prevents FOXO-induced apoptosis. We therefore propose that FOXP1 represents an important modulator of FOXO-induced transcription, promoting cellular survival.
ABSTRACT
We report the discovery and confirmation of the planetary system TOI-1288. This late G dwarf harbours two planets: TOI-1288 b and TOI-1288 c. We combine TESS space-borne and ground-based ...transit photometry with HARPS-N and HIRES high-precision Doppler measurements, which we use to constrain the masses of both planets in the system and the radius of planet b. TOI-1288 b has a period of $2.699835^{+0.000004}_{-0.000003}$ d, a radius of 5.24 ± 0.09 R⊕, and a mass of 42 ± 3 M⊕, making this planet a hot transiting super-Neptune situated right in the Neptunian desert. This desert refers to a paucity of Neptune-sized planets on short period orbits. Our 2.4-yr-long Doppler monitoring of TOI-1288 revealed the presence of a Saturn–mass planet on a moderately eccentric orbit ($0.13^{+0.07}_{-0.09}$) with a minimum mass of 84 ± 7 M⊕ and a period of $443^{+11}_{-13}$ d. The five sectors worth of TESS data do not cover our expected mid-transit time for TOI-1288 c, and we do not detect a transit for this planet in these sectors.
The microtubule-targeting compound paclitaxel is often used in the treatment of endocrine-resistant or metastatic breast cancer. We have previously shown that apoptosis of breast cancer cells in ...response to paclitaxel is mediated by induction of FOXO3a expression, a transcription factor downstream of the phosphatidylinositol-3-kinase/Akt signaling pathway. To further investigate its mechanism of action, we treated MCF-7 cells with paclitaxel and showed a dose-dependent increase in nuclear localization of FOXO3a, which coincided with decreased Akt signaling but increased c-Jun NH2-terminal kinase 1/2 (JNK1/2), p38, and extracellular signal-regulated kinase 1/2 (ERK1/2) activity. Flow cytometry revealed that paclitaxel-induced apoptosis of MCF-7 cells and of other paclitaxel-sensitive breast cancer cell lines was maintained in the presence of inhibitors of p38 (SB203580) or mitogen-activated protein/ERK kinase 1 signaling (PD98059) but abrogated when cells were treated with the JNK1/2 inhibitor SP600125. SP600125 reversed Akt inhibition and abolished FOXO3a nuclear accumulation in response to paclitaxel. Moreover, conditional activation of JNK mimicked paclitaxel activity and led to dephosphorylation of Akt and FOXO3a. Furthermore, mouse embryonic fibroblasts (MEF) derived from JNK1/2 knockout mice displayed very high levels of active Akt, and in contrast to wild-type MEFs, paclitaxel treatment did not alter Akt activity or elicit FOXO3a nuclear translocation. Taken together, the data show that cell death of breast cancer cells in response to paclitaxel is dependent upon JNK activation, resulting in Akt inhibition and increased FOXO3a activity.
Context.
Ultra-short-period planets (USPs) are a unique class of super-Earths with an orbital period of less than a day, and hence they are subject to intense radiation from their host star. These ...planets cannot retain a primordial H/He atmosphere, and most of them are indeed consistent with being bare rocky cores. A few USPs, however, show evidence for a heavyweight envelope, which could be a water layer resilient to evaporation or a secondary metal-rich atmosphere sustained by outgassing of the molten volcanic surface. Much thus remains to be learned about the nature and formation of USPs.
Aims.
The prime goal of the present work is to refine the bulk planetary properties of the recently discovered TOI-561 b through the study of its transits and occultations. This is crucial in order to understand the internal structure of this USP and to assess the presence of an atmosphere.
Methods.
We obtained ultra-precise transit photometry of TOI-561 b with CHEOPS, and performed a joint analysis of these data along with three archival visits from CHEOPS and four TESS sectors.
Results.
Our analysis of TOI-561 b transit photometry put strong constraints on its properties. In particular, we restrict the uncertainties on the planetary radius at ~2% retrieving
R
p
= 1.42 ± 0.02
R
⊕
. This result informs our internal structure modelling of the planet, which shows that the observations are consistent with a negligible H/He atmosphere; however, other lighter materials are required, in addition to a pure iron core and a silicate mantle, to explain the observed density. We find that this can be explained by the inclusion of a water layer in our model. Additionally, we ran a grid of forward models with a water-enriched atmosphere to explain the transit radius. We searched for variability in the measured
R
p
/
R
★
over time, which could trace changes in the structure of the planetary envelope. However, no temporal variations are recovered within the present data precision. In addition to the transit event, we tentatively detect an occultation signal in the TESS data with an eclipse depth
L
= 27.40
−11.35
+10.87
ppm. We use models of outgassed atmospheres from the literature to explain this eclipse signal. We find that the thermal emission from the planet can mostly explain the observation. Based on this, we predict that near- to mid-infrared observations with the
James Webb
Space Telescope should be able to detect silicate species in the atmosphere of the planet. This could also reveal important clues about the planetary interior and help disentangle planet formation and evolution models.
Summary
Vitamin D deficiency and insufficiency are highly prevalent among adolescents in Hong Kong, which is a sub-tropical city with ample sunshine. Vitamin D level is significantly correlated with ...key bone density and bone quality parameters. Further interventional studies are warranted to define the role of vitamin D supplementation for improvement of bone health among adolescents.
Introduction
The relationship between bone quality parameters and vitamin D (Vit-D) status remains undefined among adolescents. The aims of this study were to evaluate Vit-D status and its association with both bone density and bone quality parameters among adolescents.
Methods
Three hundred thirty-three girls and 230 boys (12–16 years old) with normal health were recruited in summer and winter separately from local schools. Serum 25(OH) Vit-D level, bone density and quality parameters by Dual Energy X-ray Absorptiometry (DXA) and High-Resolution peripheral Quantitative Computed Tomography (HR-pQCT), dietary calcium intake, and physical activity level were assessed.
Results
Sixty-four point seven percent and 11.4 % of subjects were insufficient 25 ≤ 25(OH)Vit-D ≤ 50 nmol/L and deficient 25(OH)Vit-D < 25 nmol/L in Vit-D, respectively. The mean level of serum 25(OH)Vit-D in summer was significantly higher than that in winter (44.7 ± 13.6 and 35.9 ± 12.6 nmol/L, respectively) without obvious gender difference. In girls, areal bone mineral density (aBMD) and bone mineral content (BMC) of bilateral femoral necks, cortical area, cortical thickness, total volumetric bone mineral density (vBMD), and trabecular thickness were significantly correlated with 25(OH)Vit-D levels. In boys, aBMD of bilateral femoral necks, BMC of the dominant femoral neck, cortical area, cortical thickness, total vBMD, trabecular vBMD, BV/TV, and trabecular separation were significantly correlated with 25(OH)Vit-D levels.
Conclusion
Vit-D insufficiency was highly prevalent among adolescents in Hong Kong with significant correlation between Vit-D levels and key bone density and bone quality parameters being detected in this study. Given that this is a cross-sectional study and causality relationship cannot be inferred, further interventional studies investigating the role of Vit-D supplementation on improving bone health among adolescents are warranted.
We report the discovery of the exoplanet K2-110 b (previously EPIC212521166b) from K2 photometry orbiting in a 13.8637d period around an old, metal-poor K3 dwarf star. With a V-band magnitude of ...11.9, K2-110 is particularly amenable to RV follow-up. A joint analysis of K2 photometry and high-precision RVs from 28 HARPS and HARPS-N spectra reveal it to have a radius of 2.6 ± 0.1R⊕ and a mass of 16.7 ± 3.2M⊕, hence a density of 5.2 ± 1.2 g cm-3, making it one of the most massive planets yet to be found with a sub-Neptune radius. When accounting for compression, the resulting Earth-like density is best fitted by a 0.2M⊕ hydrogen atmosphere over an 16.5M⊕ Earth-like interior, although the planet could also have significant water content. At 0.1 AU, even taking into account the old stellar age of 8 ± 3 Gyr, the planet is unlikely to have been significantly affected by EUV evaporation. However the planet likelydisc-migrated to its current position making the lack of a thick H2 atmosphere puzzling. This analysis has made K2-110 b one of the best-characterised mini-Neptunes with density constrained to less than 30%.
Allergen‐reactive T helper type‐2 (Th2) cells and proinflammatory cytokines have been suggested to play an important role in the induction and maintenance of the inflammatory cascade in allergic ...asthma. We compared the plasma concentrations of novel proinflammatory cytokines IL‐17 and IL‐18, other proinflammatory cytokines IL‐6 and IL‐12, Th2 cytokines IL‐10 and IL‐13, and intracellular interferon‐γ (IFN‐γ) and IL‐4 in Th cells of 41 allergic asthmatics and 30 sex‐ and age‐matched health control subjects. Plasma cytokines were measured by enzyme‐linked immunosorbent assay. Intracellular cytokines were quantified by flow cytometry. Plasma IL‐18, IL‐12, IL‐10, IL‐13 concentrations were significantly higher in allergic asthmatic patients than normal control subjects (IL‐18: median 228·35 versus 138·72 pg/ml, P < 0·001; IL‐12: 0·00 versus 0·00 pg/ml, P = 0·001; IL‐10: 2·51 versus 0·05 pg/ml, P < 0·034; IL‐13: 119·38 versus 17·89 pg/ml, P < 0·001). Allergic asthmatic patients showed higher plasma IL‐17 and IL‐6 concentrations than normal controls (22·40 versus 11·86 pg/ml and 3·42 versus 0·61 pg/ml, respectively), although the differences were not statistically significant (P = 0·077 and 0·053, respectively). The percentage of IFN‐γ‐producing Th cells was significantly higher in normal control subjects than asthmatic patients (23·46 versus 5·72%, P < 0·001) but the percentage of IL‐4 producing Th cells did not differ (0·72 versus 0·79%, P > 0·05). Consequently, the Th1/Th2 cell ratio was significantly higher in normal subjects than asthmatic patients (29·6 versus 8·38%, P < 0·001). We propose that allergic asthma is characterized by an elevation of both proinflammatory and Th2 cytokines. The significantly lower ratio of Th1/Th2 cells confirms a predominance of Th2 cells response in allergic asthma.
Context.
Despite being a prominent subset of the exoplanet population discovered in the past three decades, the nature and provenance of sub-Neptune-sized planets is still one of the open questions ...in exoplanet science.
Aims.
For planets orbiting bright stars, precisely measuring the orbital and planet parameters of the system is the best approach to distinguish between competing theories regarding their formation and evolution.
Methods.
We obtained 69 new radial velocity observations of the mid-M dwarf G 9–40 with the CARMENES instrument to measure for the first time the mass of its transiting sub-Neptune planet, G 9–40 b, discovered in data from the K2 mission.
Results.
Combined with new observations from the TESS mission during Sectors 44, 45, and 46, we are able to measure the radius of the planet to an uncertainty of 3.4% (
R
b
= 1.900 ± 0.065
R
⊕
) and determine its mass with a precision of 16% (
M
b
= 4.00 ± 0.63
M
⊕
). The resulting bulk density of the planet is inconsistent with a terrestrial composition and suggests the presence of either a water-rich core or a significant hydrogen-rich envelope.
Conclusions.
G 9–40 b is referred to as a keystone planet due to its location in period-radius space within the radius valley. Several theories offer explanations for the origin and properties of this population and this planet is a valuable target for testing the dependence of those models on stellar host mass. By virtue of its brightness and small size of the host, it joins L 98-59 d as one of the two best warm (
T
eq
~ 400 K) sub-Neptunes for atmospheric characterization with JWST, which will probe cloud formation in sub-Neptune-sized planets and break the degeneracies of internal composition models.
Infections with the fungus Talaromyces (formerly Penicillium) marneffei are rare in patients who do not have AIDS. We report disseminated T. marneffei infection in 4 hematology patients without AIDS ...who received targeted therapy with monoclonal antibodies against CD20 or kinase inhibitors during the past 2 years. Clinicians should be aware of this emerging complication, especially in patients from disease-endemic regions.
We report here four cases of continuous ambulatory peritoneal dialysis-related peritonitis caused by three different species of Gordonia. The portal of entry was likely through Tenckhoff catheters. ...16S rRNA and secA1 gene sequencing are so far the most reliable methods for the accurate identification of Gordonia species.
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