Strong HI Lyman-α\alpha variations from the 11 Gyr-old host star Kepler-444: a planetary origin ?

Kepler-444 provides a unique opportunity to probe the atmospheric composition and evolution of a compact system of exoplanets smaller than the Earth. Five planets transit this bright K star at close orbital distances, but they are too small for their putative lower atmosphere to be probed at optical/infrared wavelengths. We used the Space Telescope Imaging Spectrograph instrument onboard the Hubble Space Telescope to search for the signature of the planet's upper atmospheres at six independent epochs in the Ly-$\alpha$ line. We detect significant flux variations during the transits of both Kepler-444e and f (~20%), and also at a time when none of the known planets was transiting (~40%). Variability in the transition region and corona of the host star might be the source of these variations. Yet, their amplitude over short time scales (~2-3 hours) is surprisingly strong for this old (11.2+-1.0Gyr) and apparently quiet main-sequence star. Alternatively, we show that the in-transits variations could be explained by absorption from neutral hydrogen exospheres trailing the two outer planets (Kepler-444e and f). They would have to contain substantial amounts of water to replenish such hydrogen exospheres, which would reveal them as the first confirmed ocean-planets. The out-of-transit variations, however, would require the presence of a yet-undetected Kepler-444g at larger orbital distance, casting doubt on the planetary origin scenario. Using HARPS-N observations in the sodium doublet, we derived the properties of two Interstellar Medium clouds along the line-of-sight toward Kepler-444. This allowed us to reconstruct the stellar Ly-$\alpha$ line profile and to estimate the XUV irradiation from the star, which would still allow for a moderate mass loss from the outer planets after 11.2Gyr. Follow-up of the system at XUV wavelengths will be required to assess this tantalizing possibility.Comment: Accepted for publication in A&A Name of the system added to the title in most recent versio

Investigating Cepheid ℓ\ell Carinae's Cycle-to-cycle Variations via Contemporaneous Velocimetry and Interferometry

Baade-Wesselink-type (BW) techniques enable geometric distance measurements of Cepheid variable stars in the Galaxy and the Magellanic clouds. The leading uncertainties involved concern projection factors required to translate observed radial velocities (RVs) to pulsational velocities and recently discovered modulated variability. We carried out an unprecedented observational campaign involving long-baseline interferometry (VLTI/PIONIER) and spectroscopy (Euler/Coralie) to search for modulated variability in the long-period (P $\sim$ 35.5 d) Cepheid Carinae. We determine highly precise angular diameters from squared visibilities and investigate possible differences between two consecutive maximal diameters, $\Delta_{\rm{max}} \Theta$. We characterize the modulated variability along the line-of-sight using 360 high-precision RVs. Here we report tentative evidence for modulated angular variability and confirm cycle-to-cycle differences of $\ell$ Carinae's RV variability. Two successive maxima yield $\Delta_{\rm{max}} \Theta$ = 13.1 $\pm$ 0.7 (stat.) {\mu}as for uniform disk models and 22.5 $\pm$ 1.4 (stat.) {\mu}as (4% of the total angular variation) for limb-darkened models. By comparing new RVs with 2014 RVs we show modulation to vary in strength. Barring confirmation, our results suggest the optical continuum (traced by interferometry) to be differently affected by modulation than gas motions (traced by spectroscopy). This implies a previously unknown time-dependence of projection factors, which can vary by 5% between consecutive cycles of expansion and contraction. Additional interferometric data are required to confirm modulated angular diameter variations. By understanding the origin of modulated variability and monitoring its long-term behavior, we aim to improve the accuracy of BW distances and further the understanding of stellar pulsations.Comment: Accepted for publication in MNRAS. 19 pages, 13 figures, 10 table

The Dapsone Hypersensitivity Syndrome revisited: a potentially fatal multisystem disorder with prominent hepatopulmonary manifestations

4,4'-Diaminodiphenylsulphone (Dapsone) is widely used for a variety of infectious, immune and hypersensitivity disorders, with indications ranging from Hansen's disease, inflammatory disease and insect bites, all of which may be seen as manifestations in certain occupational diseases. However, the use of dapsone may be associated with a plethora of adverse effects, some of which may involve the pulmonary parenchyma. Methemoglobinemia with resultant cyanosis, bone marrow aplasia and/or hemolytic anemia, peripheral neuropathy and the potentially fatal dapsone hypersensitivity syndrome (DHS), the focus of this review, may all occur individually or in combination. DHS typically presents with a triad of fever, skin eruption, and internal organ (lung, liver, neurological and other systems) involvement, occurring several weeks to as late as 6 months after the initial administration of the drug. In this sense, it may resemble a DRESS syndrome (Drug Rash with Eosinophilia and Systemic Symptoms). DHS must be promptly identified, as untreated, the disorder could be fatal. Moreover, the pulmonary/systemic manifestations may be mistaken for other disorders. Eosinophilic infiltrates, pneumonitis, pleural effusions and interstitial lung disease may be seen. This syndrome is best approached with the immediate discontinuation of the offending drug and prompt administration of oral or intravenous glucocorticoids. An immunological-inflammatory basis of the syndrome can be envisaged, based on the pathological picture and excellent response to antiinflammatory therapy. Since dapsone is used for various indications, physicians from all specialties may encounter DHS and need to familiarize themselves with the salient features about the syndrome and its management

Promoter hypermethylation of SHOX2 and SEPT9 is a potential biomarker for minimally invasive diagnosis in adenocarcinomas of the biliary tract

Clinicopathological data of the 20 biliary tract cancer cases and 100 gender- and age-matched controls included in plasma study. (XLSX 116 kb

Lack of functional GABA receptors alters Kiss1 , Gnrh1 and Gad1 mRNA expression in the medial basal hypothalamus at postnatal day 4

Background/Aims: Adult mice lacking functional GABAB receptors (GABAB1KO) show altered Gnrh1 and Gad1 expressions in the preoptic area-anterior hypothalamus (POA-AH) and females display disruption of cyclicity and fertility. Here we addressed whether sexual differentiation of the brain and the proper wiring of the GnRH and kisspeptin systems were already disturbed in postnatal day 4 (PND4) GABAB1KO mice. Methods: PND4 wild-type (WT) and GABAB1KO mice of both sexes were sacrificed; tissues were collected to determine mRNA expression (qPCR), amino acids (HPLC), and hormones (RIA and/or IHC). Results: GnRH neuron number (IHC) did not differ among groups in olfactory bulbs or OVLT-POA. Gnrh1 mRNA (qPCR) in POA-AH was similar among groups. Gnrh1 mRNA in medial basal hypothalamus (MBH) was similar in WTs but was increased in GABAB1KO females compared to GABAB1KO males. Hypothalamic GnRH (RIA) was sexually different in WTs (males < females), but this sex difference was lost in GABAB1KOs; the same pattern was observed when analyzing only the MBH, but not in the POA-AH. Arcuate nucleus Kiss1 mRNA (micropunch-qPCR) was higher in WT females than in WT males and GABAB1KO females. Gad1 mRNA in MBH was increased in GABAB1KO females compared to GABAB1KO males. Serum LH and gonadal estradiol content were also increased in GABAB1KOs. Conclusion: We demonstrate that GABABRs participate in the sexual differentiation of the ARC/MBH, because sex differences in several reproductive genes, such as Gad1, Kiss1 and Gnrh1, are critically disturbed in GABAB1KO mice at PND4, probably altering the organization and development of neural circuits governing the reproductive axis. (c) 2013 S. Karger AG, Basel

Clinical Efficacy of Enzalutamide vs Bicalutamide Combined With Androgen Deprivation Therapy in Men With Metastatic Hormone-Sensitive Prostate Cancer: A Randomized Clinical Trial

Importance: Black patients have been underrepresented in prospective clinical trials of advanced prostate cancer. This study evaluated the efficacy of enzalutamide compared with bicalutamide, with planned subset analysis of Black patients with metastatic hormone-sensitive prostate cancer (mHSPC), which is a disease state responsive to androgen deprivation therapy (ADT). Objective: To compare the efficacy of enzalutamide vs bicalutamide in combination with ADT in men with mHSPC, with a subset analysis of Black patients. Design, Setting, and Participants: In this randomized clinical trial, a phase 2 screening design enabled a nondefinitive comparison of the primary outcome by treatment. Patients were stratified by race (Black or other) and bone pain (present or absent). Accrual of at least 30% Black patients was required. This multicenter trial was conducted at 4 centers in the US. Men with mHSPC with no history of seizures and adequate marrow, renal, and liver function were eligible. Data analysis was performed from February 2019 to March 2020. Interventions: Participants were randomized 1:1 to receive oral enzalutamide (160 mg daily) or bicalutamide (50 mg daily) in addition to ADT. Main Outcomes and Measures: The primary end point was the 7-month prostate-specific antigen (PSA) response (SMPR) rate, a previously accepted surrogate for overall survival (OS) outcome. Secondary end points included adverse reactions, time to PSA progression, and OS. Results: A total of 71 men (median [range] age, 65 [51-86] years) were enrolled; 29 (41%) were Black, 41 (58%) were White, and 1 (1%) was Asian. Thirty-six patients were randomized to receive enzalutamide, and 35 were randomized to receive bicalutamide. Twenty-six patients (37%) had bone pain and 37 patients (52%) had extensive disease. SMPR was achieved in 30 of 32 patients (94%; 95% CI, 80%-98%) taking enzalutamide and 17 of 26 patients (65%; 95% CI, 46%-81%) taking bicalutamide (P = .008) (difference, 29%; 95% CI, 5%-50%). Among Black patients, the SMPR was 93% (95% CI, 69%-99%) among those taking enzalutamide and 42% (95% CI, 19%-68%) among those taking bicalutamide (P = .009); among non-Black patients, the SMPR was 94% (95% CI, 74%-99%) among those taking enzalutamide and 86% (95% CI, 60%-96%) among those taking bicalutamide. The 12-month PSA response rates were 84% with enzalutamide and 34% with bicalutamide. Conclusions and Relevance: The findings of this randomized clinical trial comparing enzalutamide with bicalutamide suggest that enzalutamide is associated with improved outcomes compared with bicalutamide, in terms of the rate and duration of PSA response, in Black patients with mHSPC. Trial Registration: ClinicalTrials.gov Identifier: NCT02058706

The apoptotic response in HCT116BAX-/- cancer cells becomes rapidly saturated with increasing expression of a GFP-BAX fusion protein

Abstract Background Many chemotherapeutic agents promote tumor cell death by activating the intrinsic pathway of apoptosis. Intrinsic apoptosis involves permeabilization of the mitochondrial outer membrane and the release of cytochrome c, a process that is controlled by proteins of the BCL2 gene family. Chemoresistance is often associated with abnormalities in concentrations of BCL2 family proteins. Although stoichiometirc interactions between anti-apoptotic and BH3-only BCL2 family proteins have been well documented as affecting cell death, the association between changes in BAX concentration and intrinsic apoptosis are poorly understood. Methods Exogenous GFP-murine Bax fusion constructs were transfected into BAX-deficient HCT116 cells. To titrate the expression of the fusion protein, GFP-BAX was cloned into a tetracycline sensitive expression cassette and cotransfected with a plasmid expressing the rtTA transcription factor into HCT116 BAX-/- cells. Linear expression of the fusion gene was induced with doxycycline and monitored by quantitative PCR and immunoblotting. Cell death was assayed by DAPI staining cells after exposure to indomethacin, and scoring nuclei for condensed chromatin and fragmented nuclei. Results HCT116 BAX-/- cells were resistant to indomethacin, but susceptibility could be recovered in cells expressing a GFP-BAX fusion protein. Titration of GFP-BAX expression revealed that the concentration of BAX required to induce a saturating apoptosis response from baseline, was rapidly achieved. Increased levels of GFP-BAX were unable to stimulate higher levels of cell death. Examination of GFP-BAX distribution before and after indomethacin treatment indicated that BAX protein did not form aggregates when present at sub-lethal concentrations. Conclusion Within the limitations of this experimental system, BAX-dependent apoptosis in HCT116 cells exhibits an all-or-none response depending on the level of BAX protein present. The lack of BAX aggregation at sub-saturation levels suggests that the translocation step of BAX activation may be impaired

Adaptation of a Couple-Based HIV Intervention for Methamphetamine-Involved African American Men who have Sex with Men

In the U.S., incidence of HIV infection among men who have sex with men (MSM) has steadily increased since the 1990s. This points to a need for innovation to address both emerging trends as well as longer-standing disparities in HIV risk and transmission among MSM, such as the elevated rates of HIV/STIs among African American MSM and methamphetamine users. While couple-based sexual risk reduction interventions are a promising avenue to reduce HIV/STI transmission, prior research has been almost exclusively with heterosexual couples. We sought to adapt an existing, evidence-based intervention—originally developed and tested with heterosexual couples—for a new target population consisting of African American MSM in a longer-term same-sex relationship where at least one partner uses methamphetamine. The adaptation process primarily drew from data obtained from a series of focus groups with 8 couples from the target population. Attention is given to the methods used to overcome challenges faced in this adaptation process: limited time, a lead investigator who is phenotypically different from the target population, a dearth of descriptive information on the experiences and worldviews among the target population, and a concomitant lack of topical experts. We also describe a visualization tool used to ensure that the adaptation process promotes and maintains adherence to the theory that guides the intervention and behavior change. The process culminated with an intervention adapted for the new target population as well as preliminary indications that a couple-based sexual-risk reduction intervention for African American, methamphetamine-involved male couples is feasible and attractive

miR-346 controls release of TNF-alpha protein and stability of its mRNA in rheumatoid arthritis via tristetraprolin stabilization

TNF-alpha is a major cytokine implicated in rheumatoid arthritis. Its expression is regulated both at the transcriptional and posttranscriptional levels and recent data demonstrated that miRNAs are implicated in TNF-alpha response in macrophages. LPS-activated FLS isolated from RA patients express TNF-alpha mRNA but not the mature protein. This prompted us to look for miRNAs which could be implicated in this anti-inflammatory effect. Using a microarray, we found two miRNAs, miR-125b and miR-939 predicted to target the 3'-UTR of TNF-alpha mRNA, to be up-regulated in RA FLS in response to LPS, but their repression did not restore mature TNF-alpha expression in FLS. We showed previously that miR-346, which is upregulated in LPS-activated FLS, inhibited Btk expression that stabilized TNF-alpha mRNA. Blocking miR-346 reestablished TNF-alpha expression in activated FLS. Interestingly, transfection of miR-346 in LPS-activated THP-1 cells inhibited TNF-alpha secretion. We also demonstrated that TTP, a RNA binding protein which inhibited TNF-alpha synthesis, is overexpressed in activated FLS and that inhibition of miR-346 decreases its expression. Conversely, transfection of miR-346 in LPS-activated THP-1 cells increased TTP mRNA expression and inhibited TNF-alpha release. These results indicate that miR-346 controls TNF-alpha synthesis by regulating TTP expression

The Gaia-ESO survey: A spectroscopic study of the young open cluster NGC 3293

We present a spectroscopic analysis of the GIRAFFE and UVES data collected by the Gaia-ESO survey for the young open cluster NGC 3293. Archive spectra from the same instruments obtained in the framework of the `VLT-FLAMES survey of massive stars' are also analysed. Atmospheric parameters, non-LTE chemical abundances for six elements, or variability information are reported for a total of about 160 B stars spanning a wide range in terms of spectral types (B1 to B9.5) and rotation rate (up to 350 km/s). We take advantage of the multi-epoch observations to detect several binary systems or intrinsically line-profile variables. A deconvolution algorithm is used to infer the current, true (deprojected) rotational velocity distribution. We find a broad, Gaussian-like distribution peaking around 200-250 km/s. Although some stars populate the high-velocity tail, most stars in the cluster appear to rotate far from critical. We discuss the chemical properties of the cluster, including the low occurrence of abundance peculiarities in the late B stars and the paucity of objects showing CN-cycle burning products at their surface. We argue that the former result can largely be explained by the inhibition of diffusion effects because of fast rotation, while the latter is generally in accord with the predictions of single-star evolutionary models under the assumption of a wide range of initial spin rates at the onset of main-sequence evolution. However, we find some evidence for a less efficient mixing in two quite rapidly rotating stars that are among the most massive objects in our sample. Finally, we obtain a cluster age of ~20 Myrs through a detailed, star-to-star correction of our results for the effect of stellar rotation. This is significantly older than previous estimates from turn-off fitting that fully relied on classical, non-rotating isochrones. [abridged]Comment: 29 pages, 24 figures, accepted for publication in A&