BASP1 interacts with estrogen receptor α and modifies the tamoxifen response

AbstractTamoxifen binds to oestrogen receptor α (ERα) to elicit distinct responses that vary by cell/tissue type and status, but the factors that determine these differential effects are unknown. Here we report that the transcriptional corepressor BASP1 interacts with ERα and in breast cancer cells, this interaction is enhanced by tamoxifen. We find that BASP1 acts as a major selectivity factor in the transcriptional response of breast cancer cells to tamoxifen. In all, 40% of the genes that are regulated by tamoxifen in breast cancer cells are BASP1 dependent, including several genes that are associated with tamoxifen resistance. BASP1 elicits tumour-suppressor activity in breast cancer cells and enhances the antitumourigenic effects of tamoxifen treatment. Moreover, BASP1 is expressed in breast cancer tissue and is associated with increased patient survival. Our data have identified BASP1 as an ERα cofactor that has a central role in the transcriptional and antitumourigenic effects of tamoxifen.</jats:p

CAR-T cell. the long and winding road to solid tumors

Adoptive cell therapy of solid tumors with reprogrammed T cells can be considered the "next generation" of cancer hallmarks. CAR-T cells fail to be as effective as in liquid tumors for the inability to reach and survive in the microenvironment surrounding the neoplastic foci. The intricate net of cross-interactions occurring between tumor components, stromal and immune cells leads to an ineffective anergic status favoring the evasion from the host's defenses. Our goal is hereby to trace the road imposed by solid tumors to CAR-T cells, highlighting pitfalls and strategies to be developed and refined to possibly overcome these hurdles

Sarco/Endoplasmic Reticulum Ca2+-ATPases (SERCA) Contribute to GPCR-Mediated Taste Perception

The sense of taste is important for providing animals with valuable information about the qualities of food, such as nutritional or harmful nature. Mammals, including humans, can recognize at least five primary taste qualities: sweet, umami (savory), bitter, sour, and salty. Recent studies have identified molecules and mechanisms underlying the initial steps of tastant-triggered molecular events in taste bud cells, particularly the requirement of increased cytosolic free Ca2+ concentration ([Ca2+]c) for normal taste signal transduction and transmission. Little, however, is known about the mechanisms controlling the removal of elevated [Ca2+]c from the cytosol of taste receptor cells (TRCs) and how the disruption of these mechanisms affects taste perception. To investigate the molecular mechanism of Ca2+ clearance in TRCs, we sought the molecules involved in [Ca2+]c regulation using a single-taste-cell transcriptome approach. We found that Serca3, a member of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) family that sequesters cytosolic Ca2+ into endoplasmic reticulum, is exclusively expressed in sweet/umami/bitter TRCs, which rely on intracellular Ca2+ release for signaling. Serca3-knockout (KO) mice displayed significantly increased aversive behavioral responses and greater gustatory nerve responses to bitter taste substances but not to sweet or umami taste substances. Further studies showed that Serca2 was mainly expressed in the T1R3-expressing sweet and umami TRCs, suggesting that the loss of function of Serca3 was possibly compensated by Serca2 in these TRCs in the mutant mice. Our data demonstrate that the SERCA family members play an important role in the Ca2+ clearance in TRCs and that mutation of these proteins may alter bitter and perhaps sweet and umami taste perception

JWST MIRI/Medium Resolution Spectrograph (MRS) observations and spectral models of the underluminous yype Ia supernova 2022xkq

We present a JWST mid-infrared (MIR) spectrum of the underluminous Type Ia Supernova (SN Ia) 2022xkq, obtained with the medium-resolution spectrometer on the Mid-Infrared Instrument (MIRI) ∼130 days post-explosion. We identify the first MIR lines beyond 14 μm in SN Ia observations. We find features unique to underluminous SNe Ia, including the following: isolated emission of stable Ni, strong blends of [Ti ii], and large ratios of singly ionized to doubly ionized species in both [Ar] and [Co]. Comparisons to normal-luminosity SNe Ia spectra at similar phases show a tentative trend between the width of the [Co iii] 11.888 μm feature and the SN light-curve shape. Using non-LTE-multi-dimensional radiation hydro simulations and the observed electron capture elements, we constrain the mass of the exploding WD. The best-fitting model shows that SN 2022xkq is consistent with an off-center delayed-detonation explosion of a near-Chandrasekhar mass WD (MWD ≈1.37 M⊙) of high central density (ρc ≥ 2.0 × 109 g cm−3) seen equator-on, which produced M(56Ni) =0.324 M⊙ and M(58Ni) ≥0.06 M⊙. The observed line widths are consistent with the overall abundance distribution; and the narrow stable Ni lines indicate little to no mixing in the central regions, favoring central ignition of subsonic carbon burning followed by an off-center deflagration-to-detonation transition beginning at a single point. Additional observations may further constrain the physics revealing the presence of additional species including Cr and Mn. Our work demonstrates the power of using the full coverage of MIRI in combination with detailed modeling to elucidate the physics of SNe Ia at a level not previousl

Movement consistency during repetitive tool use action

The consistency and repeatability of movement patterns has been of long-standing interest in locomotor biomechanics, but less well explored in other domains. Tool use is one of such a domain; while the complex dynamics of the human-tool-environment system have been approached from various angles, to date it remains unknown how the rhythmicity of repetitive tool-using action emerges. To examine whether the spontaneously adopted movement frequency is a variable susceptible to individual execution approaches or emerges as constant behaviour, we recorded sawing motion across a range of 14 experimental conditions using various manipulations. This was compared to free and pantomimed arm movements. We found that a mean (SD) sawing frequency of 2.0 (0.4) Hz was employed across experimental conditions. Most experimental conditions did not significantly affect the sawing frequency, signifying the robustness of this spontaneously emerging movement. Free horizontal arm translation and miming of sawing was performed at half the movement frequency with more than double the excursion distance, showing that not all arm movements spontaneously emerge at the observed sawing parameters. Observed movement frequencies across all conditions could be closely predicted from movement time reference data for generic arm movements found in the Methods Time Measurement literature, highlighting a generic biomechanical relationship between the time taken for a given distance travelled underlying the observed behaviour. We conclude that our findings lend support to the hypothesis that repetitive movements during tool use are executed according to generic and predictable musculoskeletal mechanics and constraints, albeit in the context of the general task (sawing) and environmental constraints such as friction, rather than being subject to task-specific control or individual cognitive schemata

JWST Low-resolution MIRI Spectral Observations of SN 2021aefx: High-density Burning in a Type Ia Supernova

We present a JWST/MIRI low-resolution mid-infrared (MIR) spectroscopic observation of the normal Type Ia supernova (SN Ia) SN 2021aefx at +323 days past rest-frame B-band maximum light. The spectrum ranges from 4 to 14 μm and shows many unique qualities, including a flat-topped [Ar iii] 8.991 μm profile, a strongly tilted [Co iii] 11.888 μm feature, and multiple stable Ni lines. These features provide critical information about the physics of the explosion. The observations are compared to synthetic spectra from detailed non-local thermodynamic equilibrium multidimensional models. The results of the best-fitting model are used to identify the components of the spectral blends and provide a quantitative comparison to the explosion physics. Emission line profiles and the presence of electron capture elements are used to constrain the mass of the exploding white dwarf (WD) and the chemical asymmetries in the ejecta. We show that the observations of SN 2021aefx are consistent with an off-center delayed detonation explosion of a near-Chandrasekhar mass (M Ch) WD at a viewing angle of −30° relative to the point of the deflagration to detonation transition. From the strengths of the stable Ni lines, we determine that there is little to no mixing in the central regions of the ejecta. Based on both the presence of stable Ni and the Ar velocity distributions, we obtain a strict lower limit of 1.2 M ⊙ for the initial WD, implying that most sub-M Ch explosions models are not viable models for SN 2021aefx. The analysis here shows the crucial importance of MIR spectra in distinguishing between explosion scenarios for SNe Ia

JWST MIRI /Medium Resolution Spectrograph (MRS) Observations and Spectral Models of the Underluminous Type Ia Supernova 2022xkq

We present a JWST mid-infrared spectrum of the under-luminous Type Ia Supernova (SN Ia) 2022xkq, obtained with the medium-resolution spectrometer on the Mid-Infrared Instrument (MIRI) ~ 130 days post-explosion. We identify the first MIR lines beyond 14 um in SN Ia observations. We find features unique to under luminous SNe Ia, including: isolated emission of stable Ni, strong blends of [Ti II], and large ratios of singly ionized to doubly ionized species in both [Ar] and [Co]. Comparisons to normal-luminosity SNe Ia spectra at similar phases show a tentative trend between the width of the [Co III] 11.888 um feature and the SN light curve shape. Using non-LTE-multi-dimensional radiation hydro simulations and the observed electron capture elements we constrain the mass of the exploding white dwarf. The best-fitting model shows that SN 2022xkq is consistent with an off-center delayed-detonation explosion of a near-Chandrasekhar mass WD (Mej ≈ 1.37 M⊙) of high-central density (ρc≥2.0×109 g cm−3) seen equator on, which produced M(56Ni) =0.324 M⊙ and M(58Ni) ≥0.06 M⊙. The observed line widths are consistent with the overall abundance distribution; and the narrow stable Ni lines indicate little to no mixing in the central regions, favoring central ignition of sub-sonic carbon burning followed by an off-center DDT beginning at a single point. Additional observations may further constrain the physics revealing the presence of additional species including Cr and Mn. Our work demonstrates the power of using the full coverage of MIRI in combination with detailed modeling to elucidate the physics of SNe Ia at a level not previously possible

Ground-based and JWST observations of SN 2022pul. I. Unusual signatures of carbon, oxygen, and circumstellar interaction in a peculiar type Ia supernova

Nebular-phase observations of peculiar Type Ia supernovae (SNe Ia) provide important constraints on progenitor scenarios and explosion dynamics for both these rare SNe and the more common, cosmologically useful SNe Ia. We present observations from an extensive ground- and space-based follow-up campaign to characterize SN 2022pul, a super-Chandrasekhar mass SN Ia (alternatively "03fg-like" SN), from before peak brightness to well into the nebular phase across optical to mid-infrared (MIR) wavelengths. The early rise of the light curve is atypical, exhibiting two distinct components, consistent with SN Ia ejecta interacting with dense carbon–oxygen (C/O)-rich circumstellar material (CSM). In the optical, SN 2022pul is most similar to SN 2012dn, having a low estimated peak luminosity (MB = −18.9 mag) and high photospheric velocity relative to other 03fg-like SNe. In the nebular phase, SN 2022pul adds to the increasing diversity of the 03fg-like subclass. From 168 to 336 days after peak B-band brightness, SN 2022pul exhibits asymmetric and narrow emission from [O i] λλ6300, 6364 (FWHM ≈ 2000 km s−1), strong, broad emission from [Ca ii] λλ7291, 7323 (FWHM ≈ 7300 km s−1), and a rapid Fe iii to Fe ii ionization change. Finally, we present the first ever optical-to-MIR nebular spectrum of an 03fg-like SN Ia using data from JWST. In the MIR, strong lines of neon and argon, weak emission from stable nickel, and strong thermal dust emission (with T ≈ 500 K), combined with prominent [O i] in the optical, suggest that SN 2022pul was produced by a white dwarf merger within C/O-rich CSM

Ground-based and JWST Observations of SN 2022pul. II. Evidence from nebular spectroscopy for a violent merger in a peculiar type Ia supernova

We present an analysis of ground-based and JWST observations of SN 2022pul, a peculiar "03fg-like" (or "super-Chandrasekhar") Type Ia supernova (SN Ia), in the nebular phase at 338 days postexplosion. Our combined spectrum continuously covers 0.4–14 μm and includes the first mid-infrared spectrum of a 03fg-like SN Ia. Compared to normal SN Ia 2021aefx, SN 2022pul exhibits a lower mean ionization state, asymmetric emission-line profiles, stronger emission from the intermediate-mass elements (IMEs) argon and calcium, weaker emission from iron-group elements (IGEs), and the first unambiguous detection of neon in a SN Ia. A strong, broad, centrally peaked [Ne ii] line at 12.81 μm was previously predicted as a hallmark of "violent merger" SN Ia models, where dynamical interaction between two sub-MCh white dwarfs (WDs) causes disruption of the lower-mass WD and detonation of the other. The violent merger scenario was already a leading hypothesis for 03fg-like SNe Ia; in SN 2022pul it can explain the large-scale ejecta asymmetries seen between the IMEs and IGEs and the central location of narrow oxygen and broad neon. We modify extant models to add clumping of the ejecta to reproduce the optical iron emission better, and add mass in the innermost region (<2000 km s−1) to account for the observed narrow [O i] λλ6300, 6364 emission. A violent WD–WD merger explains many of the observations of SN 2022pul, and our results favor this model interpretation for the subclass of 03fg-like SNe Ia