Dynamic L-type CaV1.2 channel trafficking facilitates CaV1.2 clustering and cooperative gating.

L-type CaV1.2 channels are key regulators of gene expression, cell excitability and muscle contraction. CaV1.2 channels organize in clusters throughout the plasma membrane. This channel organization has been suggested to contribute to the concerted activation of adjacent CaV1.2 channels (e.g. cooperative gating). Here, we tested the hypothesis that dynamic intracellular and perimembrane trafficking of CaV1.2 channels is critical for formation and dissolution of functional channel clusters mediating cooperative gating. We found that CaV1.2 moves in vesicular structures of circular and tubular shape with diverse intracellular and submembrane trafficking patterns. Both microtubules and actin filaments are required for dynamic movement of CaV1.2 vesicles. These vesicles undergo constitutive homotypic fusion and fission events that sustain CaV1.2 clustering, channel activity and cooperative gating. Our study suggests that CaV1.2 clusters and activity can be modulated by diverse and unique intracellular and perimembrane vesicular dynamics to fine-tune Ca2+ signals

Proteolytic processing of the L-type Ca2+ channel alpha11.2 subunit in neurons [version 2; referees: 3 approved]

Background: The L-type Ca2+ channel Cav1.2 is a prominent regulator of neuronal excitability, synaptic plasticity, and gene expression. The central element of Cav1.2 is the pore-forming α11.2 subunit. It exists in two major size forms, whose molecular masses have proven difficult to precisely determine. Recent work suggests that α11.2 is proteolytically cleaved between the second and third of its four pore-forming domains (Michailidis et al,. 2014). Methods: To better determine the apparent molecular masses (MR)of the α11.2 size forms, extensive systematic immunoblotting of brain tissue as well as full length and C-terminally truncated α11.2 expressed in HEK293 cells was conducted using six different region–specific antibodies against α11.2. Results: The full length form of α11.2 migrated, as expected, with an apparent MR of ~250 kDa. A shorter form of comparable prevalence with an apparent MR of ~210 kDa could only be detected in immunoblots probed with antibodies recognizing α11.2 at an epitope 400 or more residues upstream of the C-terminus. Conclusions: The main two size forms of α11.2 are the full length form and a shorter form, which lacks ~350 distal C-terminal residues. Midchannel cleavage as suggested by Michailidis et al. (2014) is at best minimal in brain tissue

Pre-Mission Input Requirements to Enable Successful Sample Collection by a Remote Field/EVA Team

We used a field excursion to the West Clearwater Lake Impact structure as an opportunity to test factors that contribute to the decisions a remote field team (for example, astronauts conducting extravehicular activities (EVA) on planetary surfaces) makes while collecting samples for return to Earth. We found that detailed background on the analytical purpose of the samples, provided to the field team, enables them to identify and collect samples that meet specific analytical objectives. However, such samples are not always identifiable during field reconnaissance activities, and may only be recognized after outcrop characterization and interpretation by crew and/or science team members. We therefore recommend that specific time be allocated in astronaut timeline planning to collect specialized samples, that this time follow human or robotic reconnaissance of the geologic setting, and that crew member training should include exposure to the laboratory techniques and analyses that will be used on the samples upon their return to terrestrial laboratories

Development of the HT&Me intervention to support women with breast cancer to adhere to adjuvant endocrine therapy and improve quality of life.

BACKGROUND: Breast cancer is the most common cancer in women worldwide. Approximately 80% of breast cancers are oestrogen receptor positive (ER+). Patients treated surgically are usually recommended adjuvant endocrine therapy (AET) for 5-10 years. AET significantly reduces recurrence, but up to 50% of women do not take it as prescribed. OBJECTIVE: To co-design and develop an intervention to support AET adherence and improve health-related quality-of-life (QoL) in women with breast cancer. METHODS: Design and development of the HT&Me intervention took a person-based approach and was guided by the Medical Research Council framework for complex interventions, based on evidence and underpinned by theory. Literature reviews, behavioural analysis, and extensive key stakeholder involvement informed 'guiding principles' and the intervention logic model. Using co-design principles, a prototype intervention was developed and refined. RESULTS: The blended tailored HT&Me intervention supports women to self-manage their AET. It comprises initial and follow-up consultations with a trained nurse, supported with an animation video, a web-app and ongoing motivational 'nudge' messages. It addresses perceptual (e.g. doubts about necessity, treatment concerns) and practical (e.g. forgetting) barriers to adherence and provides information, support and behaviour change techniques to improve QoL. Iterative patient feedback maximised feasibility, acceptability, and likelihood of maintaining adherence; health professional feedback maximised likelihood of scalability. CONCLUSIONS: HT&Me has been systematically and rigorously developed to promote AET adherence and improve QoL, and is complemented with a logic model documenting hypothesized mechanisms of action. An ongoing feasibility trial will inform a future randomised control trial of effectiveness and cost-effectiveness

The Sloan Digital Sky Survey Reverberation Mapping Project: Investigation of Continuum Lag Dependence on Broad-Line Contamination and Quasar Properties

This work studies the relationship between accretion-disk size and quasar properties, using a sample of 95 quasars from the SDSS-RM project with measured lags between the $g$ and $i$ photometric bands. Our sample includes disk lags that are both longer and shorter than predicted by the \citet{SS73} model, requiring explanations which satisfy both cases. Although our quasars each have one lag measurement, we explore the wavelength-dependent effects of diffuse broad line region (BLR) contamination through our sample's broad redshift range, $0.1<z<1.2$. We do not find significant evidence of variable diffuse \FeII\ and Balmer nebular emission in the root-mean-square (RMS) spectra, nor from Anderson-Darling tests of quasars in redshift ranges with and without diffuse nebular emission falling in the observed-frame filters. Contrary to previous work, we do not detect a significant correlation between measured continuum and BLR lags in our luminous quasar sample, similarly suggesting that our continuum lags are not dominated by diffuse nebular emission. Similar to other studies, we find that quasars with larger-than-expected continuum lags have lower 3000~\AA\ luminosity, and we additionally find longer continuum lags with lower X-ray luminosity and black hole mass. Our lack of evidence for diffuse BLR contribution to the lags indicates that the anti-correlation between continuum lag and luminosity is not likely to be due to the Baldwin effect. Instead, these anti-correlations favor models in which the continuum lag increases in lower-luminosity AGN, including scenarios featuring magnetic coupling between the accretion disk and X-ray corona, and/or ripples or rims in the disk.Comment: 15 pages, 10 figure

The Sloan Digital Sky Survey Reverberation Mapping Project : investigation of continuum lag dependence on broad-line contamination and quasar properties

Funding: H.W.S., J.R.T., M.C.D., and L.B.F. acknowledge support from NSF grant CAREER-1945546, and with C.J.G. acknowledge support from NSF grants AST-2009539 and AST-2108668. C.R. acknowledges support from Fondecyt Regular grant 1230345 and ANID BASAL project FB210003. M.L.M.-A. acknowledges financial support from Millenium Nucleus NCN19-058 (TITANs).This work studies the relationship between accretion-disk size and quasar properties, using a sample of 95 quasars from the Sloan Digital Sky Survey Reverberation Mapping Project with measured lags between the g and i photometric bands. Our sample includes disk lags that are both longer and shorter than predicted by the Shakura and Sunyaev model, requiring explanations that satisfy both cases. Although our quasars each have one lag measurement, we explore the wavelength-dependent effects of diffuse broad-line region (BLR) contamination through our sample’s broad redshift range, 0.1 < z < 1.2. We do not find significant evidence of variable diffuse Fe ii and Balmer nebular emission in the rms spectra, nor from Anderson–Darling tests of quasars in redshift ranges with and without diffuse nebular emission falling in the observed-frame filters. Contrary to previous work, we do not detect a significant correlation between the measured continuum and BLR lags in our luminous quasar sample, similarly suggesting that our continuum lags are not dominated by diffuse nebular emission. Similar to other studies, we find that quasars with larger-than-expected continuum lags have lower 3000 Å luminosities, and we additionally find longer continuum lags with lower X-ray luminosities and black hole masses. Our lack of evidence for diffuse BLR contribution to the lags indicates that the anticorrelation between continuum lag and luminosity is not likely to be due to the Baldwin effect. Instead, these anticorrelations favor models in which the continuum lag increases in lower-luminosity active galactic nuclei, including scenarios featuring magnetic coupling between the accretion disk and X-ray corona, and/or ripples or rims in the disk.Publisher PDFPeer reviewe

The SDSS-V Black Hole Mapper Reverberation Mapping Project: Unusual Broad-Line Variability in a Luminous Quasar

We present a high-cadence multi-epoch analysis of dramatic variability of three broad emission lines (MgII, H$\beta$, and H$\alpha$) in the spectra of the luminous quasar ($\lambda L_{\lambda}$(5100\r{A}) = $4.7 \times 10^{44}$ erg s$^{-1}$) SDSS J141041.25+531849.0 at $z = 0.359$ with 127 spectroscopic epochs over 9 years of monitoring (2013-2022). We observe anti-correlations between the broad emission-line widths and flux in all three emission lines, indicating that all three broad emission lines "breathe" in response to stochastic continuum variations. We also observe dramatic radial velocity shifts in all three broad emission lines, ranging from $\Delta{v}$ $\sim$400 km s$^{-1}$ to $\sim$800 km s$^{-1}$, that vary over the course of the monitoring period. Our preferred explanation for the broad-line variability is complex kinematics in the broad-line region gas. We suggest a model for the broad-line variability that includes a combination of gas inflow with a radial gradient, an azimuthal asymmetry (e.g., a hot spot), superimposed on the stochastic flux-driven changes to the optimal emission region ("line breathing"). Similar instances of line-profile variability due to complex gas kinematics around quasars are likely to represent an important source of false positives in radial velocity searches for binary black holes, which typically lack the kind of high-cadence data we analyze here. The long-duration, wide-field, and many-epoch spectroscopic monitoring of SDSS-V BHM-RM provides an excellent opportunity for identifying and characterizing broad emission-line variability, and the inferred nature of the inner gas environment, of luminous quasars

Development of the HT&Me intervention to support women with breast cancer to adhere to adjuvant endocrine therapy and improve quality of life

Background. Breast cancer is the most common cancer in women worldwide. Approximately 80% of breast cancers are oestrogen receptor positive (ER+). Patients treated surgically are usually recommended adjuvant endocrine therapy (AET) for 5–10 years. AET significantly reduces recurrence, but up to 50% of women do not take it as prescribed. Objective. To co-design and develop an intervention to support AET adherence and improve health-related quality-of-life (QoL) in women with breast cancer. Methods. Design and development of the HT&Me intervention took a person-based approach and was guided by the Medical Research Council framework for complex interventions, based on evidence and underpinned by theory. Literature reviews, behavioural analysis, and extensive key stakeholder involvement informed ‘guiding principles’ and the intervention logic model. Using co-design principles, a prototype intervention was developed and refined. Results. The blended tailored HT&Me intervention supports women to self-manage their AET. It comprises initial and follow-up consultations with a trained nurse, supported with an animation video, a web-app and ongoing motivational ‘nudge’ messages. It addresses perceptual (e.g. doubts about necessity, treatment concerns) and practical (e.g. forgetting) barriers to adherence and provides information, support and behaviour change techniques to improve QoL. Iterative patient feedback maximised feasibility, acceptability, and likelihood of maintaining adherence; health professional feedback maximised likelihood of scalability. Conclusions. HT&Me has been systematically and rigorously developed to promote AET adherence and improve QoL, and is complemented with a logic model documenting hypothesized mechanisms of action. An ongoing feasibility trial will inform a future randomised control trial of effectiveness and cost-effectiveness