Acute Oxygen-Sensing via Mitochondria-Generated Temperature Transients in Rat Carotid Body Type I Cells

The Carotid Bodies (CB) are peripheral chemoreceptors that detect changes in arterial oxygenation and, via afferent inputs to the brainstem, correct the pattern of breathing to restore blood gas homeostasis. Herein, preliminary evidence is presented supporting a novel oxygen-sensing hypothesis which suggests CB Type I cell “hypoxic signaling” may in part be mediated by mitochondria-generated thermal transients in TASK-channel-containing microdomains. Distances were measured between antibody-labeled mitochondria and TASK-potassium channels in primary rat CB Type I cells. Sub-micron distance measurements (TASK-1: 0.33 ± 0.04 µm, n = 47 vs TASK-3: 0.32 ± 0.03 µm, n = 54) provided evidence for CB Type I cell oxygen-sensing microdomains. A temperature-sensitive dye (ERthermAC) indicated that inhibition of mitochondrial activity in isolated cells caused a rapid and reversible inhibition of mitochondrial thermogenesis and thus temperature in these microdomains. Whole-cell perforated-patch current-clamp electrophysiological recordings demonstrated sensitivity of resting membrane potential (Vm) to temperature: lowering bath temperature from 37°C to 24°C induced consistent and reversible depolarizations (Vm at 37°C: -48.4 ± 4.11 mV vs 24°C: -31.0 ± 5.69 mV; n = 5; p \u3c 0.01). These data suggest that hypoxic inhibition of mitochondrial thermogenesis may play an important role in oxygen chemotransduction in the CB. A reduction in temperature within cellular microdomains will inhibit plasma membrane ion channels, influence the balance of cellular phosphorylation–dephosphorylation, and may extend the half-life of reactive oxygen species. The characterization of a thermosensory chemotransduction mechanism, that may also be used by other oxygen-sensitive cell types and may impact multiple other chemotransduction mechanisms is critical if we are to fully understand how the CBs, and potentially other oxygen-sensitive cells, respond to hypoxia

Detailed statistical analysis plan for a cluster randomised controlled trial of the Healthy Lifestyles Programme (HeLP), a novel school-based intervention to prevent obesity in school children

This is the final version of the article. Available from the publisher via the DOI in this record.BACKGROUND: The Healthy Lifestyles Programme (HeLP) trial is being conducted to determine whether a novel school-based intervention is effective and cost-effective in preventing obesity in 9-10 year-old children. This article describes the detailed statistical analysis plan for the HeLP trial, including an amendment (and rationale for amendment) made to originally planned sensitivity analyses. METHODS AND DESIGN: The HeLP trial is a definitive, pragmatic, superiority, cluster randomised controlled trial with two parallel groups and blinded outcome assessment. This update article describes in detail (1) the primary and secondary outcomes, (2) the statistical analysis principles (including which children will be included in each analysis, how the clustered nature of the study design will be accounted for, which covariates will be included in each analysis, how the results will be presented), (3) planned sensitivity analyses, planned subgroup analyses and planned adherence-adjusted analyses for the primary outcome, (4) planned analyses for the secondary outcomes and (e) planned longitudinal analyses. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) register: ISRCTN15811706 . Registered on 1 May 2012.The definitive trial of HeLP is funded by the UK National Institute for Health Research (NIHR) Public Health Research Programme (10/3010/01) and a full report will be published on the NIHR website. KW and JL are partially supported by PenCLAHRC, the National Institute for Health Research (NIHR) CLAHRC for the Southwest Peninsul

CfAIR2: Near Infrared Light Curves of 94 Type Ia Supernovae

CfAIR2 is a large homogeneously reduced set of near-infrared (NIR) light curves for Type Ia supernovae (SN Ia) obtained with the 1.3m Peters Automated InfraRed Imaging TELescope (PAIRITEL). This data set includes 4607 measurements of 94 SN Ia and 4 additional SN Iax observed from 2005-2011 at the Fred Lawrence Whipple Observatory on Mount Hopkins, Arizona. CfAIR2 includes JHKs photometric measurements for 88 normal and 6 spectroscopically peculiar SN Ia in the nearby universe, with a median redshift of z~0.021 for the normal SN Ia. CfAIR2 data span the range from -13 days to +127 days from B-band maximum. More than half of the light curves begin before the time of maximum and the coverage typically contains ~13-18 epochs of observation, depending on the filter. We present extensive tests that verify the fidelity of the CfAIR2 data pipeline, including comparison to the excellent data of the Carnegie Supernova Project. CfAIR2 contributes to a firm local anchor for supernova cosmology studies in the NIR. Because SN Ia are more nearly standard candles in the NIR and are less vulnerable to the vexing problems of extinction by dust, CfAIR2 will help the supernova cosmology community develop more precise and accurate extragalactic distance probes to improve our knowledge of cosmological parameters, including dark energy and its potential time variation.Comment: 31 pages, 15 figures, 10 tables. Accepted to ApJS. v2 modified to more closely match journal versio

Recurring outbursts of the supernova impostor AT 2016blu in NGC 4559

We present the first photometric analysis of the supernova (SN) impostor AT 2016blu in NGC 4559. This transient was discovered by the Lick Observatory Supernova Search in 2012 and has continued its outbursts since then. Optical and infrared photometry of AT 2016blu reveals at least 19 outbursts in 2012-2022. Similar photometry from 1999-2009 shows no outbursts, indicating that the star was relatively stable in the decade before discovery. Archival {\it Hubble Space Telescope} observations suggest that the progenitor had a minimum initial mass of $M >= 33$ M$_{\odot}$ and a luminosity of $L >= 10^{5.7}$ L$_{\odot}$. AT 2016blu's outbursts show irregular variability with multiple closely spaced peaks having typical amplitudes of 1-2 mag and durations of 1-4 weeks. While individual outbursts have irregular light curves, concentrations of these peaks recur with a period of $\sim 113 \pm 2$ d. Based on this period, we predict times for upcoming outbursts in 2023 and 2024. AT 2016blu shares similarities with SN 2000ch in NGC 3432, where outbursts may arise from periastron encounters in an eccentric binary containing a luminous blue variable (LBV). We propose that AT 2016blu's outbursts are also driven by interactions that intensify around periastron in an eccentric system. Intrinsic variability of the LBV-like primary star may cause different intensity and duration of binary interaction at each periastron passage. AT 2016blu also resembles the periastron encounters of $\eta$ Carinae prior to its Great Eruption and the erratic pre-SN eruptions of SN 2009ip. This similarity and the onset of eruptions in the past decade hint that AT 2016blu may also be headed for a catastrophe, making it a target of great interest.Comment: 18 pages, 14 figures, 6 tables, MNRAS Accepte

The Peculiar SN 2005hk: Do Some Type Ia Supernovae Explode as Deflagrations?

We present extensive u'g'r'i'BVRIYJHKs photometry and optical spectroscopy of SN 2005hk. These data reveal that SN 2005hk was nearly identical in its observed properties to SN 2002cx, which has been called ``the most peculiar known type Ia supernova.'' Both supernovae exhibited high ionization SN 1991T-like pre-maximum spectra, yet low peak luminosities like SN 1991bg. The spectra reveal that SN 2005hk, like SN 2002cx, exhibited expansion velocities that were roughly half those of typical type Ia supernovae. The R and I light curves of both supernovae were also peculiar in not displaying the secondary maximum observed for normal type Ia supernovae. Our YJH photometry of SN 2005hk reveals the same peculiarity in the near-infrared. By combining our optical and near-infrared photometry of SN 2005hk with published ultraviolet light curves obtained with the Swift satellite, we are able to construct a bolometric light curve from ~10 days before to ~60 days after B maximum. The shape and unusually low peak luminosity of this light curve, plus the low expansion velocities and absence of a secondary maximum at red and near-infrared wavelengths, are all in reasonable agreement with model calculations of a 3D deflagration which produces ~0.25 M_sun of 56Ni.Comment: Accepted by PASP, to appear in April 2007 issue, 63 pages, 16 figures, 11 table

Prostate Cancer Foundation Hormone-Sensitive Prostate Cancer Biomarker Working Group Meeting Summary.

Androgen deprivation therapy remains the backbone therapy for the treatment of metastatic hormone-sensitive prostate cancer (mHSPC). In recent years, several treatments, including docetaxel, abiraterone + prednisone, enzalutamide, and apalutamide, have each been shown to demonstrate survival benefit when used upfront along with androgen deprivation therapy. However, treatment selection for an individual patient remains a challenge. There is no high level clinical evidence for treatment selection among these choices based on biological drivers of clinical disease. In August 2020, the Prostate Cancer Foundation convened a working group to meet and discuss biomarkers for hormone-sensitive prostate cancer, the proceedings of which are summarized here. This meeting covered the state of clinical and biological evidence for systemic therapies in the mHSPC space, with emphasis on charting a course for the generation, interrogation, and clinical implementation of biomarkers for treatment selection

Intervention fidelity in the definitive cluster randomised controlled trial of the Healthy Lifestyles Programme (HeLP) trial: findings from the process evaluation.

BACKGROUND: The Healthy Lifestyles Programme (HeLP) was a novel school-located intervention for 9-10 year olds, designed to prevent obesity by changing patterns of child behaviour through the creation of supportive school and home environments using dynamic and creative delivery methods. This paper reports on both the quantitative and qualitative data regarding the implementation of the HeLP intervention in the definitive cluster randomised controlled trial, which was part of the wider process evaluation. METHODS: Mixed methods were used to collect data on intervention uptake, fidelity of delivery in terms of content and quality of delivery of the intervention, as well as school and child engagement with the programme. Data were collected using registers of attendance, observations and checklists, field notes, focus groups with children and semi-structured interviews with teachers. Qualitative data were analysed thematically and quantitative data were summarized using descriptive statistics. RESULTS: All 16 intervention schools received a complete or near complete programme (94-100%), which was delivered in the spirit in which it had been designed. Of the 676 children in the intervention schools, over 90% of children participated in each phase of HeLP; 92% of children across the socio-economic spectrum were deemed to be engaged with HeLP and qualitative data revealed a high level of enjoyment by all children, particularly to the interactive drama workshops. Further evidence of child engagment with the programme was demonstrated by children's clear understanding of programme messages around marketing, moderation and food labelling. Thirteen of the intervention schools were deemed to be fully engaged with HeLP and qualitative data revealed a high level of teacher 'buy in', due to the programme's compatability with the National Curriculum, level of teacher support and use of innovative and creative delivery methods by external drama practitioners. CONCLUSION: Our trial shows that it is possible to successfully scale up complex school-based interventions, engage schools and children across the socio-economic spectrum and deliver an intervention as designed. As programme integrity was maintained throughout the HeLP trial, across all intervention schools, we can be confident that the trial findings are a true reflection of the effectiveness of the intervention, enabling policy recommendations to be made. TRIAL REGISTRATION: ISRCTN15811706

Direct Imaging of Hippocampal Epileptiform Calcium Motifs Following Kainic Acid Administration in Freely Behaving Mice

Prolonged exposure to abnormally high calcium concentrations is thought to be a core mechanism underlying hippocampal damage in epileptic patients; however, no prior study has characterized calcium activity during seizures in the live, intact hippocampus. We have directly investigated this possibility by combining whole-brain electroencephalographic (EEG) measurements with microendoscopic calcium imaging of pyramidal cells in the CA1 hippocampal region of freely behaving mice treated with the pro-convulsant kainic acid (KA). We observed that KA administration led to systematic patterns of epileptiform calcium activity: a series of large-scale, intensifying flashes of increased calcium fluorescence concurrent with a cluster of low-amplitude EEG waveforms. This was accompanied by a steady increase in cellular calcium levels (>5 fold increase relative to the baseline), followed by an intense spreading calcium wave characterized by a 218% increase in global mean intensity of calcium fluorescence (n = 8, range [114 - 349%], p<10-4; t-test). The wave had no consistent EEG phenotype and occurred before the onset of motor convulsions. Similar changes in calcium activity were also observed in animals treated with 2 different proconvulsant agents, N-methyl-D-aspartate (NMDA) and pentylenetetrazol (PTZ), suggesting the measured changes in calcium dynamics are a signature of seizure activity rather than a KA-specific pathology. Additionally, despite reducing the behavioral severity of KA-induced seizures, the anticonvulsant drug valproate (VA, 300 mg/kg) did not modify the observed abnormalities in calcium dynamics. These results confirm the presence of pathological calcium activity preceding convulsive motor seizures and support calcium as a candidate signaling molecule in a pathway connecting seizures to subsequent cellular damage. Integrating in vivo calcium imaging with traditional assessment of seizures could potentially increase translatability of pharmacological intervention, leading to novel drug screening paradigms and therapeutics designed to target and abolish abnormal patterns of both electrical and calcium excitation

Weight Loss Strategies Associated With BMI in Overweight Adults With Type 2 Diabetes at Entry Into the Look AHEAD (Action for Health in Diabetes) Trial

OBJECTIVE—Intentional weight loss is recommended for those with type 2 diabetes, but the strategies patients attempt and their effectiveness for weight management are unknown. In this investigation we describe intentional weight loss strategies used and those related to BMI in a diverse sample of overweight participants with type 2 diabetes at enrollment in the Look AHEAD (Action for Health in Diabetes) clinical trial