Striking Denervation of Neuromuscular Junctions without Lumbar Motoneuron Loss in Geriatric Mouse Muscle

Reasons for the progressive age-related loss of skeletal muscle mass and function, namely sarcopenia, are complex. Few studies describe sarcopenia in mice, although this species is the mammalian model of choice for genetic intervention and development of pharmaceutical interventions for muscle degeneration. One factor, important to sarcopenia-associated neuromuscular change, is myofibre denervation. Here we describe the morphology of the neuromuscular compartment in young (3 month) compared to geriatric (29 month) old female C57Bl/6J mice. There was no significant difference in the size or number of motoneuron cell bodies at the lumbar level (L1–L5) of the spinal cord at 3 and 29 months. However, in geriatric mice, there was a striking increase (by ∼2.5 fold) in the percentage of fully denervated neuromuscular junctions (NMJs) and associated deterioration of Schwann cells in fast extensor digitorum longus (EDL), but not in slow soleus muscles. There were also distinct changes in myofibre composition of lower limb muscles (tibialis anterior (TA) and soleus) with a shift at 29 months to a faster phenotype in fast TA muscle and to a slower phenotype in slow soleus muscle. Overall, we demonstrate complex changes at the NMJ and muscle levels in geriatric mice that occur despite the maintenance of motoneuron cell bodies in the spinal cord. The challenge is to identify which components of the neuromuscular system are primarily responsible for the marked changes within the NMJ and muscle, in order to selectively target future interventions to reduce sarcopenia

A proposed systems approach to the evaluation of integrated palliative care

<p>Abstract</p> <p>Background</p> <p>There is increasing global interest in regional palliative care networks (PCN) to integrate care, creating systems that are more cost-effective and responsive in multi-agency settings. Networks are particularly relevant where different professional skill sets are required to serve the broad spectrum of end-of-life needs. We propose a comprehensive framework for evaluating PCNs, focusing on the nature and extent of inter-professional collaboration, community readiness, and client-centred care.</p> <p>Methods</p> <p>In the absence of an overarching structure for examining PCNs, a framework was developed based on previous models of health system evaluation, explicit theory, and the research literature relevant to PCN functioning. This research evidence was used to substantiate the choice of model factors.</p> <p>Results</p> <p>The proposed framework takes a systems approach with system structure, process of care, and patient outcomes levels of consideration. Each factor represented makes an independent contribution to the description and assessment of the network.</p> <p>Conclusions</p> <p>Realizing palliative patients' needs for complex packages of treatment and social support, in a seamless, cost-effective manner, are major drivers of the impetus for network-integrated care. The framework proposed is a first step to guide evaluation to inform the development of appropriate strategies to further promote collaboration within the PCN and, ultimately, optimal palliative care that meets patients' needs and expectations.</p

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

The JWST Early Release Science Program for Direct Observations of Exoplanetary Systems. IV. NIRISS Aperture Masking Interferometry Performance and Lessons Learned

This is the final version. Available on open access from IOP Publishing via the DOI in this recordWe present a performance analysis for the aperture masking interferometry (AMI) mode on board the James Webb Space Telescope Near Infrared Imager and Slitless Spectrograph (JWST/NIRISS). Thanks to self-calibrating observables, AMI accesses inner working angles down to and even within the classical diffraction limit. The scientific potential of this mode has recently been demonstrated by the Early Release Science (ERS) 1386 program with a deep search for close-in companions in the HIP 65426 exoplanetary system. As part of ERS 1386, we use the same data set to explore the random, static, and calibration errors of NIRISS AMI observables. We compare the observed noise properties and achievable contrast to theoretical predictions. We explore possible sources of calibration errors and show that differences in charge migration between the observations of HIP 65426 and point-spread function calibration stars can account for the achieved contrast curves. Lastly, we use self-calibration tests to demonstrate that with adequate calibration NIRISS F380M AMI can reach contrast levels of ~9-10 mag at ≥λ/D. These tests lead us to observation planning recommendations and strongly motivate future studies aimed at producing sophisticated calibration strategies taking these systematic effects into account. This will unlock the unprecedented capabilities of JWST/NIRISS AMI, with sensitivity to significantly colder, lower-mass exoplanets than lower-contrast ground-based AMI setups, at orbital separations inaccessible to JWST coronagraphy.National Science Foundation (NSF)NASAEuropean Union Horizon 2020Royal Societ

The JWST Early Release Science Program for Direct Observations of Exoplanetary Systems. V. Do Self-consistent Atmospheric Models Represent JWST Spectra? A Showcase with VHS 1256–1257 b

This is the final version. Available on open access from IOP Publishing via the DOI in this recordThe unprecedented medium-resolution (Rλ ∼ 1500–3500) near- and mid-infrared (1–18 μm) spectrum provided by JWST for the young (140 ± 20 Myr) low-mass (12–20 MJup) L–T transition (L7) companion VHS 1256 b gives access to a catalog of molecular absorptions. In this study, we present a comprehensive analysis of this data set utilizing a forward-modeling approach applying our Bayesian framework, ForMoSA. We explore five distinct atmospheric models to assess their performance in estimating key atmospheric parameters: Teff, log(g), [M/H], C/O, γ, fsed, and R. Our findings reveal that each parameter's estimate is significantly influenced by factors such as the wavelength range considered and the model chosen for the fit. This is attributed to systematic errors in the models and their challenges in accurately replicating the complex atmospheric structure of VHS 1256 b, notably the complexity of its clouds and dust distribution. To propagate the impact of these systematic uncertainties on our atmospheric property estimates, we introduce innovative fitting methodologies based on independent fits performed on different spectral windows. We finally derived a Teff consistent with the spectral type of the target, considering its young age, which is confirmed by our estimate of log(g). Despite the exceptional data quality, attaining robust estimates for chemical abundances [M/H] and C/O, often employed as indicators of formation history, remains challenging. Nevertheless, the pioneering case of JWST's data for VHS 1256 b has paved the way for future acquisitions of substellar spectra that will be systematically analyzed to directly compare the properties of these objects and correct the systematics in the models