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RATIONALE The pathophysiology of interstitial lung disease (ILD) impacts body composition, whereby ILD severity is linked to lower lean mass. OBJECTIVES To determine i) if pectoralis muscle area (PMA) is a surrogate for whole-body lean mass in ILD, ii) whether PMA is associated with ILD severity, and iii) if the longitudinal change in PMA is associated with pulmonary function and mortality in ILD. METHODS Patients with ILD (n = 164) were analyzed retrospectively. PMA was quantified from a chest computed tomography scan. Peripheral oxygen saturation (SpO2), 6-min walk distance (6MWD), and pulmonary function were obtained as part of routine clinical care. Dyspnea and quality of life were assessed using the UCSD Shortness of Breath Questionnaire and European Quality of Life 5 Dimensions questionnaire, respectively. RESULTS PMA was associated with whole-body lean mass (p  0.05). The annual negative PMA slope was associated with annual negative slopes in FVC, FEV1, and DLCO (all p < 0.05), but not FEV1/FVC (p = 0.46). Annual slope in PMA was associated with all-cause mortality (hazard ratio = -0.80, 95% CI:0.889-0.959; p < 0.001). CONCLUSION In patients with ILD, PMA is a suitable surrogate for whole-body lean mass. A lower PMA is associated with indices of ILD severity, which supports the notion that ILD progression may involve sarcopenia.

Alzheimer's disease (AD) is linked to the abnormal accumulation of amyloid β peptide (Aβ) aggregates in the brain. Silybin B, a natural compound extracted from milk thistle (

The human genome encodes ∼20 mitochondrial proteases, yet we know little of how they sculpt the mitochondrial proteome, particularly during important mitochondrial events such as the initiation of apoptosis. To characterize global mitochondrial proteolysis we refined our technique, terminal amine isotopic labeling of substrates, for mitochondrial SILAC (MS-TAILS) to identify proteolysis across mitochondria and parent cells in parallel. Our MS-TAILS analyses identified 45% of the mitochondrial proteome and identified protein amino (N)-termini from 26% of mitochondrial proteins, the highest reported coverage of the human mitochondrial N-terminome. MS-TAILS revealed 97 previously unknown proteolytic sites. MS-TAILS also identified mitochondrial targeting sequence (MTS) removal by proteolysis during protein import, confirming 101 MTS sites and identifying 135 new MTS sites, revealing a wobbly requirement for the MTS cleavage motif. To examine the relatively unknown initial cleavage events occurring before the well-studied activation of caspase-3 in intrinsic apoptosis, we quantitatively compared N-terminomes of mitochondria and their parent cells before and after initiation of apoptosis at very early time points. By identifying altered levels of400 N-termini, MS-TAILS analyses implicated specific mitochondrial pathways including protein import, fission, and iron homeostasis in apoptosis initiation. Notably, both staurosporine and Bax activator molecule-7 triggered in common 7 mitochondrial and 85 cellular cleavage events that are potentially part of an essential core of apoptosis-initiating events. All mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium with the dataset identifier PXD009054.

Pregnancy complications associated with prenatal hypoxia lead to increased placental oxidative stress. Previous studies suggest that prenatal hypoxia can reduce mitochondrial respiratory capacity and mitochondrial fusion, which could lead to placental dysfunction and impaired fetal development. We developed a placenta-targeted treatment strategy using a mitochondrial antioxidant, MitoQ, encapsulated into nanoparticles (nMitoQ) to reduce placental oxidative stress and (indirectly) improve fetal outcomes. We hypothesized that, in a rat model of prenatal hypoxia, nMitoQ improves placental mitochondrial function and promotes mitochondrial fusion in both male and female placentae. Pregnant rats were treated with saline or nMitoQ on gestational day (GD) 15 and exposed to normoxia (21% O2 ) or hypoxia (11% O2 ) from GD15-21. On GD21, male and female placental labyrinth zones were collected for mitochondrial respirometry assessments, mitochondrial content, and markers of mitochondrial biogenesis, fusion and fission. Prenatal hypoxia reduced complex IV activity and fusion in male placentae, while nMitoQ improved complex IV activity in hypoxic male placentae. In female placentae, prenatal hypoxia decreased respiration through the S-pathway (complex II) and increased N-pathway (complex I) respiration, while nMitoQ increased fusion in hypoxic female placentae. No changes in mitochondrial content, biogenesis or fission were found. In conclusion, nMitoQ improved placental mitochondrial function in male and female placentae from fetuses exposed to prenatal hypoxia, which may contribute to improved placental function. However, the mechanisms (ie, changes in mitochondrial respiratory capacity and mitochondrial fusion) were distinct between the sexes. Treatment strategies targeted against placental oxidative stress could improve placental mitochondrial function in complicated pregnancies.

Machine learning (ML) methods are increasingly used in addition to conventional statistical modelling (CSM) for predicting readmission and mortality in patients with myocardial infarction (MI). However, the two approaches have not been systematically compared across studies of prognosis in patients with MI.Following PRISMA guidelines, we systematically reviewed the literature via Medline, EPub, Cochrane Central, Embase, Inspec, ACM Digital Library, and Web of Science. Eligible studies included primary research articles published from January 2000 to March 2020, comparing ML and CSM for prognostication after MI.Of 7,348 articles, 112 underwent full-text review, with the final set composed of 24 articles representing 374,365 patients. ML methods included artificial neural networks (n = 12 studies), random forests (n = 11), decision trees (n = 8), support vector machines (n = 8), and Bayesian techniques (n = 7). CSM included logistic regression (n = 19 studies), existing CSM-derived risk scores (n = 12), and Cox regression (n = 2). Thirteen of 19 studies examining mortality reported higher C-indexes with the use of ML compared with CSM. One study examined readmissions at 2 different time points, with C-indexes that were higher for ML than CSM. Across all studies, a total of 29 comparisons were performed, but the majority (n = 26, 90%) found small (0.05) absolute differences in the C-index between ML and CSM. With the use of a modified CHARMS checklist, sources of bias were identifiable in the majority of studies, and only 2 were externally validated.Although ML algorithms tended to have higher C-indexes than CSM for predicting death or readmission after MI, these studies exhibited threats to internal validity and were often unvalidated. Further comparisons are needed, with adherence to clinical quality standards for prognosis research. (Trial registration: PROSPERO CRD42019134896).

AbstractAnoxic‐epileptic seizures (AES) are rare outcomes of common childhood reflex anoxic syncope that trigger a true epileptic seizure. The term AES was coined by Stephenson in 1983, to differentiate these events from convulsive syncopes and the more common reflex anoxic syncopes. A genetic susceptibility for AES has been postulated; but, its molecular basis has up to now been elusive. We report here two illustrative cases and show the association of de novoSCN8Avariants and AES. One of them had focal or generalized seizures and autonomic symptoms triggered by orthostatism; the second had breath‐holding spells triggered by pain or exercise leading to tonic–clonic seizures; both had repeatedly normal EEGs and a family history of reflex syncope. The data of three additional AES patients further suggest, for the first time, a link betweenSCN8Apathogenic variants and AES. The neurodevelopment of four patients was abnormal. Four of the fiveSCN8Amutations observed here were previously described in patients with seizure disorders. Seizures responded particularly well to sodium channel blockers. Our observation enriches the spectrum of seizures linked withSCN8Apathogenic variants.

Skeletal muscle contains a designated population of adult stem cells, called satellite cells, which are generally quiescent. In homeostasis, satellite cells proliferate only sporadically and usually by asymmetric cell division to replace myofibres damaged by daily activity and maintain the stem cell pool. However, satellite cells can also be robustly activated upon tissue injury, after which they undergo symmetric divisions to generate new stem cells and numerous proliferating myoblasts that later differentiate to muscle cells (myocytes) to rebuild the muscle fibre, thereby supporting skeletal muscle regeneration. Recent discoveries show that satellite cells have a great degree of population heterogeneity, and that their cell fate choices during the regeneration process are dictated by both intrinsic and extrinsic mechanisms. Extrinsic cues come largely from communication with the numerous distinct stromal cell types in their niche, creating a dynamically interactive microenvironment. This Review discusses the role and regulation of satellite cells in skeletal muscle homeostasis and regeneration. In particular, we highlight the cell-intrinsic control of quiescence versus activation, the importance of satellite cell-niche communication, and deregulation of these mechanisms associated with ageing. The increasing understanding of how satellite cells are regulated will help to advance muscle regeneration and rejuvenation therapies.

Compensatory stepping is an important protective mechanism to prevent falling. To recover from sideways perturbations side steps are generally more advantageous than cross-over steps. However, there is lack of understanding of the characteristics of compensatory side steps following sideways perturbations that separate successful recoveries (i.e., no falls) from falls, the most clinically relevant outcome following a balance perturbation. We aimed to identify the critical determinants for successful side stepping after large sideways balance perturbations. Twelve healthy young adults were subjected to large leftward perturbations at varying intensities on a translating sheet. For recovery attempts started with a side step, we determined body configuration variables (frontal-plane leg and trunk angle) at first step contact, as well as spatiotemporal step variables (onset, length, duration, velocity). A logistic regression analysis was conducted to determine the predictive ability of body configuration and spatiotemporal variables on the probability of success (no fall vs. fall); perturbation intensity (peak jerk of translating sheet) and a random effect for individual were also included in the model. In the final model, leg angle and peak jerk were retained as predictors of successful balance recovery and these variables correctly classified the recovery outcome in 86% of the trials. This final 'body configuration' model yielded a -2 log likelihood of -36.3, whereas the best fitting model with only spatiotemporal variables yielded a -2 log likelihood of -45.8 (indicating a poorer fit). The leg angle at a given perturbation intensity appears to be a valid measure of reactive side step quality. The relative ease of measuring this leg angle at step contact makes it a candidate outcome for reactive stepping assessments in clinical practice.