Antagonists of myostatin, a blood-borne negative regulator of muscle growth produced in muscle cells, have shown considerable promise for enhancing muscle mass and strength in rodent studies and ...could serve as potential therapeutic agents for human muscle diseases. One of the most potent of these agents, follistatin, is both safe and effective in mice, but similar tests have not been performed in nonhuman primates. To assess this important criterion for clinical translation, we tested an alternatively spliced form of human follistatin that affects skeletal muscle but that has only minimal effects on nonmuscle cells. When injected into the quadriceps of cynomolgus macaque monkeys, a follistatin isoform expressed from an adeno-associated virus serotype 1 vector, AAV1-FS344, induced pronounced and durable increases in muscle size and strength. Long-term expression of the transgene did not produce any abnormal changes in the morphology or function of key organs, indicating the safety of gene delivery by intramuscular injection of an AAV1 vector. Our results, together with the findings in mice, suggest that therapy with AAV1-FS344 may improve muscle mass and function in patients with certain degenerative muscle disorders.
•Systems ergonomics methods are increasingly being used to optimise transport systems.•Integration of different methods potentially provides a richer more useful analysis.•The EAST analysis framework ...was modified to incorporate principles of STAMP.•The modified framework was used to analyse safety in Railway Level Crossing (RLX) systems.•The analysis revealed areas where RLX safety management practice could be enhanced.
Various systems ergonomics methods are available to support the design and analysis of rail systems. Whilst the utility of these methods is accepted, the increasing complexity of modern day systems is stretching their capabilities. The integration of distinct systems ergonomics methods provides a means of redressing this. This article presents a study in which the underpinning principles of the STAMP control structure method were added to the EAST framework, and subsequently used to examine railway level crossing safety management. Task, social and information networks for a railway level crossing system lifecycle were developed along with an additional control network showing safety controls and their interrelations. Analysis of the networks points to a need to (1) strengthen activities and controls around proactive risk management and performance monitoring, (2) tighten the coupling between organisations responsible for safety management, and (3) to increase the flexibility of design standards. The implications for future railway level crossing safety management and rail safety research and practice are discussed.
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) interconverts inactive cortisone and active cortisol. Although bidirectional, in vivo it is believed to function as a reductase generating active ...glucocorticoid at a prereceptor level, enhancing glucocorticoid receptor activation. In this review, we discuss both the genetic and enzymatic characterization of 11β-HSD1, as well as describing its role in physiology and pathology in a tissue-specific manner. The molecular basis of cortisone reductase deficiency, the putative “11β-HSD1 knockout state” in humans, has been defined and is caused by intronic mutations in HSD11B1 that decrease gene transcription together with mutations in hexose-6-phosphate dehydrogenase, an endoluminal enzyme that provides reduced nicotinamide-adenine dinucleotide phosphate as cofactor to 11β-HSD1 to permit reductase activity. We speculate that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucleotide phosphate supply may be crucial in determining the directionality of 11β-HSD1 activity. Therapeutic inhibition of 11β-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect.
Glucocorticoids (GCs) are highly detrimental to skin integrity and function both when applied topically for anti-inflammatory treatments and during conditions of circulating excess, e.g., Cushing's ...syndrome. Within target tissues, GC availability is regulated at a prereceptor level, independently of systemic levels, by isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD) that interconvert active cortisol and inactive cortisone. Many of the adverse effects of GCs on skin are also reminiscent of the natural aging process. 11β-HSD1 (which activates cortisol), but not 11β-HSD2 (which inactivates cortisol), was expressed in epidermal keratinocytes and dermal fibroblasts in human skin and also in outer hair follicle root sheath cells in murine skin. 11β-HSD1 activity was present ex vivo in both species and increased with age in human skin tissue explants. In primary human dermal fibroblasts (HDF) from both photoprotected and photoexposed sites, 11β-HSD1 also increased with donor age. Additionally, photoexposed HDF displayed higher 11β-HSD1 mRNA expression than donor-matched photoprotected HDF. GC treatment of HDF caused upregulation of 11β-HSD1 mRNA levels independent of donor age or site. The age- and site-associated increase in dermal 11β-HSD1, and the ensuing increased local GC activation, may contribute to the adverse changes in skin morphology and function associated with chronological aging and photoaging.
Military command and control is not merely evolving, it is co-evolving. Technology is creating new opportunities for different types of command and control, and new types of command and control are ...creating new aspirations for technology. The question is how to manage this process, how to achieve a jointly optimised blend of socio and technical and create the kind of agility and self-synchronisation that modern forms of command and control promise. The answer put forward in this book is to re-visit sociotechnical systems theory. In doing so, the problems of 21st century command and control can be approached from an alternative, multi-disciplinary and above all human-centred perspective.
ABSTRACT
Basic combat training (BCT) is a physically rigorous period at the beginning of a soldier's career that induces bone formation in the tibia. Race and sex are determinants of bone properties ...in young adults but their influences on changes in bone microarchitecture during BCT are unknown. The purpose of this work was to determine the influence of sex and race on changes in bone microarchitecture during BCT. Bone microarchitecture was assessed at the distal tibia via high‐resolution peripheral quantitative computed tomography at the beginning and end of 8 weeks of BCT in a multiracial cohort of trainees (552 female, 1053 male; mean ± standard deviation SD age = 20.7 ± 3.7 years) of which 25.4% self‐identified as black, 19.5% as race other than black or white (other races combined), and 55.1% as white. We used linear regression models to determine whether changes in bone microarchitecture due to BCT differed by race or sex, after adjusting for age, height, weight, physical activity, and tobacco use. We found that trabecular bone density (Tb.BMD), thickness (Tb.Th), and volume (Tb.BV/TV), as well as cortical BMD (Ct.BMD) and thickness (Ct.Th) increased following BCT in both sexes and across racial groups (+0.32% to +1.87%, all p < 0.01). Compared to males, females had greater increases in Tb.BMD (+1.87% versus +1.40%; p = 0.01) and Tb.Th (+0.87% versus +0.58%; p = 0.02), but smaller increases in Ct.BMD (+0.35% versus +0.61%; p < 0.01). Compared to black trainees, white trainees had greater increases in Tb.Th (+0.82% versus +0.61%; p = 0.03). Other races combined and white trainees had greater increases in Ct.BMD than black trainees (+0.56% and + 0.55% versus +0.32%; both p ≤ 0.01). Changes in distal tibial microarchitecture, consistent with adaptive bone formation, occur in trainees of all races and sexes, with modest differences by sex and race. Published 2023. This article is a U.S. Government work and is in the public domain in the USA. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
The changing nature of work and society, and a proliferation of complex global challenges, is increasing the need for systems Human Factors and Ergonomics (HFE). The discipline is well equipped to ...respond, but there remain a number of longstanding issues preventing systems HFE from realizing its full impact. There is a research–practice gap, a lack of reliability and validity evidence associated with systems HFE methods, and a shortage of methods that can predict behavior. In this article we revisit each issue, with each co‐author providing their own perspective on the extent and causes of each issue, and their resolution. The perspectives reveal a consensus that the issues exist and are problematic but are challenging, multi‐factorial, and require various solutions. The findings are subsequently synthesized to form an agenda for the wider discipline.
Collisions between different road users make a substantial contribution to road trauma. Although evidence suggests that different road users interpret the same road situations differently, it is not ...clear how road users' situation awareness differs, nor is it clear which differences might lead to conflicts. This article presents the findings from an on-road study conducted to examine driver, motorcyclist and cyclist situation awareness in different road environments. The findings suggest that, in addition to minor differences in the structure of different road users' situation awareness (i.e. amount of information and how it is integrated), the actual content of situation awareness in terms of road user schemata, the resulting interaction with the world and the information underpinning situation awareness is markedly different. Further examination indicates that the differences are likely to be compatible along arterial roads, shopping strips and at roundabouts, but that they may create conflicts between different road users at intersections. Interventions designed to support compatible situation awareness and behaviour between different road users are discussed.
Practitioner Summary: Incompatible situation awareness plays a key role in collisions between different road users (e.g. drivers and motorcyclists). This on-road study examined situation awareness in drivers, motorcyclists and cyclists, identifying the key differences and potential conflicts that arise. The findings are used to propose interventions designed to enhance the compatibility of situation awareness between road users.
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