An increase in force after stretch of diaphragm fibers and myofibrils is accompanied by an increase in sarcomere length nonuniformities and Ca2+ sensitivity.

When muscle fibers from limb muscles are stretched while activated, the force increases to a steady-state level that is higher than that produced during isometric contractions at a corresponding sarcomere length, a phenomenon known as residual force enhancement (RFE). The mechanisms responsible for the RFE are an increased stiffness of titin molecules that may lead to an increased Ca2+ sensitivity of the contractile apparatus, and the development of sarcomere length nonuniformities. RFE is not observed in cardiac myofibrils, which makes this phenomenon specific to certain preparations. The aim of this study was to investigate whether the RFE is present in the diaphragm, and its potential association with an increased Ca2+ sensitivity and the development of sarcomere length nonuniformities. We used two preparations: single intact fibers and myofibrils isolated from the diaphragm of mice. We investigated RFE in a variety of lengths across the force-length relationship. RFE was observed in both preparations at all lengths investigated and was larger with increasing magnitudes of stretch. RFE was accompanied by an increased Ca2+ sensitivity as shown by a change in the force-pCa2+ curve, and increased sarcomere length nonuniformities. Therefore, RFE is a phenomenon commonly observed in skeletal muscles, with mechanisms that are similar across preparations.

Erythema multiforme as a consequence of COVID-19 infection.

Cutaneous manifestations of the 2019 coronavirus disease (COVID-19) are diverse and may be the only clinical evidence of infection, particularly in children [1]. The authors report a 10-year-old girl with erythematous vesicular papules and targetoid lesions of the extremities two weeks after polymerase chain reaction (PCR) confirmed severe acute respiratory syndrome coronavirus two (SARS-COV-2) infection. Biopsy depicted classic erythema multiforme (EM) and serology confirmed positive COVID-19 antibodies. This report demonstrates one of the first reported pediatric cases of typical clinical and histopathologic EM in relation to confirmed COVID-19.

Microfluidic perfusion shows intersarcomere dynamics within single skeletal muscle myofibrils.

The sarcomere is the smallest functional unit of myofibrils in striated muscles. Sarcomeres are connected in series through a network of elastic and structural proteins. During myofibril activation, sarcomeres develop forces that are regulated through complex dynamics among their structures. The mechanisms that regulate intersarcomere dynamics are unclear, which limits our understanding of fundamental muscle features. Such dynamics are associated with the loss in forces caused by mechanical instability encountered in muscle diseases and cardiomyopathy and may underlie potential target treatments for such conditions. In this study, we developed a microfluidic perfusion system to control one sarcomere within a myofibril, while measuring the individual behavior of all sarcomeres. We found that the force from one sarcomere leads to adjustments of adjacent sarcomeres in a mechanism that is dependent on the sarcomere length and the myofibril stiffness. We concluded that the cooperative work of the contractile and the elastic elements within a myofibril rules the intersarcomere dynamics, with important consequences for muscle contraction.

A role for myosin VI in retinal pigment epithelium phagocytosis.

The retinal pigment epithelium (RPE) is a monolayer of pigmented cells adjacent to the choroid coat, the vascular layer of the eye. Among other functions, these cells are responsible for the phagocytosis of rod and cone cell waste shed from the photoreceptor outer segments. We describe here studies to understand the involvement of the motor protein myosin VI in the trafficking of internalized microspheres by a human retinal pigment epithelium primary cell line (ARPE-19). We perturbed the myosin VI-actin interaction by overexpressing a dominant negative myosin VI construct in these cells. We used single particle tracking to characterize the trajectories of internalized fluorescent microspheres. Analysis of the speed of the microspheres' motions revealed that the magnitude of the average speed over short time scales is reduced in the presence of the dominant negative motor. Analysis of the mean-squared displacement of these trajectories demonstrated that trafficking of phagosomes involves two modes of motion, a rapid, more randomly directed motion that is myosin VI dependent and a slower, more directed motion that is independent of the motor. From these data, we posit that this trafficking process involves an interplay between myosin VI motors, which are involved in motion through the actin periphery of the cell, and microtubule motors.

MgADP activation contributes to force enhancement during fast stretch of isolated skeletal myofibrils.

BACKGROUND: When an activated muscle is rapidly stretched, force rises and peaks while muscle lengthens. The peak force is normally called critical-force (Pc). The mechanism behind this increase in force is not well understood, but it has been associated with crossbridges operating in different states. METHODS: Myofibrils were attached between a cantilever and a micro-needle, and activated with Ca(2+) or MgADP. During activation, the myofibrils were stretched by 3% SLo at 10 SLo·s(-1). A crossbridge model was developed to better understand the effects of MgADP in myofibrils activation. RESULTS: Despite a similar stretch magnitude, MgADP activation produced a higher Pc (1.37 ± 0.07 P/Po) than Ca(2+) activation (Pc = 1.23 ± 0.03 P/Po). These results suggest that myofibrils activated with MgADP become stiffer than myofibrils activated with Ca(2+). CONCLUSIONS: MgADP induces a fraction of crossbridges to form a "rigor-like" state that precedes ADP release, and that may not contribute to isometric forces. Such interpretation was strengthened by the results obtained with the developed crossbridge model, which showed that MgADP bias crossbridges into the rigor-like state. This state would be crucial to initiate a cooperative activation of crossbridges and actin, and to resist to unbinding from actin when the myofibrils are stretched. SIGNIFICANCE: Our results suggest a new mechanism contributing for force output during stretch, which underlies basic mechanisms of muscle contraction.

Precise positioning of myosin VI on endocytic vesicles in vivo.

Myosin VI has been studied in both a monomeric and a dimeric form in vitro. Because the functional characteristics of the motor are dramatically different for these two forms, it is important to understand whether myosin VI heavy chains are brought together on endocytic vesicles. We have used fluorescence anisotropy measurements to detect fluorescence resonance energy transfer between identical fluorophores (homoFRET) resulting from myosin VI heavy chains being brought into close proximity. We observed that, when associated with clathrin-mediated endocytic vesicles, myosin VI heavy chains are precisely positioned to bring their tail domains in close proximity. Our data show that on endocytic vesicles, myosin VI heavy chains are brought together in an orientation that previous in vitro studies have shown causes dimerization of the motor. Our results are therefore consistent with vesicle-associated myosin VI existing as a processive dimer, capable of its known trafficking function.

Challenges in sustaining public health interventions.

Sustainability remains a key challenge in public health. The perspective article by Fagen and Flay adds to our understanding of technical factors associated with sustaining health interventions in schools. In this commentary, the Fagen and Flay article (2009) is considered within the broader literature on sustainability. By taking a broad view, public health theory and practice might be advanced further. Fagen and Flay illustrate that we have much to learn about sustainability. Questions for future research include: (a) what can we put into place at the systems level to ensure that the short-term efficacy of interventions have a fighting chance to be sustained? (b) considering the challenges inherent in sustainability, what are realistic goals against which to evaluate the cost-effectiveness of interventions found effective in the short-term? and (c) what theories, methods, and strategies in fields outside of public health can be drawn upon to improve work in public health?

En coup de sabre.

En coup de sabre (ECDS) is a rare form of localized scleroderma that typically manifests in children and women. It presents as a fibrous pansclerotic plaque extending in a bandlike distribution on the frontoparietal scalp with surrounding scarring alopecia. Many patients have comorbid central nervous system involvement in addition to the cutaneous findings. En coup de sabre is a rare entity that should be delineated from Parry-Romberg syndrome, as both entities share some common features and may coexist. Corticosteroids remain the treatment of choice, but other modalities such as methotrexate, excimer laser, and grafting have been used with varying success. We report a case of an elderly woman who presented with an asymptomatic alopecic plaque consistent with ECDS.

Tobacco farmers and tobacco manufacturers: implications for tobacco control in tobacco-growing developing countries.

Assisting tobacco farmers to transition to non-tobacco alternatives is a key element of comprehensive tobacco control's end-game strategy and specifically required by the World Health Organization (WHO) Framework Convention for Tobacco Control (FCTC). We examine the historical relationship between tobacco manufacturers and tobacco farmers in the United States, where the duration of the relationship has been longest and use information obtained to inform possible end-game strategies for tobacco control advocates working with tobacco farmers in developing countries. Tobacco Documents obtained under the Master Settlement Agreement (MSA) provide evidence of conflicts between tobacco manufacturers and tobacco farmers. Findings support WHO FCTC articles aimed at helping developing country tobacco farmers adversely affected by tobacco control efforts and highlight difficulties in discouraging tobacco cultivation as long as it remains relatively profitable. We conclude that successful end-game strategies should take a long-term approach aimed at building alliances with tobacco farmers and at creating mechanisms for tobacco farmer investment in local infrastructure.

Panniculitis, pancreatitis, and polyarthritis: a rare clinical syndrome.

A rare triad composed of lobular panniculitis in the setting of pancreatitis and polyarthritis is termed panniculitis, pancreatitis, and polyarthritis (PPP) syndrome. Pancreatic panniculitis is a rare form of subcutaneous fat necrosis associated with underlying pancreatic disease. We describe a case of PPP syndrome and review the relevant literature associated with this rare clinical syndrome. Despite numerous adjuvant therapies, definitive treatment of PPP syndrome requires correction of the underlying pancreatic disease.

Dictyostelium myosin bipolar thick filament formation: importance of charge and specific domains of the myosin rod.

Myosin-II thick filament formation in Dictyostelium is an excellent system for investigating the phenomenon of self-assembly, as the myosin molecule itself contains all the information required to form a structure of defined size. Phosphorylation of only three threonine residues can dramatically change the assembly state of myosin-II. We show here that the C-terminal 68 kDa of the myosin-II tail (termed AD-Cterm) assembles in a regulated manner similar to full-length myosin-II and forms bipolar thick filament (BTF) structures when a green fluorescent protein (GFP) "head" is added to the N terminus. The localization of this GFP-AD-Cterm to the cleavage furrow of dividing Dictyostelium cells depends on assembly state, similar to full-length myosin-II. This tail fragment therefore represents a good model system for the regulated formation and localization of BTFs. By reducing regulated BTF assembly to a more manageable model system, we were able to explore determinants of myosin-II self-assembly. Our data support a model in which a globular head limits the size of a BTF, and the large-scale charge character of the AD-Cterm region is important for BTF formation. Truncation analysis of AD-Cterm tail fragments shows that assembly is delicately balanced, resulting in assembled myosin-II molecules that are poised to disassemble due to the phosphorylation of only three threonines.

Funding of North Carolina tobacco control programs through the Master Settlement Agreement.

Changing political and economic forces in 1 tobacco-dependent state, North Carolina, demonstrate how the interplay between these forces and public health priorities has shaped current allocation of Master Settlement Agreement funds. Allocation patterns demonstrate lawmakers' changing priorities in response to changes in the economic climate; some of the agreement's funds targeted to tobacco farmers appear to reflect objectives favored by tobacco manufacturers. Funds earmarked for health have underfunded youth tobacco prevention and tobacco control initiatives, and spending for tobacco farmers in North Carolina has not lived up to the rhetoric that accompanied the original agreement. We discuss the implications of these findings for future partnerships between public health advocates and workers as well as tobacco control strategies.

Granulomatous pigmented purpuric dermatosis.

Granulomatous pigmented purpuric dermatosis (GPPD) is a rare histologic variant of pigmented purpuric dermatosis (PPD). It includes classic histology changes of PPD with superimposed granulomas. This variant is thought to be associated with hyperlipidemia and is found predominantly in individuals in the Far East; however, a review of the literature that included 26 documented cases of GPPD revealed these associations might be becoming less clear. We report a case of GPPD in an elderly white man who had an eruption involving the majority of the lower legs.

Thixotropy and rheopexy of muscle fibers probed using sinusoidal oscillations.

Length changes of muscle fibers have previously been shown to result in a temporary reduction in fiber stiffness that is referred to as thixotropy. Understanding the mechanism of this thixotropy is important to our understanding of muscle function since there are many instances in which muscle is subjected to repeated patterns of lengthening and shortening. By applying sinusoidal length changes to one end of single permeabilized muscle fibers and measuring the force response at the opposite end, we studied the history-dependent stiffness of both relaxed and activated muscle fibers. For length change oscillations greater than 1 Hz, we observed thixotropic behavior of activated fibers. Treatment of these fibers with EDTA and blebbistatin, which inhibits myosin-actin interactions, quashed this effect, suggesting that the mechanism of muscle fiber thixotropy is cross-bridge dependent. We modeled a half-sarcomere experiencing sinusoidal length changes, and our simulations suggest that thixotropy could arise from force-dependent cross-bridge kinetics. Surprisingly, we also observed that, for length change oscillations less than 1 Hz, the muscle fiber exhibited rheopexy. In other words, the stiffness of the fiber increased in response to the length changes. Blebbistatin and EDTA did not disrupt the rheopectic behavior, suggesting that a non-cross-bridge mechanism contributes to this phenomenon.

High thermal conductivity of chain-oriented amorphous polythiophene.

Polymers are usually considered thermal insulators, because the amorphous arrangement of the molecular chains reduces the mean free path of heat-conducting phonons. The most common method to increase thermal conductivity is to draw polymeric fibres, which increases chain alignment and crystallinity, but creates a material that currently has limited thermal applications. Here we show that pure polythiophene nanofibres can have a thermal conductivity up to ∼ 4.4 W m(-1) K(-1) (more than 20 times higher than the bulk polymer value) while remaining amorphous. This enhancement results from significant molecular chain orientation along the fibre axis that is obtained during electropolymerization using nanoscale templates. Thermal conductivity data suggest that, unlike in drawn crystalline fibres, in our fibres the dominant phonon-scattering process at room temperature is still related to structural disorder. Using vertically aligned arrays of nanofibres, we demonstrate effective heat transfer at critical contacts in electronic devices operating under high-power conditions at 200 °C over numerous cycles.