Defects in cell spreading and ERK1/2 activation in fibroblasts with lamin A/C mutations

AbstractIn-frame mutations in nuclear lamin A/C lead to a multitude of tissue-specific degenerative diseases known as the ‘laminopathies’. Previous studies have demonstrated that lamin A/C-null mouse fibroblasts have defects in cell polarisation, suggesting a role for lamin A/C in nucleo-cytoskeletal-cell surface cross-talk. However, this has not been examined in patient fibroblasts expressing modified forms of lamin A/C. Here, we analysed skin fibroblasts from 3 patients with Emery–Dreifuss muscular dystrophy and from 1 with dilated cardiomyopathy. The emerin–lamin A/C interaction was impaired in each mutant cell line. Mutant cells exhibited enhanced cell proliferation, collagen-dependent adhesion, larger numbers of filopodia and smaller cell spread size, compared with control cells. Furthermore, cell migration, speed and polarization were elevated. Mutant cells also showed an enhanced ability to contract collagen gels at early time points, compared with control cells. Phosphotyrosine measurements during cell spreading indicated an initial temporal lag in ERK1/2 activation in our mutant cells, followed by hyper-activation of ERK1/2 at 2 h post cell attachment. Deregulated ERK1/2 activation is linked with cardiomyopathy, cell spreading and proliferation defects. We conclude that a functional emerin–lamin A/C complex is required for cell spreading and proliferation, possibly acting through ERK1/2 signalling

Tenofovir disoproxil fumarate induces peripheral neuropathy and alters inflammation and mitochondrial biogenesis in the brains of mice.

Mounting evidence suggests that antiretroviral therapy (ART) drugs may contribute to the prevalence of HIV-associated neurological dysfunction. The HIV envelope glycoprotein (gp120) is neurotoxic and has been linked to alterations in mitochondrial function and increased inflammatory gene expression, which are common neuropathological findings in HIV+ cases on ART with neurological disorders. Tenofovir disproxil fumarate (TDF) has been shown to affect neurogenesis in brains of mice and mitochondria in neurons. In this study, we hypothesized that TDF contributes to neurotoxicity by modulating mitochondrial biogenesis and inflammatory pathways. TDF administered to wild-type (wt) and GFAP-gp120 transgenic (tg) mice caused peripheral neuropathy, as indicated by nerve conduction slowing and thermal hyperalgesia. Conversely TDF protected gp120-tg mice from cognitive dysfunction. In the brains of wt and gp120-tg mice, TDF decreased expression of mitochondrial transcription factor A (TFAM). However, double immunolabelling revealed that TFAM was reduced in neurons and increased in astroglia in the hippocampi of TDF-treated wt and gp120-tg mice. TDF also increased expression of GFAP and decreased expression of IBA1 in the wt and gp120-tg mice. TDF increased tumor necrosis factor (TNF) α in wt mice. However, TDF reduced interleukin (IL) 1β and TNFα mRNA in gp120-tg mouse brains. Primary human astroglia were exposed to increasing doses of TDF for 24 hours and then analyzed for mitochondrial alterations and inflammatory gene expression. In astroglia, TDF caused a dose-dependent increase in oxygen consumption rate, extracellular acidification rate and spare respiratory capacity, changes consistent with increased metabolism. TDF also reduced IL-1β-mediated increases in IL-1β and TNFα mRNA. These data demonstrate that TDF causes peripheral neuropathy in mice and alterations in inflammatory signaling and mitochondrial activity in the brain

Diffractive jet production in a simple model with applications to HERA

In diffractive jet production, two high energy hadrons A and B collide and produce high transverse momentum jets, while hadron A is diffractively scattered. Ingelman and Schlein predicted this phenomenon. In their model, part of the longitudinal momentum transferred from hadron A is delivered to the jet system, part is lost. Lossless diffractive jet production, in which all of this longitudinal momentum is delivered to the jet system, has been discussed by Collins, Frankfurt, and Strikman. We study the structure of lossless diffractive jet production in a simple model. The model suggests that the phenomenon can be probed experimentally at HERA, with A being a proton and B being a bremsstrahlung photon with virtuality $Q^2$. Lossless events should be present for small $Q^2$, but not for $Q^2$ larger than $1/R_{\rm P}^2$, where $R_{\rm P}$ is a characteristic size of the pomeron.Comment: 23 pages, REVTeX 3.0 with 8 postscript figures compressed with uufiles, OITS 536 and AZPH-TH/94-0

Can arbuscular mycorrhizal fungi be used to control the undesirable grass Poa annua on golf courses

Summary 1. Poa annua (annual meadow-grass or annual bluegrass) is the most problematic weed of temperate zone golf putting greens. In the UK there are no chemicals approved for its control, although several herbicides and plant growth regulators are available in the USA. Reducing P. annua levels in ®ne turf would greatly reduce the heavy reliance on pesticides and water that currently exists. 2. This paper reports on an observational and a manipulative study in golf putting greens, aimed at determining whether arbuscular mycorrhizal (AM) fungi have any potential for the reduction of this weed in ®ne turf. 3. All 18 greens on three golf courses were sampled, and in two courses a negative relation between AM fungi and P. annua abundance was found, upholding previous results. In greens where AM fungi were relatively common (as measured by root colonization), P. annua was rare, and vice versa. Furthermore, when the fungi were common, abundance of the desirable turfgrass Agrostis stolonifera was greater. 4. Two explanations are suggested for these relations, a competitive one, in which AM fungi alter the balance of competition between the two grasses, and an antagonistic one, in which the fungi may directly reduce the growth of P. annua. 5. In a manipulative experiment, where mycorrhizal inoculum was added to a golf green, the colonization level of A. stolonifera roots was enhanced, as was the abundance of this grass. Furthermore, there was a suggestion that adding inoculum could decrease the abundance of P. annua. 6. AM fungi have the potential to be a much more environmentally sound method of P. annua control in sports turf than the currently used chemicals

Understanding the causes of missingness in primary care: a realist review

Background: Although missed appointments in healthcare have been an area of concern for policy, practice and research, the primary focus has been on reducing single ‘situational’ missed appointments to the benefit of services. Little attention has been paid to the causes and consequences of more ‘enduring’ multiple missed appointments in primary care and the role this has in producing health inequalities. Methods: We conducted a realist review of the literature on multiple missed appointments to identify the causes of ‘missingness.’ We searched multiple databases, carried out iterative citation-tracking on key papers on the topic of missed appointments and identified papers through searches of grey literature. We synthesised evidence from 197 papers, drawing on the theoretical frameworks of candidacy and fundamental causation. Results: Missingness is caused by an overlapping set of complex factors, including patients not identifying a need for an appointment or feeling it is ‘for them’; appointments as sites of poor communication, power imbalance and relational threat; patients being exposed to competing demands, priorities and urgencies; issues of travel and mobility; and an absence of choice or flexibility in when, where and with whom appointments take place. Conclusions: Interventions to address missingness at policy and practice levels should be theoretically informed, tailored to patients experiencing missingness and their identified needs and barriers; be cognisant of causal domains at multiple levels and address as many as practical; and be designed to increase safety for those seeking care

Extensive production of Neospora caninum tissue cysts in a carnivorous marsupial succumbing to experimental neosporosis

Experimental infections of Sminthopsis crassicaudata, the fat-tailed dunnart, a carnivorous marsupial widely distributed throughout the arid and semi-arid zones of Australia, show that this species can act as an intermediate host for Neospora caninum. In contrast to existing models that develop relatively few N. caninum tissue cysts, dunnarts offer a new animal model in which active neosporosis is dominated by tissue cyst production. The results provide evidence for a sylvatic life cycle of N. caninum in Australia between marsupials and wild dogs. It establishes the foundation for an investigation of the impact and costs of neosporosis to wildlife

ULTRAENDURANCE CYCLING IN A HOT ENVIRONMENT: THIRST, FLUID CONSUMPTION, AND WATER BALANCE

ABSTRACT Armstrong, LE, Johnson, EC, McKenzie, AL, Ellis, LA, and Williamson, KH. Ultraendurance cycling in a hot environment: thirst, fluid consumption, and water balance. J Strength Cond Res 29(4): 869-876, 2015-The purpose of this field investigation was to identify and clarify factors that may be used by strength and conditioning professionals to help athletes drink adequately but not excessively during endurance exercise. A universal method to accomplish this goal does not exist because the components of water balance (i.e., sweat rate, fluid consumed) are different for each athlete and endurance events differ greatly. Twenty-six male cyclists (mean 6 SD; age, 41 6 8 years; height, 177 6 7 cm; body mass, 81.85 6 8.95 kg) completed a summer 164-km road cycling event in 7.0 6 2.1 hours (range, 4.5-10.4 hours). Thirst ratings, fluid consumed, indices of hydration status, and body water balance (ingested fluid volume 2 [urine excreted + sweat loss]) were the primary outcome variables. Measurements were taken before the event, at designated aid stations on the course (52, 97, and 136 km), and at the finish line. Body water balance during exercise was not significantly correlated with exercise time on the course, height, body mass, or body mass index. Thirst ratings were not significantly correlated with any variable. We also observed a wide range of total sweat losses (4.9-12.7 L) and total fluid intakes (2.1-10.5 L) during this ultraendurance event. Therefore, we recommend that strength and conditioning professionals develop an individualized drinking plan for each athlete, by calculating sweat rate (milliliter per hour) on the basis of body mass change (in kilograms), during field simulations of competition

A realist review of the causes of, and current interventions to address ‘missingness’ in health care

Background: This protocol describes a realist review exploring the problem of “missingness” in healthcare, defined as the repeated tendency not to take up offers of care that has a negative impact on the person and their life chances. More specifically, the review looks at the phenomenon of patients missing multiple appointments in primary care in the UK – at the causal factors that influence how patients come to be “missing” in this way, and what interventions might support uptake and “presence” in healthcare. Background research informing this project suggests that a high rate of missed appointments predicted high premature death rates, and patients were more likely to have multiple long-term health conditions and experience significant socioeconomic disadvantage. Most research in this field focuses on population- or service-level characteristics of patients who miss appointments, often making no distinction between causes of single missed appointments and of multiple missed appointments. There have therefore been no interventions for ‘missingness’, accounting for the complex life circumstances or common mechanisms that cause people to repeatedly miss appointments. Methods: We use a realist review approach to explore what causes missingness - and what might prevent or address it - for whom, and in what circumstances. The review uses an iterative approach of database searching, citation-tracking and sourcing grey literature, with selected articles providing insight into the causal dynamics underpinning missed appointments and the interventions designed to address them. Discussion: The findings of this review will be combined with the findings of a qualitative empirical study and the contributions of a Stakeholder Advisory Group (STAG) to inform the development of a programme theory that seeks to explain how missingness occurs, whom it affects and under what circumstances. This will be used to develop a complex intervention to address multiple missed appointments in primary care. PROSPERO registration: CRD4202234600

Vectorial capacity and vector control: reconsidering sensitivity to parameters for malaria elimination

Background: Major gains have been made in reducing malaria transmission in many parts of the world, principally by scaling-up coverage with long-lasting insecticidal nets and indoor residual spraying. Historically, choice of vector control intervention has been largely guided by a parameter sensitivity analysis of George Macdonald's theory of vectorial capacity that suggested prioritizing methods that kill adult mosquitoes. While this advice has been highly successful for transmission suppression, there is a need to revisit these arguments as policymakers in certain areas consider which combinations of interventions are required to eliminate malaria.Methods and Results: Using analytical solutions to updated equations for vectorial capacity we build on previous work to show that, while adult killing methods can be highly effective under many circumstances, other vector control methods are frequently required to fill effective coverage gaps. These can arise due to pre-existing or developing mosquito physiological and behavioral refractoriness but also due to additive changes in the relative importance of different vector species for transmission. Furthermore, the optimal combination of interventions will depend on the operational constraints and costs associated with reaching high coverage levels with each intervention.Conclusions: Reaching specific policy goals, such as elimination, in defined contexts requires increasingly non-generic advice from modelling. Our results emphasize the importance of measuring baseline epidemiology, intervention coverage, vector ecology and program operational constraints in predicting expected outcomes with different combinations of interventions.<br/