Modular cell biology: retroactivity and insulation

Modularity plays a fundamental role in the prediction of the behavior of a system from the behavior of its components, guaranteeing that the properties of individual components do not change upon interconnection. Just as electrical, hydraulic, and other physical systems often do not display modularity, nor do many biochemical systems, and specifically, genetic networks. Here, we study the effect of interconnections on the input–output dynamic characteristics of transcriptional components, focusing on a property, which we call ‘retroactivity', that plays a role analogous to non-zero output impedance in electrical systems. In transcriptional networks, retroactivity is large when the amount of transcription factor is comparable to, or smaller than, the amount of promoter-binding sites, or when the affinity of such binding sites is high. To attenuate the effect of retroactivity, we propose a feedback mechanism inspired by the design of amplifiers in electronics. We introduce, in particular, a mechanism based on a phosphorylation–dephosphorylation cycle. This mechanism enjoys a remarkable insulation property, due to the fast timescales of the phosphorylation and dephosphorylation reactions

Barriers to primary care responsiveness to poverty as a risk factor for health

<p>Abstract</p> <p>Background</p> <p>Poverty is widely recognized as a major determinant of poor health, and this link has been extensively studied and verified. Despite the strong evidentiary link, little work has been done to determine what primary care health providers can do to address their patients' income as a risk to their health. This qualitative study explores the barriers to primary care responsiveness to poverty as a health issue in a well-resourced jurisdiction with near-universal health care insurance coverage.</p> <p>Methods</p> <p>One to one interviews were conducted with twelve experts on poverty and health in primary care in Ontario, Canada. Participants included family physicians, specialist physicians, nurse practitioners, community workers, advocates, policy experts and researchers. The interviews were analysed for anticipated and emergent themes.</p> <p>Results</p> <p>This study reveals provider- and patient-centred structural, attitudinal, and knowledge-based barriers to addressing poverty as a risk to health. While many of its findings reinforce previous work in this area, this study's findings point to a number of areas front line primary care providers could target to address their patients' poverty. These include a lack of provider understanding of the lived reality of poverty, leading to a failure to collect adequate data about patients' social circumstances, and to the development of inappropriate care plans. Participants also pointed to prejudicial attitudes among providers, a failure of primary care disciplines to incorporate approaches to poverty as a standard of care, and a lack of knowledge of concrete steps providers can take to address patients' poverty.</p> <p>Conclusions</p> <p>While this study reinforces, in a well-resourced jurisdiction such as Ontario, the previously reported existence of significant barriers to addressing income as a health issue within primary care, the findings point to the possibility of front line primary care providers taking direct steps to address the health risks posed by poverty. The consistent direction and replicability of these findings point to a refocusing of the research agenda toward an examination of interventions to decrease the health impacts of poverty.</p

The Heart of the Matter. About Good Nursing and Telecare

Nurses and ethicists worry that the implementation of care at a distance or telecare will impoverish patient care by taking out ‘the heart’ of the clinical work. This means that telecare is feared to induce the neglect of patients, and to possibly hinder the development of a personal relation between nurse and patient. This study aims to analyse whether these worries are warranted by analysing Dutch care practices using telemonitoring in care for chronic patients in the Netherlands. How do clinical practices of nursing change when telecare devices are introduced and what this means for notions and norms of good nursing? The paper concludes that at this point the practices studied do not warrant the fear of negligence and compromised relations. Quite the contrary; in the practices studied, telecare lead to more frequent and more specialised contacts between nurses and patients. The paper concludes by reflecting on the ethical implications of these changes

Identification of the first ATRIP-deficient patient and novel mutations in ATR define a clinical spectrum for ATR-ATRIP Seckel Syndrome

A homozygous mutational change in the Ataxia-Telangiectasia and RAD3 related (ATR) gene was previously reported in two related families displaying Seckel Syndrome (SS). Here, we provide the first identification of a Seckel Syndrome patient with mutations in ATRIP, the gene encoding ATR-Interacting Protein (ATRIP), the partner protein of ATR required for ATR stability and recruitment to the site of DNA damage. The patient has compound heterozygous mutations in ATRIP resulting in reduced ATRIP and ATR expression. A nonsense mutational change in one ATRIP allele results in a C-terminal truncated protein, which impairs ATR-ATRIP interaction; the other allele is abnormally spliced. We additionally describe two further unrelated patients native to the UK with the same novel, heterozygous mutations in ATR, which cause dramatically reduced ATR expression. All patient-derived cells showed defective DNA damage responses that can be attributed to impaired ATR-ATRIP function. Seckel Syndrome is characterised by microcephaly and growth delay, features also displayed by several related disorders including Majewski (microcephalic) osteodysplastic primordial dwarfism (MOPD) type II and Meier-Gorlin Syndrome (MGS). The identification of an ATRIP-deficient patient provides a novel genetic defect for Seckel Syndrome. Coupled with the identification of further ATR-deficient patients, our findings allow a spectrum of clinical features that can be ascribed to the ATR-ATRIP deficient sub-class of Seckel Syndrome. ATR-ATRIP patients are characterised by extremely severe microcephaly and growth delay, microtia (small ears), micrognathia (small and receding chin), and dental crowding. While aberrant bone development was mild in the original ATR-SS patient, some of the patients described here display skeletal abnormalities including, in one patient, small patellae, a feature characteristically observed in Meier-Gorlin Syndrome. Collectively, our analysis exposes an overlapping clinical manifestation between the disorders but allows an expanded spectrum of clinical features for ATR-ATRIP Seckel Syndrome to be define

Effect of thong style flip-flops on children’s barefoot walking and jogging kinematics

BACKGROUND: Thong style flip-flops are a popular form of footwear for children. Health professionals relate the wearing of thongs to foot pathology and deformity despite the lack of quantitative evidence to support or refute the benefits or disadvantages of children wearing thongs. The purpose of this study was to compare the effect of thong footwear on children’s barefoot three dimensional foot kinematics during walking and jogging. METHODS: Thirteen healthy children (age 10.3 ± 1.6 SD years) were recruited from the metropolitan area of Sydney Australia following a national press release. Kinematic data were recorded at 200 Hz using a 14 camera motion analysis system (Cortex, Motion Analysis Corporation, Santa Rosa, USA) and simultaneous ground reaction force were measured using a force platform (Model 9281B, Kistler, Winterthur, Switzerland). A three-segment foot model was used to describe three dimensional ankle, midfoot and one dimensional hallux kinematics during the stance sub-phases of contact, midstance and propulsion. RESULTS: Thongs resulted in increased ankle dorsiflexion during contact (by 10.9°, p; = 0.005 walk and by 8.1°, p; = 0.005 jog); increased midfoot plantarflexion during midstance (by 5.0°, p; = 0.037 jog) and propulsion (by 6.7°, p; = 0.044 walk and by 5.4°, p;= 0.020 jog); increased midfoot inversion during contact (by 3.8°, p;= 0.042 jog) and reduced hallux dorsiflexion during walking 10% prior to heel strike (by 6.5°, p; = 0.005) at heel strike (by 4.9°, p; = 0.031) and 10% post toe-off (by 10.7°, p; = 0.001). CONCLUSIONS: Ankle dorsiflexion during the contact phase of walking and jogging, combined with reduced hallux dorsiflexion during walking, suggests a mechanism to retain the thong during weight acceptance. Greater midfoot plantarflexion throughout midstance while walking and throughout midstance and propulsion while jogging may indicate a gripping action to sustain the thong during stance. While these compensations exist, the overall findings suggest that foot motion whilst wearing thongs may be more replicable of barefoot motion than originally thought

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

A qualitative study of women's experiences of communication in antenatal care: Identifying areas for action

To identify key features of communication across antenatal (prenatal) care that are evaluated positively or negatively by service users. Focus groups and semi-structured interviews were used to explore communication experiences of thirty pregnant women from diverse social and ethnic backgrounds affiliated to a large London hospital. Data were analysed using thematic analysis. Women reported a wide diversity of experiences. From the users’ perspective, constructive communication on the part of health care providers was characterised by an empathic conversational style, openness to questions, allowing sufficient time to talk through any concerns, and pro-active contact by providers (e.g. text message appointment reminders). These features created reassurance, facilitated information exchange, improved appointment attendance and fostered tolerance in stressful situations. Salient features of poor communication were a lack of information provision, especially about the overal

Extramuscular myofascial force transmission alters substantially the acute effects of surgical aponeurotomy: assessment by finite element modeling

Effects of extramuscular myofascial force transmission on the acute effects of aponeurotomy were studied using finite element modeling and implications of such effects on surgery were discussed. Aponeurotomized EDL muscle of the rat was modeled in two conditions: (1) fully isolated (2) with intact extramuscular connections. The specific goal was to assess the alterations in muscle length-force characteristics in relation to sarcomere length distributions and to investigate how the mechanical mechanism of the intervention is affected if the muscle is not isolated. Major effects of extramuscular myofascial force transmission were shown on muscle length-force characteristics. In contrast to the identical proximal and distal forces of the aponeurotomized isolated muscle, substantial proximo-distal force differences were shown for aponeurotomized muscle with extramuscular connections (for all muscle lengths F dist > F prox after distal muscle lengthening). Proximal optimal length did not change whereas distal optimal length was lower (by 0.5 mm). The optimal forces of the aponeurotomized muscle with extramuscular connections exerted at both proximal and distal tendons were lower than that of isolated muscle (by 15 and 7%, respectively). The length of the gap separating the two cut ends of the intervened aponeurosis decreases substantially due to extramuscular myofascial force transmission. The amplitude of the difference in gap length was muscle length dependent (maximally 11.6% of the gap length of the extramuscularly connected muscle). Extramuscular myofascial force transmission has substantial effects on distributions of lengths of sarcomeres within the muscle fiber populations distal and proximal to the location of intervention: (a) Within the distal population, the substantial sarcomere shortening at the proximal ends of muscle fibers due to the intervention remained unaffected however, extramuscular myofascial force transmission caused a more pronounced serial distribution towards the distal ends of muscle fibers. (b) In contrast, extramuscular myofascial force transmission limits the serial distribution of sarcomere lengths shown for the aponeurotomized isolated muscle in the proximal population. Fiber stress distributions showed that extramuscular myofascial force transmission causes most sarcomeres within the aponeurotomized muscle to attain lengths favorable for higher force exertion. It is concluded that acute effects of aponeurotomy on muscular mechanics are affected greatly by extramuscular myofascial force transmission. Such effects have important implications for the outcome of surgery performed to improve impeded function since muscle in vivo is not isolated both anatomically and mechanically