Contractile deficits in engineered cardiac microtissues as a result of MYBPC3 deficiency and mechanical overload.

The integration of in vitro cardiac tissue models, human induced pluripotent stem cells (hiPSCs) and genome-editing tools allows for the enhanced interrogation of physiological phenotypes and recapitulation of disease pathologies. Here, using a cardiac tissue model consisting of filamentous three-dimensional matrices populated with cardiomyocytes derived from healthy wild-type (WT) hiPSCs (WT hiPSC-CMs) or isogenic hiPSCs deficient in the sarcomere protein cardiac myosin-binding protein C (MYBPC3-/- hiPSC-CMs), we show that the WT microtissues adapted to the mechanical environment with increased contraction force commensurate to matrix stiffness, whereas the MYBPC3-/- microtissues exhibited impaired force development kinetics regardless of matrix stiffness and deficient contraction force only when grown on matrices with high fibre stiffness. Under mechanical overload, the MYBPC3-/- microtissues had a higher degree of calcium transient abnormalities, and exhibited an accelerated decay of calcium dynamics as well as calcium desensitization, which accelerated when contracting against stiffer fibres. Our findings suggest that MYBPC3 deficiency and the presence of environmental stresses synergistically lead to contractile deficits in cardiac tissues

Post-mortem culture of Balamuthia mandrillaris from the brain and cerebrospinal fluid of a case of granulomatous amoebic meningoencephalitis, using human brain microvascular endothelial cells

The first isolation in the UK of Balamuthia mandrillaris amoebae from a fatal case of granulomatous amoebic meningoencephalitis is reported. Using primary cultures of human brain microvascular endothelial cells (HBMECs), amoebae were isolated from the brain and cerebrospinal fluid (CSF). The cultures showed a cytopathic effect at 20–28 days, but morphologically identifiable B. mandrillaris amoebae were seen in cleared plaques in subcultures at 45 days. The identification of the organism was later confirmed using PCR on Chelex-treated extracts. Serum taken while the patient was still alive reacted strongly with slide antigen prepared from cultures of the post-mortem isolate, and also with those from a baboon B. mandrillaris strain at 1 : 10 000 in indirect immunofluorescence, but with Acanthamoeba castellanii (Neff) at 1 : 160, supporting B. mandrillaris to be the causative agent. If the presence of amoebae in the post-mortem CSF reflects the condition in life, PCR studies on CSF and on biopsies of cutaneous lesions may also be a valuable tool. The role of HBMECs in understanding the interactions of B. mandrillaris with the blood–brain barrier is discussed

Combined effects of time spent in physical activity, sedentary behaviors and sleep on obesity and cardio-metabolic health markers: a novel compositional data analysis approach

<div><p>The associations between time spent in sleep, sedentary behaviors (SB) and physical activity with health are usually studied without taking into account that time is finite during the day, so time spent in each of these behaviors are codependent. Therefore, little is known about the combined effect of time spent in sleep, SB and physical activity, that together constitute a composite whole, on obesity and cardio-metabolic health markers. Cross-sectional analysis of NHANES 2005–6 cycle on N = 1937 adults, was undertaken using a compositional analysis paradigm, which accounts for this intrinsic codependence. Time spent in SB, light intensity (LIPA) and moderate to vigorous activity (MVPA) was determined from accelerometry and combined with self-reported sleep time to obtain the 24 hour time budget composition. The distribution of time spent in sleep, SB, LIPA and MVPA is significantly associated with BMI, waist circumference, triglycerides, plasma glucose, plasma insulin (all p<0.001), and systolic (p<0.001) and diastolic blood pressure (p<0.003), but not HDL or LDL. Within the composition, the strongest positive effect is found for the proportion of time spent in MVPA. Strikingly, the effects of MVPA replacing another behavior and of MVPA being displaced by another behavior are asymmetric. For example, re-allocating 10 minutes of SB to MVPA was associated with a lower waist circumference by 0.001% but if 10 minutes of MVPA is displaced by SB this was associated with a 0.84% higher waist circumference. The proportion of time spent in LIPA and SB were detrimentally associated with obesity and cardiovascular disease markers, but the association with SB was stronger. For diabetes risk markers, replacing SB with LIPA was associated with more favorable outcomes. Time spent in MVPA is an important target for intervention and preventing transfer of time from LIPA to SB might lessen the negative effects of physical inactivity.</p></div

Growing interfaces uncover universal fluctuations behind scale invariance

Stochastic motion of a point -- known as Brownian motion -- has many successful applications in science, thanks to its scale invariance and consequent universal features such as Gaussian fluctuations. In contrast, the stochastic motion of a line, though it is also scale-invariant and arises in nature as various types of interface growth, is far less understood. The two major missing ingredients are: an experiment that allows a quantitative comparison with theory and an analytic solution of the Kardar-Parisi-Zhang (KPZ) equation, a prototypical equation for describing growing interfaces. Here we solve both problems, showing unprecedented universality beyond the scaling laws. We investigate growing interfaces of liquid-crystal turbulence and find not only universal scaling, but universal distributions of interface positions. They obey the largest-eigenvalue distributions of random matrices and depend on whether the interface is curved or flat, albeit universal in each case. Our exact solution of the KPZ equation provides theoretical explanations.Comment: 5 pages, 3 figures, supplementary information available on Journal pag

Response of the mantle to flat slab evolution: Insights from local splitting beneath Peru

The dynamics of flat subduction, particularly the interaction between a flat slab and the overriding plate, are poorly understood. Here we study the (seismically) anisotropic properties and deformational regime of the mantle directly above the Peruvian flat slab. We analyze shear wave splitting from 370 local S events at 49 stations across southern Peru. We find that the mantle above the flat slab appears to be anisotropic, with modest average delay times (~0.28?s) that are consistent with ~4% anisotropy in a ~30?km thick mantle layer. The most likely mechanism is the lattice-preferred orientation of olivine, which suggests that the observed splitting pattern preserves information about the mantle deformation. We observe a pronounced change in anisotropy along strike, with predominately trench-parallel fast directions in the north and more variable orientations in the south, which we attribute to the ongoing migration of the Nazca Ridge through the flat slab system

Conservation Laws and Integrability of a One-dimensional Model of Diffusing Dimers

We study a model of assisted diffusion of hard-core particles on a line. The model shows strongly ergodicity breaking : configuration space breaks up into an exponentially large number of disconnected sectors. We determine this sector-decomposion exactly. Within each sector the model is reducible to the simple exclusion process, and is thus equivalent to the Heisenberg model and is fully integrable. We discuss additional symmetries of the equivalent quantum Hamiltonian which relate observables in different sectors. In some sectors, the long-time decay of correlation functions is qualitatively different from that of the simple exclusion process. These decays in different sectors are deduced from an exact mapping to a model of the diffusion of hard-core random walkers with conserved spins, and are also verified numerically. We also discuss some implications of the existence of an infinity of conservation laws for a hydrodynamic description.Comment: 39 pages, with 5 eps figures, to appear in J. Stat. Phys. (March 1997

Critical Behavior of O(n)-symmetric Systems With Reversible Mode-coupling Terms: Stability Against Detailed-balance Violation

We investigate nonequilibrium critical properties of $O(n)$-symmetric models with reversible mode-coupling terms. Specifically, a variant of the model of Sasv\'ari, Schwabl, and Sz\'epfalusy is studied, where violation of detailed balance is incorporated by allowing the order parameter and the dynamically coupled conserved quantities to be governed by heat baths of different temperatures $T_S$ and $T_M$, respectively. Dynamic perturbation theory and the field-theoretic renormalization group are applied to one-loop order, and yield two new fixed points in addition to the equilibrium ones. The first one corresponds to $\Theta = T_S / T_M = \infty$ and leads to model A critical behavior for the order parameter and to anomalous noise correlations for the generalized angular momenta; the second one is at $\Theta = 0$ and is characterized by mean-field behavior of the conserved quantities, by a dynamic exponent $z = d / 2$ equal to that of the equilibrium SSS model, and by modified static critical exponents. However, both these new fixed points are unstable, and upon approaching the critical point detailed balance is restored, and the equilibrium static and dynamic critical properties are recovered.Comment: 18 pages, RevTeX, 1 figure included as eps-file; submitted to Phys. Rev.

Clinical Examination, Ultrasound and MRI Imaging of The Painful Elbow in Psoriatic Arthritis and Rheumatoid Arthritis: Which is Better, Ultrasound or MR, for Imaging Enthesitis?

Introduction: The purpose of the current study was to examine the painful elbow, and in particular enthesitis, in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) using clinical examination, ultrasonography (US) and magnetic resonance imaging (MRI). Methods: Patients with elbow pain (11 with PsA and 9 with RA) were recruited. Clinical examination, US and MRI studies were performed on the same day. For enthesitis, the common extensor and flexor insertions and the triceps insertion were imaged (20 patients, giving a total of 60 sites with comparative data). Imaging was performed with the radiologists blinded to the diagnosis and clinical findings. US was used to assess ‘inflammatory activity’ (Power Doppler signal, oedema, tendon thickening and bursal swelling) and ‘damage’ (erosions, cortical roughening and enthesophytes). MRI was used to assess ‘inflammation’ (fluid in paratenon, peri-entheseal soft-tissue oedema, entheseal enhancement with gadolinium, entheseal oedema and bone oedema) and ‘damage’ (erosion, cortical roughening and enthesophyte). Results: Complete scan data were not available for all patients as one patient could not tolerate the MRI examination. No significant differences in imaging scores were found between PsA and RA. Analysis of damage scores revealed complete agreement between US and MRI data in 43/55 (78%) comparisons; in 10/55 (18%) cases the US data were abnormal but the MRI data normal; in 2/55 (4%) cases, the MRI data were abnormal and the US data normal. Analysis of the inflammation scores revealed complete agreement between US and MRI data in 33/55 (60%) comparisons; in 3/55 (5%) cases US data were abnormal but MRI data normal; in 19/55 (35%) cases the MRI data were abnormal and the US data normal. There was a poor relationship between assessments based on clinical examination and imaging studies. Readers could not accurately identify the disease from imaging findings. Conclusion: Based on our results, at the elbow, US and MR have different roles in assessing enthesitis, with US apparently the better diagnostic tool for assessing damage and MR the better tool for assessing inflammation. In this study enthesitis and synovitis in the painful elbow were found equally in cases of established RA and PsA

Ghostwriting at Elite Academic Medical Centers in the United States

Jeffrey Lacasse and Jonathan Leo assess ghostwriting policies at 50 academic medical centers in the United States and find that only 10 explicitly prohibit ghostwriting

Stochastic accumulation of feature information in perception and memory

It is now well established that the time course of perceptual processing influences the first second or so of performance in a wide variety of cognitive tasks. Over the last20 years, there has been a shift from modeling the speed at which a display is processed, to modeling the speed at which different features of the display are perceived and formalizing how this perceptual information is used in decision making. The first of these models(Lamberts, 1995) was implemented to fit the time course of performance in a speeded perceptual categorization task and assumed a simple stochastic accumulation of feature information. Subsequently, similar approaches have been used to model performance in a range of cognitive tasks including identification, absolute identification, perceptual matching, recognition, visual search, and word processing, again assuming a simple stochastic accumulation of feature information from both the stimulus and representations held in memory. These models are typically fit to data from signal-to-respond experiments whereby the effects of stimulus exposure duration on performance are examined, but response times (RTs) and RT distributions have also been modeled. In this article, we review this approach and explore the insights it has provided about the interplay between perceptual processing, memory retrieval, and decision making in a variety of tasks. In so doing, we highlight how such approaches can continue to usefully contribute to our understanding of cognition