Injectable biomimetic hydrogels have great potential for use in regenerative medicine as cellular delivery vectors. However, they can suffer from issues relating to hypoxia, including poor cell ...survival, differentiation, and functional integration owing to the lack of an established vascular network. Here we engineer a hybrid myoglobin:peptide hydrogel that can concomitantly deliver stem cells and oxygen to the brain to support engraftment until vascularisation can occur naturally. We show that this hybrid hydrogel can modulate cell fate specification within progenitor cell grafts, resulting in a significant increase in neuronal differentiation. We find that the addition of myoglobin to the hydrogel results in more extensive innervation within the host tissue from the grafted cells, which is essential for neuronal replacement strategies to ensure functional synaptic connectivity. This approach could result in greater functional integration of stem cell-derived grafts for the treatment of neural injuries and diseases affecting the central and peripheral nervous systems.
Physical activity (PA) has been hypothesized to spare gray matter volume in late adulthood, but longitudinal data testing an association has been lacking. Here we tested whether PA would be ...associated with greater gray matter volume after a 9-year follow-up, a threshold could be identified for the amount of walking necessary to spare gray matter volume, and greater gray matter volume associated with PA would be associated with a reduced risk for cognitive impairment 13 years after the PA evaluation.
In 299 adults (mean age 78 years) from the Cardiovascular Health Cognition Study, we examined the association between gray matter volume, PA, and cognitive impairment. Physical activity was quantified as the number of blocks walked over 1 week. High-resolution brain scans were acquired 9 years after the PA assessment on cognitively normal adults. White matter hyperintensities, ventricular grade, and other health variables at baseline were used as covariates. Clinical adjudication for cognitive impairment occurred 13 years after baseline.
Walking amounts ranged from 0 to 300 blocks (mean 56.3; SD 69.7). Greater PA predicted greater volumes of frontal, occipital, entorhinal, and hippocampal regions 9 years later. Walking 72 blocks was necessary to detect increased gray matter volume but walking more than 72 blocks did not spare additional volume. Greater gray matter volume with PA reduced the risk for cognitive impairment 2-fold.
Greater amounts of walking are associated with greater gray matter volume, which is in turn associated with a reduced risk of cognitive impairment.
Lack of directional bonding between two-dimensional crystals like graphene or monolayer transition metal dichalcogenides provides unusual freedom in the selection of components for vertical van der ...Waals heterostructures. However, even for identical layers, their stacking, in particular the relative angle between their crystallographic directions, modifies properties of the structure. We demonstrate that the interatomic coupling between two two-dimensional crystals can be determined from angle-resolved photoemission spectra of a trilayer structure with one aligned and one twisted interface. Each of the interfaces provides complementary information and together they enable self-consistent determination of the coupling. We parametrise interatomic coupling for carbon atoms by studying twisted trilayer graphene and show that the result can be applied to structures with different twists and number of layers. Our approach demonstrates how to extract fundamental information about interlayer coupling in a stack of two-dimensional crystals and can be applied to many other van der Waals interfaces.
Seasonal forecasts using coupled ocean–atmosphere climate models are increasingly employed to provide regional climate predictions. For the quality of forecasts to improve, regional biases in climate ...models must be diagnosed and reduced. The evolution of biases as initialized forecasts drift away from the observations is poorly understood, making it difficult to diagnose the causes of climate model biases. This study uses two seasonal forecast systems to examine drifts in sea surface temperature (SST) and precipitation, and compares them to the long-term bias in the free-running version of each model. Drifts are considered from daily to multi-annual time scales. We define three types of drift according to their relation with the long-term bias in the free-running model: asymptoting, overshooting and inverse drift. We find that precipitation almost always has an asymptoting drift. SST drifts on the other hand, vary between forecasting systems, where one often overshoots and the other often has an inverse drift. We find that some drifts evolve too slowly to have an impact on seasonal forecasts, even though they are important for climate projections. The bias found over the first few days can be very different from that in the free-running model, so although daily weather predictions can sometimes provide useful information on the causes of climate biases, this is not always the case. We also find that the magnitude of equatorial SST drifts, both in the Pacific and other ocean basins, depends on the El Niño Southern Oscillation (ENSO) phase. Averaging over all hindcast years can therefore hide the details of ENSO state dependent drifts and obscure the underlying physical causes. Our results highlight the need to consider biases across a range of timescales in order to understand their causes and develop improved climate models.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Flecainide suppresses cardiac tachyarrhythmias including paroxysmal atrial fibrillation, supraventricular tachycardia and arrhythmic long QT syndromes (LQTS), as well as the Ca2+‐mediated, ...catecholaminergic polymorphic ventricular tachycardia (CPVT). However, flecainide can also exert pro‐arrhythmic effects most notably following myocardial infarction and when used to diagnose Brugada syndrome (BrS). These divergent actions result from its physiological and pharmacological actions at multiple, interacting levels of cellular organization. These were studied in murine genetic models with modified Nav channel or intracellular ryanodine receptor (RyR2)‐Ca2+ channel function. Flecainide accesses its transmembrane Nav1.5 channel binding site during activated, open, states producing a use‐dependent antagonism. Closing either activation or inactivation gates traps flecainide within the pore. An early peak INa related to activation of Nav channels followed by rapid de‐activation, drives action potential (AP) upstrokes and their propagation. This is diminished in pro‐arrhythmic conditions reflecting loss of function of Nav1.5 channels, such as BrS, accordingly exacerbated by flecainide challenge. Contrastingly, pro‐arrhythmic effects attributed to prolonged AP recovery by abnormal late INaL following gain‐of‐function modifications of Nav1.5 channels in LQTS3 are reduced by flecainide. Anti‐arrhythmic effects of flecainide that reduce triggering in CPVT models mediated by sarcoplasmic reticular Ca2+ release could arise from its primary actions on Nav channels indirectly decreasing Ca2+i through a reduced Na+i and/or direct open‐state RyR2‐Ca2+ channel antagonism. The consequent Ca2+i alterations could also modify AP propagation velocity and therefore arrhythmic substrate through its actions on Nav1.5 channel function. This is consistent with the paradoxical differences between flecainide actions upon Na+ currents, AP conduction and arrhythmogenesis under circumstances of normal and increased RyR2 function.
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This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Cancer immunotherapy has transformed the treatment of cancer. However, increasing use of immune-based therapies, including the widely used class of agents known as immune checkpoint inhibitors, has ...exposed a discrete group of immune-related adverse events (irAEs). Many of these are driven by the same immunologic mechanisms responsible for the drugs' therapeutic effects, namely blockade of inhibitory mechanisms that suppress the immune system and protect body tissues from an unconstrained acute or chronic immune response. Skin, gut, endocrine, lung and musculoskeletal irAEs are relatively common, whereas cardiovascular, hematologic, renal, neurologic and ophthalmologic irAEs occur much less frequently. The majority of irAEs are mild to moderate in severity; however, serious and occasionally life-threatening irAEs are reported in the literature, and treatment-related deaths occur in up to 2% of patients, varying by ICI. Immunotherapy-related irAEs typically have a delayed onset and prolonged duration compared to adverse events from chemotherapy, and effective management depends on early recognition and prompt intervention with immune suppression and/or immunomodulatory strategies. There is an urgent need for multidisciplinary guidance reflecting broad-based perspectives on how to recognize, report and manage organ-specific toxicities until evidence-based data are available to inform clinical decision-making. The Society for Immunotherapy of Cancer (SITC) established a multidisciplinary Toxicity Management Working Group, which met for a full-day workshop to develop recommendations to standardize management of irAEs. Here we present their consensus recommendations on managing toxicities associated with immune checkpoint inhibitor therapy.
The wave nature of particles is rarely observed, in part because of their very short de Broglie wavelengths in most situations. However, even with wavelengths close to the size of their surroundings, ...the particles couple to their environment (for example, by gravity, Coulomb interaction, or thermal radiation). These couplings shift the wave phases, often in an uncontrolled way, and the resulting decoherence, or loss of phase integrity, is thought to be a main cause of the transition from quantum to classical behavior. How much interaction is needed to induce this transition? Here we show that a photoelectron and two protons form a minimum particle/slit system and that a single additional electron constitutes a minimum environment. Interference fringes observed in the angular distribution of a single electron are lost through its Coulomb interaction with a second electron, though the correlated momenta of the entangled electron pair continue to exhibit quantum interference.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
We present 850 m polarization observations of the L1689 molecular cloud, part of the nearby Ophiuchus molecular cloud complex, taken with the POL-2 polarimeter on the James Clerk Maxwell Telescope ...(JCMT). We observe three regions of L1689: the clump L1689N which houses the IRAS 16293-2433 protostellar system, the starless clump SMM-16, and the starless core L1689B. We use the Davis-Chandrasekhar-Fermi method to estimate plane-of-sky field strengths of 366 55 G in L1689N, 284 34 G in SMM-16, and 72 33 G in L1689B, for our fiducial value of dust opacity. These values indicate that all three regions are likely to be magnetically transcritical with sub-Alfvénic turbulence. In all three regions, the inferred mean magnetic field direction is approximately perpendicular to the local filament direction identified in Herschel Space Telescope observations. The core-scale field morphologies for L1689N and L1689B are consistent with the cloud-scale field morphology measured by the Planck Space Observatory, suggesting that material can flow freely from large to small scales for these sources. Based on these magnetic field measurements, we posit that accretion from the cloud onto L1689N and L1689B may be magnetically regulated. However, in SMM-16, the clump-scale field is nearly perpendicular to the field seen on cloud scales by Planck, suggesting that it may be unable to efficiently accrete further material from its surroundings.
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