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Abstract The potential of immune checkpoint inhibitors (ICI) may be limited in situations where immune cell fitness is impaired. Here, we show that the efficacy of cancer immunotherapies is compromised by the accumulation of senescent cells in mice and in the context of therapy-induced senescence (TIS). Resistance to immunotherapy is associated with a decrease in the accumulation and activation of CD8 T cells within tumors. Elimination of senescent cells restores immune homeostasis within the tumor micro-environment (TME) and increases mice survival in response to immunotherapy. Using single-cell transcriptomic analysis, we observe that the injection of ABT263 (Navitoclax) reverses the exacerbated immunosuppressive profile of myeloid cells in the TME. Elimination of these myeloid cells also restores CD8 T cell proliferation in vitro and abrogates immunotherapy resistance in vivo. Overall, our study suggests that the use of senolytic drugs before ICI may constitute a pharmacological approach to improve the effectiveness of cancer immunotherapies.

Echinococcus spp. is an emerging zoonotic parasite of high concern. In Canada, an increase in the number of human and animal cases diagnosed has been reported, but information regarding the parasite's distribution in wildlife reservoir remains limited. A cross-sectional study was conducted to estimate the prevalence of wild canids infected with Echinococcus spp. and Echinococcus multilocularis in areas surrounding populated zones in Québec (Canada); to investigate the presence of areas at higher risk of infection; to evaluate potential risk factors of the infection; and as a secondary objective, to compare coproscopy and RT-PCR diagnostic tests for Taenia spp. and Echinococcus identification. From October 2020 to March 2021, fecal samples were collected from 423 coyotes (Canis latrans) and 284 red foxes (Vulpes vulpes) trapped in 12 administrative regions. Real-time PCR for molecular detection of genus Echinococcus spp. and species-specific Echinococcus multilocularis were performed. A total of 38 positive cases of Echinococcus spp., of which 25 were identified as E. multilocularis, were detected. Two high-risk areas of infection were identified. The prevalence of Echinococcus spp. was 22.7% (95% CI 11.5-37.8%) in the Montérégie centered high-risk area, 26.5% (95% CI 12.9-44.4%) in the Bas-St-Laurent high-risk area, and 3.0% (95%CI 1.8-4.7%) outside those areas. For E. multilocularis, a prevalence of 20.5% (95% CI 9.8-35.3%) was estimated in the high-risk area centered in Montérégie compared to 2.4% (95% CI 1.4-3.9%) outside. Logistic regression did not show any association of infection status with species, sex, or geolocation of capture (p > 0.05). This study shows the circulation of Echinococcus in a wildlife cycle in 9/12 administrative regions of Québec.

Abstract Cycles of stress build-up and release are inherent to tectonically active planets. Such stress oscillations impart strain and damage, prompting mechanically loaded rocks and materials to fail. Here, we investigate, under uniaxial conditions, damage accumulation and weakening caused by time-dependent creep (at 60, 65, and 70% of the rocks’ expected failure stress) and repeating stress oscillations (of ± 2.5, 5.0 or 7.5% of the creep load), simulating earthquakes at a shaking frequency of ~ 1.3 Hz in volcanic rocks. The results show that stress oscillations impart more damage than constant loads, occasionally prompting sample failure. The magnitudes of the creep stresses and stress oscillations correlate with the mechanical responses of our porphyritic andesites, implicating progressive microcracking as the cause of permanent inelastic strain. Microstructural investigation reveals longer fractures and higher fracture density in the post-experimental rock. We deconvolve the inelastic strain signal caused by creep deformation to quantify the amount of damage imparted by each individual oscillation event, showing that the magnitude of strain is generally largest with the first few oscillations; in instances where pre-existing damage and/or the oscillations’ amplitude favour the coalescence of micro-cracks towards system scale failure, the strain signal recorded shows a sharp increase as the number of oscillations increases, regardless of the creep condition. We conclude that repetitive stress oscillations during earthquakes can amplify the amount of damage in otherwise mechanically loaded materials, thus accentuating their weakening, a process that may affect natural or engineered structures. We specifically discuss volcanic scenarios without wholesale failure, where stress oscillations may generate damage, which could, for example, alter pore fluid pathways, modify stress distribution and affect future vulnerability to rupture and associated hazards.

Measurement(s) Lobster sex • Lobster size • Lobster moult stage • °Brix value of hemolymph • Lobster shell hardness Technology Type(s) Eye • Vernier Caliper • Microscopic assessemnt of pleopods • Refractometer • Physical assessment of lobster carapace Factor Type(s) Year • Month • Lobster fishing area (LFA) • Location • Sampling event • Water depth Sample Characteristic - Organism Homarus americanus Sample Characteristic - Environment marine water body Sample Characteristic - Location Northwest Atlantic Ocean coastal waters of Canada

Summary: Skin plays central roles in systemic physiology, and it undergoes significant functional changes during aging. Members of the peroxisome proliferator-activated receptor-gamma coactivator (PGC-1) family (PGC-1s) are key regulators of the biology of numerous tissues, yet we know very little about their impact on skin functions. Global gene expression profiling and gene silencing in keratinocytes uncovered that PGC-1s control the expression of metabolic genes as well as that of terminal differentiation programs. Glutamine emerged as a key substrate promoting mitochondrial respiration, keratinocyte proliferation, and the expression of PGC-1s and terminal differentiation programs. Importantly, gene silencing of PGC-1s reduced the thickness of a reconstructed living human epidermal equivalent. Exposure of keratinocytes to a salicylic acid derivative potentiated the expression of PGC-1s and terminal differentiation genes and increased mitochondrial respiration. Overall, our results show that the PGC-1s are essential effectors of epidermal physiology, revealing an axis that could be targeted in skin conditions and aging.

Summary: Neutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV-2 variants of concern (VOCs). Understanding NAb epitope-dependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCs and mediate strong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinants of the epitope-driven protection and VOC evasion. While EH3 represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 mice from lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients.

Abstract SARS-CoV-2 variants of concern (VOCs) have emerged worldwide, with implications on the spread of the pandemic. Characterizing the cross-reactivity of antibodies against these VOCs is necessary to understand the humoral response of non-hospitalized individuals previously infected with SARS-CoV-2, a population that remains understudied. Thirty-two SARS-CoV-2-positive (PCR-confirmed) and non-hospitalized Canadian adults were enrolled 14–21 days post-diagnosis in 2020, before the emergence of the B.1.351 (also known as Beta), B.1.617.2 (Delta) and P.1 (Gamma) VOCs. Sera were collected 4 and 16 weeks post-diagnosis. Antibody levels and pseudo-neutralization of the ectodomain of SARS-CoV-2 spike protein/human ACE-2 receptor interaction were analyzed with native, B.1.351, B.1.617.2 and P.1 variant spike proteins. Despite a lower response observed for the variant spike proteins, we report evidence of a sustained humoral response against native, B.1.351, B.1.617.2 and P.1 variant spike proteins among non-hospitalized Canadian adults. Furthermore, this response inhibited the interaction between the spike proteins from the different VOCs and ACE-2 receptor for ≥ 16 weeks post-diagnosis, except for individuals aged 18–49 years who showed no inhibition of the interaction between B.1.617.1 or B.1.617.2 spike and ACE-2. Interestingly, the affinity (KD) measured between the spike proteins (native, B.1.351, B.1.617.2 and P.1) and antibodies elicited in sera of infected and vaccinated (BNT162b2 and ChAdOx1 nCoV-19) individuals was invariant. Relative to sera from vaccine-naïve (and previously infected) individuals, sera from vaccinated individuals had higher antibody levels (as measured with label-free SPR) and more efficiently inhibited the spike–ACE-2 interactions, even among individuals aged 18–49 years, showing the effectiveness of vaccination.

The mechanisms for replicating and segregating DNA are highly conserved across eukaryotes. A comparative genomic analysis of a free-living protist finds a surprising lack of protein complexes involved in these processes, suggesting that the organism uses alternative mechanisms to process DNA.

Magma ascending in the Earth’s crust can undergo oscillations in pressure, from ultra-low frequency changes associated with tectonics, to relatively higher frequency oscillations associated with seismicity. Seismic waves travelling through shallow magma bodies can lead to a range of unrest phenomena and potentially trigger volcanic eruptions. The mechanisms by which pressure oscillations can induce unrest or eruption remain debated. Here, we experimentally impose pressure oscillations on magma and study how they affect vesiculation processes. We use cylindrical samples (4.00 mm long, 4.85 mm diameter) of hydrous rhyolitic obsidian (0.11 ± 0.01 wt% H2O) placed in alumina (AL23) crucibles and vary pressure by the uniaxial loading of an alumina plunger in a thermo-mechanical analyzer. We monitor vesiculation at temperatures of 950–990°C and confining pressure of 177 kPa. We perform two types of experiment: 1) “static” experiments (at constant pressure) and 2) “oscillating” experiments in which we impose sinusoidal pressure oscillations of up to 71 kPa upon the static pressure (i.e., between 106 and 250 kPa). In both cases, we dilatometrically observe sample expansion driven by vesiculation. Post-experimental bubble textures reveal that bubbles formed preferentially at the sample margins. For the oscillating experiments, the sample expansion rate is lower than in the static experiments, and there are fewer vesicles at the sample margins. We examine the constituent processes of bubble formation (nucleation, growth, coalescence) and gas loss (diffusion, permeable flow) occurring during static experiments and with the added element of pressure oscillations. The most likely mechanism responsible for reduced sample expansion is that pressure oscillations drive the sample in and out of water saturation conditions and thus reduce the fraction of residence time over which bubble nucleation and/or growth are driven. Future work will be needed to confirm this hypothesis. These results are relevant to the study of earthquake-volcano interactions, where a magma body that sits close to volatile saturation is subject to pressure fluctuations.

Work-related upper extremity disorders are costly to society due to resulting medical costs, presenteeism and absenteeism. Although their aetiology is likely multifactorial, physical workplace factors are known to play an important role in their development. Promising options for preventing work-related upper extremity disorders include assistive technologies such as dynamic arm supports designed to follow the movement of the arm while compensating for its weight. The objective of this study was to assess the effects of a dynamic arm support on perceived exertion, muscle activity and movement patterns of the upper limb during repetitive manual tasks in healthy individuals. Thirty healthy right-handed individuals were allocated either a static or a dynamic task to perform with and without a dynamic arm support. During the task, surface electromyographic activity (anterior and middle deltoid, upper trapezius) and upper limb kinematics (elbow, shoulder, sternoclavicular) were measured using surface EMG and inertial sensors. Results showed that the dynamic arm support significantly reduced perceived exertion during the tasks and limited the development of muscular fatigue of the anterior and middle deltoid as demonstrated by EMG signal mean epoch amplitudes and median frequency of the EMG power spectrum. The dynamic arm support also prevented a decrease in shoulder elevation and an increase in total shoulder joint excursion during static and dynamic task, respectively. These results denote the potential benefits of dynamic arm supports in work environments. Further studies should focus on their efficacy, acceptability and implementability in work settings.

Volcanic activity at the Santiaguito dome complex (Guatemala) is characterized by lava extrusion interspersed with small, regular, gas-and-ash explosions that are believed to result from shallow magma fragmentation; yet, their triggering mechanisms remain debated. Given that the understanding of source processes at volcanoes is essential to risk assessments of future eruptions, this study seeks to shed light on those processes. We use data from a permanent seismic and infrasound network at Santiaguito volcano, Guatemala, established in 2018 and additional temporary stations, including a seismic array deployed during a 13-day field investigation in January 2019 to analyze and resolve the source characteristics of fragmentation leading to gas-and-ash explosions. Seismic data gathered within a distance of 4.5 km from the vent show a weak seismic signal 2–6 s prior to the explosions and associated main seismic signal. To resolve the source location and origin of the seismic signals, we first used ambient noise analysis to assess seismic velocities in the subsurface and then used two-dimensional spectral element modeling (SPECFEM2D) to simulate seismic waveforms. The analyzed data revealed a two-layer structure beneath the array, with a shallow, low-velocity layer (vs = 650 m/s) above deeper, high-velocity rocks (vs = 2,650 m/s). Using this velocity structure, possible source mechanisms and depths were constrained using array and particle motion analyses. The comparison of simulated and observed seismic data indicated that the precursory signal is associated with particle motion in the RZ-plane, pointing toward the opening of tensile cracks at a depth of ∼600 m below the summit; in contrast, the main signal is accompanied by a vertical single force, originating at a shallow depth of about ∼200 m. This suggests that the volcanic explosions at Santiaguito are following a bottom-up process in which tensile fractures develop at depth and enable rapid gas rise which leads to the subsequent explosion. The result indicates that explosions at Santiaguito do not occur from a single source location, but from a series of processes possibly associated with magma rupture, gas channeling and accumulation, and fragmentation. Our study provides a good foundation for further investigations at Santiaguito and shows the value of comparing seismic observations with synthetic data calculated for complex media to investigate in detail the processes leading up to gas-ash-rich explosions found at various other volcanoes worldwide.

Understanding the relationship between degassing, crystallization processes and eruption style is a central goal in volcanology, in particular how these processes modulate the magnitude and timing of cyclical Vulcanian explosions in intermediate magmas. To investigate the influence of variations in crystal micro-textures on magma rheology and eruption dynamics, we conducted high-temperature (940°C) uniaxial compression experiments at conditions simulating a shallow volcanic conduit setting on eight samples of high-crystallinity andesite with variable plagioclase microlite populations from the 2004 to 2010 Vulcanian explosions of Galeras volcano, Colombia. Experiments were conducted at different strain rates to measure the rate-dependence of apparent viscosities and assess the dominant deformation processes associated with shear. Variations in plagioclase micro-textures are associated with apparent viscosities spanning over one order of magnitude for a given strain rate. Samples with low numbers of large prismatic microlites behaved consistently with published rheological laws for crystalline dome samples, and displayed extensive micro-cracking. Samples with high numbers of small tabular microlites showed a lower apparent viscosity and were less shear-thinning. The data suggest a spectrum of rheological behavior controlled by concurrent variations in microlite number, size and shape. We use previously published micro-textural data for time-constrained samples to model the apparent viscosity of magma erupted during the 2004–2010 sequence of Vulcanian explosions and compare these results with observed SO2 fluxes. We propose that variations in magma decompression rate, which are known to produce systematic textural differences in the plagioclase microlite cargo, govern differences in magma rheology in the shallow conduit. These rheological differences are likely to affect the rate at which magma densifies as a result of outgassing, leading to magmatic plugs with a range of porosities and permeabilities. The existence of magmatic plugs with variable physical properties has important implications for the development of critical overpressure driving Vulcanian explosions, and thus for hazard assessment during volcanic crises. We suggest a new conceptual model to explain eruption style at andesitic volcanoes based on micro-textural and rheological differences between “plug-forming” and “dome-forming” magma. We advance that existing rheological laws describing the behavior of andesitic magma based on experiments on dome rocks are inappropriate for modeling large Vulcanian explosions (∼106 m3), as the magma involved in these eruptions lacks the characteristics required to form exogenous lava domes.

During shearing in geological environments, frictional processes, including the wear of sliding rock surfaces, control the nature of the slip events. Multiple studies focusing on natural samples have investigated the frictional behaviour of a large suite of geological materials. However, due to the varied and heterogeneous nature of geomaterials, the individual controls of material properties on friction and wear remain unconstrained. Here, we use variably porous synthetic glass samples (8, 19 and 30% porosity) to explore the frictional behaviour and development of wear in geomaterials at low normal stresses (≤1 MPa). We propose that porosity provides an inherent roughness to material which wear and abrasion cannot smooth, allowing material at the pore margins to interact with the slip surface. This results in an increase in measured friction coefficient from

Many of the grand challenges in volcanic and magmatic research are focused on understanding the dynamics of highly heterogeneous systems and the critical conditions that enable magmas to move or eruptions to initiate. From the formation and development of magma reservoirs, through propagation and arrest of magma, to the conditions in the conduit, gas escape, eruption dynamics, and beyond into the environmental impacts of that eruption, we are trying to define how processes occur, their rates and timings, and their causes and consequences. However, we are usually unable to observe the processes directly. Here we give a short synopsis of the new capabilities and highlight the potential insights that in situ observation can provide. We present the XRheo and Pele furnace experimental apparatus and analytical toolkit for the in situ X-ray tomography-based quantification of magmatic microstructural evolution during rheological testing. We present the first 3D data showing the evolving textural heterogeneity within a shearing magma, highlighting the dynamic changes to microstructure that occur from the initiation of shear, and the variability of the microstructural response to that shear as deformation progresses. The particular shear experiments highlighted here focus on the effect of shear on bubble coalescence with a view to shedding light on both magma transport and fragmentation processes. The XRheo system is intended to help us understand the microstructural controls on the complex and non-Newtonian evolution of magma rheology, and is therefore used to elucidate the many mobilization, transport, and eruption phenomena controlled by the rheological evolution of a multi-phase magmatic flows. The detailed, in situ characterization of sample textures presented here therefore represents the opening of a new field for the accurate parameterization of dynamic microstructural control on rheological behavior.

Abstract Even modest ash-rich volcanic eruptions can severely impact a range of human activities, especially air travel. The dispersal of ash in these eruptions depends critically on aggregation and sedimentation processes – however these are difficult to quantify in volcanic plumes. Here, we image ash dynamics from mild explosive activity at Santiaguito Volcano, Guatemala, by measuring the depolarisation of scattered sunlight by non-spherical ash particles, allowing the dynamics of diffuse ash plumes to be investigated with high temporal resolution (>1 Hz). We measure the ash settling velocity downwind from the main plume, and compare it directly with ground sampled ash particles, finding good agreement with a sedimentation model based on particle size. Our new, cost-effective technique leverages existing technology, opening a new frontier of integrated ash visualisation and ground collection studies which could test models of ash coagulation and sedimentation, leading to improved ash dispersion forecasts. This will provide risk managers with improved data quality on ash location, reducing the economic and societal impacts of future ash-rich eruptions.

Many Amyotrophic Lateral Sclerosis (ALS)-linked mutations cause accumulation of stress granules, and most ALS cases are caused by repeat expansions in C9ORF72. Here the authors show that C9ORF72 and the autophagy receptor p62 interact to associate with proteins symmetrically dimethylated on arginines such as FUS, to eliminate stress granules by autophagy.

Columnar joints in lavas form during cooling, but the temperature this occurs at is unclear. Here, the authors perform thermo-mechanical experiments on basaltic rocks to examine the temperature of columnar joints in lavas and find that failure occurs at 890–840 °C, which is below the solidus temperature of 980 °C.

The rheological behaviour of magma in shallow conditions may help determine a volcano’s eruptive style. Here, the authors perform deformation experiments on lava from Volcán de Colima to demonstrate that crystal plasticity may preclude failure at certain shallow magmatic conditions.

Abstract The connectivity of rocks’ porous structure and the presence of fractures influence the transfer of fluids in the Earth’s crust. Here, we employed laboratory experiments to measure the influence of macro-fractures and effective pressure on the permeability of volcanic rocks with a wide range of initial porosities (1–41 vol. %) comprised of both vesicles and micro-cracks. We used a hand-held permeameter and hydrostatic cell to measure the permeability of intact rock cores at effective pressures up to 30 MPa; we then induced a macro-fracture to each sample using Brazilian tensile tests and measured the permeability of these macro-fractured rocks again. We show that intact rock permeability increases non-linearly with increasing porosity and decreases with increasing effective pressure due to compactional closure of micro-fractures. Imparting a macro-fracture both increases the permeability of rocks and their sensitivity to effective pressure. The magnitude of permeability increase induced by the macro-fracture is more significant for dense rocks. We finally provide a general equation to estimate the permeability of intact and fractured rocks, forming a basis to constrain fluid flow in volcanic and geothermal systems.

Soft-shelled lobsters pose economic challenges to the lobster industry due to low meat yields and survivability during holding and transportation. Our objectives were to describe spatio-temporal patterns of soft-shelled lobsters in southwestern Nova Scotia, and identify environmental and lobster-related factors associated with shell quality. We analyzed data obtained from a broad-scale, intensive monitoring project and remotely sensed water temperatures. Mixed-effect logistic regression and linear regression methods analyzed more than 130 000 samples collected between 2004 and 2014. The annual overall prevalence of soft-shelled lobsters ranged from 9% to 38% and varied significantly among fishing areas. Shell quality was influenced by sex and size, and in the 2 months before the fishing season, lower water temperatures (4–6 weeks prior to sampling) were associated with reduced prevalence of soft-shells. High annual variability of soft-shell prevalence, that water temperature alone could not explain, suggests that adjusting fishing seasons, arbitrarily, in two fishing areas will not improve the overall shell quality of landed lobsters. Further research is needed to evaluate the effects of long-term temperature and ecosystem changes on lobster health in eastern Canada.

Rapid transitions in eruptive activity during lava dome eruptions pose significant challenges for monitoring and hazard assessment. A comprehensive understanding of the dynamic evolution of active lava dome systems requires extensive sets of multi-parametric datasets to fully constrain and understand shifts in eruptive behavior, but few such datasets have been compiled. The Santiaguito lava dome complex, Guatemala, is a remarkable example of an open-vent volcanic system where continuous eruptive activity has typically been characterized by cycles of effusion and frequent, small to moderate, gas-and-ash explosions. During 2015–2016 the volcano experienced a rapid intensification of activity including large vulcanian explosions, frequently accompanied by pyroclastic density currents. Here we present a chronology of the eruptive activity at Santiaguito from November 2014–May 2017, compiled from field observations (visual and thermal) and activity reports. We also present seismic and acoustic infrasound data collected during the same period, the longest and largest dataset collected at Santiaguito to date. Three major phases of eruptive activity took place during the study period. The first phase was consistent with the long-term eruptive behavior reported at Santiaguito by previous studies: lava effusion simultaneous with small (

Lava dome collapses pose a hazard to surrounding populations, but equally represent important processes for deciphering the eruptive history of a volcano. Models examining lava dome instability rely on accurate physical and mechanical properties of volcanic rocks. Here we focus on determining the physical and mechanical properties of a suite of temporally-constrained rocks from different phases of the 1995–2010 eruption at Soufrière Hills volcano in Montserrat. We determine the uniaxial compressive strength, tensile strength, density, porosity, permeability, and Young’s modulus using laboratory measurements, complemented by Schmidt hammer testing in the field. By viewing a snapshot of each phase, we find the highest tensile and compressive strengths in the samples attributed to Phase 4, corresponding to a lower permeability and an increasing proportion of isolated porosity. Samples from Phase 5 show lower compressive and tensile strengths, corresponding to the highest permeability and porosity of the tested materials. Overall, this demonstrates a reliance of mechanical properties primarily on porosity, however, a shift toward increasing prevalence of pore connectivity in weaker samples identified by microtextural analysis demonstrates that here pore connectivity also contributes to the strength and Young’s Modulus, as well as controlling permeability. The range in UCS strengths are supported using Schmidt hammer field testing. We determine a narrow range in mineralogy across the sample suite, but identify a correlation between increasing crystallinity and increasing strength. We correlate these changes to residency-time in the growing lava dome during the eruption, where stronger rocks have undergone more crystallization. In addition, subsequent recrystallization of silica polymorphs from the glass phase may further strengthen the material. We suggest the variation in physical and mechanical rock properties shown within the Soufrière Hills eruptive products be included in future structural stability models of the remaining over-steepened dome on Montserrat, and that consideration of rock heterogeneity and its temporal variation if possible, be made in other, similar systems.

Rett syndrome (RTT) is a pervasive developmental disorder caused by mutations in MECP2. Complete loss of MECP2 function in males causes congenital encephalopathy, neurodevelopmental arrest, and early lethality. Induced pluripotent stem cell (iPSC) lines from male patients harboring mutations in MECP2, along with control lines from their unaffected fathers, give us an opportunity to identify some of the earliest cellular and molecular changes associated with MECP2 loss-of-function (LOF). We differentiated iPSC-derived neural progenitor cells (NPCs) using retinoic acid (RA) and found that astrocyte differentiation is perturbed in iPSC lines derived from two different patients. Using highly stringent quantitative proteomic analyses, we found that LIN28, a gene important for cell fate regulation and developmental timing, is upregulated in mutant NPCs compared to WT controls. Overexpression of LIN28 protein in control NPCs suppressed astrocyte differentiation and reduced neuronal synapse density, whereas downregulation of LIN28 expression in mutant NPCs partially rescued this synaptic deficiency. These results indicate that the pathophysiology of RTT may be caused in part by misregulation of developmental timing in neural progenitors, and the subsequent consequences of this disruption on neuronal and glial differentiation.

Volcanic ash is hazardous to jet engines, with high temperatures in turbines causing ash particles to melt and stick to the engine, adversely affecting turbine function. Here, the authors explore the spectrum of natural ash compositions and their behaviour and impact at high temperatures.

The structures and textures preserved in lava domes reflect underlying magmatic and eruptive processes, and may provide evidence of how eruptions initiate and evolve. This study explores the remarkable cycles in lava extrusion style produced between 1922 and 2012 at the Santiaguito lava dome complex, Guatemala. By combining an examination of eruptive lava morphologies and textures with a review of historical records, we aim to constrain the processes responsible for the range of erupted lava type and morphologies. The Santiaguito lava dome complex is divided into four domes (El Caliente, La Mitad, El Monje, El Brujo), containing a range of proximal structures (e.g., spines) from which a series of structurally contrasting lava flows originate. Vesicular lava flows (with a'a like, yet non-brecciated flow top) have the highest porosity with interconnected spheroidal pores and may transition into blocky lava flows. Blocky lava flows are high volume and texturally variable with dense zones of small tubular aligned pore networks and more porous zones of spheroidal shaped pores. Spines are dense and low volume and contain small skeletal shaped pores, and subvertical zones of sigmoidal pores. We attribute the observed differences in pore shapes to reflect shallow inflation, deflation, flattening, or shearing of the pore fraction. Effusion rate and duration of the eruption define the amount of time available for heating or cooling, degassing and outgassing prior to and during extrusion, driving changes in pore textures and lava type. Our new textural data when reviewed with all the other published data allow a cyclic model to be developed. The cyclic eruption models are influenced by viscosity changes resulting from (1) initial magmatic composition and temperature, and (2) effusion rate which in turn affects degassing, outgassing and cooling time in the conduit. Each lava type presents a unique set of hazards and understanding the morphologies and dome progression is useful in hazard forecasting.

As the first step of social information processing, visual encoding underlies the interpretation of social cues. Faces, in particular, convey a large amount of affective information, which can be subsequently used in the planning and production of adaptive social behaviors. Sociomoral reasoning is a specific social skill that is associated with engagement in appropriate social behaviors when faced with dilemmas. Previous studies using eye tracking suggest that visual encoding may play an important role in decision-making when individuals are faced with extreme moral dilemmas, but it is not known if this is generalizable to everyday situations. The main objective of this study was to assess the contribution of visual encoding to everyday sociomoral reasoning using eye tracking and ecological visual dilemmas. Participants completed the SocioMoral Reasoning Aptitude Level (SoMoral) task while their eye movements and pupil dilation were recorded. While visual encoding was not a predictor of sociomoral decision-making, sociomoral maturity was predicted by fixation count. Thus, in an ecological context, visual encoding of social cues appears to be associated with sociomoral maturity: the production of a justification is associated with volitional encoding strategies. Implications with regards to the dual-process theory of sociomoral reasoning and social information processing are discussed.

During magma ascent, bubbles nucleate, grow, coalesce, and form a variably permeable porous network. The reorganization, failing and sealing of bubble walls may contribute to the opening and closing of the volcanic system. In this contribution we cause obsidian to nucleate and grow bubbles to high gas volume fraction at atmospheric pressure by heating samples to 950°C for different times and we image the growth through a furnace. Following the experiment, we imaged the internal pore structure of selected samples in 3D and then dissected for analysis of textures and dissolved water content remnant in the glass. We demonstrate that in these high viscosity systems, during foaming and subsequent foam-maturation, bubbles near a free surface resorb via diffusion to produce an impermeable skin of melt around a foam. The skin thickens non-linearly through time. The water concentrations at the outer and inner skin margins reflect the solubility of water in the melt at the partial pressure of water in atmospheric and water-rich bubble conditions, respectively. In this regime, mass transfer of water out of the system is diffusion limited and the sample shrinks slowly. In a second set of experiments in which we polished off the skin of the foamed samples and placed them back in the furnace to allow open system outgassing, we observe rapid sample contraction and collapse of the connected pore network under surface tension as the system efficiently outgasses. In this regime, mass transfer of water is permeability limited. We conclude that diffusion-driven skin formation can efficiently seal connectivity in foams. When rupture of melt film around gas bubbles (i.e., skin removal) occurs, then rapid outgassing and consequent foam collapse modulate gas pressurization in the vesiculated magma. The mechanisms described here are relevant to the evolution of pore network heterogeneity in permeable magmas.

BACKGROUND:The American College of Surgeons' National Surgical Quality Improvement Program (NSQIP) is the first nationally validated, risk-adjusted, outcomes-based program to measure and compare the quality of surgical care across North America. Participation in this program may provide an opportunity to reduce the incidence of adverse events related to surgery. STUDY DESIGN:A systematic review of the literature was performed. MedLine, EMBASE and PubMed were searched for studies relevant to NSQIP. Patient characteristics, intervention, and primary outcome measures were abstracted. The intervention was participation in NSQIP and monitoring of Individual Site Summary Reports with or without implementation of a quality improvement program. The outcomes of interest were change in peri-operative adverse events and mortality represented by pooled risk ratios (pRR) and 95% confidence intervals (CI). RESULTS:Eleven articles reporting on 35 health care institutions were included. Nine (82%) of the eleven studies implemented a quality improvement program. Minimal improvements in superficial (pRR 0.81; 95% CI 0.72-0.91), deep (pRR 0.82; 95% CI0.64-1.05) and organ space (pRR 1.15; 95% CI 0.96-1.37) infections were observed at centers that did not institute a quality improvement program. However, centers that reported formal interventions for the prevention and treatment of infections observed substantial improvements (superficial pRR 0.55, 95% CI 0.39-0.77; deep pRR 0.61, 95% CI 0.50-0.75, and organ space pRR 0.60, 95% CI 0.50-0.71). Studies evaluating other adverse events noted decreased incidence following NSQIP participation and implementation of a formal quality improvement program. CONCLUSIONS:These data suggest that NSQIP is effective in reducing surgical morbidity. Improvement in surgical quality appears to be more marked at centers that implemented a formal quality improvement program directed at the reduction of specific morbidities.

Conditions under which a single oscillator model coupled with Dieterich-Ruina's rate and state dependent friction exhibits chaotic dynamics is studied. Properties of spring-block models are discussed. The parameter values of the system are explored and the corresponding numerical solutions presented. Bifurcation analysis is performed to determine the bifurcations and stability of stationary solutions and we find that the system undergoes a Hopf bifurcation to a periodic orbit. This periodic orbit then undergoes a period doubling cascade into a strange attractor, recognized as broadband noise in the power spectrum. The implications for earthquakes are discussed.

OBJECTIVE: To characterize the frequency and timing of complications following radical cystectomy in a cohort of patients treated at community and academic hospitals. PATIENTS AND METHODS: Radical cystectomy patients captured from NSQIP hospitals from January 1 2006 to December 31 2012 were included. Baseline information and complications were abstracted by study surgical clinical reviewers through a validated process of medical record review and direct patient contact. We determined the incidence and timing of each complication and calculated their associations with patient and operative characteristics. RESULTS: 2303 radical cystectomy patients met inclusion criteria. 1115 (48%) patients were over 70 years old and 1819 (79%) were male. Median hospital stay was 8 days (IQR 7-13 days). 1273 (55.3%) patients experienced at least 1 post-operative complication of which 191 (15.6%) occurred after hospital discharge. The most common complication was blood transfusion (n = 875; 38.0%), followed by infectious complications with 218 (9.5%) urinary tract infections, 193 (8.4%) surgical site infections, and 223 (9.7%) sepsis events. 73 (3.2%) patients had fascial dehiscence, 82 (4.0%) developed a deep vein thrombosis, and 67 (2.9%) died. Factors independently associated with the occurrence of any post-operative complication included: age, female gender, ASA class, pre-operative sepsis, COPD, low serum albumin concentration, pre-operative radiotherapy, pre-operative transfusion >4 units, and operative time >6 hours (all p

There is no consensus on optimal use of radiotherapy following radical prostatectomy. The purpose of this study was to describe opinions of urologists and radiation oncologists regarding adjuvant and salvage radiotherapy following radical prostatectomy.Urologists and genitourinary radiation oncologists were solicited to participate in an online survey. Respondent characteristics included demographics, training, practice setting, patient volume/experience, and access to radiotherapy. Participant practice patterns and attitudes towards use of adjuvant and salvage radiotherapy in standardized clinical scenarios were assessed.One hundred and forty-six staff physicians participated in the survey (104 urologists and 42 genitourinary radiation oncologists). Overall, high Gleason score (Gleason 7 vs. 6, RR 1.37 95% CI 1.19-1.56, p

Over wide ranges of scale, orographic processes have no obvious scale; this has provided the justification for both deterministic and monofractal scaling models of the earth's topography. These models predict that differences in altitude (Δh) vary with horizontal separation (l) as Δh ≈ lH. The scaling exponent has been estimated theoretically and empirically to have the value H=1/2. Scale invariant nonlinear processes are now known to generally give rise to multifractals and we have recently empirically shown that topography is indeed a special kind of theoretically predicted "universal" multifractal. In this paper we provide a multifractal generalization of the l1/2 law, and propose two distinct multifractal models, each leading via dimensional arguments to the exponent 1/2. The first, for ocean bathymetry assumes that the orographic dynamics are dominated by heat fluxes from the earth's mantle, whereas the second - for continental topography - is based on tectonic movement and gravity. We test these ideas empirically on digital elevation models of Deadman's Butte, Wyoming.

Progression towards type 1 diabetes (T1D) in susceptible patients is linked to a progressive decline in the capacity of regulatory T cells (Treg) to maintain tolerance. As such, therapies aimed at redressing the failing Treg compartment have been the subject of intense investigation. Treg dysfunction in T1D has recently been linked to a reduced capacity of antigen presenting cells (APCs) to maintain Treg function rather than Treg intrinsic defects. This suggests that therapies aimed simply at addressing the failing Treg compartment are unlikely to provide long-term protection. Here, we demonstrate that modulation of the inflammatory status of CD11b+CD11c- APCs favors the upregulation of protective Tregs in a mouse model of T1D. We further demonstrate that reduced expression of the costimulatory molecule CD40 plays a role in this increased immunoregulatory capacity. Strikingly, Treg upregulation resulted exclusively from an increase in natural Tregs rather than the peripheral conversion of conventional T cells. This suggests that modulation of CD11b+ CD11c- APCs inflammatory properties favors the establishment of natural Treg responses that, unlike adaptive Treg responses, are likely to maintain tolerance to a broad range of antigens. As such, modulation of this APC subset represents a potential therapeutic avenue to reestablish peripheral tolerance and protect from autoimmune diseases such as T1D.

Toll-like receptor 3 (TLR3) has been proposed to play a central role in the early recognition of viruses by sensing double stranded RNA, a common intermediate of viral replication. However, several reports have demonstrated that TLR3 signaling is either dispensable or even harmful following infection with certain viruses. Here, we asked whether TLR3 plays a role in the response to coxsackievirus B4 (CB4), a prevalent human pathogen that has been associated with pancreatitis, myocarditis and diabetes. We demonstrate that TLR3 signaling on macrophages is critical to establish protective immunity to CB4. TLR3 deficient mice produced reduced pro-inflammatory mediators and are unable to control viral replication at the early stages of infection resulting in severe cardiac damage. Intriguingly, the absence of TLR3 did not affect the activation of several key innate and adaptive cellular effectors. This suggests that in the absence of TLR3 signaling on macrophages, viral replication outpaces the developing adaptive immune response. We further demonstrate that the MyD88-dependent signaling pathways are not only unable to compensate for the loss of TLR3, they are also dispensable in the response to this RNA virus. Our results demonstrate that TLR3 is not simply part of a redundant system of viral recognition, but rather TLR3 plays an essential role in recognizing the molecular signatures associated with specific viruses including CB4.