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Background: Cerebral cavernous malformations, also known as cavernous angiomas, are blood vessel abnormalities comprised of clusters of grossly enlarged and hemorrhage-prone capillaries. The prevalence in the general population, including asymptomatic cases, is estimated to be 0.5%. Some patients develop severe symptoms, including seizures and focal neurological deficits, whereas others remain asymptomatic. The causes of this remarkable presentation heterogeneity within a primarily monogenic disease remain poorly understood. Methods: We established a chronic mouse model of cerebral cavernous malformations, induced by postnatal ablation of Krit1 with Pdgfb-CreERT2 , and examined lesion progression in these mice with T2-weighted 7T magnetic resonance imaging (MRI). We also established a modified protocol for dynamic contrast-enhanced MRI and produced quantitative maps of gadolinium tracer gadobenate dimeglumine. After terminal imaging, brain slices were stained with antibodies against microglia, astrocytes, and endothelial cells. Results: These mice develop cerebral cavernous malformations lesions gradually over 4 to 5 months of age throughout the brain. Precise volumetric analysis of individual lesions revealed nonmonotonous behavior, with some lesions temporarily growing smaller. However, the cumulative lesional volume invariably increased over time and after about 2 months followed a power trend. Using dynamic contrast-enhanced MRI, we produced quantitative maps of gadolinium in the lesions, indicating a high degree of heterogeneity in lesional permeability. MRI properties of the lesions were correlated with cellular markers for endothelial cells, astrocytes, and microglia. Multivariate comparisons of MRI properties of the lesions with cellular markers for endothelial and glial cells revealed that increased cell density surrounding lesions correlates with stability, whereas denser vasculature within and surrounding the lesions may correlate with high permeability. Conclusions: Our results lay a foundation for better understanding individual lesion properties and provide a comprehensive preclinical platform for testing new drug and gene therapies for controlling cerebral cavernous malformations.

Modified teeth and jaws have long been recognized as important ceremonial objects during the Middle Woodland period of eastern North America. Direct evidence for the manufacture of the objects is exceedingly rare because they are typically recovered from mortuary contexts or ceremonial caches. Here, we present multiple lines of evidence pointing to the manufacture of modified teeth and jaws at the Moorehead Circle post enclosure within the Fort Ancient Earthworks. The convergence of protein residue, lithic use-wear, and faunal data indicate that bear and likely canid bones were modified by artisans working within the Moorehead Circle. These findings add an important new layer of understanding to our knowledge of these objects, human–animal relations, and craft production in the Middle Woodland.

The Mielke site (33SH26) is a multicomponent locality in western Ohio, in an upland portion of the state that forms a drainage divide between the Great Lakes and Ohio River watersheds. The site possesses a prominent Clovis component that we describe here and assessed via test excavations, geochemical sourcing, technological descriptions, geometric morphometrics, microwear, and GIS analysis. Five different raw materials, whose outcrops are located 150+ km from the site in several different directions, appear to be present. Although our inferences about the activities that occurred here in Clovis times are constrained by the presence of later components and the collecting history of the site, its location and artifacts are suggestive of what type of Clovis site Mielke may have been and how its Late Pleistocene inhabitants may have moved across North America's midcontinent.

Temperate reefs are at the forefront of warming-induced community alterations resulting from poleward range shifts. This tropicalisation is exemplified and amplified by tropical species’ invasions of temperate herbivory functions. However, whether other temperate ecosystem functions are similarly invaded by tropical species, and by what drivers, remains unclear. We examine tropicalisation footprints in nine reef fish functional groups using trait-based analyses and biomass of 550 fish species across tropical to temperate gradients in Japan and Australia. We discover that functional niches in transitional communities are asynchronously invaded by tropical species, but with congruent invasion schedules for functional groups across the two hemispheres. These differences in functional group tropicalisation point to habitat availability as a key determinant of multi-species range shifts, as in the majority of functional groups tropical and temperate species share functional niche space in suitable habitat. Competition among species from different thermal guilds played little part in limiting tropicalisation, rather available functional space occupied by temperate species indicates that tropical species can invade. Characterising these drivers of reef tropicalisation is pivotal to understanding, predicting, and managing marine community transformation.

PURPOSE: Glioblastoma (GB) poses formidable challenges to systemic immunotherapy approaches owing to the paucity of immune infiltration and presence of the blood brain/tumor barriers (BBB/BTB). We hypothesize that BBB/BTB disruption (BBB/BTB-D) with focused ultrasound (FUS) and microbubbles (MB) increases immune infiltration in GB. As a prelude to rational combination of FUS with ITx, we herein investigate the impact of localized BBB/BTB-D on innate and adaptive immune responses in an orthotopic murine GB model. METHODS: Mice with GL261 gliomas received i.v. MB and underwent FUS BBB/BTB-D (1.1 MHz, 0.5 Hz pulse repetition frequency, 10 ms bursts, 0.4–0.6 MPa). Brains, meninges, and peripheral lymphoid organs were excised and examined by flow cytometry 1–2 weeks following FUS. RESULTS: The number of dendritic cells (DC) was significantly elevated in GL261 tumors and draining cervical LN in response to sonication. CD86+ DC frequency was also upregulated with 0.6 MPa FUS, suggesting increased maturity. While FUS did not significantly alter CD8+ T cell frequency across evaluated organs, these cells upregulated checkpoint molecules at one week post-FUS, suggesting increased activation. By two weeks post-FUS, we noted emergence of adaptive resistance mechanisms, including upregulation of TIGIT on CD4+ T cells and CD155 on non-immune tumor and stromal cells. CONCLUSIONS: FUS BBB/BTB-D exerts mild, transient inflammatory effects in gliomas - suggesting that its combination with adjunct therapeutic strategies targeting adaptive resistance may improve outcomes. The potential for FUS-mediated BBB/BTB-D to modify immunological signatures is a timely and important consideration for ongoing clinical trials investigating this regimen in GB.

Seeman, Morris, and Summers misrepresent or misunderstand the arguments we have made, as well as their own previous work. Here, we correct these inaccuracies. We also reiterate our support for hypothesis-driven and evidence-based research.

Hyperpolarized (HP) 129 Xe MRI uniquely images pulmonary ventilation, gas exchange, and terminal airway morphology rapidly and safely, providing novel information not possible using conventional imaging modalities or pulmonary function tests. As such, there is mounting interest in expanding the use of biomarkers derived from HP 129 Xe MRI as outcome measures in multi-site clinical trials across a range of pulmonary disorders. Until recently, HP 129 Xe MRI techniques have been developed largely independently at a limited number of academic centers, without harmonizing acquisition strategies. To promote uniformity and adoption of HP 129 Xe MRI more widely in translational research, multi-site trials, and ultimately clinical practice, this position paper from the 129 Xe MRI Clinical Trials Consortium (https://cpir.cchmc.org/XeMRICTC) recommends standard protocols to harmonize methods for image acquisition in HP 129 Xe MRI. Recommendations are described for the most common HP gas MRI techniques-calibration, ventilation, alveolar-airspace size, and gas exchange-across MRI scanner manufacturers most used for this application. Moreover, recommendations are described for 129 Xe dose volumes and breath-hold standardization to further foster consistency of imaging studies. The intention is that sites with HP 129 Xe MRI capabilities can readily implement these methods to obtain consistent high-quality images that provide regional insight into lung structure and function. While this document represents consensus at a snapshot in time, a roadmap for technical developments is provided that will further increase image quality and efficiency. These standardized dosing and imaging protocols will facilitate the wider adoption of HP 129 Xe MRI for multi-site pulmonary research.

Cerebral cavernous malformations (CCM), also known as cavernous angiomas, are blood vessel abnormalities comprised of clusters of grossly enlarged and hemorrhage-prone capillaries. The prevalence in the general population, including asymptomatic cases, is estimated to be 0.5%. Some patients develop severe symptoms, including seizures and focal neurologic deficits, while others have no symptoms. The causes of this remarkable presentation heterogeneity within a primarily monogenic disease remain poorly understood. To address this problem, we have established a chronic mouse model of CCM, induced by postnatal ablation ofKrit1withPdgfb-CreERT. These mice develop CCM lesions gradually over 4-6 months of age throughout of the brain. We examined lesion progression in these mice with T2-weighted 7T MRI protocols. Precise volumetric analysis of individual lesions revealed non-monotonous behavior, with some lesions temporarily growing smaller. However, the cumulative lesional volume invariably increased over time and accelerated after about 3 months. Next, we established a modified protocol for dynamic contrast enhanced (DCE) MR imaging and produced quantitative maps of gadolinium tracer MultiHance in the lesions, indicating a high degree of heterogeneity in lesional permeability. Multivariate comparisons of MRI properties of the lesions with cellular markers for endothelial cells, astrocytes, and microglia revealed that increased cell density surrounding lesions correlates with stability, while increased vasculature within and surrounding lesions may correlate with instability. Our results lay a foundation for better understanding individual lesion properties and provide a comprehensive pre-clinical platform for testing new drug and gene therapies for controlling CCM.

Issues of labor mobilization for monumental construction are central to inquiries based in anthropological archaeology in particular as well as collective action theory in general. Societies at all...

The Antelope Springs Folsom locality is located near Trout Creek Pass, which connects South Park, a high elevation basin in the Rocky Mountains, with the headwaters region of the Arkansas River. Th...

Regional fisheries organisations globally are feeling the impacts of non-compliant behaviour by both contracting and non-contracting parties. Non-compliance arising from activities such as illegal, unreported and unregulated fishing, or failures by flag states to appropriately report the activities of their vessels, has resulted in damage to the environment and damage to the performance of regional fisheries management organisations themselves. As a result, many of these organisations are adopting and implementing a relatively new mechanism to tackle non-compliance: the compliance evaluation procedure. This article demonstrates that by adopting a compliance evaluation procedure, regional fisheries organisations are better placed to identify and address non-compliance in an effort to improve compliance with their conservation measures. It analyses in detail the procedure adopted by one particular organisation, the Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR), to suggest that implementation of their procedure has improved transparency, accountability and enforcement. It is argued that the CCAMLR compliance evaluation procedure represents a model for other polar and high seas areas to promote sustainable, and responsible, fishing practices globally.

Specialty drugs are expensive, but spending on specialty drugs is difficult to measure because of proprietary rebate payments by manufacturers to insurers, pharmacy benefit managers, and state Medi...

Elaborate Middle Woodland (ca. cal 200 BC–cal AD 500) mounds and exotic artifacts traded over long distances provide evidence for institutions that helped coordinate the gathering of large communal groups on the ancient midcontinent. However, the material heterogeneity archaeologists have documented for these societies suggests diverse material, historical, and social forces motivated communal gatherings. In this article, we introduce Middle Woodland Ceremonial Situations in the North American Midcontinent, our guest-edited issue of the Midcontinental Journal of Archaeology. Contributions to this issue wrestle with the notion of “situations,” as developed by sociocultural anthropologists, to better understand the archaeological record of the Middle Woodland midcontinent. In doing so, the contributors propose new ways to frame the scalar and temporal diversity of Middle Woodland ceremonialism by focusing on the material evidence for situations where people, earth, and things converged in different ways and times to shape the ceremonial landscape of the midcontinent.

Chipped-stone bladelets are common at Middle Woodland sites throughout Ohio and many other areas of the midcontinent, reflecting both broad patterns and local diversity characteristic of situations as explored in this special issue. In previous studies, bladelets were often viewed through dichotomous categories such as sacred and secular. In this article, I attempt to break down these artificial oppositions imposed by archaeologists and refocus the interpretation of these artifacts using notions of situations and assemblages. I argue that doing so provides new insights into the use of bladelets at sites throughout southern Ohio and beyond. The related concepts of citations and capacities help illustrate the connections between bladelets and other material elements of Middle Woodland institutions. Examination of bladelet use illustrates how situations lead to shared conditions of action while individuals engage in multiple outcomes during manifestations of Middle Woodland ceremonies.

In 2011, the University of Toledo, Ohio, transferred five Clovis fluted points to the Department of Archaeology at the Cleveland Museum of Natural History for permanent curation. Here, following several similar previous efforts, we describe these five Late Pleistocene artifacts with technological descriptions, illustrations, morphometrics, and microwear. These specimens support long-distance lithic procurement (> 200 km) from central Ohio to NW Ohio, as well as the exploitation of the NW Ohio and southern Michigan landscape by Clovis Paleoindian foragers.

Texturally complex monazite grains contained in two granulite-facies pelitic migmatites from southern Baffin Island, Arctic Canada, were mapped by laser ablation-inductively coupled plasma-mass spectrometry (using spot sizes < 5 µm) to quantitatively determine the spatial variation in trace element chemistry (with up to 1883 analyses per grain). The maps highlight the chemical complexity of monazite grains that have experienced multiple episodes of growth, resorption and chemical modification by dissolution-precipitation during high-grade metamorphism. Following detailed chemical characterisation of monazite compositional zones, a related U-Pb dataset is re-interpreted, allowing petrologically-significant ages to be extracted from a continuum of concordant data. Synthesis of these data with pseudosection modelling of prograde and peak conditions allows for the temporal evolution of monazite trace element chemistry to be placed in the context of the evolving P-T conditions and major phase assemblage. This approach enables a critical evaluation of three commonly used petrochronological indicators: linking Y to garnet abundance, the Eu anomaly to feldspar content, and Th/U to anatectic processes. Europium anomalies and Th/U behave in a relatively systematic fashion, suggesting that they are reliable petrochronological witnesses. However, Y systematics are variable, both within domains interpreted to have grown in a single event, between grains interpreted to be part of the same age population, and between samples that experienced similar metamorphic conditions and mineral assemblages. These observations caution against generalised petrological interpretations on the basis of Y content, as it suggests Y concentrations in monazite are controlled by domainal equilibria. The results reveal a ~45 Myr interval between prograde metamorphism and retrograde melt crystallisation in the study area, emphasising the long-lived nature of heat flow in high-grade metamorphic terranes. Such long timescales of metamorphism would be assisted by the growth, retention and dominance of high-Th suprasolidus monazite, as observed in this study, contributing to the radiogenic heating budget of mid- to lower-crustal environments. Careful characterisation of monazite grains suggests that continuum-style U-Pb datasets can be decoded to provide insights into the duration of metamorphic processes.

Agricultural soils are important sources of greenhouse gases (GHGs). Soil properties and environmental factors have complex interactions which influence the dynamics of these GHG fluxes. Four arable and five grassland soils which represent the range of soil textures and climatic conditions of the main agricultural areas in the UK were incubated at two different moisture contents (50 or 80% water holding capacity) and with or without inorganic fertiliser application (70 kg N ha⁻¹ ammonium nitrate) over 22 days. Emissions of N₂O, CO₂ and CH₄ were measured twice per week by headspace gas sampling, and cumulative fluxes were calculated. Multiple regression modelling was carried out to determine which factors (soil mineral N, organic carbon and total nitrogen contents, C:N ratios, clay contents and pH) that best explained the variation in GHG fluxes. Clay, mineral N and soil C contents were found to be the most important explanatory variables controlling GHG fluxes in this study. However, none of the measured variables explained a significant amount of variation in CO₂ fluxes from the arable soils. The results were generally consistent with previously published work. However, N₂O emissions from the two Scottish soils were substantially more sensitive to inorganic N fertiliser application at 80% water holding capacity than the other soils, with the N₂O emissions being up to 107 times higher than the other studied soils.

Bacterial brGDGT lipids are a prevalent tool in studies of terrestrial paleoclimate. Their distributions correlate empirically with environmental temperature and pH, and their ubiquity in terrestrial, freshwater, and marine environments gives them wide applicability. Whether correlations with temperature and pH emerge due to a physiological response of source organisms and/or a shift in bacterial community composition remains an open question with important implications for proxy development and application. We applied a newly described technique for grouping brGDGTs to a globally compiled dataset ( n = 3129) consisting of all modern sample media known to host brGDGTs. We found strong resemblances in the relationships between brGDGT fractional abundances and both temperature and pH across nearly all sample types examined. We also found near-universal connections between the brGDGTs themselves. Given the markedly different bacterial communities expected to inhabit these settings, these widespread relationships may suggest physiological and/or biochemical bases for observed brGDGT distributions.

Up to 32% of patients with COVID-19 pneumonia may require intensive care unit (ICU) admission or mechanical ventilation. Data from low- and middle-income countries on COVID-19 acute respiratory distress syndrome (ARDS) are limited. Groote Schuur Hospital in Cape Town, South Africa, expanded its intensive care service to support patients with COVID-19 ARDS requiring invasive mechanical ventilation (IMV).To report on patients' characteristics and outcomes from the first two pandemic waves.All patients with COVID-19 ARDS admitted to the ICU for IMV were included in this prospective cohort study. Data were collected from 5 April 2020 to 5 April 2021.Over the 12-month study period, 461 patients were admitted to the designated COVID-19 ICU. Of these, 380 met the study criteria and 377 had confirmed hospital discharge outcomes. The median (range) age of patients was 51 (17 - 71) years, 50.5% were female, and the median (interquartile range (IQR)) body mass index was 32 (28 - 38) kg/m2. The median (IQR) arterial oxygen partial pressure to fractional inspired oxygen (P/F) ratio was 97 (71 - 128) after IMV was initiated. Comorbidities included diabetes (47.6%), hypertension (46.3%) and HIV infection (10.5%). Of the patients admitted, 30.8% survived to hospital discharge with a median (IQR) ICU length of stay of 19.5 (9 - 36) days. Predictors of mortality after adjusting for confounders were male sex (odds ratio (OR) 1.74), increasing age (OR 1.04) and higher Sequential Organ Failure Assessment (SOFA) score (OR 1.29).In a resource-limited environment, the provision of IMV support in the ICU achieved 30.8% hospital survival in patients with COVID-19 ARDS. The ability to predict survival remains difficult given this complex disease.

In semiarid agricultural regions, aquifers have watered widespread economic development. Falling water tables, however, drive up energy costs and can make the water toxic for human consumption. The study area is located in central Mexico, where arsenic and fluoride are widely present at toxic concentrations in well water. We simulated the holistic outcomes from three pumping scenarios over 100 years (2020–2120); (S1) pumping rates increase at a similar rate to the past 40 years, (S2) remain constant, or (S3) decrease. Under scenario S1, by 2120, the depth to water table increased to 426 m and energy consumption for irrigation increased to 4 × 109 kWh/yr. Arsenic and fluoride concentrations increased from 14 to 46 μg/L and 1.0 to 3.6 mg/L, respectively. The combined estimated IQ point decrements from drinking untreated well water lowered expected incomes in 2120 by 27% compared to what they would be with negligible exposure levels. We calculated the 100-year Net Present Value (NPV) of each scenario assuming the 2020 average crop value to water footprint ratio of 0.12 USD/m3. Without drinking water mitigation, S1 and S3 yielded relative NPVs of −5.96 × 109 and 1.51 × 109 USD, respectively, compared to the base case (S2). The relative NPV of providing blanket reverse osmosis treatment, while keeping pumping constant (S2), was 11.55 × 109 USD and this gain increased when combined with decreased pumping (S3). If a high value, low water footprint crop was substituted (broccoli, 1.51 USD/m3), the net gains from increasing pumping were similar in size to those of implementing blanket drinking water treatment.

Localized stressors compound the ongoing climate-driven decline of coral reefs, requiring natural resource managers to work with rapidly shifting paradigms. Trait-based adaptive management (TBAM) is a new framework to help address changing conditions by choosing and implementing management actions specific to species groups that share key traits, vulnerabilities, and management responses. In TBAM maintenance of functioning ecosystems is balanced with provisioning for human subsistence and livelihoods. We first identified trait-based groups of food fish in a Pacific coral reef with hierarchical clustering. Positing that trait-based groups performing comparable functions respond similarly to both stressors and management actions, we ascertained biophysical and socioeconomic drivers of trait-group biomass and evaluated their vulnerabilities with generalized additive models. Clustering identified 7 trait groups from 131 species. Groups responded to different drivers and displayed divergent vulnerabilities; human activities emerged as important predictors of community structuring. Biomass of small, solitary reef-associated species increased with distance from key fishing ports, and large, solitary piscivores exhibited a decline in biomass with distance from a port. Group biomass also varied in response to different habitat types, the presence or absence of reported dynamite fishing activity, and exposure to wave energy. The differential vulnerabilities of trait groups revealed how the community structure of food fishes is driven by different aspects of resource use and habitat. This inherent variability in the responses of trait-based groups presents opportunities to apply selective TBAM strategies for complex, multispecies fisheries. This approach can be widely adjusted to suit local contexts and priorities.Grupos de Atributos como Entidades de Manejo en una Pesquería de Arrecife Compleja y Multiespecie Resumen Los estresantes localizados agravan la continua declinación de los arrecifes de coral causada por el clima, lo que requiere que los administradores de recursos naturales trabajen con paradigmas en constante cambio. El manejo adaptativo basado en caracteres (TBAM, en inglés) es un marco de trabajo nuevo que ayuda a enfrentar las condiciones cambiantes mediante la selección e implementación de acciones de manejo específicas para grupos de especies que comparten atributos, vulnerabilidades y respuestas al manejo esenciales. En el TBAM, el mantenimiento de los ecosistemas funcionales está balanceado con el suministro para la subsistencia humana. Identificamos mediante un agrupamiento jerárquico los grupos basados en atributos de peces para la alimentación en un arrecife de coral del Pacífico. Al plantear que los grupos basados en atributos que desempeñan funciones comparables responden similarmente a los estresantes y las acciones de manejo, determinamos los impulsores biofísicos y socioeconómicos de la biomasa de un grupo de atributos y evaluamos sus vulnerabilidades mediante modelos aditivos generalizados. Identificamos siete grupos de atributos a partir de 131 especies. Los grupos respondieron a diferentes impulsores y desplegaron vulnerabilidades divergentes; las actividades humanas aparecieron como predictores importantes de la estructuración de la comunidad. La biomasa de las especies solitarias asociadas al arrecife incrementó con la distancia desde puertos importantes de pesca y los piscívoros solitarios de gran tamaño exhibieron una declinación en la biomasa junto con la distancia desde un puerto. La biomasa de los grupos también varió en respuesta a los diferentes tipos de hábitat, la presencia o ausencia reportada de actividad pesquera con dinamita y la exposición a la energía del oleaje. Las vulnerabilidades diferenciales de los grupos de atributos revelaron cómo la estructura de la comunidad de peces para la alimentación está impulsada por aspectos diferentes del uso de recursos y del hábitat. Esta variabilidad inherente en las respuestas de los grupos basados en atributos presenta la oportunidad de aplicar estrategias selectivas de manejo basado en atributos en las pesquerías complejas y multiespecie. Este enfoque puede ajustarse abiertamente para adaptarse a los contextos y las prioridades locales.【摘要】局部压力因素加剧了气候导致的珊瑚礁持续减少, 这要求自然资源管理者在快速变化的形式下开展工作。基于性状的适应性管理 (TBAM) 是一个新的框架, 通过对具有关键性状、脆弱性和管理响应的物种群选择和实施针对性的管理行动, 以应对不断变化情况。TBAM要求平衡维持生态系统功能与为人类提供生计。本研究首先利用层次聚类确定了太平洋珊瑚礁中基于性状的可食用鱼类物种群。由于基于性状的物种群有类似的功能, 对压力因素和管理行动也有相似的响应, 因此, 我们确定了影响性状群生物量的生物物理和社会经济驱动因素, 并用广义可加模型评估了它们的脆弱性。我们还通过聚类分析确定了 131 个物种构成的7个性状群。每个性状群会对不同的驱动因素做出响应, 表现出不同的脆弱性, 而人类活动是群落结构的重要预测因素。珊瑚礁中单独活动的小型物种的生物量随着与主要渔港的距离增加而增加, 而单独活动的大型食鱼性鱼类的生物量则随着与港口的距离增加而下降。性状群生物量也随着不同的生境类型、有无炸鱼行为, 以及波能暴露情况而变化。性状群之间的脆弱性差异揭示了资源利用和栖息地不同方面的因素如何驱动了可食用鱼类的群落结构变化。性状群做出响应时内在的差异为复杂、多物种渔业中应用选择性的基于性状的适应性管理策略提供了机会。这种方法可以广泛地调整, 以适应局部地区的情况和优先事项。【翻译: 胡怡思; 审校: 聂永刚】.

Effects of gaps (rectangular surface cavities) on boundary-layer transition are investigated using a combination of linear stability theory and experiments, for boundary layers where the smooth-surface transition results from Tollmien–Schlichting (TS) instability. Results are presented for a wide range of gap characteristics, with the associated transition locations ranging from the smooth-surface location all the way forward to the gap location. The transition movement is well described by a variable $N$ -factor, which links the gap characteristics to the level of instability amplification $e^N$ leading to transition. The gap effects on TS-wave transition are characterized by two limiting behaviours. For shallow gaps $d/w < 0.017$ , the reduction in $N$ -factor is a function of the gap depth $d$ and is independent of the gap width $w$ . For deep gaps $d/w > 0.028$ , the reduction in $N$ -factor is a function of the gap width and is independent of the gap depth. When both the gap width and depth are sufficiently large relative to the displacement thickness $\delta ^*$ , the TS-wave transition is bypassed, resulting in transition at the gap location. These behaviours are mapped out in terms of ( $w/ \delta ^*$ , $d/ \delta ^*$ ), providing a predictive model for gap effects on transition.

This study provides a comprehensive overview of the electrochemical characteristics of intermetallic compounds (IMCs) commonly encountered in the 3rd generation Al–Cu–Li alloys. The electrochemical measurements were carried out on a AA2070-T8 alloy and surrogate alloys that have the compositions of select IMCs, typically found in AA2070-T8. The effects of environmental variables such as [Cl−] and pH on the corrosion potential, pitting potential, repassivation potential, corrosion rate, and galvanic current of these IMCs were thoroughly evaluated utilizing the electrochemical microcell method. An electrochemical database was documented that covers eight groups of common IMCs in various Al alloys. The findings improve the understanding of interactions between matrix and IMCs in Al alloys, with implications for corrosion mitigation and new materials design.

Transcranial focused ultrasound with the InSightec Exablate system uses thermal ablation for the treatment of movement and mood disorders and blood brain barrier disruption for tumor therapy. The system uses computed tomography (CT) images to calculate phase corrections that account for aberrations caused by the human skull. This work investigates whether magnetic resonance (MR) images can be used as an alternative to CT images to calculate phase corrections. Phase corrections were calculated using the gold standard hydrophone method and the standard of care InSightec ray tracing method. MR binary image mask, MR-simulated-CT (MRsimCT), and CT images of three ex vivo human skulls were supplied as inputs to the InSightec ray tracing method. The degassed ex vivo human skulls were sonicated with a 670 kHz hemispherical phased array transducer (InSightec Exablate 4000). 3D raster scans of the beam profiles were acquired using a hydrophone mounted on a 3-axis positioner system. Focal spots were evaluated using six metrics: pressure at the target, peak pressure, intensity at the target, peak intensity, positioning error, and focal spot volume. Targets at the geometric focus and 5 mm lateral to the geometric focus were investigated. There was no statistical difference between any of the metrics at either target using either MRsimCT or CT for phase aberration correction. As opposed to the MRsimCT, the use of CT images for aberration correction requires registration to the treatment day MR images; CT misregistration within a range of ± 2 degrees of rotation error along three dimensions was shown to reduce focal spot intensity by up to 9.4%. MRsimCT images used for phase aberration correction for the skull produce similar results as CT-based correction, while avoiding both CT to MR registration errors and unnecessary patient exposure to ionizing radiation.

This study aimed to estimate the impact of sharing drug rebates at the point of sale on out-of-pocket spending by linking estimated rebates to administrative claims data for employer-sponsored insurance enrollees in 2018.We applied the drug rebate rate to the retail price of each brand name drug fill, allocated the reductions to out-of-pocket spending based on cost-sharing provisions, and aggregated each individual's out-of-pocket spending across drug fills. We assumed that generic drugs have no rebates for employer-sponsored insurance. We assessed the impact of sharing rebates at the point of sale on out-of-pocket spending overall, for the therapeutic classes and specific drugs with the highest average out-of-pocket spending per user, and by health plan type.Across 4 simulations with different assumptions about the degree of cross-fill effects, we found that 10.4% to 12.2% of enrollees in our sample would have realized savings on out-of-pocket spending if rebates were shared to the point of sale. Among those with savings, approximately half would save $50 or less, and 10% would save$500 annually. We calculated that a premium increase of $1.06 to $1.41 per member per month among the continuously enrolled, insured population would be sufficient to finance the out-of-pocket savings in our sample.Our study suggests that, for a small percentage of enrollees, sharing drug rebates at the point of sale would likely improve the affordability of high-priced brand name drugs, especially drugs that face significant competition.

Worldwide, there is a trend towards increased herd sizes, and the animal-to-stockman ratio is increasing within the beef and dairy sectors; thus, the time available to monitoring individual animals is reducing. The behaviour of cows is known to change in the hours prior to parturition, for example, less time ruminating and eating and increased activity level and tail-raise events. These behaviours can be monitored non-invasively using animal-mounted sensors. Thus, behavioural traits are ideal variables for the prediction of calving. This study explored the potential of two sensor technologies for their capabilities in predicting when calf expulsion should be expected. Two trials were conducted at separate locations: (i) beef cows (n = 144) and (ii) dairy cows (n = 110). Two sensors were deployed on each cow: (1) Afimilk Silent Herdsman (SHM) collars monitoring time spent ruminating (RUM), eating (EAT) and the relative activity level (ACT) of the cow, and (2) tail-mounted Axivity accelerometers to detect tail-raise events (TAIL). The exact time the calf was expelled from the cow was determined by viewing closed-circuit television camera footage. Machine learning random forest algorithms were developed to predict when calf expulsion should be expected using single-sensor variables and by integrating multiple-sensor data-streams. The performance of the models was tested using the Matthew’s correlation coefficient (MCC), the area under the curve, and the sensitivity and specificity of predictions. The TAIL model was slightly better at predicting calving within a 5-h window for beef cows (MCC = 0.31) than for dairy cows (MCC = 0.29). The TAIL + RUM + EAT models were equally as good at predicting calving within a 5-h window for beef and dairy cows (MCC = 0.32 for both models). Combining data-streams from SHM and tail sensors did not substantially improve model performance over tail sensors alone; therefore, hour-by-hour algorithms for the prediction of time of calf expulsion were developed using tail sensor data. Optimal classification occurred at 2 h prior to calving for both beef (MCC = 0.29) and dairy cows (MCC = 0.25). This study showed that tail sensors alone are adequate for the prediction of parturition and that the optimal time for prediction is 2 h before expulsion of the calf.

Despite decades of study of post-depositional surface modification by lithic use-wear analysts, the impact of heat remains underexplored. In this paper, we present the results of an experiment desi...

Differences in the prevalence and presentation of psychiatric illnesses in men and women suggest that neurobiological sex differences confer vulnerability or resilience in these disorders. Rodent behavioral models are critical for understanding the mechanisms of these differences. Reward processing and punishment avoidance are fundamental dimensions of the symptoms of psychiatric disorders. Here we explored sex differences along these dimensions using multiple and distinct behavioral paradigms. We found no sex difference in reward-guided associative learning but a faster punishment-avoidance learning in females. After learning, females were more sensitive than males to probabilistic punishment but less sensitive when punishment could be avoided with certainty. No sex differences were found in reward-guided cognitive flexibility. Thus, sex differences in goal-directed behaviors emerged selectively when there was an aversive context. These differences were critically sensitive to whether the punishment was certain or unpredictable. Our findings with these new paradigms provide conceptual and practical tools for investigating brain mechanisms that account for sex differences in susceptibility to anxiety and impulsivity. They may also provide insight for understanding the evolution of sex-specific optimal behavioral strategies in dynamic environments.

The rate of change in the relative size of SOC pools (sensitivity) due to land management may vary depending on their level of chemical and/or physical protection from decomposition, but has rarely been directly measured. The availability of archived (1975) soils from an abandoned long term tillage treatment experiment provided a unique opportunity to assess the sensitivity of SOC pools with different levels of stability to uniform land management after divergent tillage treatments. There were four initial treatments (1968–1991): 1) deep plough then no till, 2) shallow plough, 3) reduced till then rotary cultivation and 4) no till. The treatments were followed by uniform long-term grassland management (17 years) and subsequent short-term arable (two years). The sensitivity of SOC to land management was assessed by fractionation and direct comparison of archived soils and soils sampled in 2014 from this site. Both reductions and increases in SOC stocks were observed over time in comparable treatments but the overall effect was a trend towards an equilibration of SOC stocks across all plots. The labile fractions (particulate and dissolved organic matter) were sensitive to land management regardless of initial tillage treatment, but were more sensitive in the reduced till + rotary cultivation and no till treatments (2.3–5.3 times more sensitive than the whole soil) than the deep plough + no till and shallow plough treatments (1.12.2 times more sensitive than the whole soil). The chemically resistant fraction of the soils was surprisingly sensitive to land management (0.9–1.3 times more sensitive than the whole soil). This study shows that the degree of sensitivity of SOC fractions to land management can vary significantly depending on previous tillage management practices.

This paper examines the Affordable Care Act’s (ACA’s) excise tax on high-cost health plans and simulates how tax threshold adjustments and potential behavioral responses by employers and enrollees ...

The neuronal underpinning of learning cause-and-effect associations in the adolescent brain remains poorly understood. Two fundamental forms of associative learning are Pavlovian (classical) conditioning, where a stimulus is followed by an outcome, and operant (instrumental) conditioning, where outcome is contingent on action execution. Both forms of learning, when associated with a rewarding outcome, rely on midbrain dopamine neurons in the ventral tegmental area (VTA) and substantia nigra (SN). We find that in adolescent male rats, reward-guided associative learning is encoded differently by midbrain dopamine neurons in each conditioning paradigm. Whereas simultaneously recorded VTA and SN adult neurons have a similar phasic response to reward delivery during both forms of conditioning, adolescent neurons display a muted reward response during operant but a profoundly larger reward response during Pavlovian conditioning suggesting that adolescent neurons assign a different value to reward when it is not gated by action. The learning rate of adolescents and adults during both forms of conditioning was similar further supporting the notion that differences in reward response in each paradigm are due to differences in motivation and independent of state versus action value learning. Static characteristics of dopamine neurons such as dopamine cell number and size were similar in the VTA and SN but there were age differences in baseline firing rate, stimulated release and correlated spike activity suggesting that differences in reward responsiveness by adolescent dopamine neurons are not due to differences in intrinsic properties of these neurons but engagement of different networks.

Neuronal underpinning of learning cause-and-effect associations in the adolescent brain remains poorly understood. Two fundamental forms of associative learning are Pavlovian (classical) conditioning, where a stimulus is followed by an outcome, and operant (instrumental) conditioning, where outcome is contingent on action execution. Both forms of learning, when associated with a rewarding outcome, rely on midbrain dopamine neurons in the ventral tegmental area (VTA) and substantia nigra (SN). We find that, in adolescent male rats, reward-guided associative learning is encoded differently by midbrain dopamine neurons in each conditioning paradigm. Whereas simultaneously recorded VTA and SN adult neurons have a similar phasic response to reward delivery during both forms of conditioning, adolescent neurons display a muted reward response during operant but a profoundly larger reward response during Pavlovian conditioning. These results suggest that adolescent neurons assign a different value to reward when it is not gated by action. The learning rate of adolescents and adults during both forms of conditioning was similar, supporting the notion that differences in reward response in each paradigm may be because of differences in motivation and independent of state versus action value learning. Static characteristics of dopamine neurons, such as dopamine cell number and size, were similar in the VTA and SN of both ages, but there were age-related differences in stimulated dopamine release and correlated spike activity, suggesting that differences in reward responsiveness by adolescent dopamine neurons are not because of differences in intrinsic properties of these neurons but engagement of different dopaminergic networks.SIGNIFICANCE STATEMENTReckless behavior and impulsive decision-making by adolescents suggest that motivated behavioral states are encoded differently by the adolescent brain. Motivated behavior, which is dependent on the function of the dopamine system, follows learning of cause-and-effect associations in the environment. We find that dopamine neurons in adolescents encode reward differently depending on the cause-and-effect relationship of the means to receive that reward. Compared with adults, reward contingent on action led to a muted response, whereas reward that followed a cue but was not gated by action produced an augmented phasic response. These data demonstrate an age-related difference in dopamine neuron response to reward that is not uniform and is guided by processes that differentiate between state and action values.

PURPOSE To characterize the differences between histogram-based and image-based algorithms for segmentation of hyperpolarized gas lung images. METHODS Four previously published histogram-based segmentation algorithms (ie, linear binning, hierarchical k-means, fuzzy spatial c-means, and a Gaussian mixture model with a Markov random field prior) and an image-based convolutional neural network were used to segment 2 simulated data sets derived from a public (n = 29 subjects) and a retrospective collection (n = 51 subjects) of hyperpolarized 129Xe gas lung images transformed by common MRI artifacts (noise and nonlinear intensity distortion). The resulting ventilation-based segmentations were used to assess algorithmic performance and characterize optimization domain differences in terms of measurement bias and precision. RESULTS Although facilitating computational processing and providing discriminating clinically relevant measures of interest, histogram-based segmentation methods discard important contextual spatial information and are consequently less robust in terms of measurement precision in the presence of common MRI artifacts relative to the image-based convolutional neural network. CONCLUSIONS Direct optimization within the image domain using convolutional neural networks leverages spatial information, which mitigates problematic issues associated with histogram-based approaches and suggests a preferred future research direction. Further, the entire processing and evaluation framework, including the newly reported deep learning functionality, is available as open source through the well-known Advanced Normalization Tools ecosystem.

Magnetic resonance imaging (MRI) using hyperpolarized gases has made possible the novel visualization of airspaces in the human lung, which has advanced research into the growth, development, and pathologies of the pulmonary system. In conjunction with the innovations associated with image acquisition, multiple image analysis strategies have been proposed and refined for the quantification of such lung imaging with much research effort devoted to semantic segmentation, or voxelwise classification, into clinically oriented categories based on ventilation levels. Given the functional nature of these images and the consequent sophistication of the segmentation task, many of these algorithmic approaches reduce the complex spatial image information to intensity-only considerations, which can be contextualized in terms of the intensity histogram. Although facilitating computational processing, this simplifying transformation results in the loss of important spatial cues for identifying salient image features, such as ventilation defects (a well-studied correlate of lung pathophysiology), as spatial objects. In this work, we discuss the interrelatedness of the most common approaches for histogram-based optimization of hyperpolarized gas lung imaging segmentation and demonstrate how certain assumptions lead to suboptimal performance, particularly in terms of measurement precision. In contrast, we illustrate how a convolutional neural network is optimized (i.e., trained) directly within the image domain to leverage spatial information. This image-based optimization mitigates the problematic issues associated with histogram-based approaches and suggests a preferred future research direction. Importantly, we provide the entire processing and evaluation framework, including the newly reported deep learning functionality, as open-source through the well-known Advanced Normalization Tools ecosystem.

Bovine respiratory disease (BRD) represents one of the major disease challenges affecting preweaning dairy-bred calves. Previous studies have shown that differences in feeding and activity behaviors exist between healthy and diseased calves affected by BRD. The aim of this study was to develop and assess the accuracy of models designed to predict BRD from feeding and activity behaviors. Feeding and activity behaviors were recorded for 100 male preweaning calves between ~8 to 42 d of age. Calves were group housed with ad libitum access to milk via automatic milk feeders, water, starter diet, and straw. Activity was monitored via a leg-mounted accelerometer. Health status of individual calves was monitored daily using an adapted version of the Wisconsin Scoring System to identify BRD. Three models were created to predict disease: (1) deviation from normal lying time based on moving averages (MA); (2) random forest (RF), a machine learning technique based on feeding and activity variables; and (3) a combination of RF and MA output. For the MA model, lying time was predicted based on behavior over previous days (3- and 7-d MA) and the expected value for the current day (based on calf age; measured using accelerometers). Data were not split into training and test data sets. Occasions when the actual lying time increased >9% of predicted lying time were classified as a deviation from normal and a disease alert was provided. Both feeding and activity behaviors were included within the RF model. Data were split into training (70%) and test (30%) data sets based on disease events. Events were classified as 2 d before, the day(s) of the disease event, and 2 d after the event. Accuracy of models was assessed using sensitivity, specificity, balanced accuracy, and Matthews correlation coefficient (MCC). If a positive disease prediction agreed with an actual disease event within a 3-d rolling window, it was classified as a true positive. Stand-alone models (RF; MA) showed high specificity (0.95; 0.97), moderate sensitivity (0.35; 0.43), balanced accuracy (0.65; 0.64), and MCC (0.25; 0.29). Combining outputs increased accuracy (specificity = 0.95, sensitivity = 0.54, balanced accuracy = 0.75, MCC = 0.36). The work presented is the first to demonstrate the use of modeling data derived from precision livestock farming techniques that monitor feeding and activity behaviors for early detection of BRD in preweaning calves, offering a significant advance in health management of youngstock.

Designating and managing marine protected areas (MPAs) can mitigate many ocean threats. Banning fishing activities within MPAs enhances the robustness of food-web dynamics and thus increases trophic resilience. Ecosystem function indicators, such as mean trophic level, are increasingly applied in conservation management. Stable isotope analysis is a common tool in trophodynamic studies as it provides information about food sources and trophic level within food webs. In contrast to the traditional top-down approaches in conservation management (mainly for fisheries), this study focuses on bottom-up responses to protection according to the target species in regional small-scale fisheries. The present study aimed to examine how MPA status affects trophodynamics in the rocky reefs of the Illas Atlanticas Marine-Terrestrial National Park (Galicia, NW Spain). Results showed no differences between inside and outside the MPA in species stable isotopic signatures or trophic level. However, these results should be considered with caution due to some limitations in the study design (small number of sites per location, biogeographic differences associated with the island nature of the MPA, or seasonal variability). Nevertheless, the lax fishing management, the lack of proper implementation (the MPA was established in 2002 without a management plan until 2019), and the small size of the studied MPA may result in ineffective conservation outcomes that could have been reflected in the stable isotopic content of the food web. The large number of “paper park” MPAs existing worldwide are not only detrimental to the perception of marine protection, but also provide poor protection of marine ecosystems. Subject to further studies accounting for both environmental and management factors on stable isotope signatures, trophic interactions can form a cost-effective tool for monitoring MPA effectiveness.

Focused ultrasound (FUS) mediated blood–brain barrier disruption (BBBD) targets the delivery of systemically‐administered therapeutics to the central nervous system. Preclinical investigations of BBBD have been performed on different anesthetic backgrounds; however, the influence of the choice of anesthetic on the molecular response to BBBD is unknown, despite its potential to critically affect interpretation of experimental therapeutic outcomes. Here, using bulk RNA sequencing, we comprehensively examined the transcriptomic response of both normal brain tissue and brain tissue exposed to FUS‐induced BBBD in mice anesthetized with either isoflurane with medical air (Iso) or ketamine/dexmedetomidine (KD). In normal murine brain tissue, Iso alone elicited minimal differential gene expression (DGE) and repressed pathways associated with neuronal signaling. KD alone, however, led to massive DGE and enrichment of pathways associated with protein synthesis. In brain tissue exposed to BBBD (1 MHz, 0.5 Hz pulse repetition frequency, 0.4 MPa peak‐negative pressure), we systematically evaluated the relative effects of anesthesia, microbubbles, and FUS on the transcriptome. Of particular interest, we observed that gene sets associated with sterile inflammatory responses and cell–cell junctional activity were induced by BBBD, regardless of the choice of anesthesia. Meanwhile, gene sets associated with metabolism, platelet activity, tissue repair, and signaling pathways, were differentially affected by BBBD, with a strong dependence on the anesthetic. We conclude that the underlying transcriptomic response to FUS‐mediated BBBD may be powerfully influenced by anesthesia. These findings raise considerations for the translation of FUS‐BBBD delivery approaches that impact, in particular, metabolism, tissue repair, and intracellular signaling.