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Immunohistochemistry (IHC) assays play a central role in evaluating biomarker expression in tissue sections for diagnostic and research applications. Manual scoring of IHC images, which is the current standard of practice, is known to have several shortcomings in terms of reproducibility and scalability to large scale studies. Here, by using a digital image analysis-based approach, we introduce a new metric called the pixelwise H-score (pix H-score) that quantifies biomarker expression from whole-slide scanned IHC images. The pix H-score is an unsupervised algorithm that only requires the specification of intensity thresholds for the biomarker and the nuclear-counterstain channels. We present the detailed implementation of the pix H-score in two different whole-slide image analysis software packages Visiopharm and HALO. We consider three biomarkers P-cadherin, PD-L1, and 5T4, and show how the pix H-score exhibits tight concordance to multiple orthogonal measurements of biomarker abundance such as the biomarker mRNA transcript and the pathologist H-score. We also compare the pix H-score to existing automated image analysis algorithms and demonstrate that the pix H-score provides either comparable or significantly better performance over these methodologies. We also present results of an empirical resampling approach to assess the performance of the pix H-score in estimating biomarker abundance from select regions within the tumor tissue relative to the whole tumor resection. We anticipate that the new metric will be broadly applicable to quantify biomarker expression from a wide variety of IHC images. Moreover, these results underscore the benefit of digital image analysis-based approaches which offer an objective, reproducible, and highly scalable strategy to quantitatively analyze IHC images.

A growing body of evidence points to the important role of spirituality in treating medical and psychological conditions. The authors suggest that spirituality is a 5th force in counseling and psychology. Consequently, the assessment of spirituality is a new and growing area of interest for counselors. Assessment can assist both the counselor and client in obtaining a better understanding of the role of spirituality in the issues that bring the client to counseling and in designing treatment interventions appropriate for resolution of those issues. Selected instruments currently in use are described and their psychometric properties and potential uses are examined.

Examines the importance of the induction phase for graduates of Transforming School Counseling Initiative programs, offering a rationale for strengthening the involvement of counselor educators in this process, reviewing relevant literature, and discussing: current practices in practicum and internship, mentoring and supervision, the need to develop onsite supervisors, the need for novice counselors to develop relationships with stakeholders, and the continuing need for professional development for practicing school counselors. (SM)

Matthew Nelson and colleagues investigate how well genetic evidence for disease susceptibility predicts drug mechanisms. They find a correlation between gene products that are successful drug targets and genetic loci associated with the disease treated by the drug and predict that selecting genetically supported targets could increase the success rate of drugs in clinical development. Over a quarter of drugs that enter clinical development fail because they are ineffective. Growing insight into genes that influence human disease may affect how drug targets and indications are selected. However, there is little guidance about how much weight should be given to genetic evidence in making these key decisions. To answer this question, we investigated how well the current archive of genetic evidence predicts drug mechanisms. We found that, among well-studied indications, the proportion of drug mechanisms with direct genetic support increases significantly across the drug development pipeline, from 2.0% at the preclinical stage to 8.2% among mechanisms for approved drugs, and varies dramatically among disease areas. We estimate that selecting genetically supported targets could double the success rate in clinical development. Therefore, using the growing wealth of human genetic data to select the best targets and indications should have a measurable impact on the successful development of new drugs.

Mineral aerosols from dust are an important influence on climate and on marine and terrestrial biogeochemical cycles. These aerosols are generated from wind erosion of surface soils. The amount of dust emission can therefore be affected by human activities that alter surface sediments. However, changes in regional- and global-scale dust fluxes following the rapid expansion of human populations and settlements over the past two centuries are not well understood. Here we determine the accumulation rates and geochemical properties of alpine lake sediments from the western interior United States for the past 5,000 years. We find that dust load levels increased by 500% above the late Holocene average following the increased western settlement of the United States during the nineteenth century. We suggest that the increased dust deposition is caused by the expansion of livestock grazing in the early twentieth century. The larger dust flux, which persists into the early twenty-first century, results in a more than fivefold increase in inputs of K, Mg, Ca, N and P to the alpine ecosystems, with implications for surface-water alkalinity, aquatic productivity and terrestrial nutrient cycling. Dust input to alpine lakes in the western United States has risen dramatically following westward expansion of human settlements and increased livestock grazing over the past two centuries. The increased dust flux deposits additional nutrients and minerals to the lakes, with important implications for water chemistry, productivity and nutrient cycling.

Feathers are arranged in a precise pattern in avian skin. They first arise during development in a row along the dorsal midline, with rows of new feather buds added sequentially in a spreading wave. We show that the patterning of feathers relies on coupled fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signalling together with mesenchymal cell movement, acting in a coordinated reaction-diffusion-taxis system. This periodic patterning system is partly mechanochemical, with mechanical-chemical integration occurring through a positive feedback loop centred on FGF20, which induces cell aggregation, mechanically compressing the epidermis to rapidly intensify FGF20 expression. The travelling wave of feather formation is imposed by expanding expression of Ectodysplasin A (EDA), which initiates the expression of FGF20. The EDA wave spreads across a mesenchymal cell density gradient, triggering pattern formation by lowering the threshold of mesenchymal cells required to begin to form a feather bud. These waves, and the precise arrangement of feather primordia, are lost in the flightless emu and ostrich, though via different developmental routes. The ostrich retains the tract arrangement characteristic of birds in general but lays down feather primordia without a wave, akin to the process of hair follicle formation in mammalian embryos. The embryonic emu skin lacks sufficient cells to enact feather formation, causing failure of tract formation, and instead the entire skin gains feather primordia through a later process. This work shows that a reaction-diffusion-taxis system, integrated with mechanical processes, generates the feather array. In flighted birds, the key role of the EDA/Ectodysplasin A receptor (EDAR) pathway in vertebrate skin patterning has been recast to activate this process in a quasi-1-dimensional manner, imposing highly ordered pattern formation.

The effects of soil property uncertainties on permafrost thaw projections are studied using a three-phase subsurface thermal hydrology model and calibration-constrained uncertainty analysis. The null-space Monte Carlo method is used to identify soil hydrothermal parameter combinations that are consistent with borehole temperature measurements at the study site, the Barrow Environmental Observatory. Each parameter combination is then used in a forward projection of permafrost conditions for the 21st century (from calendar year 2006 to 2100) using atmospheric forcings from the Community Earth System Model (CESM) in the Representative Concentration Pathway (RCP) 8.5 greenhouse gas concentration trajectory. A 100-year projection allows for the evaluation of predictive uncertainty (due to soil property (parametric) uncertainty) and the inter-annual climate variability due to year to year differences in CESM climate forcings. After calibrating to measured borehole temperature data at this well-characterized site, soil property uncertainties are still significant and result in significant predictive uncertainties in projected active layer thickness and annual thaw depth-duration even with a specified future climate. Inter-annual climate variability in projected soil moisture content and Stefan number are small. A volume- and time-integrated Stefan number decreases significantly, indicating a shift in subsurface energy utilization in the future climate (latent heat of phase change becomes more important than heat conduction). Out of 10 soil parameters, ALT, annual thaw depth-duration, and Stefan number are highly dependent on mineral soil porosity, while annual mean liquid saturation of the active layer is highly dependent on the mineral soil residual saturation and moderately dependent on peat residual saturation. By comparing the ensemble statistics to the spread of projected permafrost metrics using different climate models, we quantify the relative magnitude of soil property uncertainty to another source of permafrost uncertainty, structural climate model uncertainty. We show that the effect of calibration-constrained uncertainty in soil properties, although significant, is less than that produced by structural climate model uncertainty for this location.

Climate change is profoundly transforming the carbon-rich Arctic tundra landscape, potentially moving it from a carbon sink to a carbon source by increasing the thickness of soil that thaws on a seasonal basis. However, the modeling capability and precise parameterizations of the physical characteristics needed to estimate projected active layer thickness (ALT) are limited in Earth system models (ESMs). In particular, discrepancies in spatial scale between field measurements and Earth system models challenge validation and parameterization of hydrothermal models. A recently developed surface–subsurface model for permafrost thermal hydrology, the Advanced Terrestrial Simulator (ATS), is used in combination with field measurements to achieve the goals of constructing a process-rich model based on plausible parameters and to identify fine-scale controls of ALT in ice-wedge polygon tundra in Barrow, Alaska. An iterative model refinement procedure that cycles between borehole temperature and snow cover measurements and simulations functions to evaluate and parameterize different model processes necessary to simulate freeze–thaw processes and ALT formation. After model refinement and calibration, reasonable matches between simulated and measured soil temperatures are obtained, with the largest errors occurring during early summer above ice wedges (e.g., troughs). The results suggest that properly constructed and calibrated one-dimensional thermal hydrology models have the potential to provide reasonable representation of the subsurface thermal response and can be used to infer model input parameters and process representations. The models for soil thermal conductivity and snow distribution were found to be the most sensitive process representations. However, information on lateral flow and snowpack evolution might be needed to constrain model representations of surface hydrology and snow depth.

The integration of nanophotonics and atomic physics has been a long-sought goal that would open new frontiers for optical physics, including novel quantum transport and many-body phenomena with photon-mediated atomic interactions. Reaching this goal requires surmounting diverse challenges in nanofabrication and atomic manipulation. Here we report the development of a novel integrated optical circuit with a photonic crystal capable of both localizing and interfacing atoms with guided photons. Optical bands of a photonic crystal waveguide are aligned with selected atomic transitions. From reflection spectra measured with average atom number , we infer that atoms are localized within the waveguide by optical dipole forces. The fraction of single-atom radiative decay into the waveguide is Γ 1D /Γ′≃(0.32±0.08), where Γ 1D is the rate of emission into the guided mode and Γ′ is the decay rate into all other channels. Γ 1D /Γ′ is unprecedented in all current atom–photon interfaces. The use of photonic crystals to trap atoms on a chip offers unique possibilities for atom–light interactions. Advancing towards this goal, the authors realize photonic crystal waveguides where the electronic transition frequencies of localized caesium atoms are aligned with the band edges of the waveguides.