Epithelial IL-2 is critical for NK cell-mediated cancer immunosurveillance in mammary glands.

Interleukin 2 (IL-2) is the first identified cytokine and its interaction with receptors has been known to shape the immune responses in many lymphoid or non-lymphoid tissues for more than four decades. Active T cells are the primary cellular source for IL-2 production and epithelial cells have never been considered the major cellular source of IL-2 under physiological conditions. It is, however, tempting to speculate that epithelial cells could potentially express IL-2 that regulates the intricate interactions between epithelial cells and lymphocytes. Datamining our recently published single-cell RNAseq in the mouse mammary gland identified IL-2 expression in mammary epithelial cells, which is induced by prolactin via the STAT5 signaling pathway. Furthermore, epithelial IL-2 plays a crucial role in maintaining the physiological functions of natural killer (NK) cells within the mammary glands. IL-2 deletion in the mammary epithelial cells leads to a significant reduction in the number and function of NK cells, which in turn results in defective immunosurveillance, expansion of luminal epithelial cells, and tumor development. Interestingly, T cells in the mammary glands are not changed, indicating the specific regulation of NK cells by epithelial IL-2 production. In agreement, we also found that human epithelial cells express IL-2 and NK cells express the highest level of IL2RB among all the immune cells. Here, we provide the first evidence that epithelial cells produce IL-2, which is critical for maintaining the physiological functions of NK cells in immunosurveillance.

Strong damped Lyman-α absorption in young star-forming galaxies at redshifts 9 to 11.

Primordial neutral atomic gas, mostly composed of hydrogen, is the raw material for star formation in galaxies. However, there are few direct constraints on the amount of neutral atomic hydrogen (H i) in galaxies at early cosmic times. We analyzed James Webb Space Telescope (JWST) near-infrared spectroscopy of distant galaxies, at redshifts ≳8. From a sample of 12 galaxies, we identified three that show strong damped Lyman-α absorption due to H i in their local surroundings. The galaxies are located at spectroscopic redshifts of 8.8, 10.2, and 11.4, corresponding to 400 to 600 million years after the Big Bang. They have H i column densities ≳1022 cm-2, which is an order of magnitude higher than expected for a fully neutral intergalactic medium, and constitute a gas-rich population of young star-forming galaxies.

Development and validation of a deep learning-based microsatellite instability predictor from prostate cancer whole-slide images.

Microsatellite instability-high (MSI-H) is a tumor-agnostic biomarker for immune checkpoint inhibitor therapy. However, MSI status is not routinely tested in prostate cancer, in part due to low prevalence and assay cost. As such, prediction of MSI status from hematoxylin and eosin (H&E) stained whole-slide images (WSIs) could identify prostate cancer patients most likely to benefit from confirmatory testing to evaluate their eligibility for immunotherapy and need for Lynch syndrome testing. Prostate biopsies and surgical resections from prostate cancer patients referred to our institution were analyzed. MSI status was determined by next-generation sequencing. Patients sequenced before a cutoff date formed an algorithm development set (n = 4015, MSI-H 1.8%) and a paired validation set (n = 173, MSI-H 19.7%) that consisted of two serial sections from each sample, one stained and scanned internally and the other at an external site. Patients sequenced after the cutoff date formed a temporally independent validation set (n = 1350, MSI-H 2.3%). Attention-based multiple instance learning models were trained to predict MSI-H from H&E WSIs. The predictor achieved area under the receiver operating characteristic curve values of 0.78 (95% CI [0.69-0.86]), 0.72 (95% CI [0.63-0.81]), and 0.72 (95% CI [0.62-0.82]) on the internally prepared, externally prepared, and temporal validation sets, respectively, showing effective predictability and generalization to both external staining/scanning processes and temporally independent samples. While MSI-H status is significantly correlated with Gleason score, the model remained predictive within each Gleason score subgroup.

Star formation shut down by multiphase gas outflow in a galaxy at a redshift of 2.45.

Large-scale outflows driven by supermassive black holes are thought to have a fundamental role in suppressing star formation in massive galaxies. However, direct observational evidence for this hypothesis is still lacking, particularly in the young universe where star-formation quenching is remarkably rapid1-3, thus requiring effective removal of gas4 as opposed to slow gas heating5,6. Although outflows of ionized gas are frequently detected in massive distant galaxies7, the amount of ejected mass is too small to be able to suppress star formation8,9. Gas ejection is expected to be more efficient in the neutral and molecular phases10, but at high redshift these have only been observed in starbursts and quasars11,12. Here we report JWST spectroscopy of a massive galaxy experiencing rapid quenching at a redshift of 2.445. We detect a weak outflow of ionized gas and a powerful outflow of neutral gas, with a mass outflow rate that is sufficient to quench the star formation. Neither X-ray nor radio activity is detected; however, the presence of a supermassive black hole is suggested by the properties of the ionized gas emission lines. We thus conclude that supermassive black holes are able to rapidly suppress star formation in massive galaxies by efficiently ejecting neutral gas.

Measurement of in vivo lens shapes using IOLMaster 700 B-scan images: Comparison with phakometry.

PURPOSE: This study compared in vivo crystalline lens shape measurements using B-scan images from the IOLMaster 700 with phakometry. METHODS: Twenty-four young adult participants underwent IOLMaster 700 and phakometry measurements under cycloplegia (1% cyclopentolate). The IOLMaster 700 generated B-scan images along six meridians in 30° increments, which were analysed using custom MATLAB software to determine lens surface radii of curvature. Phakometry measurements were obtained using Purkinje images reflected from the lens surfaces. RESULTS: The IOLMaster 700 image analysis method yielded a lower mean anterior lens surface spherical equivalent power (+6.20 D) than phakometry (+7.55 D); however, the two measurements were strongly correlated (R(21) = 0.97, p < 0.0001). The astigmatic power vectors (J0 and J45) for the anterior lens surface were significantly higher for the IOLMaster 700 measurements, with only J0 showing a significant moderate positive correlation (R(21) = 0.57, p = 0.005). For the posterior lens surface, the IOLMaster 700 measurements had a higher mean spherical power (+14.28 D) compared to phakometry (+13.70 D); however, a strong positive correlation (R(21) = 0.90, p < 0.0001) was observed. No significant correlations were noted for posterior lens surface astigmatic vectors (J0 and J45). The IOLMaster 700 estimates for the equivalent lens mean spherical power were slightly lower than those for phakometry, with a mean difference of -0.72 D, and both methods were positively correlated (R(21) = 0.94, p < 0.0001). CONCLUSIONS: The findings demonstrate that IOLMaster 700 B-scan image analysis technique provides similar estimates of lens surface powers to phakometry. These results highlight the potential of the IOLMaster 700 to provide measurements of lens shape, informing future research and clinical use.

Prediction of MET Overexpression in Lung Adenocarcinoma from Hematoxylin and Eosin Images.

Mesenchymal epithelial transition (MET) protein overexpression is a targetable event in non-small cell lung cancer and is the subject of active drug development. Challenges in identifying patients for these therapies include lack of access to validated testing, such as standardized immunohistochemistry assessment, and consumption of valuable tissue for a single gene/protein assay. Development of prescreening algorithms using routinely available digitized hematoxylin and eosin (H&E)-stained slides to predict MET overexpression could promote testing for those who will benefit most. Recent literature reports a positive correlation between MET protein overexpression and RNA expression. In this work, a large database of matched H&E slides and RNA expression data were leveraged to train a weakly supervised model to predict MET RNA overexpression directly from H&E images. This model was evaluated on an independent holdout test set of 300 overexpressed and 289 normal patients, demonstrating a receiver operating characteristic area under curve of 0.70 (95th percentile interval: 0.66 to 0.74) with stable performance characteristics across different patient clinical variables and robust to synthetic noise on the test set. These results suggest that H&E-based predictive models could be useful to prioritize patients for confirmatory testing of MET protein or MET gene expression status.

PROTAC-mediated NR4A1 degradation as a novel strategy for cancer immunotherapy.

An effective cancer therapy requires killing cancer cells and targeting the tumor microenvironment (TME). Searching for molecules critical for multiple cell types in the TME, we identified NR4A1 as one such molecule that can maintain the immune suppressive TME. Here, we establish NR4A1 as a valid target for cancer immunotherapy and describe a first-of-its-kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 degrades NR4A1 within hours in vitro and exhibits long-lasting NR4A1 degradation in tumors with an excellent safety profile. NR-V04 inhibits and frequently eradicates established tumors. At the mechanistic level, NR-V04 induces the tumor-infiltrating (TI) B cells and effector memory CD8+ T (Tem) cells and reduces monocytic myeloid-derived suppressor cells (m-MDSC), all of which are known to be clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anticancer immune responses and offers a new avenue for treating various types of cancers such as melanoma.

Unleashing the Power of NR4A1 Degradation as a Novel Strategy for Cancer Immunotherapy.

An effective cancer therapy requires both killing cancer cells and targeting tumor-promoting pathways or cell populations within the tumor microenvironment (TME). We purposely search for molecules that are critical for multiple tumor-promoting cell types and identified nuclear receptor subfamily 4 group A member 1 (NR4A1) as one such molecule. NR4A1 has been shown to promote the aggressiveness of cancer cells and maintain the immune suppressive TME. Using genetic and pharmacological approaches, we establish NR4A1 as a valid therapeutic target for cancer therapy. Importantly, we have developed the first-of-its kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 effectively degrades NR4A1 within hours of treatment in vitro and sustains for at least 4 days in vivo, exhibiting long-lasting NR4A1-degradation in tumors and an excellent safety profile. NR-V04 leads to robust tumor inhibition and sometimes eradication of established melanoma tumors. At the mechanistic level, we have identified an unexpected novel mechanism via significant induction of tumor-infiltrating (TI) B cells as well as an inhibition of monocytic myeloid derived suppressor cells (m-MDSC), two clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anti-cancer immune responses and offers a new avenue for treating various types of cancer.

Evolutionary History of Oxysterol-Binding Proteins Reveals Complex History of Duplication and Loss in Animals and Fungi.

Cells maintain the specific lipid composition of distinct organelles by vesicular transport as well as non-vesicular lipid trafficking via lipid transport proteins. Oxysterol-binding proteins (OSBPs) are a family of lipid transport proteins that transfer lipids at various membrane contact sites (MCSs). OSBPs have been extensively investigated in human and yeast cells where 12 have been identified in Homo sapiens and 7 in Saccharomyces cerevisiae. The evolutionary relationship between these well-characterized OSBPs is still unclear. By reconstructing phylogenies of eukaryote OSBPs, we show that the ancestral Saccharomycotina had four OSBPs, the ancestral fungus had five OSBPs, and the ancestral animal had six OSBPs, whereas the shared ancestor of animals and fungi as well as the ancestral eukaryote had only three OSBPs. Our analyses identified three undescribed ancient OSBP orthologues, one fungal OSBP (Osh8) lost in the lineage leading to yeast, one animal OSBP (ORP12) lost in the lineage leading to vertebrates, and one eukaryotic OSBP (OshEu) lost in both the animal and fungal lineages.

Higher order aberrations and retinal image quality during short-term accommodation in myopic and non-myopic children.

INTRODUCTION: Despite the known associations between near work and myopia, and retinal image quality and eye growth, accommodation-induced changes in higher order aberrations (HOA's) and retinal image quality in children with different refractive errors are poorly understood. METHODS: Ocular HOA's were measured using a Hartmann-Shack wavefront sensor (COAS-HD, Wavefront Sciences) in 18 myopic and 18 age- and sex-matched non-myopic children during short-term accommodation tasks (four demands of 0, 3, 6 and 9 D) presented using a Badal optometer. Eighth order Zernike polynomials were fitted across a 2.3 mm pupil diameter to determine refractive power vectors (M, J180 and J45 ) and the accommodation error, and a 4 mm pupil was used for HOA analyses. Retinal image quality was examined using the visual Strehl ratio based on the optical transfer function (VSOTF) for third to eighth radial orders only. RESULTS: Most refractive error group differences were observed for the 6 and 9 D demands. Myopic children underwent greater changes in with-the-rule astigmatism (J180 ), higher order and third order RMS values, primary vertical ( C 3 - 1 ) and horizontal coma ( C 3 1 ), and several other individual Zernike coefficients compared with non-myopic children (all refractive error group by demand interaction p-values of ≤0.02). Non-myopic children exhibited a greater negative shift in primary ( C 4 0 ) and positive shift in secondary spherical aberration ( C 6 0 ) (both refractive error group by demand interaction p-values of ≤0.002). The VSOTF degraded for the 6 and 9 D demands in both groups, but the myopic children underwent a greater mean (SE) reduction from 0 D of -0.274 (0.048) for the 9 D demand, compared with -0.131 (0.052) for the non-myopic children (p = 0.001). CONCLUSION: These results may have implications for the association between near work, accommodation and myopia development, particularly related to the use of short working distances during near tasks.

Intraocular composition of higher order aberrations in non-myopic children.

This study examined anterior corneal, internal ocular, and total ocular higher order aberrations (HOA's), and retinal image quality in a non-myopic, paediatric cohort. Anterior corneal aberrations were derived from corneal topography data captured using a Placido disk videokeratoscope (E300, Medmont International), and whole eye HOA's were measured using a Hartmann-Shack wavefront sensor (COAS-HD, Wavefront Sciences). The associations between HOA's and age, sex, refractive error, and axial length were explored using correlation analyses. Data for 84 children aged between 5 and 12 years (mean ± standard deviation spherical equivalent refraction (SER), +0.63 ± 0.35 D; range 0.00 to +1.75 D) were included, and an eighth order Zernike polynomial was fit for 4 and 6 mm pupil diameters for both the anterior corneal and total ocular HOA's, from which internal ocular HOA's were calculated via subtraction following alignment to a common reference axis (pupil centre). Internal ocular HOA's were of greater magnitude than previous studies of adolescents and adults, however partial internal "compensation" of HOA's was observed, which resulted in reduced levels of HOA's and excellent retinal image quality. Few significant associations were observed between HOA's and age, SER, and axial length (all correlations, p > 0.001), and there were minimal sex-based differences (all comparisons, p > 0.005). Coefficients for vertical coma ( C 3 - 1 and C 5 - 1 ) and spherical aberration ( C 4 0 and C 6 0 ), were most strongly associated with the visual Strehl ratio based on the optical transfer function (VSOTF), which indicated that the absolute magnitudes of these Zernike coefficients have the greatest impact on retinal image quality in this paediatric cohort. These findings provide an improved understanding of the optics and retinal image quality of children's eyes.

Artificial intelligence-augmented histopathologic review using image analysis to optimize DNA yield from formalin-fixed paraffin-embedded slides.

To achieve minimum DNA input requirements for next-generation sequencing (NGS), pathologists visually estimate macrodissection and slide count decisions. Unfortunately, misestimation may cause tissue waste and increased laboratory costs. We developed an artificial intelligence (AI)-augmented smart pathology review system (SmartPath) to empower pathologists with quantitative metrics for accurately determining tissue extraction parameters. SmartPath uses two deep learning architectures, a U-Net based network for cell segmentation and a multi-field-of-view convolutional network for tumor area segmentation, to extract features from digitized H&E-stained formalin-fixed paraffin-embedded slides. From the segmented tumor area, SmartPath suggests a macrodissection area. To predict DNA yield per slide, the extracted features from within the macrodissection area are correlated with known DNA yields to fit a regularized linear model (R = 0.85). Then, a pathologist-defined target yield divided by the predicted DNA yield per slide gives the number of slides to scrape. Following model development, an internal validation trial was conducted within the Tempus Labs molecular sequencing laboratory. We evaluated our system on 501 clinical colorectal cancer slides, where half received SmartPath-augmented review and half traditional pathologist review. The SmartPath cohort had 25% more DNA yields within a desired target range of 100-2000 ng. The number of extraction attempts was statistically unchanged between cohorts. The SmartPath system recommended fewer slides to scrape for large tissue sections, saving tissue in these cases. Conversely, SmartPath recommended more slides to scrape for samples with scant tissue sections, especially those with degraded DNA, helping prevent costly re-extraction due to insufficient extraction yield. A statistical analysis was performed to measure the impact of covariates on the results, offering insights on how to improve future applications of SmartPath. With these improvements, AI-augmented histopathologic review has the potential to decrease tissue waste, sequencing time, and laboratory costs by optimizing DNA yields, especially for samples with scant tissue and/or degraded DNA.

Iron overload and neurodegenerative diseases: What can we learn from Caenorhabditis elegans?

Iron (Fe) is an essential trace element required for several physiological processes. It plays important roles in mitochondrial function, synthesis, and metabolism of the neurotransmitter, as well as oxygen transport. However, excess Fe can cause toxicity. Particularly, Fe overload may result in neurotoxicity, contributing to the development and progression of neurodegenerative diseases, although the molecular mechanisms underlying Fe-induced neurodegeneration have yet to be entirely understood. Alternative (non-rodent) experimental models have been pointed as important approaches to elucidate molecular and physiological events mediating Fe-induced pathology. Among such alternative strategies, an advantageous experimental worm-model system, Caenorhabditis elegans (C. elegans), has been used to investigate Fe-induced neurotoxicity and neurodegenerative disorders. Its genome has been fully sequenced, corroborating that it shares significant homology with mammalians, and has approximately 40% of human disease-related genes. As part of this review, we discuss studies using the C. elegans model to study molecular mechanisms such as oxidative stress, mitochondrial dysfunction, disturbed homeostasis, and its potential contribution to the study of metal-induced neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD).

Breast Cancer Stem Cells: Signaling Pathways, Cellular Interactions, and Therapeutic Implications.

Breast cancer stem cells (BCSCs) constitute a small population of cells within breast cancer and are characterized by their ability to self-renew, differentiate, and recapitulate the heterogeneity of the tumor. Clinically, BCSCs have been correlated with cancer progression, metastasis, relapse, and drug resistance. The tumorigenic roles of BCSCs have been extensively reviewed and will not be the major focus of the current review. Here, we aim to highlight how the crucial intrinsic signaling pathways regulate the fate of BCSCs, including the Wnt, Notch, Hedgehog, and NF-κB signaling pathways, as well as how different cell populations crosstalk with BCSCs within the TME, including adipocytes, endothelial cells, fibroblasts, and immune cells. Based on the molecular and cellular activities of BCSCs, we will also summarize the targeting strategies for BCSCs and related clinical trials. This review will highlight that BCSC development in breast cancer is impacted by both BCSC endogenous signaling and external factors in the TME, which provides an insight into how to establish a comprehensively therapeutic strategy to target BCSCs for breast cancer treatments.

Axial Elongation During Short-Term Accommodation in Myopic and Nonmyopic Children.

Purpose: Axial length increases during accommodation in adults and children; however, refractive error group differences are conflicting and have not been explored in pediatric populations. This study aimed to evaluate differences in accommodation-induced axial elongation between myopic and nonmyopic children. Methods: A range of ocular biometric measurements were captured during brief accommodation tasks (0, 3, 6, and 9 D) using a Badal optometer mounted to a noncontact optical biometer (Zeiss IOLMaster 700). Reliable measurements were captured for 15 myopic and 15 age- and sex-matched nonmyopic children. The average central corneal thickness (CCT), anterior chamber depth (ACD), crystalline lens thickness (LT), anterior segment length (ASL), vitreous chamber depth (VCD), and axial length (AL) were determined for each accommodation stimulus. Raw measurements of AL and VCD were corrected for the estimated error associated with LT increases during accommodation. Results: All biometric parameters, except CCT, changed significantly during accommodation (all P < 0.001). Myopic children exhibited significantly greater accommodation-induced axial elongation than nonmyopic children (P = 0.002) at the 3, 6, and 9 D accommodation stimuli, with a mean difference of 7, 10, and 16 µm, respectively (all pairwise comparisons, P ≤ 0.03). The changes in all other biometric parameters were not different between the refractive error groups (P ≥ 0.23). Conclusions: Accommodation-induced axial elongation was greater in myopic than nonmyopic children. This finding could support a potential mechanism linking near work, axial elongation, and myopia development in children or may reflect greater susceptibility to accommodation-induced axial elongation in children with established myopia.

Société de Biomécanique Young Investigator Award 2021: Numerical investigation of the time-dependent stress-strain mechanical behaviour of skeletal muscle tissue in the context of pressure ulcer prevention.

BACKGROUND: Pressure-induced tissue strain is one major pathway for Pressure Ulcer development and, especially, Deep Tissue Injury. Biomechanical investigation of the time-dependent stress-strain mechanical behaviour of skeletal muscle tissue is therefore essential. In the literature, a viscoelastic formulation is generally assumed for the experimental characterization of skeletal muscles, with the limitation that the underlying physical mechanisms that give rise to the time dependent stress-strain behaviour are not known. The objective of this study is to explore the capability of poroelasticity to reproduce the apparent viscoelastic behaviour of passive muscle tissue under confined compression. METHODS: Experimental stress-relaxation response of 31 cylindrical porcine samples tested under fast and slow confined compression by Vaidya and collaborators were used. An axisymmetric Finite Element model was developed in ABAQUS and, for each sample a one-to-one inverse analysis was performed to calibrate the specimen-specific constitutive parameters, namely, the drained Young's modulus, the void ratio, hydraulic permeability, the Poisson's ratio, the solid grain's and fluid's bulk moduli. FINDINGS: The peak stress and consolidation were recovered for most of the samples (N=25) by the poroelastic model (normalised root-mean-square error ≤0.03 for fast and slow confined compression conditions). INTERPRETATION: The strength of the proposed model is its fewer number of variables (N=6 for the proposed poroelastic model versus N=18 for the viscohyperelastic model proposed by Vaidya and collaborators). The incorporation of poroelasticity to clinical models of Pessure Ulcer formation could lead to more precise and mechanistic explorations of soft tissue injury risk factors.

Single cell genomics reveals plastid-lacking Picozoa are close relatives of red algae.

The endosymbiotic origin of plastids from cyanobacteria gave eukaryotes photosynthetic capabilities and launched the diversification of countless forms of algae. These primary plastids are found in members of the eukaryotic supergroup Archaeplastida. All known archaeplastids still retain some form of primary plastids, which are widely assumed to have a single origin. Here, we use single-cell genomics from natural samples combined with phylogenomics to infer the evolutionary origin of the phylum Picozoa, a globally distributed but seemingly rare group of marine microbial heterotrophic eukaryotes. Strikingly, the analysis of 43 single-cell genomes shows that Picozoa belong to Archaeplastida, specifically related to red algae and the phagotrophic rhodelphids. These picozoan genomes support the hypothesis that Picozoa lack a plastid, and further reveal no evidence of an early cryptic endosymbiosis with cyanobacteria. These findings change our understanding of plastid evolution as they either represent the first complete plastid loss in a free-living taxon, or indicate that red algae and rhodelphids obtained their plastids independently of other archaeplastids.

Time, cost and carbon-efficiency: a silver lining of COVID era virtual urology clinics?

INTRODUCTION: The COVID-19 pandemic has demanded radical changes in service delivery. Our centre adopted the use of outpatient telemedicine to reduce close-contact interactions between patients and staff. We hypothesised that incidental gains may be associated with this. We evaluated financial, practical and environmental implications of substituting virtual clinics (VCs) for in-person urology outpatient appointments. METHODS: VCs were studied over a 3-month period. Based on patient-reported 'usual mode of transport' to the hospital, travel distance, time, petrol and parking costs, and the carbon emissions avoided by virtue of remote consultations were calculated. The underlying symptom/diagnosis and the 'effectiveness' of the VC were evaluated. RESULTS: Of 1,016 scheduled consultations, 736 (72.44%) were conducted by VCs over the study period. VCs resulted in an agreed treatment plan in 98.4% of a representative patient sample. The use of VCs was associated with an overall travel distance saving for patients of 31,038 miles (49,951km) over 3 months, with an average round-trip journey of 93.8 miles (151km) avoided for each rural-dwelling patient and an average financial saving of £25.91 (€28.70) per rural-dwelling car traveller. An estimated 1,257.8 hours of patient time were saved by avoidance of travel and clinic waiting times. Based on car-travelling patients alone, a 6.07-tonne reduction in carbon emissions was achieved with the use of VCs. CONCLUSIONS: In appropriate clinical circumstances, VCs appear to provide efficiency across a number of domains. Future healthcare may involve offering outpatients the option of telemedicine as an alternative to physical attendance.

Higher order aberrations and retinal image quality during short-term accommodation in children.

Changes in higher order aberrations (HOA's) and retinal image quality during accommodation have not previously been examined in children. This study measured ocular HOA's in ninety non-myopic, school-aged children during short-term accommodation tasks at 0, 3, 6, and 9 D demands presented via a Badal optometer mounted to a Hartmann-Shack wavefront aberrometer (COAS-HD, Wavefront Sciences). Eighty-four participants who exhibited active accommodation were included in the analyses. An eighth order Zernike polynomial was fit across a 2.3 mm, 4 mm, and natural pupil diameter to evaluate changes in refractive power vectors (M, J180, and J45), accommodation errors (lags and leads), HOA root mean square (RMS) variables, individual Zernike coefficients, and the visual Strehl ratio based on the optical transfer function (VSOTF). All HOA RMS variables changed significantly with accommodation, with the greatest change observed for the 9 D demand. Of the individual Zernike coefficients, primary (C40) and secondary spherical aberration (C60) exhibited the greatest magnitude of change, becoming negative and positive with increasing accommodation, respectively. The VSOTF changed significantly with greater accommodation for both the 4 mm and natural pupil size, becoming significantly worse for the 9 D demand. HOA's increase and retinal image quality decreases significantly during higher levels of accommodation in children, similar to adults. These findings provide a greater understanding of the optical properties of children's eyes and insights into possible mechanisms for the association between accommodation, near work, and refractive error development.

All-sky dynamical response of the Galactic halo to the Large Magellanic Cloud.

Gravitational interactions between the Large Magellanic Cloud (LMC) and the stellar and dark matter halo of the Milky Way are expected to give rise to disequilibrium phenomena in the outer Milky Way1-7. A local wake is predicted to trail the orbit of the LMC, and a large-scale overdensity is predicted to exist across a large area of the northern Galactic hemisphere. Here we report the detection of both the local wake and northern overdensity (hereafter the 'collective response') in a map of the Galaxy based on 1,301 stars at Galactocentric distances between 60 and 100 kiloparsecs. The location of the wake is in good agreement with an N-body simulation that includes the dynamical effect of the LMC on the Milky Way halo. The density contrast of the wake and collective response are stronger in the data than in the simulation. The detection of a strong local wake is independent evidence that the Magellanic clouds are on their first orbit around the Milky Way. The wake traces the path of the LMC, which will provide insight into the orbit of the LMC, which in turn is a sensitive probe of the mass of the LMC and the Milky Way. These data demonstrate that the outer halo is not in dynamical equilibrium, as is often assumed. The morphology and strength of the wake could be used to test the nature of dark matter and gravity.