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The Integrated Science Investigation of the Sun (ISIS) is a complete science investigation on the Solar Probe Plus (SPP) mission, which flies to within nine solar radii of the Sun’s surface. ISIS comprises a two-instrument suite to measure energetic particles over a very broad energy range, as well as coordinated management, science operations, data processing, and scientific analysis. Together, ISIS observations allow us to explore the mechanisms of energetic particles dynamics, including their: (1) Origins—defining the seed populations and physical conditions necessary for energetic particle acceleration; (2) Acceleration—determining the roles of shocks, reconnection, waves, and turbulence in accelerating energetic particles; and (3) Transport—revealing how energetic particles propagate from the corona out into the heliosphere. The two ISIS Energetic Particle Instruments measure lower (EPI-Lo) and higher (EPI-Hi) energy particles. EPI-Lo measures ions and ion composition from ∼20 keV/nucleon–15 MeV total energy and electrons from ∼25–1000 keV. EPI-Hi measures ions from ∼1–200 MeV/nucleon and electrons from ∼0.5–6 MeV. EPI-Lo comprises 80 tiny apertures with fields-of-view (FOVs) that sample over nearly a complete hemisphere, while EPI-Hi combines three telescopes that together provide five large-FOV apertures. ISIS observes continuously inside of 0.25 AU with a high data collection rate and burst data (EPI-Lo) coordinated with the rest of the SPP payload; outside of 0.25 AU, ISIS runs in low-rate science mode whenever feasible to capture as complete a record as possible of the solar energetic particle environment and provide calibration and continuity for measurements closer in to the Sun. The ISIS Science Operations Center plans and executes commanding, receives and analyzes all ISIS data, and coordinates science observations and analyses with the rest of the SPP science investigations. Together, ISIS’ unique observations on SPP will enable the discovery, untangling, and understanding of the important physical processes that govern energetic particles in the innermost regions of our heliosphere, for the first time. This paper summarizes the ISIS investigation at the time of the SPP mission Preliminary Design Review in January 2014.

The Medium Energy Neutral Atom (MENA) imager was developed in response to the Imaging from the Magnetopause to the Aurora for Global Exploration (IMAGE) requirement to produce images of energetic neutral atoms (ENAs) in the energy range from 1 to 30 keV. These images will be used to infer characteristics of magnetospheric ion distributions. The MENA imager is a slit camera that images incident ENAs in the polar angle (based on a conventional spherical coordinate system defined by the spacecraft spin axis) and utilizes the spacecraft spin to image in azimuth. The speed of incident ENAs is determined by measuring the time-of-flight (TOF) from the entrance aperture to the detector. A carbon foil in the entrance aperture yields secondary electrons, which are imaged using a position-sensitive Start detector segment. This provides both the one-dimensional (1D) position at which the ENA passed through the aperture and a Start time for the TOF system. Impact of the incident ENA on the 1D position-sensitive Stop detector segment provides both a Stop-timing signal and the location that the ENA impacts the detector. The ENA incident polar angle is derived from the measured Stop and Start positions. Species identification (H vs. O) is based on variation in secondary electron yield with mass for a fixed ENA speed. The MENA imager is designed to produce images with 8°×4° angular resolution over a field of view 140°×360°, over an energy range from 1 keV to 30 keV. Thus, the MENA imager is well suited to conduct measurements relevant to the Earth's ring current, plasma sheet, and (at times) magnetosheath and cusp.[PUBLICATION ABSTRACT]

Background As a result of climate change, temperatures and the burdens on human health are rising. This study investigates the relationship between acute heat and hospitalizations for specific diseases at the University Hospital Carl Gustav Carus in Dresden, Germany. Methods A statistical analysis was conducted using clinical data from 4,363 patients treated between January 1, 2018, and December 31, 2023. Data included demographic information and heat-related diagnoses categorized by codes from the International Classification of Diseases. Climatic data was sourced from the Dresden-Klotzsche weather station, focusing on days with air temperatures exceeding 23 °C (warm days) and 30 °C (heat days). Correlation analyses were performed to assess the relationship between heat events and hospital admissions on these days. Results We found a positive correlation between hospital admissions and heat at temperatures ≥ 23 °C for all included diseases combined ( p  < 0.05). A positive correlation was observed between temperatures ≥ 23 °C and hospitalizations for the diseases dehydration (E86), stroke (I63) and chronic obstructive pulmonary disease (J44) (all p  < 0.05). At temperatures of ≥ 30 °C, no statistically significant correlation was identified. We discovered that men, young children and older people were particularly affected by heat-related diseases. Conclusions The findings based on routine data from one German university hospital indicate that moderate heat can impact hospitalizations for certain diseases, at temperatures above 30 °C, no evidence for a statistically significant association was found, possibly due to a lack of statistical power or behavioural adaptations. This underlines the need for low-threshold preventive measures in response to the health risks associated with rising temperatures.

Paxillin is an intracellular adaptor protein involved in focal adhesions, cell response to stress, steroid signaling, and apoptosis in reproductive tissues. To investigate the role of paxillin in granulosa cells, we created a granulosa-specific paxillin knockout mouse model using Cre recombinase driven by the Anti-Müllerian hormone receptor 2 gene promoter. Female granulosa-specific paxillin knockout mice demonstrated increased fertility in later reproductive age, resulting in higher number of offspring when bred continuously up to 26 weeks of age. This was not due to increased numbers of estrous cycles, ovulated oocytes per cycle, or pups per litter, but this was due to shorter time to pregnancy and increased number of litters in the granulosa-specific paxillin knockout mice. The number of ovarian follicles was not significantly affected by the knockout at 30 weeks of age. Granulosa-specific paxillin knockout mice had slightly altered estrous cycles but no difference in circulating reproductive hormone levels. Knockout of paxillin using clustered regularly interspaced short palindromic repeat-associated protein 9 (CRISPR-Cas9) in human granulosa-derived immortalized KGN cells did not affect cell proliferation or migration. However, in cultured primary mouse granulosa cells, paxillin knockout reduced cell death under basal culture conditions. We conclude that paxillin knockout in granulosa cells increases female fecundity in older reproductive age mice, possibly by reducing granulosa cell death. This study implicates paxillin and its signaling network as potential granulosa cell targets in the management of age-related subfertility. Summary Sentence Granulosa cell-specific knockout of adaptor protein paxillin in mice leads to increased fecundity and may reduce granulosa cell death. Graphical Abstract

Background Advanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the genetic architecture of early AMD. Methods To identify genetic factors for early AMD, we conducted a genome-wide association study (GWAS) meta-analysis (14,034 cases, 91,214 controls, 11 sources of data including the International AMD Genomics Consortium, IAMDGC, and UK Biobank, UKBB). We ascertained early AMD via color fundus photographs by manual grading for 10 sources and via an automated machine learning approach for > 170,000 photographs from UKBB. We searched for early AMD loci via GWAS and via a candidate approach based on 14 previously suggested early AMD variants. Results Altogether, we identified 10 independent loci with statistical significance for early AMD: (i) 8 from our GWAS with genome-wide significance ( P  < 5 × 10 − 8 ), (ii) one previously suggested locus with experiment-wise significance ( P  < 0.05/14) in our non-overlapping data and with genome-wide significance when combining the reported and our non-overlapping data (together 17,539 cases, 105,395 controls), and (iii) one further previously suggested locus with experiment-wise significance in our non-overlapping data. Of these 10 identified loci, 8 were novel and 2 known for early AMD. Most of the 10 loci overlapped with known advanced AMD loci (near ARMS2/HTRA1, CFH , C2 , C3 , CETP , TNFRSF10A , VEGFA, APOE ), except two that have not yet been identified with statistical significance for any AMD. Among the 17 genes within these two loci, in-silico functional annotation suggested CD46 and TYR as the most likely responsible genes. Presence or absence of an early AMD effect distinguished the known pathways of advanced AMD genetics (complement/lipid pathways versus extracellular matrix metabolism). Conclusions Our GWAS on early AMD identified novel loci, highlighted shared and distinct genetics between early and advanced AMD and provides insights into AMD etiology. Our data provide a resource comparable in size to the existing IAMDGC data on advanced AMD genetics enabling a joint view. The biological relevance of this joint view is underscored by the ability of early AMD effects to differentiate the major pathways for advanced AMD.

Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis 1 . However, both the exact origin and the role of macrophages in inflammatory joint disease remain unclear. Here we use fate-mapping approaches in conjunction with three-dimensional light-sheet fluorescence microscopy and single-cell RNA sequencing to perform a comprehensive spatiotemporal analysis of the composition, origin and differentiation of subsets of macrophages within healthy and inflamed joints, and study the roles of these macrophages during arthritis. We find that dynamic membrane-like structures, consisting of a distinct population of CX 3 CR1 + tissue-resident macrophages, form an internal immunological barrier at the synovial lining and physically seclude the joint. These barrier-forming macrophages display features that are otherwise typical of epithelial cells, and maintain their numbers through a pool of locally proliferating CX 3 CR1 − mononuclear cells that are embedded into the synovial tissue. Unlike recruited monocyte-derived macrophages, which actively contribute to joint inflammation, these epithelial-like CX 3 CR1 + lining macrophages restrict the inflammatory reaction by providing a tight-junction-mediated shield for intra-articular structures. Our data reveal an unexpected functional diversification among synovial macrophages and have important implications for the general role of macrophages in health and disease. Analysis of macrophage subsets within joints reveals a population of CX 3 CR1 + tissue-resident macrophages that form a tight-junction-mediated barrier at the synovial lining, protecting the joint from the invasion of inflammatory cells.

Robust quantum control is crucial for realizing practical quantum technologies. Energy landscape shaping offers an alternative to conventional dynamic control, providing theoretically enhanced robustness and simplifying implementation for certain applications. This work demonstrates the feasibility of robust energy landscape control in a practical implementation with ultracold atoms. We leverage a digital mirror device (DMD) to shape optical potentials, creating complex energy landscapes. To achieve a desired objective, such as efficient quantum state transfer, we formulate a novel hybrid optimization approach that effectively handles both continuous (laser power) and discrete (DMD pixel activation) control parameters. This approach combines constrained quasi-Newton methods with surrogate models for efficient exploration of the vast parameter space. Furthermore, we introduce a framework for analyzing the robustness of the resulting control schemes against experimental uncertainties. By modeling uncertainties as structured perturbations, we systematically assess controller performance and identify robust solutions. We apply these techniques to maximize spin transfer in a chain of trapped atoms, achieving high-fidelity control while maintaining robustness. Our findings provide insights into the experimental viability of controlled spin transfer in cold atom systems. More broadly, the presented optimization and robustness analysis methods apply to a wide range of quantum control problems, offering a toolkit for designing and evaluating robust controllers in complex experimental settings.

In this study, irradiation of the internal mammary and medial supraclavicular nodes plus whole breast or thoracic-wall radiation therapy in women with localized breast cancer was linked to increased disease-free survival but only a marginal gain in overall survival. The first filter stations for the lymphatic drainage of the breast are the axillary and internal mammary lymph nodes. 1 Surgical studies have shown that the incidence of metastatic involvement of the internal mammary nodes varies between 4% and 9% in patients with axillary node–negative breast cancer and between 16% and 65% in patients with axillary node–positive breast cancer. 2 – 4 As a consequence, surgical dissection of the internal mammary nodes was attempted but abandoned in the 1970s, since no improvement in survival was observed. 4 , 5 Elective irradiation of the regional nodes remained widely used until the late 1980s, when it became . . .

Spin coating is used by several industries to apply thin but uniform liquid films to a given substrate. While this method produces very uniform coatings over much of the substrate, near the periphery of the substrate, defects in the coating, sometimes referred to as edge beading, often occur. This paper explores the usage of a two-axis spin coating technology that leads to a more uniform film thickness near the edge of the substrate. By rotating the substrate on an axis parallel to the substrate, centrifugal forces are generated that act both normal and parallel to the substrate. These forces are known as elevated gravity and act to even out any existing coating irregularities and also to drain liquid toward the edge of the substrate. This study investigates the effect of elevated gravity on the coating dynamics of a photoresist liquid film on a circular silicon wafer. Using lubrication theory, we derive a modified evolution equation that includes the effects of elevated gravity. We solve this equation numerically using implicit finite differences. Four layers of a photoresist film are spin coated on 3-inch circular wafers using a two-axes spin technology under various elevated gravity conditions. The thickness of the dried coating layers near the periphery of the substrate is measured using a SEM device. Both the experiments and the simulations show that edge beading defects can be substantially reduced for the 500 g elevated gravity case compared to the normal 1 g gravity case.

During tumor progression, immune system phagocytes continually clear apoptotic cancer cells in a process known as efferocytosis. However, the impact of efferocytosis in metastatic tumor growth is unknown. In this study, we observed that macrophage-driven efferocytosis of prostate cancer cells in vitro induced the expression of proinflammatory cytokines such as CXCL5 by activating Stat3 and NF-κB(p65) signaling. Administration of a dimerizer ligand (AP20187) triggered apoptosis in 2 in vivo syngeneic models of bone tumor growth in which apoptosis-inducible prostate cancer cells were either coimplanted with vertebral bodies, or inoculated in the tibiae of immunocompetent mice. Induction of 2 pulses of apoptosis correlated with increased infiltration of inflammatory cells and accelerated tumor growth in the bone. Apoptosis-induced tumors displayed elevated expression of the proinflammatory cytokine CXCL5. Likewise, CXCL5-deficient mice had reduced tumor progression. Peripheral blood monocytes isolated from patients with bone metastasis of prostate cancer were more efferocytic compared with normal controls, and CXCL5 serum levels were higher in metastatic prostate cancer patients relative to patients with localized prostate cancer or controls. Altogether, these findings suggest that the myeloid phagocytic clearance of apoptotic cancer cells accelerates CXCL5-mediated inflammation and tumor growth in bone, pointing to CXCL5 as a potential target for cancer therapeutics.