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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.

Background. High mortality and uncertainty about the effectiveness of neuraminidase inhibitors (NAIs) in humans infected with influenza A(H7N9) viruses are public health concerns. Methods. Susceptibility of N9 viruses to NAIs was determined in a fluorescence-based assay. The NAI oseltamivir (5, 20, or 80 mg/kg/day) was administered to BALB/c mice twice daily starting 24, 48, or 72 hours after A/Anhui/1/2013 (H7N9) virus challenge. Results. All 12 avian N9 and 3 human H7N9 influenza viruses tested were susceptible to NAIs. Without prior adaptation, A/Anhui/1/2013 (H7N9) caused lethal infection in mice that was restricted to the respiratory tract and resulted in pulmonary edema and acute lung injury with hyaline membrane formation, leading to decreased oxygenation, all characteristics of human acute respiratory distress syndrome. Oseltamivir at 20 and 80 mg/kg protected 80% and 88% of mice when initiated after 24 hours, and the efficacy decreased to 70% and 60%, respectively, when treatment was delayed by 48 hours. Emergence of oseltamivir-resistant variants was not detected. Conclusions. H7N9 viruses are comparable to currently circulating influenza A viruses in susceptibility to NAIs. Based on these animal studies, early treatment is associated with improved outcomes.

Multiple sclerosis (MS) is a chronic disease characterized by focal demyelination of the white matter of the brain and spinal cord. Central nervous system damage appears to be mediated by infiltrating T lymphocytes and macrophages, and a central role for autoreactive CD4+T cells has been proposed. However, the initial immune events that lead to the chronic process of MS remain unidentified. We now present evidence that a subset of T lymphocytes bearing γ/δ T-cell antigen receptors has been activated in patients with recentonset disease. Cells recovered from the cerebrospinal fluid of subjects with MS were cultured for short periods of time in medium supplemented with T-cell growth factors. Expansions of Vδ1 and Vδ2 T-cell receptor-bearing lymphocytes were found only in cell populations obtained from subjects with recent-onset disease. Similar populations were not expanded in subjects with chronic MS or other neurological diseases. Junctional region sequencing showed the expanded γ/δ T cells to be oligoclonal in nature, suggestive of specific stimulation by antigen. These results reveal a fundamental difference in the immunopathogenesis of acute vs. chronic disease and provide additional insight into the autoimmune nature of MS.

We report our progress on the development of pixellated imaging CZT detector arrays for our first-generation balloon-borne wide-field hard X-ray (20 - 600 keV) telescope, ProtoEXIST1. Our ProtoEXIST program is a pathfinder for the High Energy Telescope (HET) on the Energetic X-ray Imaging Survey telescope (EXIST), a proposed implementation of the Black Hole Finder Probe. ProtoEXIST1 consists of four independent coded-aperture telescopes with close-tiled (~0.4 mm gaps) CZT detectors that preserve their 2.5mm pixel pitch. Multiple shielding/field-of-view configurations are planned to identify optimal geometry for the HET in EXIST. The primary technical challenge in ProtoEXIST is the development of large area, close-tiled modules of imaging CZT detectors (1000 cm2 for ProtoEXIST1), with all readout and control systems for the ASIC readout vertically stacked. We describe the overall telescope configuration of ProtoEXIST1 and review the current development status of the CZT detectors, from individual detector crystal units (DCUs) to a full detector module (DM). We have built the first units of each component for the detector plane and have completed a few Rev2 DCUs (2x2 cm2), which are under a series of tests. Bare DCUs (pre-crystal bonding) show high, uniform ASIC yield (~70%) and ~30% reduction in electronics noise compared to the Rev1 equivalent. A Rev1 DCU already achieved ~1.2% FWHM at 662 keV, and preliminary analysis of the initial radiation tests on a Rev2 DCU shows ~ 4 keV FWHM at 60 keV (vs. 4.7 keV for Rev1). We therefore expect about <~1% FWHM at 662 keV with the Rev2 detectors.

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 approx. 20 keV/nucleon-15 MeV total energy and electrons from approx.25-1000 keV. EPI-Hi measures ions from approx. 1-200 MeV/nucleon and electrons from approx. 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.

We describe the detector development for a balloon-borne wide-field hard X-ray (20 - 600 keV) telescope, ProtoEXIST. ProtoEXIST is a pathfinder for both technology and science of the proposed implementation of the Black Hole Finder Probe, Energetic X-ray Imaging Survey telescope (EXIST). The principal technology challenge is the development of large area, close-tiled modules of imaging CZT detectors (1000 cm2 for ProtoEXIST1). We review the updates of the detector design and package concept for ProtoEXIST1 and report the current development status of the CZT detectors, using calibration results of our basic detector unit - 2 x 2 x 0.5 cm CZT crystals with 2.5 mm pixels (8 x 8 array). The current prototype (Rev1) of our detector crystal unit (DCU) shows ~4.5 keV electronics noise (FWHM), and the radiation measurements show the energy resolution (FWHM) of the units is 4.7 keV (7.9%) at 59.5 keV, 5.6 keV (4.6%) at 122 keV, and 7.6 keV (2.1%) at 356 keV. The new (Rev2) DCU with revised design is expected to improve the resolution by ~30%.

The oldest known samples of Earth, with ages of up to 4.4 Gyr, are detrital zircon grains in meta-sedimentary rocks of the Jack Hills in Australia. These zircons offer insights into the magmas from which they crystallized, and, by implication, igneous activity and tectonics in the first 500 million years of Earth’s history, the Hadean eon. However, the compositions of these magmas and the relative contributions of igneous and sedimentary components to their sources have not yet been resolved. Here we compare the trace element concentrations of the Jack Hills zircons to those of zircons from the locality where igneous (I-) and sedimentary (S-) type granites were first distinguished. We show that the Hadean zircons crystallized predominantly from I-type magmas formed by melting of a reduced, garnet-bearing igneous crust. Further, we propose that both the phosphorus content of zircon and the ratio of phosphorus to rare earth elements can be used to distinguish between detrital zircon grains from I- and S-type sources. These elemental discriminants provide a new geochemical tool to assess the relative contributions of primeval magmatism and melting of recycled sediments to the continents over geological time. The formation process for the oldest mineral grains on Earth has remained elusive. A comparison of trace element concentrations of these ancient zircons with known material suggests melting of igneous crust as their source.

Sepsis arises from diverse and incompletely understood dysregulated host response processes following infection that leads to life-threatening organ dysfunction. Here we showed that neutrophils and emergency granulopoiesis drove a maladaptive response during sepsis. We generated a whole-blood single-cell multiomic atlas (272,993 cells, n  = 39 individuals) of the sepsis immune response that identified populations of immunosuppressive mature and immature neutrophils. In co-culture, CD66b + sepsis neutrophils inhibited proliferation and activation of CD4 + T cells. Single-cell multiomic mapping of circulating hematopoietic stem and progenitor cells (HSPCs) (29,366 cells, n  = 27) indicated altered granulopoiesis in patients with sepsis. These features were enriched in a patient subset with poor outcome and a specific sepsis response signature that displayed higher frequencies of IL1R2 + immature neutrophils, epigenetic and transcriptomic signatures of emergency granulopoiesis in HSPCs and STAT3-mediated gene regulation across different infectious etiologies and syndromes. Our findings offer potential therapeutic targets and opportunities for stratified medicine in severe infection. Knight and colleagues report altered granulopoiesis and increased frequency of immature neutrophil subsets with immunosuppressive properties in a subset of patients with sepsis with poor outcome.

The increasing antimicrobial resistance of uropathogens is challenging the continued efficacy of empiric antibiotic therapy for UTIs, which are among the most frequent bacterial infections worldwide. It has been suggested that drug-resistant uropathogens could persist in the intestine after the resolution of UTI and cause recurrences following periurethral contamination. A better understanding of the transmission dynamics between the intestinal and urinary tracts, combined with phenotypic characterization of the uropathogen populations in both habitats, could inform prudent therapies designed to overcome the rising resistance of uropathogens. Here, we integrate genomic surveillance with clinical microbiology to show that drug-resistant clones persist within and are readily transmitted between the intestinal and urinary tracts of patients affected by recurrent and nonrecurrent UTIs. Thus, our results advocate for understanding persistent intestinal uropathogen colonization as part of the pathophysiology of UTIs, particularly in patients affected by recurrent episodes of symptomatic disease. The rise of antimicrobial resistance in uropathogens has complicated the management of urinary tract infections (UTIs), particularly in patients who are afflicted by recurrent episodes of UTIs. Antimicrobial-resistant (AR) uropathogens persistently colonizing individuals at asymptomatic time points have been implicated in the pathophysiology of UTIs. The dynamics of uropathogen persistence following the resolution of symptomatic disease are, however, mostly unclear. To further our understanding, we determined longitudinal AR uropathogen carriage and clonal persistence of uropathogenic Escherichia coli , Proteus mirabilis , and Klebsiella pneumoniae isolates in the intestinal and urinary tracts of patients affected by recurrent and nonrecurrent UTIs. Clonal tracking of isolates in consecutively collected urine and fecal specimens indicated repeated transmission of uropathogens between the urinary tract and their intestinal reservoir. Our results further implicate three independent routes of recurrence of UTIs: (i) following an intestinal bloom of uropathogenic bacteria and subsequent bladder colonization, (ii) reinfection of the urinary tract from an external source, and (iii) bacterial persistence within the urinary tract. Taken together, our observation of clonal persistence following UTIs and uropathogen transmission between the intestinal and urinary tracts warrants further investigations into the connection between the intestinal microbiome and recurrent UTIs. IMPORTANCE The increasing antimicrobial resistance of uropathogens is challenging the continued efficacy of empiric antibiotic therapy for UTIs, which are among the most frequent bacterial infections worldwide. It has been suggested that drug-resistant uropathogens could persist in the intestine after the resolution of UTI and cause recurrences following periurethral contamination. A better understanding of the transmission dynamics between the intestinal and urinary tracts, combined with phenotypic characterization of the uropathogen populations in both habitats, could inform prudent therapies designed to overcome the rising resistance of uropathogens. Here, we integrate genomic surveillance with clinical microbiology to show that drug-resistant clones persist within and are readily transmitted between the intestinal and urinary tracts of patients affected by recurrent and nonrecurrent UTIs. Thus, our results advocate for understanding persistent intestinal uropathogen colonization as part of the pathophysiology of UTIs, particularly in patients affected by recurrent episodes of symptomatic disease.