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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 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.

Climate extremes are projected to cause unprecedented deviations in the emission and transformation of volatile organic compounds (VOCs), which trigger feedback mechanisms that will impact the atmospheric oxidation and formation of aerosols and clouds. However, the response of VOCs to future conditions such as extreme heat and wildfire events is still uncertain. This study explored the modification of the mixing ratio and distribution of several anthropogenic and biogenic VOCs in a temperate oak–hickory–juniper forest as a response to increased temperature and transported biomass burning plumes. A chemical ionization mass spectrometer was deployed on a tower at a height of 32 m in rural central Missouri, United States, for the continuous and in situ measurement of VOCs from June to August of 2023. The maximum observed temperature in the region was 38 °C, and during multiple episodes the temperature remained above 32 °C for several hours. Biogenic VOCs such as isoprene and monoterpene followed closely the temperature daily profile but at varying rates, whereas anthropogenic VOCs were insensitive to elevated temperature. During the measurement period, wildfire emissions were transported to the site and substantially increased the mixing ratios of acetonitrile and benzene, which are produced from burning of biomass. An in-depth analysis of the mass spectra revealed more than 250 minor compounds, such as formamide and methylglyoxal. Extreme heat and presence of wildfire plumes modified the overall volatility, reactivity, O : C, and H : C ratios of the extended list of VOCs. The calculated OH reactivities during extreme temperature condition and transport of biomass burning plumes were 106.37±4.27 and 106.22±5.15 s−1, respectively, which are substantially higher than background level of 98.78±1.16 s−1. Multivariate analysis also clustered the compounds into five factors, which highlighted the sources of the unaccounted-for VOCs. Ultimately, results here underscore the effect of extreme heat and wildfire emissions on the overall chemical properties VOC in a temperate forest.

Although treatment with standard frontline therapies, including a FLT3 inhibitor (FLT3i) reduces AML burden and achieves clinical remissions, most patients with AML with FLT3 mutation relapse due to therapy-resistant stem/progenitor cells. The core ATPases, BRG1 (SMARCA4) and BRM (SMARCA2) of the canonical (c) BAF (BRG1/BRM-associated factor) complex is a dependency in AML cells, including those harboring FLT3 mutations. We have previously reported that treatment with FHD-286, a BRG1/BRM ATPases inhibitor, induces differentiation and loss of viability of AML stem/progenitor cells. Findings of present studies demonstrate that treatment with FHD-286 induces lethality in AML cells, regardless of sensitivity or resistance to FLT3i. This efficacy is associated with the induction of gene-expression perturbations responsible for growth inhibition, differentiation, as well as a reduced AML-initiating potential of the AML cells. Additionally, co-treatment with FHD-286 and FLT3i exerts superior pre-clinical efficacy against AML cells and patient-derived (PD) xenograft (PDX) models of AML with FLT3 mutations.

In this trans-ethnic multi-omic study, we reinterpret the genetic architecture of blood pressure to identify genes, tissues, phenomes and medication contexts of blood pressure homeostasis. We discovered 208 novel common blood pressure SNPs and 53 rare variants in genome-wide association studies of systolic, diastolic and pulse pressure in up to 776,078 participants from the Million Veteran Program (MVP) and collaborating studies, with analysis of the blood pressure clinical phenome in MVP. Our transcriptome-wide association study detected 4,043 blood pressure associations with genetically predicted gene expression of 840 genes in 45 tissues, and mouse renal single-cell RNA sequencing identified upregulated blood pressure genes in kidney tubule cells. Analysis of blood pressure data from the Million Veteran Program trans-ethnic cohort identifies common and rare variants, and genetically predicted gene expression across multiple tissues associated with systolic, diastolic and pulse pressure in over 775,000 individuals.

Mutations of the gene Lps selectively impede lipopolysaccharide (LPS) signal transduction in C3H/HeJ and C57BL/10ScCr mice, rendering them resistant to endotoxin yet highly susceptible to Gram-negative infection. The codominant Lps$^d$ allele of C3H/HeJ mice was shown to correspond to a missense mutation in the third exon of the Toll-like receptor-4 gene (Tlr4), predicted to replace proline with histidine at position 712 of the polypeptide chain. C57BL/10ScCr mice are homozygous for a null mutation of Tlr4. Thus, the mammalian Tlr4 protein has been adapted primarily to subserve the recognition of LPS and presumably transduces the LPS signal across the plasma membrane. Destructive mutations of Tlr4 predispose to the development of Gram-negative sepsis, leaving most aspects of immune function intact.