Genotype-immunophenotype relationships in -mutant AML clonal evolution uncovered by single cell multiomic analysis.

Acute myeloid leukemia (AML) is a multi-clonal disease, existing as a milieu of clones with unique but related genotypes as initiating clones acquire subsequent mutations. However, bulk sequencing cannot fully capture AML clonal architecture or the clonal evolution that occurs as patients undergo therapy. To interrogate clonal evolution, we performed simultaneous single cell molecular profiling and immunophenotyping on 43 samples from 32 -mutant AML patients at different stages of disease.

In vivo models of subclonal oncogenesis and dependency in hematopoietic malignancy.

Cancer evolution is a multifaceted process leading to dysregulation of cellular expansion and differentiation through somatic mutations and epigenetic dysfunction. Clonal expansion and evolution is driven by cell-intrinsic and -extrinsic selective pressures, which can be captured with increasing resolution by single-cell and bulk DNA sequencing. Despite the extensive genomic alterations revealed in profiling studies, there remain limited experimental systems to model and perturb evolutionary processes.

Confidence limits in pulse dipolar EPR spectroscopy: estimates for individual measurements.

The distribution of inter-label distances obtained by electron paramagnetic resonance (EPR) pulse dipolar spectroscopies (PDS), such as DEER aka PELDOR, gives a valuable characterization of structure on the nanometer scale. The impact of random experimental noise on such experiments is examined for three independent methods for analysing PDS data: the model-free method with Tikhonov regularization, model-free with Mellin-transformation, and a model-based method. All three methods show negative bias for the mean distance and positive bias for the distribution width.

Divergent Metabolic Changes in Rhizomes of Lowland and Upland Switchgrass () from Early Season through Dormancy Onset.

High-biomass-yielding southerly adapted switchgrasses ( L.) frequently suffer from unpredictable winter hardiness at more northerly sites arising from damage to rhizomes that prevent effective spring regrowth. Previously, changes occurring over the growing season in rhizomes sampled from a cold-adapted tetraploid upland cultivar, Summer, demonstrated a role for abscisic acid (ABA), starch accumulation, and transcriptional reprogramming as drivers of dormancy onset and potential keys to rhizome health during winter dormancy.

Sugars and cuticular waxes impact sugarcane aphid (Melanaphis sacchari) colonization on different developmental stages of sorghum.

Sugarcane aphid (SCA; Melanaphis sacchari) is a devastating pest of sorghum (Sorghum bicolor) that colonizes sorghum plants at different growth stages. Leaf surface characteristics and sugars often influence aphid settling and feeding on host plants. However, how changes in cuticular waxes and sugar levels affect SCA establishment and feeding at different development stages of sorghum have not been explored.

Autoinhibitory structure of preligand association state implicates a new strategy to attain effective DR5 receptor activation.

Members of the tumor necrosis factor receptor superfamily (TNFRSF) are important therapeutic targets that can be activated to induce death of cancer cells or stimulate proliferation of immune cells. Although it has long been implicated that these receptors assemble preligand associated states that are required for dominant interference in human disease, such states have so far eluded structural characterization. Here, we find that the ectodomain of death receptor 5 (DR5-ECD), a representative member of TNFRSF, can specifically self-associate when anchored to lipid bilayer, and we report this self-association structure determined by nuclear magnetic resonance (NMR).

Experimental Observation of a Peculiar Effect in Saturated Electron Paramagnetic Resonance Spectra Undergoing Spin Exchange. Magnetic Polariton?

We report the experimental observation of a spectral manifestation of a magnetic polariton that was theoretically predicted last year. This unprecedented manifestation is demonstrated not only for N-enriched peroxylamine disulfonate, a radical that adheres strictly to the assumptions of the theory, but also for a radical, 4-oxo-2,2,6,6-tetramethylpiperidine-;1-15N-1-oxyl, that departs somewhat from the assumptions, as well as the Galvinoxyl radical that represents a severe departure. The magnetic polariton is likely to be of interest to physical chemists in other fields because of the intrinsic advantage of a finite basis set in developing theories.

Microbial dysbiosis and childhood asthma development: Integrated role of the airway and gut microbiome, environmental exposures, and host metabolic and immune response.

Asthma is a chronic and heterogeneous respiratory disease with many risk factors that typically originate during early childhood. A complex interplay between environmental factors and genetic predisposition is considered to shape the lung and gut microbiome in early life. The growing literature has identified that changes in the relative abundance of microbes (microbial dysbiosis) and reduced microbial diversity, as triggers of the airway-gut axis crosstalk dysregulation, are associated with asthma development.

Magnetic Ordering in a High-Spin Donor-Acceptor Conjugated Polymer.

The development of open-shell organic molecules that magnetically order at room temperature,which can be practically applied, remains a grand challenge in chemistry, physics, and materials science. Despite the exploration of vast chemical space, design paradigms for organic paramagnetic centers generally result in unpaired electron spins that are unstable or isotropic. Here, a high-spin conjugated polymer is demonstrated, which is composed of alternating cyclopentadithiophene and benzo[1,2-c;4,5-c']bis[1,2,5]thiadiazole heterocycles, in which macromolecular structure and topology coalesce to promote the spin center generation and intermolecular exchange coupling.

Fusarium head blight resistance exacerbates nutritional loss of wheat grain at elevated CO.

The nutritional integrity of wheat is jeopardized by rapidly rising atmospheric carbon dioxide (CO) and the associated emergence and enhanced virulence of plant pathogens. To evaluate how disease resistance traits may impact wheat climate resilience, 15 wheat cultivars with varying levels of resistance to Fusarium Head Blight (FHB) were grown at ambient and elevated CO. Although all wheat cultivars had increased yield when grown at elevated CO, the nutritional contents of FHB moderately resistant (MR) cultivars were impacted more than susceptible cultivars At elevated CO, the MR cultivars had more significant differences in plant growth, grain protein, starch, fructan, and macro and micro-nutrient content compared with susceptible wheat.

Non-uniform sampling in pulse dipolar spectroscopy by EPR: the redistribution of noise and the optimization of data acquisition.

Pulse dipolar spectroscopy (PDS) in Electron Paramagnetic Resonance (EPR) is the method of choice for determining the distance distribution function for mono-, bi- or multi- spin-labeled macromolecules and nanostructures. PDS acquisition schemes conventionally use uniform sampling of the dipolar trace, but non-uniform sampling (NUS) schemes can decrease the total measurement time or increase the accuracy of the resulting distance distributions. NUS requires optimization of the data acquisition scheme, as well as changes in data processing algorithms to accommodate the non-uniformly sampled data.

Energetics and kinetics of various cyano radical hydrogen abstractions.

The cyano radical (CN) is an abundant, open-shell molecule found in a variety of environments, including the atmosphere, the interstellar medium and combustion processes. In these environments, it often reacts with small, closed-shell molecules via hydrogen abstraction. Both carbon and nitrogen atoms of the cyano radical are reactive sites, however the carbon is more reactive with reaction barrier heights generally between 2-15 kcal mol lower than those of the analogous nitrogen.

Reversible Dimerization of Human Serum Albumin.

Pulsed Dipolar Spectroscopy (PDS) methods of Electron Paramagnetic Resonance (EPR) were used to detect and characterize reversible non-covalent dimers of Human Serum Albumin (HSA), the most abundant protein in human plasma. The spin labels, MTSL and OX063, were attached to Cys-34 and these chemical modifications of Cys-34 did affect the dimerization of HSA, indicating that other post-translational modifications can modulate dimer formation. At physiologically relevant concentrations, HSA does form weak, non-covalent dimers with a well-defined structure.

Dibridged, Monobridged, Vinylidene-Like, and Linear Structures for the Alkaline Earth Dihydrides BeH, MgH, CaH, SrH, and BaH. Proposals for Observations.

This research reports a search for peculiar monobridged structures of the EH molecules (E = Be, Mg, Ca, Sr, Ba). For BeH and MgH, the monobridged geometry is not an equilibrium but rather a transition state between the vinylidene-like structure and the global minimum HE-EH linear geometry. However, for CaH, SrH, and BaH, this situation changes significantly; the linear structure is no longer the global minimum but lies higher in energy than two other equilibria, the dibridged and monobridged structures.

Electron Spin Relaxation of Photoexcited Porphyrin in Water-Glycerol Glass.

Recently, the photoexcited triplet state of porphyrin was proposed as a promising spin-label for pulsed dipolar electron paramagnetic resonance (EPR). Herein, we report the factors that determine the electron spin echo dephasing of the photoexcited porphyrin in a water-glycerol matrix. The electron spin relaxation of a water-soluble porphyrin was measured by Q-band EPR, and the temperature dependence and the effect of solvent deuteration on the relaxation times were studied.

Changes in Wheat Nutritional Content at Elevated [CO] Alter Growth and Mycotoxin Production on Grain.

Rising atmospheric [CO] has been shown to impact plant primary metabolism and the severity of head blight (FHB) in wheat. In this study, we evaluated how changes in grain nutritional content due to growth at elevated [CO] affected growth and mycotoxin production. Susceptible (Norm) and moderately resistant (Alsen) hard spring wheat grains that had been grown at ambient (400 ppm) or elevated [CO] (800 ppm) were independently inoculated with two fungal strains, which produce the trichothecene mycotoxin, deoxynivalenol.

Brevibacillus fortis NRS-1210 produces edeines that inhibit the in vitro growth of conidia and chlamydospores of the onion pathogen Fusarium oxysporum f. sp. cepae.

Onions can be damaged by Fusarium basal rot caused by the soilborne fungus Fusarium oxysporum f. sp. cepae (FOC).

Human Serum Albumin Labelled with Sterically-Hindered Nitroxides as Potential MRI Contrast Agents.

Four albumin-nitroxide conjugates were prepared and tested as metal-free organic radical contrast agents (ORCAs) for magnetic resonance imaging (MRI). Each human serum albumin (HSA) carrier bears multiple nitroxides conjugated via homocysteine thiolactones. These molecular conjugates retain important physical and biological properties of their HSA component, and the resistance of their nitroxide groups to bioreduction was retained or enhanced.

Protein modification by thiolactone homocysteine chemistry: a multifunctionalized human serum albumin theranostic.

As the most abundant protein with a variety of physiological functions, albumin has been used extensively for the delivery of therapeutic molecules. Thiolactone chemistry provides a powerful tool to prepare spin-labeled albumin-based multimodal imaging probes and therapeutic agents. We report the synthesis of a tamoxifen homocysteine thiolactone derivative and its use in thiol-'click' chemistry to prepare multi-functionalized serum albumin.