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Progress in precision medicine is limited by insufficient knowledge of transcriptomic or proteomic features in involved tissues that define pathobiological differences between patients. Here, myectomy tissue from patients with obstructive hypertrophic cardiomyopathy and heart failure is analyzed using RNA-Seq, and the results are used to develop individualized protein-protein interaction networks. From this approach, hypertrophic cardiomyopathy is distinguished from dilated cardiomyopathy based on the protein-protein interaction network pattern. Within the hypertrophic cardiomyopathy cohort, the patient-specific networks are variable in complexity, and enriched for 30 endophenotypes. The cardiac Janus kinase 2-Signal Transducer and Activator of Transcription 3-collagen 4A2 (JAK2-STAT3-COL4A2) expression profile informed by the networks was able to discriminate two hypertrophic cardiomyopathy patients with extreme fibrosis phenotypes. Patient-specific network features also associate with other important hypertrophic cardiomyopathy clinical phenotypes. These proof-of-concept findings introduce personalized protein-protein interaction networks (reticulotypes) for characterizing patient-specific pathobiology, thereby offering a direct strategy for advancing precision medicine. Understanding patient-specific pathobiological pathways is a critical step for advancing precision medicine. Here the authors show that individualized protein-protein interaction networks provide key insight on patient-level pathobiology and clinically relevant pathophenotypic characteristics in a complex disease.

Imatinib mesylate (Gleevec) is a small-molecule inhibitor of the fusion protein Bcr-Abl, the causal agent in chronic myelogenous leukemia. Here we report ten individuals who developed severe congestive heart failure while on imatinib and we show that imatinib-treated mice develop left ventricular contractile dysfunction. Transmission electron micrographs from humans and mice treated with imatinib show mitochondrial abnormalities and accumulation of membrane whorls in both vacuoles and the sarco- (endo-) plasmic reticulum, findings suggestive of a toxic myopathy. With imatinib treatment, cardiomyocytes in culture show activation of the endoplasmic reticulum (ER) stress response, collapse of the mitochondrial membrane potential, release of cytochrome c into the cytosol, reduction in cellular ATP content and cell death. Retroviral gene transfer of an imatinib-resistant mutant of c-Abl, alleviation of ER stress or inhibition of Jun amino-terminal kinases, which are activated as a consequence of ER stress, largely rescues cardiomyocytes from imatinib-induced death. Thus, cardiotoxicity is an unanticipated side effect of inhibition of c-Abl by imatinib.

Certain hydroxylated polychlorinated biphenyls (OH-PCBs) inhibit the human estrogen sulfotransferase (hEST) at subnanomolar concentrations, suggesting a possible pathway for PCB toxicity due to environmental exposure in humans. To address the structural basis of the inhibition, we have determined the crystal structure of hEST in the presence of the sulfuryl donor product 3′-phosphoadenosine 5′-phosphate and the OH-PCB 4,4′-OH 3,5,3′,5′-tetraCB. The OH-PCB binds in the estrogen binding site with the position of the first phenolic ring in an orientation similar to the phenolic ring of 17β-estradiol. Interestingly, the OH-PCB does not bind in a planar conformation, but rather with a 30-degree twist between the phenyl rings. The crystal structure of hEST with the OH-PCB bound gives physical evidence that certain OH-PCBs can mimic binding of estrogenic compounds in biological systems.

Azimuthal shear interferometry is a versatile tool for analyzing wavefront asymmetries. However, conventional systems are bulky, alignment-sensitive, and prone to nonuniform shear. We present a broadband, compact, and robust meta-optics-based azimuthal shear interferometer in a common-path configuration, reducing the system size to the millimeter scale. Unlike conventional designs, the meta-optic azimuthal shear interferometer utilizes the localized wavefront modulation capabilities of meta-optics to achieve uniform azimuthal shear displacement independent of radial position, significantly enhancing accuracy and stability. Our approach eliminates the need for bulky optical components and precise multi-path alignment, making it more resilient to environmental disturbances. Its multifunctionality is demonstrated through applications in all-optical edge detection, differential interference contrast microscopy, and aberrated wavefront sensing. These results underscore its potential for real-time analog image processing, advanced optical imaging, and optical testing.

The use of structured light to drive highly nonlinear processes in matter not only enables imprinting spatially-resolved properties onto short-wavelength radiation, but also opens alternative avenues for exploring the dynamics of nonlinear laser-matter interactions. In this work, we experimentally and theoretically explore the unique properties of driving high-order harmonic generation (HHG) with Hermite-Gaussian beams. HHG driven by Laguerre-Gauss modes results in harmonics that inherit the azimuthal Laguerre-Gauss modal structure, with their topological charge scaling according to orbital angular momentum conservation. In contrast, when HHG is driven by Hermite-Gauss beams, the harmonic modes do not show a direct correspondence to the driving modal profile. Our experimental measurements using HG\\(_0,1\\) and HG\\(_1,1\\) modes, which are in excellent agreement with our numerical simulations, show that the lobes of the Hermite-Gauss driving beams effectively produce a set of separate phase-locked harmonic beamlets which can interfere downstream. This self-interference, which can be adjusted through the relative position between the gas target and the driving beam focus, can be exploited for precision extreme-ultraviolet interferometry. We demonstrate a simple application to calibrate the dispersion of an extreme-ultraviolet diffraction grating. In addition, we show through simulations that the array of harmonic beamlets can be used as an illumination source for single-shot extreme-ultraviolet ptychography.

We used polymerase chain reaction‐single‐strand conformation polymorphism (PCR‐SSCP) analysis to detect LDL receptor gene defects in the St. Petersburg population. We have found a deltaG197 mutation in several patients of Jewish origin. The mutation named is shown to be responsible for one‐third (7/23) of familial hypercholesterolemia (FH) cases in St. Petersburg Jews and absent in patients of Russian descent. The prevalence of a deltaG197 mutation in St. Petersburg Jews is consistent with its origin in Lithuania or Poland. The deltaG197 mutation can be easily detected in polyacrylamide minigels because of formation of specific heteroduplexes during PCR with DNA of heterozygous patients. Taken together with high prevalence of the mutation in St. Petersburg Jews, this observation provides an opportunity for DNA diagnostics of FH in this ethnic group. Hum Mutat 12:255–258, 1998. © 1998 Wiley‐Liss, Inc.

The growth and phase formation features, along with the influence of structure and morphology on the electronic, optical, and transport properties of Cr2GeC and Cr2-xMnxGeC MAX phase thin films synthesized by magnetron sputtering technique, were studied. It was found that the Cr:Ge:C atomic ratios most likely play the main role in the formation of a thin film of the MAX phase. A slight excess of carbon and manganese doping significantly improved the phase composition of the films. Cr2GeC films with a thicknesses exceeding 40 nm consisted of crystallites with well-developed facets, exhibiting metallic optical and transport properties. The hopping conduction observed in the Cr2-xMnxGeC film could be attributed to the columnar form of crystallites. Calculations based on a two-band model indicated high carrier concentrations N, P and mobility μ in the best-synthesized Cr2GeC film, suggesting transport properties close to single crystal material. The findings of this study can be utilized to enhance the growth technology of MAX phase thin films.

The growth and phase formation features, along with the influence of structure and morphology on the electronic, optical, and transport properties of Cr[sub.2]GeC and Cr[sub.2-x]Mn[sub.x]GeC MAX phase thin films synthesized by magnetron sputtering technique, were studied. It was found that the Cr:Ge:C atomic ratios most likely play the main role in the formation of a thin film of the MAX phase. A slight excess of carbon and manganese doping significantly improved the phase composition of the films. Cr[sub.2]GeC films with a thicknesses exceeding 40 nm consisted of crystallites with well-developed facets, exhibiting metallic optical and transport properties. The hopping conduction observed in the Cr[sub.2-x]Mn[sub.x]GeC film could be attributed to the columnar form of crystallites. Calculations based on a two-band model indicated high carrier concentrations N, P and mobility μ in the best-synthesized Cr[sub.2]GeC film, suggesting transport properties close to single crystal material. The findings of this study can be utilized to enhance the growth technology of MAX phase thin films.