Biomineralization is mediated by specialized proteins that guide and control mineral sedimentation. In many cases, the active regions of these biomineralization proteins are intrinsically disordered. ...High-resolution structures of these proteins while they interact with minerals are essential for understanding biomineralization processes and the function of intrinsically disordered proteins (IDPs). Here we used the cavity of ferritin as a nanoreactor where the interaction between M6A, an intrinsically disordered iron-binding domain, and an iron oxide particle was visualized at high resolution by cryo-EM. Taking advantage of the differences in the electron-dose sensitivity of the protein and the iron oxide particles, we developed a method to determine the irregular shape of the particles found in our density maps. We found that the folding of M6A correlates with the detection of mineral particles in its vicinity. M6A interacts with the iron oxide particles through its C-terminal side, resulting in the stabilization of a helix at its N-terminal side. The stabilization of the helix at a region that is not in direct contact with the iron oxide particle demonstrates the ability of IDPs to respond to signals from their surroundings by conformational changes. These findings provide the first glimpse toward the long-suspected mechanism for biomineralization protein control over mineral microstructure, where unstructured regions of these proteins become more ordered in response to their interaction with the nascent mineral particles.
Terahertz and IR spectra of dielectric response of dense and porous Pb(Zr,Ti)O
3
films deposited on single-crystal magnesia and alumina substrates and on silicon substrates with a conducting platinum ...sublayer are measured in the and analyzed. We consider the key mechanisms of electric dipole absorption that give rise to absorption bands observed in experimentally measured reflection and transmission spectra, and discuss the relationship between the type of substrate and the parameters characterizing the absorption bands in the spectra of the prepared PZT films.
Activation of the Wnt signaling pathway promotes lung cancer progression and contributes to poor patient prognosis. The porcupine inhibitor LGK974, a novel orally bioavailable cancer therapeutic in ...Phase I clinical trials, induces potent Wnt signaling inhibition and leads to suppressed growth and progression of multiple types of cancers. The clinical use of LGK974, however, is limited in part due to its low solubility and high toxicity in tissues that rely on Wnt signaling for normal homeostasis. Here, we report the use of host-guest chemistry to enhance the solubility and bioavailability of LGK974 in mice through complexation with cyclodextrins (CD). We assessed the effects of these complexes to inhibit Wnt signaling in lung adenocarcinomas that are typically driven by overactive Wnt signaling. 2D 1H NMR confirmed host-guest complexation of CDs with LGK974. CD:LGK974 complexes significantly decreased the expression of Wnt target genes in lung cancer organoids and in lung cancer allografts in mice. Further, CD:LGK974 complexes increased the bioavailability upon oral administration in mice compared to free LGK974. In a mouse lung cancer allograft model, CD:LGK974 complexes induced potent Wnt signaling inhibition with reduced intestinal toxicity compared to treatment with free drug. Collectively, the development of these complexes enables safer and repeated oral or parenteral administration of Wnt signaling inhibitors, which hold promise for the treatment of multiple types of malignancies.
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•CD-Wnt inhibitor complexes via host-guest chemistry enhanced oral delivery.•CD:LGK974 complexes induced potent Wnt signaling inhibition in lung cancer organoids in vitro and allografts in vivo.•Orally administered CD:LGK974 complexes were well-tolerated in vivo, with reduced intestinal toxicity compared to free drug.•CD:LGK974 complexes enable safe, repeated administration of Wnt signaling inhibitors in vivo for potential use in lung cancer therapy.
The exceptional performance of some High Entropy Alloys (HEAs) under extreme conditions holds out the possibility of new and exciting materials for engineers to exploit in future applications. In ...this work, instead of focusing solely on the effects of high temperature on HEAs, the effects of combined high temperature and high pressure were observed. Phase transformations occurring in a pristine HEA, the as-cast bcc–Al2CoCrFeNi, are heavily influenced by temperature, pressure, and by scandium additions. As-cast bcc–Al2CoCrFeNi and fcc–Al0.3CoCrFeNi HEAs are structurally stable below 60 GPa and do not undergo phase transitions. Addition of scandium to bcc–Al2CoCrFeNi results in the precipitation of hexagonal AlScM intermetallic (W-phase), which dissolves in the matrix after high-pressure high-temperature treatment. Addition of scandium and high-pressure sintering improve hardness and thermal stability of well-investigated fcc- and bcc- HEAs. The dissolution of the intermetallic in the main phase at high pressure suggests a new strategy in the design and optimization of HEAs.
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•Sc addition to bcc-Al2CoCrFeNi high entropy alloy results in precipitation of W-phase.•W-phase dissolves in the matrix with pressure.•Addition of Sc and high-pressure treatment improve mechanical properties of HEA.
Using methods of infrared, terahertz, and submillimeter spectroscopy, experimental transmission and reflection spectra of α-lactose monohydrate have been obtained at room temperature in the frequency ...range from 5 to 5000 cm
–1
. The experimental spectra of dense pressed tablets and powdered samples have been analyzed in terms of the model of a classical oscillator. Certain parameters of absorption bands of the resonant and quasi-relaxation types are markers by which components can be selected in heterogeneous pharmacological and organic preparations using the methods of coherent submillimeter and pulsed terahertz spectroscopy.
The development of new dielectric materials for insulating layer of interconnects with low loss on high frequencies (low-
k
) is one of main directions of modern microelectronics. At present, various ...modifications of SiO
2
-based dielectric structures standard for modern integrated circuits differ in composition and morphological characteristics are being studied. In this work, the dielectric loss of thin-film SiO
2
samples on Al substrate are studied by methods of terahertz (THz) and IR spectroscopy. It is found that the spectra of such structures are substantially different, including the resonant Berreman modes, as compared to the spectra of a bulk fused silica.
Solid Immersion (SI) microscopy is a modern imaging modality that overcomes the Abbe diffraction limit and offers novel applications in various branches of visible, infrared, terahertz, and ...millimeter-wave optics. Despite the widespread use, SI microscopy usually results in qualitative imaging. Indeed, it presents only the raw distributions (in the image plane) of the backscattered field intensity, while unlocking the information about the physical properties of an imaged object, such as its complex refractive index (RI) distribution, requires resolving the inverse problem and remains a daunting task. In this paper, a method for resolving the SI microscopy inverse problem is developed, capable of reconstructing the RI distribution at the object imaging plane with subwavelength spatial resolution, while performing only intensity measurements. The sample RI is retrieved via minimization of the error function that characterizes discrepancy between the experimental data and the predictions of analytical model. This model incorporates all the key features of the electromagnetic-wave interaction with the SI lens and an imaged object, including contributions of the evanescent and ordinary-reflected waves, as well as effects of light polarization and wide beam aperture. The model is verified numerically, using the finite-element frequency-domain method, and experimentally, using the in-house reflection-mode continuous-wave terahertz SI microscope. Spatial distributions of the terahertz RIs of different low-absorbing optical materials and highly absorbing biological objects were studied and compared to
a priori
known data to demonstrate the potential of the novel SI microscopy modality. Given the linear nature of the Maxwell’s equations, the developed method can be applied for subwavelength-resolution SI microscopy at other spectral ranges.
Patients with metastatic melanoma, renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC) are increasingly treated with immune checkpoint blockade targeting the programed death (PD)-1 ...receptor, often with palliative radiation therapy. Outcome data are limited in this population.
We retrospectively reviewed consecutive patients with metastatic NSCLC, melanoma, and RCC who received radiation and anti-PD-1 therapy at four centers.
We identified 137 patients who received radiation and PD-1 inhibition. Median survival from first PD-1 therapy was 192, 394, and 121days for NSCLC, melanoma, and RCC patients. Among 59 patients who received radiation following the start of PD-1 blockade, 25 continued to receive PD-1 inhibition for a median of 179days and survived for a median of 238 additional days. Median survival following first course of radiation for brain metastases was 634days. Melanoma patients received brain directed radiation relatively less frequently following the start of PD-1 inhibitor treatment.
Incorporation of palliative radiation does not preclude favorable outcomes in patients treated with PD-1 inhibitors; patients irradiated after the start of PD-1 inhibition can remain on therapy and demonstrate prolonged survival. Of note, patients irradiated for brain metastases demonstrate favorable outcomes compared with historical controls.
Transmission spectra of pressed microcrystalline α-lactose monohydrate samples have been measured by THz time-domain spectroscopy in the temperature range of existence of the solid phase (10–475 K). ...An analysis of the observed absorption lines using the model of classical oscillator have revealed complex temperature evolution of resonance eigenfrequencies and determined the range of existence of a phase of α-lactose monohydrate response. The obtained data can be used in practice in various fields of THz optics, including pharmacology, food industry, analytical chemistry, and biophotonics.
The transmission and reflection spectra of a CdSiP
2
single crystal are measured in the temperature interval from 80 to 300 K using the terahertz (THz) pulsed and infrared Fourier spectroscopy ...methods. A significant influence of postgrowth defects on the absorption in the THz frequency range is revealed. This absorption is found to depend weakly on temperature compared to that observed previously for other chalcopyrite crystal with substantially lower concentration of defects. Upon cooling, intrinsic absorption mechanisms are minimized, and the contribution of defects to absorption is separated.
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