An inlier of Jurassic rocks is identified for the first time at the surface of the first terrace above a floodplain composed of Holocene sediments on the left side of the Lena River. It represents a ...block of Jurassic rocks similar compositionally to rocks in outcrops on the left slope of the river valley. It is shown that the block was displaced along faults in the Holocene. The rocks of the inlier are deformed, and the Paleogene–Neogene sequence covering the plateau (altitude approximately 200 m) is displaced in the stepwise mode to the level corresponding to the bottom of the Lena River valley (altitude approximately 100 m). The Holocene alluvium enveloping the inlier belongs to the constratal type being up to 40 m thick. Steep faceted morphostructures on the left slope of the Lena River valley coincide with the faults. The left slope of the valley is crossed exclusively by young incisions. It is assumed that Holocene movements may be reactivated in the future.
To understand gene expression changes mediated by a polyglutamine repeat expansion in the human huntingtin protein, we used oligonucleotide DNA arrays to profile approximately 6000 striatal mRNAs in ...the R6/2 mouse, a transgenic Huntington's disease (HD) model. We found diminished levels of mRNAs encoding components of the neurotransmitter, calcium and retinoid signaling pathways at both early and late symptomatic time points (6 and 12 weeks of age). We observed similar changes in gene expression in another HD mouse model (N171-82Q). These results demonstrate that mutant huntingtin directly or indirectly reduces the expression of a distinct set of genes involved in signaling pathways known to be critical to striatal neuron function.
Small cell lung cancer (SCLC) accounts for 15% of lung cancers and is almost always linked to inactivating
and
mutations. SCLC frequently responds, albeit briefly, to chemotherapy. The canonical ...function of the
gene product RB1 is to repress the E2F transcription factor family. RB1 also plays both E2F-dependent and E2F-independent mitotic roles. We performed a synthetic lethal CRISPR/Cas9 screen in an
SCLC cell line that conditionally expresses
to identify dependencies that are caused by RB1 loss and discovered that
SCLC cell lines are hyperdependent on multiple proteins linked to chromosomal segregation, including Aurora B kinase. Moreover, we show that an Aurora B kinase inhibitor is efficacious in multiple preclinical SCLC models at concentrations that are well tolerated in mice. These results suggest that RB1 loss is a predictive biomarker for sensitivity to Aurora B kinase inhibitors in SCLC and perhaps other
cancers. SIGNIFICANCE: SCLC is rarely associated with actionable protooncogene mutations. We did a CRISPR/Cas9-based screen that showed that
SCLC are hyperdependent on
, likely because both genes control mitotic fidelity, and confirmed that Aurora B kinase inhibitors are efficacious against
SCLC tumors in mice at nontoxic doses.
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To analyze immune-related adverse events (ir-AEs) in patients treated with radiation and immune checkpoint blockade.
We retrospectively reviewed records from patients with metastatic non-small cell ...lung cancer, melanoma, or renal cell cancer who received at least 1 cycle of a CTLA-4 or PD-1 inhibitor and radiation. Immune-related adverse events, defined using Common Terminology Criteria for Adverse Events version 4.0, were tabulated in relation to treatment variables, and associations with sequencing and timing were assessed.
We identified 133 patients, of whom 28 received a CTLA-4 inhibitor alone, 88 received a PD-1 inhibitor alone, and 17 received both classes of inhibitors either sequentially (n=13) or concurrently (n=4). Fifty-six patients received radiation within 14 days of an immune checkpoint inhibitor. Forty-six patients experienced at least 1 ir-AE (34.6%). Patients receiving both CTLA-4 and PD-1 inhibitors experienced more any-grade ir-AEs as compared with either individually (71% vs 29%, P=.0008). Any-grade ir-AEs occurred in 39% of patients in whom radiation was administered within 14 days of immunotherapy, compared with 23% of other patients (P=.06) and more often in patients who received higher equivalent dose in 2-Gy fractions (EQD2) EQD2 (P=.01). However, most toxicities were mild. There were no associations between site irradiated and specific ir-AEs.
Our data suggest the combination of focal palliative radiation and CTLA-4 and/or PD-1 inhibitors is well tolerated, with manageable ir-AEs that did not seem to be associated with the particular site irradiated. Although conclusions are limited by the heterogeneity of patients and treatments, and future confirmatory studies are needed, this information can help guide clinical practice for patients receiving immune checkpoint therapy who require palliative radiation therapy.
In this paper, artificial opals, made of 300-nm-diameter nanoporous SiO2 globules by sedimentation of a colloidal suspension and annealing at different temperatures in the range of 200–1500 °C, are ...studied as a promising material platform for terahertz (THz) optics. Our findings reveal that THz optical properties of such materials can be predictably varied in a wide range by annealing, while being a deterministic function of the material porosity. Thus, when increasing annealing temperature, the resultant material refractive index increases from 1.65 to 1.95 at 1.0 THz, while the material absorption coefficient (by field) reduces from 10 to 1 cm−1. The Bruggeman effective medium theory was then successfully applied to model optical properties of the nanoporous SiO2 at THz frequencies as a function of the material porosity and the annealing temperature. Finally, bulk nanoporous SiO2 were shaped using conventional grinding techniques into plates and cylindrical lenses to demonstrate robustness of the novel THz optical materials. A wide range of the nanoporous SiO2 refractive indices, their low-to-moderate THz-wave absorption, as well as their mechanical robustness make such materials a promising platform for THz optics.
The exact route of iron through the kidney and its regulation during iron overload are not completely elucidated. Under physiologic conditions, non-transferrin and transferrin bound iron passes the ...glomerular filter and is reabsorbed through kidney epithelial cells, so that hardly any iron is found in the urine. To study the route of iron reabsorption through the kidney, we analyzed the location and regulation of iron metabolism related proteins in kidneys of mice with iron overload, elicited by iron dextran injections. Transferrin Receptor 1 was decreased as expected, following iron overload. In contrast, the multi-ligand hetero-dimeric receptor-complex megalin/cubilin, which also mediates the internalization of transferrin, was highly up-regulated. Moreover, with increasing iron, intracellular ferritin distribution shifted in renal epithelium from an apical location to a punctate distribution throughout the epithelial cells. In addition, in contrast to many other tissues, the iron exporter ferroportin was not reduced by iron overload in the kidney. Iron accumulated mainly in interstitial macrophages, and more prominently in the medulla than in the cortex. This suggests that despite the reduction of Transferrin Receptor 1, alternative pathways may effectively mediate re-absorption of iron that cycles through the kidney during parenterally induced iron-overload. The most iron consuming process of the body, erythropoiesis, is regulated by the renal erythropoietin producing cells in kidney interstitium. We propose, that the efficient re-absorption of iron by the kidney, also during iron overload enables these cells to sense systemic iron and regulate its usage based on the systemic iron state.
The reflection spectra of pure single-phase pressed samples of saccharides are measured by the methods of coherent submillimeter, pulsed terahertz, and broadband Fourier-transform infrared ...spectroscopy; the parameters of the absorption bands of samples are estimated using the additive classical oscillator model. The possibility of analyzing the vibrational spectrum with correction for scattering using calibration data for the visible and terahertz ranges is shown. The sensitivity and accuracy of this approach are limited by low reflection coefficients and, as a result, by a low signal-to-noise ratio, as well as by the asymmetric broadening of bands due to anharmonicity of vibrations and overlap of absorption bands.
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.
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