A previously unknown rigid helical structure of zinc oxide consisting of a superlattice-structured nanobelt was formed spontaneously in a vapor-solid growth process. Starting from a single-crystal ...stiff nanoribbon dominated by the c-plane polar surfaces, an abrupt structural transformation into the superlattice-structured nanobelt led to the formation of a uniform nanohelix due to a rigid lattice rotation or twisting. The nanohelix was made of two types of alternating and periodically distributed long crystal stripes, which were oriented with their c axes perpendicular to each other. The nanohelix terminated by transforming into a single-crystal nanobelt dominated by nonpolar (Formula: see text) surfaces. The nanohelix could be manipulated, and its elastic properties were measured, which suggests possible uses in electromechanically coupled sensors, transducers, and resonators.
Deciphering the conformations of RNAs in their cellular environment allows identification of RNA elements with potentially functional roles within biological contexts. Insight into the conformation ...of RNA in cells has been achieved using chemical probes that were developed to react specifically with flexible RNA nucleotides, or the Watson-Crick face of single-stranded nucleotides. The most widely used probes are either selective SHAPE (2'-hydroxyl acylation and primer extension) reagents that probe nucleotide flexibility, or dimethyl sulfate (DMS), which probes the base-pairing at adenine and cytosine but is unable to interrogate guanine or uracil. The constitutively charged carbodiimide
-cyclohexyl-
-(2-morpholinoethyl)carbodiimide metho-
-toluenesulfonate (CMC) is widely used for probing G and U nucleotides, but has not been established for probing RNA in cells. Here, we report the use of a smaller and conditionally charged reagent, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), as a chemical probe of RNA conformation, and the first reagent validated for structure probing of unpaired G and U nucleotides in intact cells. We showed that EDC demonstrates similar reactivity to CMC when probing transcripts in vitro. We found that EDC specifically reacted with accessible nucleotides in the 7SK noncoding RNA in intact cells. We probed structured regions within the Xist lncRNA with EDC and integrated these data with DMS probing data. Together, EDC and DMS allowed us to refine predicted structure models for the 3' extension of repeat C within Xist. These results highlight how complementing DMS probing experiments with EDC allows the analysis of Watson-Crick base-pairing at all four nucleotides of RNAs in their cellular context.
Genetic variants affecting pancreatic islet enhancers are central to T2D risk, but the gene targets of islet enhancer activity are largely unknown. We generate a high-resolution map of islet ...chromatin loops using Hi-C assays in three islet samples and use loops to annotate target genes of islet enhancers defined using ATAC-seq and published ChIP-seq data. We identify candidate target genes for thousands of islet enhancers, and find that enhancer looping is correlated with islet-specific gene expression. We fine-map T2D risk variants affecting islet enhancers, and find that candidate target genes of these variants defined using chromatin looping and eQTL mapping are enriched in protein transport and secretion pathways. At IGF2BP2, a fine-mapped T2D variant reduces islet enhancer activity and IGF2BP2 expression, and conditional inactivation of IGF2BP2 in mouse islets impairs glucose-stimulated insulin secretion. Our findings provide a resource for studying islet enhancer function and identifying genes involved in T2D risk.
The conservation status of small cetaceans has significantly worsened since the 1980s, when the baiji was the only species of small cetacean listed as Endangered by IUCN. Now the baiji is almost ...certainly extinct and 13 other species, subspecies, or populations (hereafter units-to-conserve or units) of small cetaceans are listed as Critically Endangered (CR) on the IUCN Red List. Bycatch is the main threat to 11 of the CR units. Entanglement in gillnets contributed to the extinction of the baiji and is responsible for the imminent extinction of the vaquita. Unfortunately, there is no simple technical solution to the problem of bycatch of small cetaceans. If the 8 CR units with 100 or fewer remaining individuals are to be saved, conservation zones must be established where gillnets are eliminated and bans on their use are strictly enforced. Recent experience with the vaquita in Mexico demonstrates that enforcement of such conservation zones can be very difficult. Ineffective enforcement is also a problem for at least 4 of the other CR units. Time is very short and, unless major efforts are made now to address the bycatch problem, the prospects for CR small cetaceans and other at-risk aquatic megafauna are grim. The ultimate long-term solution to the bycatch problem is the development of efficient, inexpensive, alternative fishing gear that can replace gillnets without jeopardizing the livelihoods of fishermen. Good fishery governance and the direct involvement of fishing communities are also essential to the successful conservation of most threatened populations of small cetaceans.
IL-6 and downstream JAK-dependent signaling pathways have critical roles in the pathophysiology of multiple myeloma (MM). We investigated the effects of a novel small-molecule JAK inhibitor (AZD1480) ...on IL-6/JAK signal transduction and its biological consequences on the human myeloma-derived cell lines U266 and Kms.11. At low micromolar concentrations, AZD1480 blocks cell proliferation and induces apoptosis of myeloma cell lines. These biological responses to AZD1480 are associated with concomitant inhibition of phosphorylation of JAK2, STAT3 and MAPK signaling proteins. In addition, there is inhibition of expression of STAT3 target genes, particularly Cyclin D2. Examination of a wider variety of myeloma cells (RPMI 8226, OPM-2, NCI-H929, Kms.18, MM1.S and IM-9), as well as primary myeloma cells, showed that AZD1480 has broad efficacy. In contrast, viability of normal peripheral blood (PB) mononuclear cells and CD138(+) cells derived from healthy controls was not significantly inhibited. Importantly, AZD1480 induces cell death of Kms.11 cells grown in the presence of HS-5 bone marrow (BM)-derived stromal cells and inhibits tumor growth in a Kms.11 xenograft mouse model, accompanied with inhibition of phospho-FGFR3, phospho-JAK2, phospho-STAT3 and Cyclin D2 levels. In sum, AZD1480 blocks proliferation, survival, FGFR3 and JAK/STAT3 signaling in myeloma cells cultured alone or cocultured with BM stromal cells, and in vivo. Thus, AZD1480 represents a potential new therapeutic agent for patients with MM.
Revascularization is important for symptom treatment and limb salvage in peripheral artery disease, yet little data exist on the incidence of post-procedure major adverse limb events (MALE) and ...longer-term outcomes.
This study sought to characterize hospitalizations and outpatient endovascular revascularizations after peripheral artery revascularization, assess temporal trends for outcomes, and identify factors associated with subsequent MALE hospitalization.
Patients undergoing peripheral artery revascularization between January 1, 2009, and September 30, 2014, in the Premier Healthcare Database were examined for the primary outcome of 1-year MALE hospitalization. Secondary outcomes included 1-year outpatient endovascular revascularization and limb-related, cardiovascular, and all-cause inpatient hospitalizations. Multivariable logistic regression was used to identify factors associated with 1-year MALE hospitalization.
Among 381,415 revascularized patients, within 1 year post-index revascularization, 10.3% (n = 10,182) had a hospitalization for MALE, 11.0% (n = 42,056) had an outpatient endovascular revascularization, 18.8% (n = 71,663) had a limb-related hospitalization, 12.8% (n = 48,875) had a cardiovascular hospitalization, and 38.9% (n = 148,457) had any inpatient hospitalization. Over the study period, limb-related, cardiovascular, and all-cause hospitalizations decreased, whereas rates of outpatient endovascular revascularizations increased. Male sex, black race, Medicare and Medicaid insurance, diabetes, renal insufficiency, heart failure, smoking, baseline critical or acute limb ischemia, surgical revascularization, and noncardiology operator specialty were significantly associated with increased risk of MALE hospitalization.
In contemporary practice, hospitalization for MALE occurs in 1 in 10 patients within 1 year after peripheral revascularization and is associated with patient and procedural factors. These data may inform efforts to improve post-procedure outcomes and limb-related clinical trial design.
Display omitted
Structural modification of vitreous SiO2 by Au ion irradiation is investigated over an energy regime (∼0.3– 15 MeV) in which the decrease of the nuclear energy loss with increasing energy is ...compensated by the increase of the electronic energy loss, leading to a nearly constant total energy loss of ∼4 keV/nm. The radii of damaged zones resulting from the ion impact, deduced from changes in infrared bands as a function of ion fluence, decrease from 4.9 nm at 0.3 MeV to 2.5 and 2.6 nm at 9.8 and 14.8 MeV, respectively. Based on previous data where vitreous SiO2 was irradiated with much higher energy Au ions, the damage zone radius increases from 2.4 nm at 22.7 MeV to 5.4 nm at 168 MeV, and a U-shaped dependence on energy is observed is observed in the energy region from 0.3 to 168 MeV. The current results demonstrate that large damage radii at low and high ion energy can be explained by the elastic or inelastic thermal spike model, respectively. In the transition regime where both nuclear and electronic energy loss are significant, a unified thermal spike model consisting of a coherent synergy of the elastic collision spike model with the inelastic thermal spike model is suggested to interpret and describe the radius evolution from the nuclear to the electronic energy regime.
Task Group 101 of the AAPM has prepared this report for medical physicists, clinicians, and therapists in order to outline the best practice guidelines for the external-beam radiation therapy ...technique referred to as stereotactic body radiation therapy (SBRT). The task group report includes a review of the literature to identify reported clinical findings and expected outcomes for this treatment modality. Information is provided for establishing a SBRT program, including protocols, equipment, resources, and QA procedures. Additionally, suggestions for developing consistent documentation for prescribing, reporting, and recording SBRT treatment delivery is provided.
Many oncogenic insults deregulate RNA splicing, often leading to hypersensitivity of tumors to spliceosome-targeted therapies (STTs). However, the mechanisms by which STTs selectively kill cancers ...remain largely unknown. Herein, we discover that mis-spliced RNA itself is a molecular trigger for tumor killing through viral mimicry. In MYC-driven triple-negative breast cancer, STTs cause widespread cytoplasmic accumulation of mis-spliced mRNAs, many of which form double-stranded structures. Double-stranded RNA (dsRNA)-binding proteins recognize these endogenous dsRNAs, triggering antiviral signaling and extrinsic apoptosis. In immune-competent models of breast cancer, STTs cause tumor cell-intrinsic antiviral signaling, downstream adaptive immune signaling, and tumor cell death. Furthermore, RNA mis-splicing in human breast cancers correlates with innate and adaptive immune signatures, especially in MYC-amplified tumors that are typically immune cold. These findings indicate that dsRNA-sensing pathways respond to global aberrations of RNA splicing in cancer and provoke the hypothesis that STTs may provide unexplored strategies to activate anti-tumor immune pathways.
Display omitted
•Spliceosome-targeted therapies (STTs) induce widespread mis-spliced mRNA in cancer•Mis-spliced, intron-retained mRNAs are an unexplored source of endogenous dsRNA•STTs trigger antiviral signaling and extrinsic apoptosis in TNBCs via dsRNA sensors•RNA mis-splicing in human breast cancers correlates with immune signatures
Spliceosome-targeted therapies generate intron-retained, double-stranded RNAs that activate downstream antiviral signaling and extrinsic apoptosis in breast cancer.
PDF
