We report a hierarchically branched TiO2 nanorod structure that serves as a model architecture for efficient photoelectrochemical devices as it simultaneously offers a large contact area with the ...electrolyte, excellent light-trapping characteristics, and a highly conductive pathway for charge carrier collection. Under Xenon lamp illumination (UV spectrum matched to AM 1.5G, 88 mW/cm2 total power density), the branched TiO2 nanorod array produces a photocurrent density of 0.83 mA/cm2 at 0.8 V versus reversible hydrogen electrode (RHE). The incident photon-to-current conversion efficiency reaches 67% at 380 nm with an applied bias of 0.6 V versus RHE, nearly two times higher than the bare nanorods without branches. The branches improve efficiency by means of (i) improved charge separation and transport within the branches due to their small diameters, and (ii) a 4-fold increase in surface area which facilitates the hole transfer at the TiO2/electrolyte interface.
Phospholipid bilayers that constitute endo-lysosomal vesicles can pose a barrier to delivery of biologic drugs to intracellular targets. To overcome this barrier, a number of synthetic drug carriers ...have been engineered to actively disrupt the endosomal membrane and deliver cargo into the cytoplasm. Here, we describe the hemolysis assay, which can be used as rapid, high-throughput screen for the cytocompatibility and endosomolytic activity of intracellular drug delivery systems. In the hemolysis assay, human red blood cells and test materials are co-incubated in buffers at defined pHs that mimic extracellular, early endosomal, and late endo-lysosomal environments. Following a centrifugation step to pellet intact red blood cells, the amount of hemoglobin released into the medium is spectrophotometrically measured (405 nm for best dynamic range). The percent red blood cell disruption is then quantified relative to positive control samples lysed with a detergent. In this model system the erythrocyte membrane serves as a surrogate for the lipid bilayer membrane that enclose endo-lysosomal vesicles. The desired result is negligible hemolysis at physiologic pH (7.4) and robust hemolysis in the endo-lysosomal pH range from approximately pH 5-6.8.
RNA recombination in positive-strand RNA viruses is a molecular-genetic process, which permits the greatest evolution of the genome and may be essential to stabilizing the genome from the deleterious ...consequences of accumulated mutations. Enteroviruses represent a useful system to elucidate the details of this process. On the biochemical level, it is known that RNA recombination is catalyzed by the viral RNA-dependent RNA polymerase using a template-switching mechanism. For this mechanism to function in cells, the recombining genomes must be located in the same subcellular compartment. How a viral genome is trafficked to the site of genome replication and recombination, which is membrane associated and isolated from the cytoplasm, is not known. We hypothesized that genome translation was essential for colocalization of genomes for recombination. We show that complete inactivation of internal ribosome entry site (IRES)-mediated translation of a donor enteroviral genome enhanced recombination instead of impairing it. Recombination did not occur by a nonreplicative mechanism. Rather, sufficient translation of the nonstructural region of the genome occurred to support subsequent steps required for recombination. The noncanonical translation initiation factors, eIF2A and eIF2D, were required for IRES-independent translation. Our results support an eIF2A/eIF2D-dependent mechanism under conditions in which the eIF2-dependent mechanism is inactive. Detection of an IRES-independent mechanism for translation of the enterovirus genome provides an explanation for a variety of debated observations, including nonreplicative recombination and persistence of enteroviral RNA lacking an IRES. The existence of an eIF2A/eIF2D-dependent mechanism in enteroviruses predicts the existence of similar mechanisms in other viruses.
A system is engineered for temporally controlled delivery of siRNA from biodegradable tissue regenerative scaffolds. Therapeutic application of this approach to silence PHD2 promotes expression of ...pro‐angiogenic genes controlled by HIF1α and enhanced scaffold vascularization in vivo. This technology provides a new standard for efficient and controllable gene silencing to modulate host response within regenerative biomaterials.
The importance of the p53 stress response pathway in the suppression of tumor formation is well documented. In a previous report, a single nucleotide polymorphism (SNP309 T/G) was found in the ...promoter of the MDM2 gene resulting in higher levels of MDM2 RNA and protein and, consequently, in the attenuation of the p53 pathway both in vitro and in vivo. As the SNP309 locus is found in a region of the MDM2 promoter, which is regulated by hormonal signaling pathways, and the G-allele of SNP309 increases the affinity of a well-described cotranscriptional activator of nuclear hormone receptors (i.e., Sp1), the hypothesis that the SNP309 locus could alter the effects of hormones on tumorigenesis was tested in vivo in humans. Data obtained from patients with three different sporadic cancers, from four independent case studies, support this hypothesis, providing an example for the genetic basis of gender differences in cancer and showing that the genotype at a specific locus can affect how hormones, like estrogen, affect tumorigenesis in humans.
We report maps of the concentrations of H, Si, Cl, K, Fe, and Th as determined by the Gamma Ray Spectrometer (GRS) on board the 2001 Mars Odyssey Mission for ±∼45° latitudes. The procedures by which ...the spectra are processed to yield quantitative concentrations are described in detail. The concentrations of elements determined over the locations of the various Mars landers generally agree well with the lander values except for Fe, although the mean of the GRS Fe data agrees well with that of Martian meteorites. The water‐equivalent concentration of hydrogen by mass varies from about 1.5% to 7.5% (by mass) with the most enriched areas being near Apollinaris Patera and Arabia Terra. Cl shows a distribution similar to H over the surface except that the Cl content over Medusae Fossae is much greater than elsewhere. The map of Fe shows enrichment in the northern lowlands versus the southern highlands. Silicon shows only very modest variation over the surface with mass fractions ranging from 19% to 22% over most of the planet, though a significant depletion in Si is noted in a region west of Tharsis Montes and Olympus Mons where the Si content is as low as 18%. K and Th show a very similar pattern with depletions associated with young volcanic deposits and enrichments associated with the TES Surface Type‐2 material. It is noted that there appears to be no evidence of significant globally distributed thick dust deposits of uniform composition.
Purpose The limitations imposed by human clinical studies and mammalian models of nephrolithiasis have hampered the development of effective medical treatments and preventive measures for decades. ...The simple but elegant Drosophila melanogaster is emerging as a powerful translational model of human disease, including nephrolithiasis. It may provide important information essential to our understanding of stone formation. We present the current state of research using D. melanogaster as a model of human nephrolithiasis. Materials and Methods We comprehensively reviewed the English language literature using PubMed®. When necessary, authoritative texts on relevant subtopics were consulted. Results The genetic composition, anatomical structure and physiological function of Drosophila malpighian tubules are remarkably similar to those of the human nephron. The direct effects of dietary manipulation, environmental alteration and genetic variation on stone formation can be observed and quantified in a matter of days. Several Drosophila models of human nephrolithiasis have been developed, including genetically linked and environmentally induced stones. A model of calcium oxalate stone formation is among the most recent fly models of human nephrolithiasis. Conclusions The ability to readily manipulate and quantify stone formation in D. melanogaster models of human nephrolithiasis presents the urological community with a unique opportunity to increase our understanding of this enigmatic disease.
Electronic cigarettes are a harm reduction strategy for individuals who smoke cigarettes who cannot or do not want to quit using FDA-approved cessation methods. Identifying perceived facilitators and ...barriers to switching among people who smoke cigarettes is critical to optimizing health impact. This is particularly important for the most dominant e-cigarette device, nicotine salt pod electronic cigarettes. We investigate the experience using pod electronic cigarettes among African American and Latinx individuals who smoke, the two largest racial/ethnic minority groups who experience significant health disparities.
From July 2018 to May 2019, adults who smoked cigarettes, age 21 + (N = 114; M age = 44.6, 59.6% male, 52.6% African American from Kansas City, 47.4% Latinx from San Diego) received JUUL-brand electronic cigarettes (referred to hereafter as JUUL) for 6 weeks and answered interview questions at week six. We inquired what they liked and disliked about using JUUL, what helped with switching and made switching difficult, future intentions for continued JUUL use, and how JUUL compared to past smoking reduction methods. Responses were coded into themes by independent raters. Theme frequencies were analyzed separately by race/ethnicity and week 6 use trajectory (exclusive JUUL use, dual JUUL and cigarette use, exclusive cigarette use).
Clean/smell was the aspect of using JUUL most commonly liked (23%), followed by convenience (19%). Coughing/harshness was a more common barrier to switching for African American (44%) than Latinx (9%), and for continuing cigarette use (56%) than for those who exclusively switched or dually used JUUL and combustible cigarettes (15-21%). Most (78% African American; 90% Latinx) reported that the benefits of using JUUL outweighed barriers, and this varied by JUUL use trajectory: 94% exclusive switch, 86% dual use, and 42% continued cigarette use. The majority said they would continue using JUUL to replace cigarettes (83% African American; 94% Latinx) and that JUUL worked better than other methods to reduce cigarettes (72%).
African American and Latinx individuals who smoked experience using pod electronic cigarettes was generally positive. Understanding facilitators and impediments to switching to electronic cigarettes among racial/ethnic minority people who smoke can inform harm reduction interventions and reduce tobacco-related health disparities. Trial Registration ClinicalTrials.gov Identifier: NCT03511001 posted April 27, 2018.
Pathogenic or likely pathogenic (P/LP) germline TP53 variants are the primary cause of Li-Fraumeni syndrome (LFS), a hereditary cancer predisposition disorder characterized by early-onset cancers. ...The population prevalence of P/LP germline TP53 variants is estimated to be approximately one in every 3,500 to 20,000 individuals. However, these estimates are likely impacted by ascertainment biases and lack of clinical and genetic data to account for potential confounding factors, such as clonal hematopoiesis. Genome-first approaches of cohorts linked to phenotype data can further refine these estimates by identifying individuals with variants of interest and then assessing their phenotypes. This study evaluated P/LP germline (variant allele fraction ≥30%) TP53 variants in three cohorts: UK Biobank (UKB, n = 200,590), Geisinger (n = 170,503), and Penn Medicine Biobank (PMBB, n = 43,731). A total of 109 individuals were identified with P/LP germline TP53 variants across the three databases. The TP53 p.R181H variant was the most frequently identified (9 of 109 individuals, 8%). A total of 110 cancers, including 47 hematologic cancers (47 of 110, 43%), were reported in 71 individuals. The prevalence of P/LP germline TP53 variants were conservatively estimated as 1:10,439 in UKB, 1:3,790 in Geisinger, and 1:2,983 in PMBB after removing related individuals and heterozygotes who had ever developed a hematologic cancer due to the potential confounding impact of clonal hematopoiesis. These varying estimates likely reflect intrinsic selection biases of each database, such as healthcare or population-based contexts. Prospective studies of diverse, young cohorts are required to better understand the population prevalence of germline TP53 variants and their associated cancer penetrance.
Genome-first analysis of cohorts with linked clinical data demonstrates that the prevalence estimates of pathogenic germline TP53 variants is approximately 1:3,000 in health care-based cohorts and 1:10,000 in a predominantly older, healthy cohort. These findings highlight the importance of carefully assessing the impact of database-specific selection biases on these estimates.
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