Sequence- and structural-selective nucleic acid binding revealed by the melting of mixtures

A simple method for the detection of sequence- and structural-selective ligand binding to nucleic acids is described. The method is based on the commonly used thermal denaturation method in which ligand binding is registered as an elevation in the nucleic acid melting temperature (T(m)). The method can be extended to yield a new, higher -throughput, assay by the simple expediency of melting designed mixtures of polynucleotides (or oligonucleotides) with different sequences or structures of interest. Upon addition of ligand to such mixtures at low molar ratios, the T(m) is shifted only for the nucleic acid containing the preferred sequence or structure. Proof of principle of the assay is provided using first a mixture of polynucleotides with different sequences and, second, with a mixture containing DNA, RNA and two types of DNA:RNA hybrid structures. Netropsin, ethidium, daunorubicin and actinomycin, ligands with known sequence preferences, were used to illustrate the method. The applicability of the approach to oligonucleotide systems is illustrated by the use of simple ternary and binary mixtures of defined sequence deoxyoligonucleotides challenged by the bisanthracycline WP631. The simple mixtures described here provide proof of principle of the assay and pave the way for the development of more sophisticated mixtures for rapidly screening the selectivity of new nucleic acid binding compounds

A Comparison of Error Rates Between Intravenous Push Methods: A Prospective, Multisite, Observational Study

Objectives Current literature estimates the error rate associated with the preparation and administration of all intravenous (IV) medications to be 9.4% to 97.7% worldwide. This study aims to compare the number of observed medication preparation and administration errors between the only commercially available ready-to-administer product (Simplist) and IV push traditional practice, including a cartridge-based syringe system (Carpuject) and vials and syringes. Methods A prospective, multisite, observational study was conducted in 3 health systems in various states within the United States between December 2015 and March 2016 to observe IV push medication preparation and administration. Researchers observed a ready-to-administer product and IV push traditional practice using a validated observational method and a modified data collection sheet. All observations were reconciled to the original medication order to determine if any errors occurred. Results Researchers collected 329 observations (ready to administer = 102; traditional practice = 227) and observed 260 errors (ready to administer = 25; traditional practice = 235). The overall observed error rate for ready-to-administer products was 2.5%, and the observed error rate for IV push traditional practice was 10.4%. Conclusions The ready-to-administer group demonstrated a statistically significant lower observed error rate, suggesting that use of this product is associated with fewer observed preparation and administration errors in the clinical setting. Future studies should be completed to determine the potential for patient harm associated with these errors and improve clinical practice because it relates to the safe administration of IV push medications

Temporal Model Adaptation for Person Re-Identification

Person re-identification is an open and challenging problem in computer vision. Majority of the efforts have been spent either to design the best feature representation or to learn the optimal matching metric. Most approaches have neglected the problem of adapting the selected features or the learned model over time. To address such a problem, we propose a temporal model adaptation scheme with human in the loop. We first introduce a similarity-dissimilarity learning method which can be trained in an incremental fashion by means of a stochastic alternating directions methods of multipliers optimization procedure. Then, to achieve temporal adaptation with limited human effort, we exploit a graph-based approach to present the user only the most informative probe-gallery matches that should be used to update the model. Results on three datasets have shown that our approach performs on par or even better than state-of-the-art approaches while reducing the manual pairwise labeling effort by about 80%

Clinical application of CSF biomarkers for Alzheimer's disease:From rationale to ratios

Biomarker testing is recommended for the accurate and timely diagnosis of Alzheimer's disease (AD). Using illustrative case narratives we consider how cerebrospinal fluid (CSF) biomarker tests may be used in different presentations of cognitive impairment to facilitate timely and differential diagnosis, improving diagnostic accuracy, providing prognostic information, and guiding personalized management in diverse scenarios. Evidence shows that (1) CSF ratios are superior to amyloid beta (Aβ)1‐42 alone; (2) concordance of CSF ratios to amyloid positron emission tomography (PET) is better than Aβ1‐42 alone; and (3) phosphorylated tau (p‐tau)/Aβ1‐42 ratio is superior to p‐tau alone. CSF biomarkers are recommended for the exclusion of AD as the underlying cause of cognitive impairment, diagnosis of AD at an early stage, differential diagnosis of AD in individuals presenting with other neuropsychiatric symptoms, accurate diagnosis of AD in an atypical presentation, and for clinical trial enrichment. HIGHLIGHTS:  : Cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker testing may be underused outside specialist centers. CSF biomarkers improve diagnostic accuracy, guiding personalized management of AD. CSF ratios (amyloid beta [Aβ]1‐42/Aβ1‐40 and phosphorylated tau/Aβ1‐42) perform better than single markers. CSF ratios produce fewer false‐negative and false‐positive results than individual markers. CSF biomarkers should be included in diagnostic work‐up of AD and mild cognitive impairment due to AD

Regulation of X-linked gene expression during early mouse development by

Mammalian X-linked gene expression is highly regulated as female cells contain two and male one X chromosome (X). To adjust the X gene dosage between genders, female mouse preimplantation embryos undergo an imprinted form of X chromosome inactivation (iXCI) that requires both Rlim (also known as Rnf12) and the long non-coding RNA Xist. Moreover, it is thought that gene expression from the single active X is upregulated to correct for bi-allelic autosomal (A) gene expression. We have combined mouse genetics with RNA-seq on single mouse embryos to investigate functions of Rlim on the temporal regulation of iXCI and Xist. Our results reveal crucial roles of Rlim for the maintenance of high Xist RNA levels, Xist clouds and X-silencing in female embryos at blastocyst stages, while initial Xist expression appears Rlim-independent. We find further that X/A upregulation is initiated in early male and female preimplantation embryos

Rlim-Dependent and -Independent Pathways for X Chromosome Inactivation in Female ESCs

During female mouse embryogenesis, two forms of X chromosome inactivation (XCI) ensure dosage compensation from sex chromosomes. Beginning at the four-cell stage, imprinted XCI (iXCI) exclusively silences the paternal X (Xp), and this pattern is maintained in extraembryonic cell types. Epiblast cells, which give rise to the embryo proper, reactivate the Xp (XCR) and undergo a random form of XCI (rXCI) around implantation. Both iXCI and rXCI depend on the long non-coding RNA Xist. The ubiquitin ligase RLIM is required for iXCI in vivo and occupies a central role in current models of rXCI. Here, we demonstrate the existence of Rlim-dependent and Rlim-independent pathways for rXCI in differentiating female ESCs. Upon uncoupling these pathways, we find more efficient Rlim-independent XCI in ESCs cultured under physiological oxygen conditions. Our results revise current models of rXCI and suggest that caution must be taken when comparing XCI studies in ESCs and mice

Miocene Volcaniclastic Sequence Within the Xiyu Formation from Source to Sink: Implications for Drainage Development and Tectonic Evolution in Eastern Pamir, NW Tibetan Plateau

©2018. American Geophysical Union. All Rights Reserved. The formation of the Pamir salient and the Tashkorgan-Yarkand River is highly debated with the ages ranging from pre-Cenozoic to late Miocene. One approach to resolve these issues is to draw support from the sedimentary record in the surrounding basins. A volcaniclastic sequence, which divides into Lower and Upper Members, was identified in the southwestern Tarim Basin. The Lower Member was transported by dilute streamflows, which likely flowed during or soon after eruptions, while the Upper Member was formed by a syneruptive volcanic debris flow. Chronological, petrologic, and geochemical data consistently indicate that the sequence was derived from the Central Pamir at ~11 Ma. The ~11 Ma emplacement of the volcaniclastic sequence provides unique constraints for the evolution of the Tashkorgan-Yarkand River and the Pamir salient. Provenance data indicate a multistage evolutionary history of the Tashkorgan-Yarkand River. The paleo-Tashkorgan River was initially formed in the piedmont of the Pamir marginal range before ~15 Ma. This river cut back into the Tashkorgan region at ~15 Ma, after which it has eroded the Central Pamir by ~11 Ma. The N-S trending upper reaches of the Tashkorgan River and the Yarkand River were established after ~11 Ma. The emplacement of the volcanic debris flow, together with regional deformation evidence, indicates limited strike-slip motion between Pamir and the Tarim at least since ~11 Ma, which refutes hundreds of kilometers offset between the Pamir and the Tarim after this time and supports an earlier indention of the Pamir salient

Genetic Variants in Platelet Factor 4 Modulate Inflammatory and Platelet Activation Biomarkers

African Americans suffer from higher prevalence and severity of atherosclerosis compared to Whites, highlighting racial and ethnic disparities in cardiovascular disease. Previous studies have pointed to the role of vascular inflammation and platelet activation in the formation of atherosclerotic lesions

Investment Case for a Comprehensive Package of Interventions Against Hepatitis B in China: Applied Modeling to Help National Strategy Planning.

BACKGROUND content: In 2016, the first global viral hepatitis elimination targets were endorsed. An estimated one-third of the world's population of individuals with chronic hepatitis B virus (HBV) infection live in China and liver cancer is the sixth leading cause of mortality, but coverage of first-line antiviral treatment was low. In 2015, China was one of the first countries to initiate a consultative process for a renewed approach to viral hepatitis. We present the investment case for the scale-up of a comprehensive package of HBV interventions. METHODS content: A dynamic simulation model of HBV was developed and used to simulate the Chinese HBV epidemic. We evaluated the impact, costs, and return on investment of a comprehensive package of prevention and treatment interventions from a societal perspective, incorporating costs of management of end-stage liver disease and lost productivity costs. RESULTS content: Despite the successes of historical vaccination scale-up since 1992, there will be a projected 60 million people still living with HBV in 2030 and 10 million HBV-related deaths, including 5.7 million HBV-related cancer deaths between 2015 and 2030. This could be reduced by 2.1 million by highly active case-finding and optimal antiviral treatment regimens. The package of interventions is likely to have a positive return on investment to society of US$1.57 per US dollar invested. CONCLUSIONS content: Increases in HBV-related deaths for the next few decades pose a major public health threat in China. Active case-finding and access to optimal antiviral treatment are required to mitigate this risk. This investment case approach provides a real-world example of how applied modeling can support national dialog and inform policy planning